Contents Book of Abstracts · Poster boards will be marked with the final poster number. Mounting...

Contents

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 1B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9

Book of Abstracts

Contents

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 3I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S2

Book of Abstracts: Instructions for Use

ORAL COMMUNICATIONS

Thursday, 19 September

Young Investigator Session .................................................................................................................. 9

O-28 METABOLOMIC LANDSCAPES OF NON-ALCOHOLIC FATTY LIVER-ASSOCIATED HEPATOCELLULAR CARCINOMA AND ITS DIAGNOSTIC POTENTIAL ...............................9

O-29 PVRL1/TIGIT REPRESENTS A NOVEL MOLECULAR MECHANISM FOR PD1 BLOCKADE RESISTANCE IN HEPATOCELLULAR CARCINOMA ..........................................................9

O-30 EFFECT OF THE MICROBIOTA ON THE PERIPHERAL IMMUNE RESPONSE IN PATIENTS WITH NAFLD-ASSOCIATED HEPATOCELLULAR CARCINOMA* ........................................9

O-31 EVALUATION OF THE AFP MODEL IN PATIENTS WITH LOW RISK RECURRENCE PROFILE: FURTHER EVIDENCE TO SUPPORT ITS INCLUSION FOR CANDIDATE’S SELECTION. .......10

Friday, 20 September

General Session 1: Molecular Pathogenesis .............................................................................. 11

O-07 TYRO3 PLAYS A PIVOTAL ROLE IN THE HEPATITIS-MEDIATED TUMORIGENESIS: A POTENTIAL THERAPEUTIC TARGET FOR LIVER CANCERS .........................................11

O-08 THE IMPRINTED DLK1/DIO3 LOCUS AS A KEY PLAYER IN ß-CATENIN DRIVEN TUMORIGENESIS ......................................................................................................11

O-09 UNIQUE MOLECULAR TRAITS FOR NASH-RELATED HEPATOCELLULAR CARCINOMA ....11

O-10 CHARACTERIZATION OF HEPATITIS B VIRUS-RELATED INSERTIONAL MUTAGENESIS IN HEPATOCELLULAR CARCINOMAS FROM EUROPEAN AND AFRICAN PATIENTS ..........12

O-11 DIFFERENTIAL ROLE OF HIPPO CASCADE IN C-MET/ß-CATENIN AND C-MET/SGAXIN1 DRIVEN MOUSE HCC.................................................................................................12

O-12 A NOVEL IMMUNOGENIC MOUSE MODEL OF HEPATOCELLULAR CARCINOMA FOR STUDYING MECHANISMS OF IMMUNE ESCAPE AND RESPONSE TO IMMUNOTHERAPIES .................................................................................................13

General Session 2: Clinical Trials .................................................................................................... 13

O-13 SAFETY PROFILE OF NIVOLUMAB (NIVO) PLUS IPILIMUMAB (IPI) COMBINATION THERAPY IN PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR CARCINOMA (HCC) IN THE CHECKMATE 040 STUDY ................................................................................13

O-14 ALPHA-FETOPROTEIN (AFP) RESPONSE AND EFFICACY OUTCOMES IN THE PHASE 3 CELESTIAL TRIAL OF CABOZANTINIB VERSUS PLACEBO IN ADVANCED HEPATOCELLULAR CARCINOMA (HCC).......................................................................14

O-15 MULTICENTRIC PROSPETTIVE STUDY OF VALIDATION OF ANGIOGENESIS-RELATED GENE POLYMORPHISMS IN HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH SORAFENIB: FINAL RESULTS OF INNOVATE STUDY ............................................14

O-16 ECONOMIC ANALYSIS OF OPEN VERSUS MINIMALLY-INVASIVE HEPATECTOMY: A SYSTEMATIC REVIEW AND META-ANALYSIS ............................................................15

O-17 A MULTI-NATIONAL, MULTI-INSTITUTIONAL STUDY OF COMPARING AN EFFICACY OF STEREOTACTIC BODY RADIATION THERAPY AND RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA ................................................................................15

O-32 PHASE IB STUDY RESULTS: SAFETY AND EFFICACY OF ATEZOLIZUMAB + BEVACIZUMAB VERSUS ATEZOLIZUMAB IN PATIENTS WITH PREVIOUSLY UNTREATED, UNRESECTABLE OR ADVANCED HEPATOCELLULAR CARCINOMA ................................16

Saturday, 21 September

Presidential Session ................................................................................................................................ 17

O-01 RESULTS OF A PHASE 3 STUDY OF PEMBROLIZUMAB VERSUS BEST SUPPORTIVE CARE FOR SECOND-LINE THERAPY IN ADVANCED HEPATOCELLULAR CARCINOMA: KEYNOTE-240 ..........................................................................................................17

O-02 RANDOMIZED, OPEN-LABEL, PERIOPERATIVE PHASE II STUDY EVALUATING NIVOLUMAB ALONE OR NIVOLUMAB PLUS IPILIMUMAB IN PATIENTS WITH RESECTABLE HCC. ........17

O-03 PROFILING OF ROUTINE SERUM PARAMETERS AND APP EVOLUTION IN CIRRHOSIS FOLLOWING HCV ERADICATION FOR STRATIFICATION OF HCC RISK: A TRAJECTORY CLUSTERING ANALYSIS FROM THE ANRS CO12 CIRVIR COHORT. ................................17

O-04 MRI RADIOMICS FEATURES PREDICT IMMUNO-ONCOLOGICAL CHARACTERISTICS AND RECURRENCE OF HEPATOCELLULAR CARCINOMA ..............................................18

O-05 IDENTIFICATION OF A PAN-GAMMA-SECRETASE INHIBITOR RESPONSE SIGNATURE FOR NOTCH-DRIVEN CHOLANGIOCARCINOMA ...........................................................18

O-06 GENOMIC ANALYSIS OF HEPATOCELLULAR CARCINOMA WITH ACTIVE HEPATITIS B VIRUS REPLICATION..................................................................................................19

General session 3: Epidemiology, Diagnosis, Staging ........................................................... 19

O-18 EVALUATION OF THE PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF HEPATOCELLULAR CARCINOMA CIRCULATING TUMOR CELLS EXPRESSING PROGRAMMED DEATH-LIGAND 1 (PD-L1)..................................................................19

O-19 ADDITION OF 18F-FLUORODEOXYGLUCOSE (FDG) PET-CT TO CROSS SECTIONAL IMAGING IMPROVES STAGING AND ALTERS MANAGEMENT IN PATIENTS WITH HCC- RESULTS FROM A NORTH AMERICAN PROSPECTIVE STUDY...............................19

O-20 HEPATOCELLULAR CARCINOMA INCIDENCE IS DECREASING AMONG YOUNG AND MIDDLE-AGED ADULTS IN THE UNITED STATES ..........................................................20

O-21 ASSOCIATIONS BETWEEN PREDIAGNOSTIC CONCENTRATIONS OF CIRCULATING SEX STEROID HORMONES AND PRIMARY LIVER CANCER AMONG WOMEN ..................20

O-22 A GENE EXPRESSION SIGNATURE OF MICROVASCULAR INVASION IN HEPATOCELLULAR CARCINOMA IN FORMALIN FIXED-PARAFFIN EMBEDDED BIOPSIES .............................21

O-33 VETC (VESSELS ENCAPSULATING TUMOR CLUSTERS) IS A POWERFUL PREDICTOR OF AGGRESSIVE HEPATOCELLULAR CARCINOMA. ......................................................21

Sunday, 22 September

General Session 4: Novel Targets and Prognostics Markers ........................................... 23

O-23 FIRST-IN-HUMAN, FIRST-IN-CLASS PHASE I TRIAL OF MTL-CEBPA, A RNA OLIGONUCLEOTIDE TARGETING THE TRANSCRIPTION FACTOR C/EBP-ALPHA, GIVEN AS A SINGLE AGENT OR IN COMBINATION WITH SORAFENIB, IN PATIENTS WITH ADVANCED HEPATOCELLULAR CANCER (HCC) ..................................................23

O-24 INTEGRATED ANALYSIS OF THE CERNA NETWORK REVEALING A 4-GENE-BASED PROGNOSTIC SIGNATURE ASSOCIATED WITH OVERALL SURVIVAL IN HEPATOCELLULAR CARCINOMA ................................................................................23

O-25 DEVELOPMENT OF EFFICIENT COMBINATION IMMUNOTHERAPY FOR PRIMARY AND METASTATIC LIVER CANCER BY BOOSTING INNATE AND ADAPTIVE IMMUNITY SIMULTANEOUSLY ....................................................................................................23

O-26 AU-409: PRECLINICAL ACTIVITY OF A NOVEL ORAL DNA BINDING AGENT FOR HEPATOCELLULAR CARCINOMA ................................................................................24

O-27 THE SAFETY AND EFFICACY OF NAMODENOSON IN THE SECOND LINE TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA (HCC) PATIENTS WITH UNDERLYING CHILD-PUGH B (CPB) LIVER CIRRHOSIS: A PHASE 2 , RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED ...........................................................................................24

O-34 DEVELOPMENT OF NOVEL CAR-T CELLS FOR IMMUNOTHERAPY OF HEPATOCELLULAR CARCINOMA ................................................................................25

TOP-SCORED POSTERS

Saturday, 21 September

P-001 MECHANISMS OF IMMUNE-MEDIATED ANTITUMOR ACTIVITY OF COMBINED LENVATINIB AND PD-1 BLOCKADE IN MURINE MODELS OF HEPATOCELLULAR CARCINOMA ............................................................................................................27

P-002 ADAPTIVE IMMUNITY REGULATES THE DEVELOPMENT OF NASH/ASH-RELATED FIBROSIS, THEREBY INFLUENCING THE PROGRESSION OF HCC AND ITS RESPONSE TO IMMUNOTHERAPY ...............................................................................................27

P-003 THERAPEUTIC MODULATION OF THE DUCTULAR REACTION AS A CHEMOPREVENTATIVE STRATEGY AGAINST LIVER CANCER ..........................................................................27

P-004 PRECLINICAL STUDIES OF CABOZANTINIB FOR HCC TREATMENT ...............................28

P-005 LINKING EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH CLINICAL PROGNOSIS AND NEW THERAPEUTIC TARGETS .........................................................28

P-006 CHROMOSOMAL STABILITY CORRELATES WITH THE IMMUNE CLASS OF HEPATOCELLULAR CARCINOMA ................................................................................29

P-007 DEVELOPMENT OF A PORCINE HEPATOCELLULAR CARCINOMA MODEL FOR TARGETED THERAPEUTIC TESTING ............................................................................29

P-008 CHOLANGIOCARCINOMA (CCA) DERIVED EXTRACELLULAR VESICLES REPROGRAM HEPATIC MACROPHAGES TO A PD-L1+ PRO-TUMOR PHENOTYPE ..............................30

P-009 GENOME-WIDE DNA METHYLATION PROFILING REVEALS NOVEL CANDIDATE EPIGENETIC GATEKEEPERS IN HEPATOCARCINOGENESIS ...........................................30

P-010 RNA-SEQUENCING OF PLASMA EXOSOMES REVEALS SPECIFIC TRANSCRIPTOMIC PROFILES IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ....................................30

P-011 MELD EXCEPTION: THE EFFECT OF THE OCTOBER 2015 POLICY CHANGE ..................31

P-013 ALPHA-FETOPROTEIN (AFP) RESPONSE AND OUTCOMES IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH REGORAFENIB OR PLACEBO IN THE PHASE 3 RESORCE TRIAL ..........................................................31

All abstracts listed in ILCA’s 13th Annual Conference Book of Abstracts have been assigned a prefix for the type of presentation, and a sequential abstract number. The authors’ whose names are in bold and followed by an asterisk are the presenting authors.

Oral Communication = O Poster = P

In the Book of Abstracts’ section, you will first find the Oral Communications, listed by day and time of presentation. You will then find then the Top Scored Posters and the Posters (e-Posters).

Poster Viewing Tour (Saturday 21 September, 09:45 to 10:45)

Top Scored Posters will be presented in the form of paper board posters at the beginning of the Poster Viewing Tour in the Poster Area. Viewing of all e-Posters will take place in at the same time.

The Top Scored Posters are:P-001, P-002, P-003, P-004, P-005, P-006, P-007, P-008, P-009, P-010, P-011, P-013, P-014, P-015, P-016, P-017, P-018, P-019, P-020

Hanging and removal of paper board posters

Poster boards will be marked with the final poster number.

Mounting time: Thursday, 19 September 2019 from 17:00 to 18:00 and Friday, 20 September 2019 from 09:30 to 10:00. Posters need to be mounted prior to Friday, 20 September 2019 at 10:00.

Removal time: Sunday, 22 September 2019 as of 10:00. Posters that have not been removed by 13:00 will be disposed of by the organisers. Top Scored Posters will be available also in a form of e-Poster on all e-Poster screens throughout the conference.

All Posters (e-Posters)

During the Poster Viewing Tour, e-Posters can be viewed only on their dedicated screens in the Exhibition and Poster Area.

Index of Authors

The Index of Authors lists all abstract authors in alphabetical order. To locate the page of the abstract, first take note of the abstract number (Example: P-002) and then locate the abstract, listed by type of presentation and in sequential order, in the table of contents, where you will find a reference for the page number.

Disclaimer

This Book of Abstracts has been produced using author-supplied copies. Editing has been restricted to minor spelling corrections where appropriate, otherwise every effort has been made to reproduce the abstracts as originally submitted. The organiser and publishers assume no responsibility for any injury and/or damage to persons or property as a matter of product liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. In view of rapid advances in medical sciences, independent verification of diagnoses and drug doses is recommended.

Contents Contents


P-014 PROVIDER ATTITUDES AND PRACTICE PATTERNS FOR DIRECT-ACTING ANTIVIRAL THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA IN THE UNITED STATES ..31

P-015 ADVANCED HEPATOCELLULAR CARCINOMA (HCC) TUMOR STAGE AT DIAGNOSIS AND POOR SURVIVAL REFLECT INEFFECTIVE IMPLEMENTATION OF HCC SCREENING AT FIVE UNDERSERVED, ETHNICALLY DIVERSE UNITED STATES SAFETY-NET HEALTH SYSTEMS .................................................................................................................32

P-016 CHECKMATE 040: HEALTH-RELATED QUALITY OF LIFE (HRQOL) IN PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR CARCINOMA (AHCC) AND CHILD-PUGH B STATUS TREATED WITH NIVOLUMAB (NIVO) ...............................................................32

P-017 PERIOPERATIVE ANALGESIA WITH PARECOXIB SODIUM IMPROVES POSTOPERATIVE PAIN AND IMMUNE FUNCTION IN PATIENTS UNDERGOING HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA：A RANDOMIZED CONTROLLED TRIAL .......................33

P-018 PHASE II CLINICAL TRIAL OF STEREOTACTIC BODY RADIATION THERAPY FOR SMALL (≤ 5 CM) HEPATOCELLULAR CARCINOMA NOT AMENABLE TO CURATIVE TREATMENT .33

P-019 INTRA-TUMOUR HETEROGENEITY IN THE REGULATION OF IMMUNE-TOLEROGENIC PATHWAYS IN PRIMARY AND METASTATIC HEPATOCELLULAR CARCINOMA. ................34

P-020 A POST HOC ANALYSIS OF NEUTROPHIL-LYMPHOCYTE RATIOS (NLR) IN THE REFLECT STUDY: FIRST-LINE LENVATINIB (LEN) OR SORAFENIB (SOR) IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (UHCC). ...........................................34

POSTERS

Molecular Pathogenesis, Molecular Pathology, Cell Biology and

Translational Research

P-024 THE MECHANISM OF ITGB3/SRC FROM PLATELET-EXOSOMES ON REGULATING CD155+ CIRCULATING TUMOR CELLS TO PROMOTE IMMUNE ESCAPE AND ITS CLINICAL SIGNIFICANCE AS A NEW BIOMARKER IN HEPATOCELLULAR CARCINOMA ....35

P-034 IDENTIFICATION OF IGF2 AS GENOMIC DRIVER AND THERAPEUTIC TARGET IN HEPATOBLASTOMA ..................................................................................................40

P-051 INTEGRATED MOLECULAR PROFILING REVEALS ETIOLOGICALLY DISTINCT LANDSCAPES OF GALLBLADDER CANCER .................................................................46

P-052 INTRA-HEPATIC IMMUNE CHANGES AFTER HEPATITIS C VIRUS ERADICATION BY DIRECT-ACTING ANTIVIRAL THERAPY ........................................................................46

P-053 ROLE OF RPS6KA3 GENE INACTIVATION IN HEPATOCELLULAR CARCINOMA ................47

P-054 POLYPLOID HEPATOCYTES CONTRIBUTE TO REGENERATION BUT ARE PROTECTED FROM CANCER EVEN AFTER CHRONIC LIVER INJURY .................................................47

P-056 ADVANCES IN THE ETIOLOGY AND THERAPEUTICS OF A LETHAL CHILDHOOD CANCER, FIBROLAMELLAR HEPATOCELLULAR CARCINOMA .......................................47

P-057 LIQUID BIOPSY FOR HEPATOCELLULAR CARCINOMA: POTENTIAL USEFULNESS OF MASSIVE SEQUENCING OF CIRCULATING DNA AS A TOOL FOR DIAGNOSIS AND FOLLOW-UP OF HCC PATIENTS .................................................................................48

P-058 CD73 PROMOTES HEPATOCELLULAR CARCINOMA PROGRESSION AND METASTASIS VIA ACTIVATING PI3K/AKT SIGNALING BY INDUCING RAP1-MEDIATED MEMBRANE LOCALIZATION OF P110： AND PREDICTS POOR PROGNOSIS .....................................48

P-059 A NOVEL LIQUID BIOPSY USING A HIGHLY SENSITIVE METHYLATED SEPT9 ASSAY TO DIAGNOSE HEPATOCELLULAR CARCINOMA ...............................................................49

P-060 EPHRIN-A3 (EFNA3) IS A KEY PLAYER IN HYPOXIC MICROENVIRONMENT OF HEPATOCELLULAR CARCINOMA ................................................................................49

P-090 HUMAN SMALL HEPATOCYTE PROGENITOR CELLS: A NOVEL TOOL TO STUDY HEPATOCELLULAR CARCINOMA ................................................................................59

P-091 SOMATIC COPY NUMBER PROFILING OF HEPATOCELLULAR CARCINOMA CIRCULATING TUMOR CELLS ....................................................................................60

P-092 MIR181A LEVELS IN CHOLANGIOCARCINOMA CORRELATE WITH TYROSINE PHOSPHORYLATION OF YAP AND SENSITIVITY TO SRC FAMILY KINASE INHIBITION .......60

P-093 HEPTOCELLULAR CARCINOMA DERIVED FOXO1 INHIBITED TUMOR PROGRESSION THROUGH SUPPRESSING IL-6 SECRETION FROM MACROPHAGE ................................61

P-094 LIM PROTEIN AJUBA PROMOTES CANCER CELL PROLIFERATION AND SURVIVAL IN HEPATOCELLULAR CARCINOMA ................................................................................61

P-095 SOMATIC TERT PROMOTOR VARIANTS IN EARLY HEPATOCARCINOGENESIS ................61

P-096 MOLECULAR CHARACTERISTICS ASSOCIATED WITH 18F-FDG UPTAKE IN INTRAHEPATIC CHOLANGIOCARCINOMA ....................................................................61

P-097 PRECLINICAL TESTING OF IMMUNE CHECKPOINT INHIBITION AS LIVER CANCER CHEMOPREVENTION .................................................................................................61

P-098 IMMUNOGENOMIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA WITH 11Q13.3 AMPLIFICATION ........................................................................................................62

P-099 ALTERED TRANSCRIPTIONAL PROFILES OF TUMOR-RELATED AND TUMOR-SUPPRESSOR GENES IN HCV-INFECTED INDIVIDUALS WITH EARLY FIBROSIS EVIDENCED BY SINGLE HEPATOCYTE RNA SEQUENCING. .............................62

P-100 DIET-VARIANTS AND IMMUNE CHARACTERIZATION OF A STAGE-DEFINED, TRANSGENIC IMMUNOCOMPETENT MOUSE MODEL OF HCC (ASV-B) .........................63

P-101 ALPHA-FETOPROTEIN INHIBITION ENHANCES THE IN VITRO AND IN VIVO ANTI-TUMOR EFFECTS OF SORAFENIB ON HEPATOCELLULAR CARCINOMA ................63

P-102 CELLULAR AND MOLECULAR CHARACTERIZATION OF HEPATOCELLULAR CARCINOMA UNDER DIFFERENT STEATOGENIC DIETS ...............................................63

P-103 SATB2-DEPENDENT CD24 ACTIVATION MAINTAINS SELF-RENEWAL OF HUMAN LIVER CANCER STEM CELLS.........................................................................64

P-104 DELETION OF MCC PROMOTES THE PROGRESSION OF PRIMARY LIVER CANCER IN MICE ......................................................................................................64

P-118 RAS PATHWAY ACTIVATION OF LIN28B, WHICH IN TURN SUPPRESSES METTL7A, TO DRIVE HEPATOCELLULAR CARCINOMA DEVELOPMENT .........................................72

P-119 THE ENGINEERED ANTI-GPC3 IMMUNOTOXIN, HN3-ABD-T20, HAS PROLONGED SERUM RETENTION AND CAUSES REGRESSION IN MOUSE LIVER CANCER XENOGRAFTS ...........................................................................................................72

P-120 HISTONE CHAPERONE FACT COMPLEX MEDIATES OXIDATIVE STRESS RESPONSE TO PROMOTE LIVER CANCER PROGRESSION ..................................................................72

P-121 ONCOGENIC ARGONAUTE 2 PROMOTES HEPATOCELLULAR CARCINOGENEIS THROUGH DEREGULATION OF THE MRNA TRANSCRIPTOME .......................................73

P-122 LHPP INHIBIT THE CELL PROLIFERATION EPITHELIAL-TO-MESENCHYMAL TRANSITION VIA THE TGF：/SMAD3 SIGNALING PATHWAY IN INTRAHEPATIC CHOLANGIOCARCINOMA ..........................................................................................73

P-123 INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 3 EXPRESSION UPREGULATION IS INVOLVED IN PROGRESSION OF HEPATOCELLULAR CARCINOMA ............................73

P-124 THE DEGREE OF HCC DIFFERENTIATION DETERMINES THE DRUG DIFFUSION IN MCTS ..................................................................................................................74

P-125 STUDY OF THE LIPOGENESIS REGULATORY PROTEINS IN HEPATOCELLULAR CARCINOMA ............................................................................................................74

P-145 THE MECHANISMS RESPONSIBLE FOR TUMOR INVASIVENESS IN CK19-POSITIVE HEPATOCELLULAR CARCINOMA ................................................................................83

P-146 MESSENGER RNA HYPERMETHYLATION FUELS CANCER-PROMOTING INFLAMMATION IN HEPATOCELLULAR CARCINOMA ...................................................83

P-147 REDUCTION OF SPECIFIC POLYUNSATURATED FATTY ACIDS WITH TUMOR PROGRESSION IN A LEAN NONALCOHOLIC STEATOHEPATITIS-ASSOCIATED HEPATOCELLULAR CARCINOMA MOUSE MODEL ........................................................84

P-148 EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND ITS RECEPTORS IN HEPATOCELLULAR CARCINOMA. ........................................................84

P-149 MYELOID-DERIVED SUPPRESSOR CELLS EXPAND IN PATIENTS WITH HEPATOBILIARY MALIGNANCIES AND PREDICT POOR PROGNOSIS ......................................................85

P-150 SUPPRESSING DRP1-MEDIATED MITOPHAGY INCREASES THE APOPTOSIS OF HEPATOCELLULAR CARCINOMA IN THE SETTING OF CHEMOTHERAPY ........................85

P-151 TMEM88 INHIBITED PROLIFERATION AND METASTASIS VIA GSK-3β/β-CATENIN SIGNALING IN HCC ...................................................................................................85

P-152 TARGETING THE ESTROGEN RECEPTOR ALPHA-MEDIATED CIRC-SMG1.72/MIR-141-3P/GELSOLIN SIGNALING TO BETTER SUPPRESS THE HCC CELL INVASION ..........................................................................................86

P-153 TRANSCRIPTION FACTOR ACTIVATING ENHANCER-BINDING PROTEIN-4 (TFAP4) IS INVOLVED IN REACTIVATION OF TELOMERASE REVERSE TRANSCRIPTASE (TERT) IN HEPATOCELLULAR CARCINOMA ............................................................................87

P-177 KNOCKDOWN OF ATG7 SUPPRESSES TUMORIGENESIS IN HCC MOUSE MODELS INDUCED BY HRASG12V AND SHP53 ........................................................................95

P-178 TUMOR-ASSOCIATED ANTIGEN SPECIFIC T-CELL IMMUNE RESPONSE IN HEPATOCELLULAR CARCINOMA ................................................................................95

P-179 CHARACTERISTICS OF TP53 AND CTNNB1 MUTATION ACCORDING TO THE SERUM TUMOR MARKERS IN HEPATOCELLULAR CARCINOMA ................................................96

P-180 THE PROGNOSTIC VALUE OF EPITHELIAL-MESENCHYMAL TRANSITION MARKERS IN HCV-ASSOCIATED HEPATOCELLULAR CARCINOMA: A MULTIVARIATE FOLLOW UP STUDY ................................................................................................................96

P-181 LINK BETWEEN M1/M2 HUMAN MACROPHAGES AND EPITHELIAL-MESENCHYMAL STATUS IN LIVER CANCER CELL LINES ......................................................................97

P-182 IMEGLIMIN ALONE OR IN COMBINATION WITH SORAFENIB SHOWED POTENT ANTI-TUMOR EFFECT IN HUMAN HEPATOCELLULAR CARCINOMA ...............................97

P-183 BASAL NOTCH4 ACTIVATION IS A DRUGGABLE MARKER OF AGGRESSIVENESS IN A PANEL OF HUMAN LIVER CANCER CELL LINES ....................................................97

P-220 CLAUSENIDIN INDUCES A G0/G1 AND G2/M CELL CYCLE ARREST

IN HEPG2 CELLS ....................................................................................................110

Clinical Trials and Treatment Research & Miscellaneous

P-021 MATCHING-ADJUSTED INDIRECT COMPARISON OF CABOZANTINIB VERSUS REGORAFENIB IN ADVANCED HEPATOCELLULAR CARCINOMA ....................................35

P-025 MAJOR IMPACT OF PERSONALIZED DOSIMETRY ON THE TARGETED TUMOR RESPONSE USING 90Y LOADED GLASS MICROSPHERES SIRT IN HCC: RESULTS OF A PROSPECTIVE AND MULTICENTRIC RANDOMIZED STUDY .....................36

P-026 TREATMENT WITH DIRECT-ACTING ANTIVIRALS DOES NEITHER INCREASE THE RISK OF HEPATOCELLULAR CARCINOMA PROGRESSION DURING WAITING LIST NOR RECURRENCE AFTER LIVER TRANSPLANTATION .........................................................36

P-027 STEREOTACTIC BODY RADIOTHERAPY AS A SALVAGE THERAPY AFTER INCOMPLETE RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA: A RETROSPECTIVE PROPENSITY SCORE MATCHING STUDY ........................................37

P-028 CLINICAL OUTCOMES OF STEREOTACTIC BODY RADIATION THERAPY FOR SINGLE VIABLE HEPATOCELLULAR CARCINOMA AT THE SITE OF INCOMPLETE TRANSARTERIAL CHEMOEMBOLIZATION ...................................................................38

P-029 SAFETY AND EFFICACY OF 12 MG/D LENVATINIB (LEN) IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (UHCC) AND BODYWEIGHT (BW) >80 KG IN REFLECT ....................................................................38

P-035 MULTICENTER PHASE II STUDY OF STEREOTACTIC ABLATIVE RADIOTHERAPY FOR HEPATOCELLULAR CARCINOMA ≤ 5 CM (KROG 12-02) ..............................................40

P-036 RECURRENCE OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH COMPLETE RESPONSE TREATED WITH DIRECT-ACTING ANTIVIRALS IN CLINICAL PRACTICE ..........41

P-037 RETROSPECTIVE, EXPLORATORY ANALYSIS OF THE OPTIMIS STUDY IN A SUBGROUP OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH TRANSARTERIAL CHEMOEMBOLIZATION (TACE) WHO RECEIVED SORAFENIB...............41

P-038 A DECISION-MAKING ALGORITHM FOR REPEATED TRANSARTERIAL CHEMOEMBOLIZATION OF INTERMEDIATE-STAGE HEPATOCELLULAR CARCINOMA: A MULTI-COHORT STUDY ..........................................................................................42

P-039 REAL-WORLD APPROACHES TO TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA WITH LENVATINIB IN JAPANESE PATIENTS: COMPLEMENTARY DATA FROM THE REFLECT TRIAL ........................................................................................42

P-041 EFFECTIVENESS OF PARECOXIB SODIUM COMBINED WITH TRANSVERSUS ABDOMINIS PLANE BLOCK FOR PAIN MANAGEMENT AFTER HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA: A RANDOMIZED CONTROLLED STUDY ......................42

P-042 INCREASED NEED OF LOCOREGIONAL THERAPIES IS A SURROGATE OF TUMOR BIOLOGY IN PATIENTS UNDERGOING LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA ................................................................................43

P-061 COMPARISON OF SURVIVAL OUTCOMES FOR ADVANCED HEPATOCELLULAR CARCINOMA BEFORE AND DURING THE FIRST AND SECOND ERAS OF TYROSINE KINASE INHIBITORS ..................................................................................................49

P-062 MULTICENTER RETROSPECTIVE ANALYSIS OF THE EFFICACY OF REGORAFENIB AFTER PROGRESSION ON SORAFENIB WITH HEPATOCELLULAR CARCINOMA ..............50

P-063 HCC SCREENING: ULTRASOUND VERSUS CROSS-SECTIONAL IMAGING .......................50

P-064 A PHASE 3 STUDY OF DURVALUMAB WITH OR WITHOUT BEVACIZUMAB AS ADJUVANT THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AT HIGH RISK OF RECURRENCE AFTER CURATIVE HEPATIC RESECTION OR ABLATION: EMERALD-2 ........50

P-065 OUTCOME AND SAFETY OF SECOND OR THIRD-LINE NIVOLUMAB TREATMENT IN REAL LIFE: A SINGLE CENTER EXPERIENCE ............................................................51

P-066 EFFECT OF RAMUCIRUMAB ON ALBUMIN-BILIRUBIN GRADE DURING TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND ELEVATED ALPHA-FETOPROTEIN FOLLOWING SORAFENIB: OUTCOMES FROM TWO RANDOMIZED PHASE 3 STUDIES (REACH, REACH-2) .......................................................................51

P-067 ANALYSIS OF EFFICACY AND SAFETY IN A REAL LIFE COHORT OF HEPATOCELLULAR CARCINOMA TREATED WITH SORAFENIB-REGORAFENIB ............................................52

P-068 DOWNSTAGING WITH RADIOEMBOLIZATION OR CHEMOTHERAPY FOR INITIALLY UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA ...........................................52

P-069 LIVER CANCER CELL LINES AS PHARMACOGENOMICS MODELS TO PREDICT DRUG SENSITIVITY IN HEPATOCELLULAR CARCINOMA .........................................................52

P-070 A PRELIMINARY ANALYSIS OF EARLY LIVER ADVERSE EVENTS (LAE) IN PATIENTS WITH HEPATOCELLULAR CARCINOMA TREATED WITH SELECTIVE INTERNAL RADIATION THERAPY (SIRT) AND NIVOLUMAB ............................................................53

P-071 TRANS-ARTERIAL CHEMOEMBOLIZATION (TACE) AS A LOCO-REGIONAL INDUCER OF IMMUNOGENIC CELL DEATH IN HEPATOCELLULAR CARCINOMA ............................53

P-072 PHASE 3 (COSMIC-312) STUDY OF CABOZANTINIB IN COMBINATION WITH ATEZOLIZUMAB VS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA (AHCC) WHO HAVE NOT RECEIVED PREVIOUS SYSTEMIC ANTICANCER THERAPY .................................................................................................................54

P-073 WHICH CURATIVE TREATMENT FOR STAGES 0-A HEPATOCELLULAR CARCINOMA IN HIV-INFECTED PATIENTS ? AN INTENTION-TO-TREAT ANALYSIS ..............................54

P-074 BETTER PREDICTION OF OUTCOMES BY RESPONSE EVALUATION USING THE MODIFIED RECIST COMPARED WITH THE RECIST 1.1 IN PATIENTS WITH HCC TREATED WITH YTTRIUM-90 RADIOEMBOLISATION...................................................................54

P-078 COMPARISON OF SURGICAL MICROWAVE ABLATION AND HEPATIC RESECTION FOR SINGLE HEPATOCELLULAR CARCINOMA ≤ 5CM: A PROPENSITY SCORE-MATCHED ANALYSIS .................................................................................................................55

P-079 DOWNSTAGING HEPATOCELLULAR CARCINOMA: ARE OUTCOMES EQUIVALENT? ........55

P-080 THE EFFECT OF UREA CREAM ON SORAFENIB-ASSOCIATED HAND-FOOT SKIN REACTION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA: MULTICENTER, PROSPECTIVE RANDOMIZED DOUBLE-BLIND CONTROLLED STUDY ............................55

P-105 EFFECT OF ENHANCED RECOVERY AFTER SURGERY PROGRAM ON PATIENT-REPORTED OUTCOMES AND FUNCTION RECOVERY IN PATIENTS UNDERGOING LIVER RESECTION FOR HCC .................................................................65

P-106 PROGNOSTIC IMPACT OF POSTOPERATIVE COMPLICATION AFTER HEPATIC RESECTION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA ..................................65

P-107 THE INTERACTION OF STRESS AND IMMUNITY AFTER THERMAL ABLATION FOR HEPATOCELLULAR CARCINOMA ................................................................................66

P-108 SAFETY AND OUTCOME OF HEPATOCELULLUAR CARCINOMA PATIENTS TREATED WITH NIVOLUMAB IN REAL LIFE OF HEPATO-ONCOLOGY UNITS ..................................67

P-109 COMPARISON OF THE EFFICACY AND SAFETY OF CONVENTIONAL TRANSARTERIAL CHEMOEMBOLIZATION COMBINED WITH AND WITHOUT CALLISPHERES DRUG-ELUTING BEADS EMBOLIZATION FOR THE TREATMENT OF UNRESECTABLE LARGE HEPATOCELLULAR CARCINOMA ................................................................................67

P-110 DOES POSTOPERATIVE ADJUVANT TRANSARTERIAL CHEMOEMBOLIZATION BENEFIT FOR ALL PATIENTS WITH HEPATOCELLULAR CARCINOMA COMBINED WITH MICROVASCULAR INVASION: A META-ANALYSIS .........................................................68

P-111 PEMBROLIZUMAB VS PLACEBO AS ADJUVANT THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AND COMPLETE RADIOLOGIC RESPONSE AFTER SURGICAL RESECTION OR LOCAL ABLATION: PHASE 3 KEYNOTE-937 TRIAL ...............68

P-112 ADVANTAGES OF CONTROLLED LOW CENTRAL VENOUS PRESSURE IN LAPAROSCOPIC HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA - A RANDOMIZED CLINICAL TRIAL ...............................................................................69

P-126 DOSE ESCALATION BY INTENSITY MODULATED RADIOTHERAPY IN LIVER-DIRECTED CONCURRENT CHEMORADIOTHERAPY FOR LOCALLY ADVANCED BCLC STAGE C HEPATOCELLULAR CARCINOMA ................................................................................74

P-128 ENDOSCOPIC BILIARY DRAINAGE IS SUPERIOR TO PERCUTANEOUS TRANSHEPATIC BILIARY DRAINAGE FOR RESECTABLE MALIGNANT BILIARY OBSTRUCTION IN THE PREVENTION OF SEEDING METASTASIS: A META-ANALYSIS ........................................75

P-129 ENDOSCOPIC ULTRASOUND-GUIDED BILIARY DRAINAGE VERSUS ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY FOR THE PRIMARY PALLIATION OF MALIGNANT BILIARY OBSTRUCTION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS ...............................................................................................76

P-130 ALPHA FETOPROTEIN LEVELS: WHEN DO THEY CORRELATE STRONGEST WITH OUTCOMES? ............................................................................................................77

P-131 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF TRANSARTERIAL CHEMOEMBOLIZATION COMBINED WITH DURVALUMAB OR DURVALUMAB PLUS BEVACIZUMAB THERAPY IN PATIENTS WITH LOCOREGIONAL HEPATOCELLULAR CARCINOMA (HCC): EMERALD-1...................................................77

P-138 IMPROVED OUTCOMES OF LIVE DONOR LIVER TRANSPLANTATION COMPARED TO RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA LESS THAN 3CM: AN INTENTION-TO-TREAT AND PROPENSITY SCORE MATCHING ANALYSIS ..................81

P-139 LYMPHOCYTES AND NEUTROPHILS TO LYMPHOCYTES RATIO (NLR) CHANGES AFTER SELECTIVE INTERNAL RADIATION TREATMENT (SIRT) FOR HCC ...................................81

P-140 SAFETY AND EFFECTIVENESS OF ENHANCED RECOVERY AFTER SURGERY (ERAS) IN PATIENTS WITH HEPATOCELLULAR CARCINOMA UNDERGOING PARTIAL HEPATECTOMY: A MULTICENTRE, RANDOMISED, CONTROLLED CLINICAL STUDY ................................81

P-141 SAFETY OF TRANSARTERIAL CHEMOEMBOLIZATION IN PATIENTS WITH RECURRENT HEPATOCELLULAR CARCINOMA AFTER LIVER TRANSPLANTATION ..............................82

P-154 DOSE ESCALATION IN RADIOTHERAPY FOR INCOMPLETE TRANSARTERIAL CHEMOEMBOLIZATION OF HEPATOCELLULAR CARCINOMA ........................................87

P-155 THE INFLUENCE OF ABO BLOOD GROUP ON WAITLIST AND TRANSPLANT OUTCOMES ..............................................................................................................88

P-156 COULD POSTOPERATIVE ADJUVANT CHEMO (EMBOLIZATION) THERAPY REDUCE THE RECURRENCE OF HEPATOCELLULAR CARCINOMA WITH PORTAL VEIN TUMOR THROMBOSIS: A META-ANALYSIS ..............................................................................88

Contents Contents


P-162 MATHEMATICAL MODELLING OF BURDEN OF HEPATOCELLULAR CARCINOMA IN WESTERN KENYA .....................................................................................................90

P-174 CHANGING EPIDEMIOLOGY AND AETIOLOGY OF HEPATOCELLULAR CARCINOMA IN NEW ZEALAND: AUDIT FROM NZ LIVER TRANSPLANT UNIT ....................................94

P-175 CLINICAL CHARACTERISTICS AND OUTCOMES OF CRYPTOGENIC HEPATOCELLULAR CARCINOMA IN TAIWAN ............................................................................................95

P-176 PREOPERATIVE PRACTICAL AND PERSONALIZED PREDICTORS OF EARLY OUTCOMES AFTER MAJOR HEPATECTOMY FOR CHOLANGIOCARCINOMAS LOCATED NEAR TO THE HILUM ................................................................................................95

P-198 TREATMENT STRATEGY FOR PATIENTS WITH A SOLITARY HUGE (> 10CM) HEPATOCELLULAR CARCINOMA (HCC) – LIVER RESECTION IS BETTER THAN TRANSARTERIAL CHEMOEMBOLIZATION (TACE) .......................................................102

P-199 IMPACT OF BASELINE CHARACTERISTICS ON THE OVERALL SURVIVAL OF HCC PATIENTS TREATED WITH SORAFENIB: A TEN-YEAR EXPERIENCE IN FIELD-PRACTICE ....................................................................................................103

P-200 TO IDENTIFY THE BENEFICIAL BODY MASS INDEX (BMI) FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA TO ACHIEVE A LONGER SURVIVAL TIME AFTER CURATIVE MICROWAVE ABLATION ...........................................................................103

P-201 HEPATOCELLULAR CARCINOMA IN ETHIOPIA: SINGLE-CENTER ANALYSIS OF THERAPY AND OUTCOMES .....................................................................................103

P-203 VITAMIN B12 SUPPLEMENTATION IS ASSOCIATED WITH LOWER RATES OF HEPATOCELLULAR CANCER ....................................................................................104

P-204 CLINICAL MANIFESTATION, STAGING AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA IN GAMBIAN PATIENTS ........................................................................104

P-205 THE CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS OF HEPATOCELLULAR CARCINOMA OF DIFFERENT ETIOLOGIES .................................................................104

P-209 RISK STRATIFICATIONS AND VALIDATION OF 50-50 CRITERIA AND POST-HEPATECTOMY LIVER FAILURE (PHLF) SCORE IN PATIENTS WITH CIRRHOSIS UNDERWENT CURATIVE RESECTION FOR HCC .........................................................105

P-210 POSTOPERATIVE HEPATOBILIARY SURGERIES' FUNGAL INFECTIONS EPIDEMIOLOGY (PREVALENCE AND RISK FACTORS) .........................................................................105

P-212 DIABETES INCREASED THE RISKS OF DISTANT METASTASIS IN HCC PATIENTS WITH TRANSARTERIAL CHEMOEMBOLIZATION .........................................................106

P-213 CIRCULATING D DIMER LEVEL CORRELATES WITH TUMOR GRADE IN CHRONIC HEPATITIS C RELATED HEPATOCELLULAR CARCINOMA ............................................106

P-215 TUMOR SIZE, PRESENCE OF ASCITES, AND TREATMENT RESPONSE DETERMINED THE PROGNOSIS OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND WITH ESOPHAGOGASTRIC VARICES AFTER TRANSARTERIAL CHEMOEMBOLIZATION ..........107

P-224 OUTCOMES OF LIVER TRANSPLANTATION FOR NASH-ASSOCIATED HEPATOCELLULAR CARCINOMA ..............................................................................111

P-225 CLINICAL CHARACTERISTICS AND SURVIVALS IN HUGE (≥8CM) ADVANCED HEPATOCELLULAR CARCINOMA ..............................................................................112

Diagnosis, Imaging and Biomarkers

P-045 BREATH METABOLOMICS ACCURATELY CLASSIFIES PATIENTS WITH CHRONIC LIVER DISEASE, PRIMARY, AND SECONDARY LIVER CANCERS ..............................................43

P-046 RELATIONSHIP BETWEEN PRE-SARCOPENIA AND EVENT OCCURRENCE IN PATIENTS WITH PRIMARY HEPATOCELLULAR CARCINOMA ........................................................44

P-047 RADIOLOGICAL RESPONSE OF HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH NIVOLUMAB IN REAL LIFE. MULTICENTRIC ANALYSIS FROM REFERRAL CENTERS IN SPAIN ...................................................................................................44

P-081 LIQUID BIOPSY FOR DIAGNOSIS AND PROGNOSIS IN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW AND METAANALYSIS .........................................56

P-083 IDENTIFICATION OF MULTIMARKER PANELS FOR EARLY DETECTION OF HEPATOCELLULAR CARCINOMA THROUGH EXHAUSTIVE SEARCH ...............................56

P-113 TUMOR-ASSOCIATED VASCULAR MARKER IN LIVER CANCER......................................70

P-114 ELEVATED LEVEL OF SOLUBLE PROGRAMMED DEATH-LIGAND 1 INDICATED IMMUNOSUPPRESSION AND POOR PROGNOSIS IN HEPATOCELLULAR CARCINOMA PATIENTS UNDERGOING TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION ..............70

P-115 PROGNOSTIC ROLE OF SERUM WISTERIA FLOIRBUNDA AGGLUTININ-POSITIVE MAC-2 BINDING PROTEIN LEVEL AFTER HEPATOCELLULAR CARCINOMA RESECTION ..............................................................................................................71

P-116 SAFETY, RISK STRATIFICATION AND COST OF ERCP IN PATIENTS WITH CIRRHOSIS ......71

P-142 CHANGES IN ALPHA-FETOPROTEIN (AFP) AND SYSTEMIC THERAPY OUTCOMES IN ADVANCED HEPATOCELLULAR CARCINOMA (HCC): A MULTICENTER RETROSPECTIVE ANALYSIS .......................................................................................82

P-171 OPTIMIZING THE DIAGNOSTIC ROLE OF ALPHA-FETOPROTEIN AND ABDOMINAL ULTRASOUND BY ADDING OVEREXPRESSED BLOOD MRNA MATRIX METALLOPROTEINASE-12 FOR DIAGNOSIS OF HCV-RELATED HEPATOCELLULAR CARCINOMA ............................................................................................................93

P-172 LOW LEVELS OF TUMOR SUPPRESSOR CANDIDATE 3 PREDICT POOR PROGNOSIS OF PATIENTS WITH HEPATOCELLULAR CARCINOMA ...................................................94

P-173 INCREASED LEVELS OF HNRNP L IN HCC CORRELATE WITH THE POLARIZATION OF MACROPHAGES ..................................................................................................94

P-196 UTILITY OF CONTRAST ENHANCED ULTRASONOGRAPHY IN MONITORING RECURRENCE AFTER A FIRST THERAPEUTIC PROCEDURE FOR HEPATOCELLULAR CARCINOMA ..........................................................................................................101

P-197 SURVIVAL RATE FOLLOWING TRANSARTERIAL CHEMOEMBOLIZATION (TACE) AS ONLY TREATMENT: DECREASED SURVIVAL MARKERS ...............................................102

P-208 SERUM TRANSFORMING GROWTH FACTOR ALPHA (TGF：) AS A BIOMARKER FOR HEPATOCELLULAR CARCINOMA (HCC).....................................................................105

P-219 A CASE OF HEPATOID ADENOCARCINOMA PRESENTING AS ACUTE PANCREATITIS AND ELEVATED AFP AND B-HCG- FIRST REPORTED CASE OF HEPATOID ADENOCARCINOMA IN A VICENARIAN ......................................................................109

P-222 A NEW PROTOCOL OF GADOXETIC ACID-ENHANCED LIVER MAGNETIC RESONANCE IMAGING MINIMIZES RESPIRATORY ARTIFACT AND IMPROVE IMAGE QUALITY ...........110

Authors Index ......................................................................................................................................... 113

P-163 CLINICAL OUTCOME AND BIOMARKERS IN JAPANESE PATIENTS TREATED WITH REGORAFENIB IN REAL WORLD PRACTICE .................................................................91

P-164 TREATMENT STRATEGY USING BODY COMPOSITION FOR ADVANCED HEPATOCELLULAR CARCINOMA: HEPATIC ARTERIAL INFUSION CHEMOTHERAPY VS. SORAFENIB ........................................................................................................91

P-165 ACUTE STROKE AFTER TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA ................................................................................91

P-166 MONOCYTE-TO-LYMPHOCYTE RATIO WAS CORRELATED WITH NIVOLUMAB RESPONSE IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA .................92

P-167 EFFICACY OF RADIOFREQUENCY ABLATION IN THE TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND COMPENSATED LIVER DISEASE: A PATHOLOGICAL EVALUATION OF LIVER EXPLANTS ..................................................92

P-168 PREDISPOSING FACTORS OF HEPATOCELLULAR CARCINOMA RECURRENCES FOLLOWING COMPLETE REMISSION BY TRANSARTERIAL CHEMOEMBOLIZATION: FOCUSED ON THE RECURRENCE PATTERNS ..............................................................93

P-169 HEPATIC ARTERIAL INFUSION CHEMOTHERAPY (HAIC) USING 5-FLUOROURACIL WITH SYSTEMIC PEGYLATED INTERFERONα-2B FOR UNRESECTABLE ADVANCED INTRAHEPATIC CHOLANGIOCARCINOMA. ...................................................................93

P-170 RISK FACTORS ASSOCIATED WITH FAILURE OF ENHANCED RECOVERY AFTER HEPATECTOMY: ESTABLISHMENT OF A PREDICTION MODEL ......................................93

P-184 EFFICACY AND SAFETY OF LENVATINIB FOR UNRESECTABLE HEPATOCELLULAR CARCINOMA IN CLINICAL PRACTICE ..........................................................................98

P-185 PROSPECTIVE PHASE 2 STUDY OF STEREOTACTIC BODY RADIATION THERAPY IN HCC PATIENTS AFTER FAILURE OF TACE ................................................................98

P-187 PREDICTORS OF RADIOLOGICAL COMPLETE RESPONSE IN PATIENTS WITH INTRAHEPATIC HEPATOCELLULAR CARCINOMA TREATED WITH TRANSARTERIAL RADIOEMBOLIZATION ...............................................................................................98

P-188 IMPROVED OUTCOMES OF LAPAROSCOPIC LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA LOCATED IN POSTEROSUPERIOR SEGMENTS OF THE LIVER ...........................................................................................................99

P-189 SIZE OF INTRAHEPATIC LESIONS PREDICTS EFFICACY OF SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA. .....................................................99

P-190 PRESENCE OF PORTAL VEIN TUMOR THROMBOSIS IS AN INDEPENDENT FACTOR FOR SURVIVAL IN HCC PATIENTS WHO UNDERWENT TRANS-ARTERIAL RADIOEMBOLIZATION ...............................................................................................99

P-191 CLINICAL STUDY OF APATINIB COMBINED WITH TACE IN ADVANCED HEPATOCELLULAR CARCINOMA APATINIB COMBINED WITH TACE IN THE TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA ..............................................................................100

P-192 DYNAMIC CHANGES OF THE TUMOR THROMBOSIS AFTER STEROTACTIC BODY RADIOTHERAPY OF HEPATOCELLULAR CARCINOMA ................................................100

P-193 COST-EFFECTIVENESS ANALYSIS OF METAL VERSUS PLASTIC STENTS IN HEPATOCELLULAR CARCINOMA PATIENTS’ WITH OBSTRUCTIVE JAUNDICE, BASED ON A RANDOMIZED CONTROLLED TRIAL ......................................................100

P-194 ESCALON: EARLY DIAGNOSIS AND MECHANISMS OF HEPATOBILIARY MALIGNANCIES IN SOUTH AMERICA ........................................................................101

P-195 FIRST-LINE COMBINATION THERAPY WITH LENVATINIB PLUS PEMBROLIZUMAB FOR PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA: PHASE 3 LEAP-002 STUDY .....................................................................................101

P-206 ASSESSMENT OF LIVER FUNCTION USING ALBI SCORE IN PATIENTS TREATED WITH LENVATINIB FOR HEPATOCELLULAR CARCINOMA ............................................105

P-211 ADJUVANT CHEMOTHERAPY FOR RESECTED INTRAHEPATIC CHOLANGIOCARCINOMA: IS THERE STILL A ROLE FOR GEMCITABINE? ............................................................106

P-214 SAFETY AND EFFICACY OF YTTRIUM-90 RADIOEMBOLIZATION FOR ADVANCED HCC PATIENTS: A 35 PROCEDURES CASE-SERIES ...........................................................107

P-216 THE CHALLENGE OF HEPATOCELLULAR CARCINOMA MANAGEMENT IN THE ERA OF INDIVIDUALIZED THERAPY: THE EXPERIENCE OF A GREEK TERTIARY CENTER IN THE MIDDLE OF A FINANCIAL CRISIS ......................................................107

P-217 NIVOLUMAB (ANTI PROGRAMMED DEATH 1 INHIBITOR) IN PATIENTS WITH PROGRESSION AFTER SORAFENIB CAN BE EFFECTIVE AS BOTH GROUP (2ND LINE AND 3RD LINE) .......................................................................................108

P-218 HOW TO IMPROVE RESPONSE TO SORAFENIB? A SINGLE TERTIARY CENTER EXPERIENCE ..........................................................................................................109

P-221 FEASIBILITY AND EFFICACY OF RADIOFREQUENCY-ASSISTED ALPPS UNDER LAPAROSCOPY IN PATIENTS WITH LIVER TUMORS ...................................................110

P-223 TREATMENT OF RECURRENT HEPATOCELLULAR CARCINOMA AFTER LIVER TRANSPLANTATION: REGORAFENIB PROVIDES SURVIVAL BENEFIT AS COMPARED

TO BEST SUPPORTIVE CARE ...................................................................................110

Epidemiology, Staging and Prognosis

P-023 MIRNA-MRNA REGULATORY NETWORK AND FACTORS ASSOCIATED WITH PREDICTION OF PROGNOSIS IN HEPATOCELLULAR CARCINOMA.................................36

P-030 ASSOCIATION BETWEEN ESOPHAGOGASTRIC VARICES IN HEPATOCELLULAR CARCINOMA AND POOR PROGNOSIS AFTER TRANSARTERIAL CHEMOEMBOLIZATION: A PROPENSITY SCORE MATCHING ANALYSIS .............................................................38

P-031 OBESITY AND THE RISK OF PRIMARY LIVER CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS ...............................................................................................39

P-032 RISK OF HEPATOCELLULAR CARCINOMA IN DANISH OUTPATIENTS WITH ALCOHOLIC CIRRHOSIS ............................................................................................39

P-033 FINANCIAL BURDEN IS COMMON IN U.S. PATIENTS WITH CIRRHOSIS AND ASSOCIATED WITH LOWER HCC SURVEILLANCE RECEIPT ...........................................39

P-048 EVALUATION OF THE AFP SCORE IN HEPATOCELLULAR CARCINOMA PROGRESSION DURING WAITING LIST AND RECURRENCE AFTER LIVER TRANSPLANTATION ................45

P-049 RESPONSE TO SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA: PREDICTIVE ANALYTICS USING MACHINE LEARNING WITH A NEIGHBORHOOD-GROUP DETECTION METHOD ..........................................................45

P-050 DIETARY FAT INTAKE AND RISK OF HEPATOCELLULAR CARCINOMA IN TWO LARGE PROSPECTIVE COHORT STUDIES ...............................................................................46

P-084 EFFECT OF FRAGMENTATION OF CANCER CARE ON TREATMENT USE AND SURVIVAL IN HEPATOCELLULAR CARCINOMA ............................................................57

P-085 ALBUMIN-BILIRUBIN GRADE CAN SUBCLASSIFY PATIENTS WITH A CHILD-PUGH SCORE OF 5 TREATED WITH SORAFENIB FOR HEPATOCELLULAR CARCINOMA ............57

P-086 THE TORONTO POST LIVER TRANSPLANT HCC RECURRENCE CALCULATOR: A MACHINE-LEARNING APPROACH ...........................................................................57

P-087 COMPARISON OF LONG-TERM OUTCOMES OF MICROWAVE ABLATION VERSUS SURGICAL RESECTION FOR HCC ...............................................................................58

P-088 FACTORS ASSOCIATED WITH DETECTION OF THE SINGLE LESS THAN 2CM HEPATOCELLULAR CARCINOMA IN THE UNITED STATES .............................................58

P-089 LISTING, DROPOUT AND TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA IN LATIN AMERICA: UNEXPECTED AND PREVIOUSLY NOT REPORTED RESULTS ...........59

P-117 PROGNOSTIC VALUES OF TUMOR MARKERS IN PATIENTS WHO ACHIEVED COMPLETE RESPONSE TO TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA ................................................................................71

P-132 IMPORTANCE OF COMORBIDITY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH PERCUTANEOUS TERMOABLATION............................................78

P-133 A COMPARISON OF PROGNOSIS BETWEEN SURGICAL RESECTION AND RADIOFREQUENCY ABLATION THERAPY FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA AND WITH ESOPHAGOGASTRIC VARICES................................................78

P-134 ANALYSIS OF PROGNOSTIC AND PREDICTIVE FACTORS OF POST RECURRENCE SURVIVAL AFTER LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA: A MULTICENTER COHORT STUDY FROM LATIN AMERICA ............................................79

P-135 DEVELOPMENT AND EXTERNAL VALIDATION OF PROGNOSTIC NOMOGRAMS IN HEPATOCELLULAR CARCINOMA PATIENTS: A POPULATION BASED STUDY ..............79

P-136 ESTABLISHMENT OF A RISK PREDICTION MODEL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA TREATED WITH TRANS-ARTERIAL RADIOEMBOLIZATION ...............................................................................................80

P-137 GOING OUTSIDE MILAN AND WITHIN SAN FRANCISCO CRITERIA DOES NOT INCREASE RECURRENCE RATE OF HCC POST LIVER TRANSPLANT ..............................80

P-143 NON-CURATIVE TREATMENT IN VERY EARLY AND EARLY HEPATOCELLULAR CARCINOMA: A PROGNOSTIC MIGRATION TO BCLC STAGE B......................................82

P-144 PATHOLOGIC COMPLETE RESPONSE TO CHEMOEMBOLIZATION IMPROVES SURVIVAL OUTCOMES AFTER CURATIVE SURGERY FOR HEPATOCELLULAR CARCINOMA: PREDICTIVE FACTORS OF RESPONSE ...................................................83

P-157 MANAGEMENT OF PATIENTS WITH UNRESECTED HEPATOCELLULAR CARCINOMA AFTER RADIOLOGICALLY CONFIRMED DISEASE PROGRESSION ON SYSTEMIC FIRST-LINE TREATMENT. RESULTS OF THE RETROSPECTIVE HERACLES STUDY ...........88

P-158 SURVIVAL DIFFERENCES IN LIVER CANCER DUE TO PATIENT RACE AND RACIAL RESIDENTIAL SEGREGATION .....................................................................................89

P-159 THE EFFECT OF METABOLIC FACTORS ON PROGNOSIS OF HBV-ASSOCIATED HEPATOCELLULAR CARCINOMA ................................................................................89

P-160 IMPACT OF SPLEEN SIZE ON CLINICAL OUTCOME OF PATIENTS WITH HEPATOCELLULAR CARCINOMA TREATED BY TRANSARTERIAL CHEMOEMBOLIZATION .............................................................................................90

P-161 FACTORS ASSOCIATED WITH POSTPROGRESSION SURVIVAL IN ADVANCED HEPATOCELLULAR CARCINOMA PATIENTS WITH POST-SORAFENIB PROGRESSION NOT ELIGIBLE FOR REGORAFENIB .............................................................................90

Oral Communications


Thursday, 19 September 2019

Young Investigator Session

O-28 METABOLOMIC LANDSCAPES OF NON-ALCOHOLIC FATTY LIVER-ASSOCIATED HEPATOCELLULAR CARCINOMA AND ITS DIAGNOSTIC POTENTIAL

Monika Lewinska* 1, Alvaro Santos-Laso 2, Raúl Jiménez-Agüero2, Emma Eizaguirre2, Maria J. Pareja3, Enara Arretxe4, Cristina Alonso4, Bruno Sangro5, 6, Rocio I. Macias6, 7, Jesus M. Banales2, 6, 8, Jesper B. Andersen1

1Department of Health and Medical Sciences, Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark, 2Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, San Sebastian, 3Unidad de Gestión Clínica de Aparato Digestivo, Hospital Juan Ramón Jiménez, Huelva, 4OWL Metabolomics, Derio, 5Clinica Universidad de Navarra, Pamplona, 6National Institute for the Study of Liver and Gastrointestinal Diseases , Madrid, 7Biomedical Research Institute of Salamanca , University of Salamanca, Salamanca, 8IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

Introduction: Non-alcoholic fatty liver (NAFL) is a highly prevalent progressive liver disorder (24% of population globally)[1], ranging from hepatic steatosis to non-alcoholic steatohepatitis and cirrhosis. NAFL is emerging as the leading risk factor of hepatocellular carcinoma (HCC) (HR 16.73)[2]. The molecular mechanisms of NAFL-associated HCC (NAFL-HCC) tumorigenesis remain elusive and surveillance of NAFL patients poses a clinical challenge. In this study, we elucidate the deregulated metabolic landscapes in NAFL-HCC patients, characterizing the role of lipids in disease onset and their diagnostic utility.

Methods: We have generated large-scale metabolomic data investigating 1,295 metabolites in 195 human serum samples with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) and detected 470 metabolites including amino acids (aa), aa-derivatives and lipids. Patients with biopsy-proved diagnosis were stratified into healthy controls (HC=86), NAFL (n=51), NAFL-HCC (n=27) and viral/alcoholic HCC (v/a-HCC=31). Importantly, fresh-frozen tissues (NAFL-HCC, n=27), matched adjacent tissues (AT, n=27), healthy control (HC, n=27) and NAFL (n=23) underwent metabolomic profiling. Univariate and multivariate analyses were performed for biomarker discovery and associated with clinical and hepatological variables.

Results: Supervised PLS-DA analysis using all detected metabolites significantly distinguished patient groups (Q2=0.55). Importantly, we compared the predictive ability of serum alanine aminotransferase (ALT), alpha-fetoprotein (AFP) and our 5-metabolite model (DG36:4, hypogeic acid, 9,10-DiHOME, TG42:0, TG54:7) identified by PLS-DA. In pair-wise comparison, our model performed superior to ALT and AFP distinguishing NAFL-HCC from HC (AUCmodel=0.959 vs AUCALT=0.810 or AUCAFP=0.869), NAFL-HCC from NAFL (AUCmodel=0.957 vs AUCALT=0.637) and NAFL-HCC from a/v-HCC (AUCmodel=0.877 vs AUCALT=0.455 and AUCAFP=0.489). Next, pattern analysis identified 176 metabolites (81 up and 95 downregulated) that progressively change in HC->NAFL->NAFL-HCC axis (FDR p<0.001). Of note, we identified accumulation of triglycerides (TG) rich in saturated FA. Liver deterioration inversely correlated with serum polyunsaturated FA including linoleic acid (LA) and products of its oxidation (p<0.0001). Moreover, LA was diminished (p<0.0001) in NAFL-HCC when adjusted for sex, age and BMI, and is independent of serum biochemistry (AST, ALT, GGT) and type 2 diabetes. Interestingly, tissue metabolomics revealed upregulation of FFA and depletion of TG in NAFL-HCCs compared to AT (p=0.007) and NAFL (p=0.011), implying increased lipid dependence in NAFL-HCC. Serum TG and FFA positively correlated with tissue metabolomes of HC, NAFL and AT subsets, inferring an upregulated de novo lipogenesis and TG synthesis in non-tumorous tissues as protective responses to metabolic stress.

Conclusions: This study represents the first metabolome characterization of human NAFL-HCC. Results presented provide important biological insights in NAFL-HCC development, emphasizing how serum levels of FFA and TG progressively change with liver deterioration. Significantly, linoleic acid presents an independent diagnostic biomarker with potential in NASH-HCC. Further studies are currently attempting to functionally trace lipidomic alterations to assess their therapeutic potential.

References: [1] Younossi, Z., et al Nat Rev Gastroenterol Hepatol 2018;15:11-20. [2] Kim, GA. et al J Hepatol 2017

Disclosure of Interest: M. Lewinska: None Declared, A. Santos-Laso : None Declared, R. Jiménez-Agüero: None Declared, E. Eizaguirre: None Declared, M. Pareja: None Declared, E. Arretxe Conflict with: Honoraria - Dr. Arretxe is employed by OWL Metabolomics, C. Alonso Conflict with: Honoraria - Dr. Alonso is employed by OWL Metabolomics, B. Sangro: None Declared, R. Macias: None Declared, J. Banales Conflict with: Advisory Board - Dr. Banales is member of the scientific advisory board of OWL Metabolomics, J. Andersen: None Declared

O-29 PVRL1/TIGIT REPRESENTS A NOVEL MOLECULAR MECHANISM FOR PD1 BLOCKADE RESISTANCE IN HEPATOCELLULAR CARCINOMA

Carmen Chak-Lui Wong* 1, 2, David Kung-Chun Chiu1, 2, Irene Oi-Lin Ng1, 2

1Pathology, 2State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong

Introduction: Immune checkpoint inhibitor, Nivolumab (anti-PD1 monoclonal antibody, anti-PD1 Mab), has been recently approved by FDA as a second-line hepatocellular carcinoma (HCC) treatment for patients who are resistant to conventional treatments. A recent clinical trial demonstrated that Nivolumab has a response rate of 20% in HCC patients. Our study aims to dissect the molecular mechanisms that contribute to anti-PD1 Mab resistance in HCC.

Methods: Mass cytometry was employed to study over 30 markers of immune cells including markers involved in T cell trafficking, differentiation, exhaustion, and activation in mouse HCC resistant to anti-PD1 Mab treatment. High-dimensional clustering analysis of tumor infiltrated lymphocytes (TILs) was performed. In vivo CRISPR-Cas9 system and transposon system were employed to knock out tumor suppressors or activate oncogenes respectively to initiate mouse HCC. Flow cytometry was employed to validate the properties of TILs.

Results: In a mouse HCC model (p53-/-, c-MycOE) which resists anti-PD1 Mab, we found that another immune checkpoint, TIGIT, was elevated in tumor-infiltrating T cells. TIGIT is an inhibitory T cell receptor. When TIGIT binds to ligands in the PVR family, TIGIT inactivates T cells. We found that PVRL1 was significantly over-expressed in human HCC and was closely associated with poor survival in HCC patients. Knockdown or knockout of PVRL1 in mouse HCC cells repressed HCC growth and reinstated T cell infiltration in mouse HCC. In a T and HCC cell co-culture experiment, mouse HCC cells with PVRL1 knockdown could restore T cell proliferation. Interestingly, PVRL1 allowed HCC cells to evade immune surveillance not by directly binding to TIGIT but through releasing PVR onto the surface of HCC cells. PVRL1 competed with PVRL3 for PVR binding, preventing PVRL3 from mediating PVR endocytosis. With PVRL1, PVR was stabilized on HCC cell surface and bound to TIGIT of T cells to silence T cells. Blockade of TIGIT was able to unleash T cells in HCC in vivo. Excitingly, combination treatment of anti-TIGIT Mab and anti-PD1 Mab synergistically extended the survival of mice with HCC expressing high level of PVRL1.

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Conclusion: Our study has identified the molecular mechanisms by which HCC cells interact with T cells to overcome anti-PD1 Mab treatment and suggested that combination therapy involving blockade of TIGIT and PD1 represents a novel and effective therapeutic strategy for HCC patients.

Disclosure of Interest: None Declared

O-30 EFFECT OF THE MICROBIOTA ON THE PERIPHERAL IMMUNE RESPONSE IN PATIENTS WITH NAFLD-ASSOCIATED HEPATOCELLULAR CARCINOMA*

Lan Gong1, Jason Behary* 1, 2, 3, Nadia Amorim1, 3, Anita Raposo1, Xiao-Tao Jiang1, Carlie Stephens2, Hazem Jebeili2, Francis Chu4, Emad El-Omar1, 2, Amany Zekry1, 2, 3

1Microbiome Research Centre (MRC), University of New South Wales, 2Department of Gastro-enterology and Hepatology, St George Hospital, 3Translational Cancer Research Network (TCRN), University of New South Wales, 4Department of Surgery, St George and Sutherland Hospital, Sydney, Australia

Introduction: Emerging evidence suggests that the microbiome is a contributing factor in the progression of non-alcoholic fatty liver disease (NAFLD) and the subsequent development of hepatocellular carcinoma (HCC). In HCC, upregulation of regulatory T cells (Tregs) and impairment of the adaptive immune responses have been shown to promote HCC progression and to be associated

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with poorer treatment outcomes. Taken together, the aim of this study was to investigate whether gut dysbiosis occurs in NAFLD-associated HCC (NAFLD-HCC) and produces altered host peripheral immune responses.

Methods: The faecal microbiome from 60 subjects: 30 patients undergoing surgical resection for NAFLD-HCC, and 30 age-matched healthy controls, was investigated by 16S rRNA V3V4 sequencing. Kruskal-Wallis and PERMANOVA tests were used to identify faecal samples from NAFLD-HCC subjects with severe dysbiosis (reduced alpha diversity and altered microbial composition). Bacterial extracts were prepared from identified dysbiotic NAFLD-HCC subjects (n=5) and from healthy controls (n=5). To investigate whether NAFLD-HCC associated dysbiosis affects immune functions, we stimulated PBMCs from NAFLD-HCC patients (n=5) or healthy controls (n=5), using total bacteria extracts from the stool samples of the same PBMC donor subjects (ie “self” faecal extracts). Further, we exposed healthy donor PBMCs to the highly dysbiotic faecal extracts of the NAFLD-HCC patients. 70 samples were tested, using standard Treg differentiation protocols. PBMCs were immunostained followed by standard flow cytometry protocols. Statistical analysis was performed by 2-way ANOVA test after normalisation of % T-cell subset populations to % total T cells (CD3+) at baseline.

Results: The microbiome of patients with NAFLD-HCC was characterised by dysbiosis (reduction in alpha- and beta-diversity) and an increased abundance of the taxa Lachnospiraceae and Ruminococcaceae compared with healthy controls (p<0.05). In Treg stimulated PBMCs at baseline, T-helper cells (CD3+CD4+) were significantly elevated in NAFLD-HCC patients compared to healthy controls (44.0±2.2% vs. 7.2±5.3% p<0.05). In addition, Treg cells (CD3+CD4+CD25+FOXP3+) were significantly elevated in NAFLD-HCC patients compared to controls (6.2±0.2% vs 2.1±0.9%, p<0.05). Exposure of PBMCs to “self” faecal extracts did not significantly alter these results. Importantly however, the exposure of healthy PBMCs to the highly dysbiotic faecal extracts from NAFLD-HCC patients resulted in a significant decrease in CD8+ T cell (CD3+CD8+) populations (17.7±2.9% vs 6.8±7.1%, p=0.008) and an increase in Treg cell (CD3+CD4+CD25+FOXP3+) populations (3.7%±0.6%, vs 12.0±3.2%, p=0.002) as compared to exposure to healthy faecal extracts.

Conclusions: The results suggest that in the presence of gut dysbiosis, subjects with NAFLD-HCC exhibit a peripheral immune response known to be associated with worse clinical outcomes. Importantly, exposing normal PBMCs to dysbiotic faecal extracts from NAFLD-HCC subjects, elicited a pro-carcinogenic immune profile characterised by a reduction in anti-cancer CD8+ T cells and an increase in anti-inflammatory Treg-cell differentiation. Further work is presently in progress to expand on this data. Confirming this work could plausibly guide early identification of patients who would benefit from manipulation of the gut microbiota in order to shift their immune profile towards a more robust, anti-carcinogenic response, central to better treatment outcomes for NAFLD-HCC patients.

References: *This study was funded by a donation from Sir Owen Glenn to the St George and Sutherland Medical Research Foundation (SSMRF).


O-31 EVALUATION OF THE AFP MODEL IN PATIENTS WITH LOW RISK RECURRENCE PROFILE: FURTHER EVIDENCE TO SUPPORT ITS INCLUSION FOR CANDIDATE’S SELECTION

Federico Piñero* 1, Charlotte Costentin2, Andrea Notarpaolo3, Marcelo Silva1, Christophe Duvoux4

and the French-Italian-Latin American collaborative groups for HCC and liver transplantation.

1Liver Unit, Hospital Universitario Austral, Pilar, Argentina, 2Gastroenterology, Hepatology and Transplant unit, CHU Grenoble-Alpes, Grenoble, France, 3Hepatology, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy, 4Hepatology, Hospital Henri Mondor, University of Paris-Est, Creteil, Paris, France

Introduction: Either the presence of microvascular invasion (mvi) or dedifferentiation or tumors beyond the Up-to 7 criteria in the explanted liver defines a group of patients with a “high-risk” of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT). We aimed to evaluate and compare pre-LT risk assessment of the AFP model against Milan criteria in patients with a “low-risk profile” for HCC recurrence.

Methods: A multicenter multinational cohort study of consecutive adult patients with a first LT in 40 centers from France, Italy and Latin America was included (2003-2011). Recipient characteristics, pre-transplant tumor characteristics and serum ：-fetoprotein (AFP) levels were obtained at listing. Explanted liver findings included macroscopic and microscopic evaluation of each nodule, number and diameter (cm) of each, presence of mvi, and degree of tumor differentiation according to Edmonson-Steiner grading system (dedifferentiated tumors considered when a nuclear grade >II was observed in the specimen). Multivariate Cox regression models, with hazard ratios (HR) and 95% confidence intervals (CI) were conducted. AFP model and Milan criteria at listing were compared evaluating its performance to stratify risk of HCC-mortality and recurrence among “low-risk” patients by a competing risk regression analysis.

Results: From 1,270 included patients, a multivariable analysis identified independent explanted liver variables associated with 5-year recurrence: tumors beyond Up-to 7 HR 0.43 (CI 0.28;0.65), presence of mvi HR 2.96 (CI 2.18; 4.02), and the presence of dedifferentiated tumors HR 1.87 (CI 1.36;2.57). From this analysis, two populations were identified, 48% of the patients with a “High-risk profile” (n=610) and 52% with a “Low-risk profile” (n=660) for HCC recurrence after LT. Patients with “Low-risk profile” did not have either mvi or dedifferentiated tumor and were all within Up-to 7 in the explanted liver. Mortality and recurrence rates were higher in patients with “high” when compared with “low-risk” profile. Among patients with “low-profile” (n=660), 86.8% were within Milan criteria and 94.8% had an AFP score ≤2 points. In “low rik profile” patients, Milan criteria was not associated with death [HR 1.37 (CI 0.83;3.90)] or HCC recurrence [HR 0.77 (CI 0.34;1.73)]; whereas the AFP model was associated with mortality [HR 0.25 (CI 0.11;0.56)] and recurrence [HR 0.27 (CI 0.12;0.62)]. From a multivariable competing risk model, the AFP model was independently associated with HCC recurrence in patients with “low-risk” profile. In a sensitivity analysis, among patients with a last pre-transplant evaluation after bridging therapies, 94% of the patients with “low-risk” profile had an AFP score ≤2 points (n=424/451). In this sub-population, the AFP model but not Milan criteria was further associated with recurrence risk in a competing risk regression sensitivity analysis with a SHR of 0.26 (CI 0.09;0.68; P=0.006).

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Conclusion: Among patients with a low risk of HCC recurrence, our results showed further evidence to support the AFP model as inclusion for candidate’s hyper-selection.

References: 1. Duvoux C, et al. Gastroenterology. 2012 Oct;143(4):986-94.e3; quiz e14-5. doi: 10.1053/j.

gastro.2012.05.052. 2. Notarpaolo A, et al. J Hepatol. 2017 Mar;66(3):552-559. doi: 10.1016/j.jhep.2016.10.038.

Epub 2016 Nov 27.3. Costentin C, et al. Liver Int. 2017 May;37(5):717-726. doi: 10.1111/liv.13388. Epub 2017

Mar 24.4. Piñero F, et al. Liver Int. 2016 Nov;36(11):1657-1667. doi: 10.1111/liv.13159. Epub 2016 Jun 15.


General Session 1: Molecular Pathogenesis

O-07 TYRO3 PLAYS A PIVOTAL ROLE IN THE HEPATITIS-MEDIATED TUMORIGENESIS: A POTENTIAL THERAPEUTIC TARGET FOR LIVER CANCERS

Sen-Yung Hsieh* 1, Jeng-Shou Chang1, Wei-Lang Kuo1, Chen-Chun Lin1

1Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan, Province of China

Introduction: Hepatitis contributes to the development and recurrence of hepatocellular carcinoma (HCC). Receptor tyrosine kinases (RTKs) play a fundamental role in the development of many cancers. We explored the roles and mechanisms of RTKs in hepatitis-induced hepatocellular carcinogenesis.

Methods: Loss-of-function screening on the human RTK family was used to identify the RTKs crucial for HCC growth in vitro and in vivo. Immunohistochemistry and real-time RT-PCR was used to correlate TYRO3 expression and hepatitis activity. Thioacetamide-induced chronic hepatitis in mice was used to examine the relationship between TYRO3 expression and hepatitis.

Results: Multiple RTKs were co-expressed in HCC samples and involved in the regulation of tumor growth. Of these, TYRO3 promoted tumor growth and progression. Upregulation of TYRO3 was associated with higher Ishak’s hepatitis indices and higher serum AST/ALT levels. In mice, chemical-induced hepatitis upregulated Tyro3. TYRO3 was a target of the transcriptional factor STAT3 and was transcriptionally activated by the IL-6/IL6R—STAT3 signaling. TYRO3 activation elicited intracellular SRC- and STAT3-oncogenic signaling. Apoptotic bodies further activated TYRO3-mediated signaling by facilitating GAS6 (a TYRO3 ligand) presentation to TYRO3. Silencing or inhibiting TYRO3 suppressed xenograft HCC growth in mice. Figure. Hepatitis plays dual roles in activation of the STAT3—TYRO3—STAT3 signaling loop involved in the tumor transformation of hepatocytes. TYRO3 is a direct target of STAT3 transcriptional activator. Hepatitis induces the activation of IL-6—IL-6R—STAT3-mediated signaling to upregulate TYRO3 expression. Meanwhile, inflammation-induced cell apoptosis further activates TYRO3-mediated intracellular signaling through facilitating the presentation of GAS6 (a TYRO3 ligand) on apoptotic bodies to TYRO3. The activation of TYRO3 elicits the intracellular STAT3/SRC signaling, The resulted ‘STAT3—TYRO3—STAT3’ pathway forms a positive signaling loop for tumor transformation and progression. Inhibition of TYRO3 suppressed tumor development and growth.

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Conclusions: TYRO3 is upregulated in about 30% of HCCs and is associated with poor prognosis. Hepatitis induces the expression and activation of TYRO3 respectively via inflammatory cytokines and apoptotic bodies, resulting in “TYRO3—STAT3—TYRO3” oncogenic signaling loop for hepatocyte tumorigenesis. Our findings suggest a molecular link between hepatitis and carcinogenesis and provide a target for anti-HCC therapy. Significance: Hepatitis plays dual roles in the activation of TYRO3-mediated signaling: inducing TYRO3 expression and activating TYRO3-mediated signaling via facilitating GAS6 presentation. Moreover, TYRO3 serves both a target and an inducer of hepatitis-associated STAT3-mediated oncogenic signaling. Targeting the “STAT3—TYRO3—STAT3” signaling loop suppressed hepatoma growth in vitro and in vivo. Therefore, TYRO3 is a potential therapeutic target for HCCs with TYRO3 upregulation.


O-08 THE IMPRINTED DLK1/DIO3 LOCUS AS A KEY PLAYER IN ß-CATENIN DRIVEN TUMORIGENESIS

Angélique Gougelet* 1, 2, Julie Sanceau1, 2, Christèle Desbois-Mouthon1, 2, Cécile Godard1, 2, Sabine Colnot1, 2

1INSERM UMRS1138, Centre de Recherche des Cordeliers, 2USPC, Sorbonne Université, Paris, France

Introduction: Our current projects aspire to propose microRNAs (miRNAs) as therapeutic targets for hepatocellular carcinoma (HCC) with activation of the Wnt/ß-catenin pathway (≈1/3 of HCC). Using miRNA sequencing, we have identified a hundred miRNAs deregulated following ß-catenin activation in hepatocytes. We promisingly showed that miR-34a inhibition halves tumor progression of HCC with ß-catenin activation [1]. Our aim now is to determine if the targeting of a panel of 54 miRNAs produced from the DLK1/DIO3 locus could be of therapeutic benefit.

Methods: This project is realized on transgenic mice exhibiting an aberrant activation of ß-catenin signaling following the deletion of its main inhibitor Apc in hepatocytes (ApcΔHep). This Cre-lox-based model is liver-specific and inducible by tamoxifen injection. Depending on the dose of tamoxifen, mice either wholly exhibit hepatocytes with aberrant ß-catenin activation or develop tumors, with a genetic program similar to those of human HCCs [2, 3].

Results: In ApcΔHep hepatocytes and tumors, ß-catenin activation was associated with a global upregulation of all RNAs, coding or non-coding, derived from the imprinted DLK1/DIO3 locus. These RNAs are either expressed from the maternal or the paternal strand meaning that ß-catenin activation altered the DLK1/DIO3 locus imprinting. Such a global upregulation in response to ß-catenin overactivation was also observed in a subgroup of human HCC exhibiting mutations in CTNNB1 gene encoding ß-catenin. Using deep-sequencing approaches in ApcΔHep hepatocytes, we showed that ß-catenin directly bound upstream of the locus, only in case of aberrant activation. Additionally, DNA hypermethylation in intragenic regions was observed in ApcΔHep hepatocytes, presuming regulations by ß-catenin and DNA methylation – the locus induction being lower in ApcΔHep hepatocytes in the presence of demethylating agents. Interestingly, we showed that macrophage-enriched non-parenchymal cells also participate to locus expression in precancerous hepatocytes performing coculture experiments. This argues for an epigenetic crosstalk between non-parenchymal cells and hepatocytes probably implicating exosomes and immune-modulators. Regarding these observations, we decided to edit by Crispr/Cas9 the ß-catenin binding site located upstream of the DLK1/DIO3 locus to explore how this locus affects liver function and tumorigenesis driven by the ß-catenin (ΔDLK1). Using Hepa1-6 cells, a murine HCC cell line exhibiting ß-catenin activation, we showed that editing of the ß-catenin binding site inhibited cell proliferation in vitro. Anti-proliferative features of ΔDLK1 have also been confirmed in ApcΔHep livers exhibiting weaker hepatomegaly than ApcΔHep livers edited in Rosa26 locus. Promisingly, ΔDLK1 editing significantly slowed tumor progression after Hepa1-6 allografting into athymic mice, a phenomenon accompanied with decrease in Ki-67 labeling and increase in caspase 3 cleavage.

Conclusions: This project supports that ß-catenin-dependent upregulation of the DLK1/DIO3 locus in hepatocytes, together with material transfer towards immune cells, which sustains the locus induction, is implicated in hepatocyte transformation. An early inhibition of this locus in liver could offer an innovative therapeutic opportunity for HCC.

References: 1. Gougelet A, Sartor C, Bachelot L, Godard C, Marchiol C, Renault G, Tores F, Nitschke P, Cavard C,

Terris B, Perret C, Colnot S. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut 2016; 65: 1024 [PMID: 25792709 doi: 10.1136/gutjnl-2014-308969]

2. Colnot S, Decaens T, Niwa-Kawakita M, Godard C, Hamard G, Kahn A, Giovannini M, Perret C. Liver-targeted disruption of Apc in mice activates beta-catenin signaling and leads to hepatocellular carcinomas. Proc Natl Acad Sci U S A 2004; 101: 17216 [PMID: 15563600 doi: 10.1073/pnas.0404761101]

3. Gougelet A, Torre C, Veber P, Sartor C, Bachelot L, Denechaud PD, Godard C, Moldes M, Burnol AF, Dubuquoy C, Terris B, Guillonneau F, Ye T, Schwarz M, Braeuning A, Perret C, Colnot S. T-cell factor 4 and beta-catenin chromatin occupancies pattern zonal liver metabolism in mice. Hepatology 2014; 59: 2344 [PMID: 24214913 doi: 10.1002/hep.26924]


O-09 UNIQUE MOLECULAR TRAITS FOR NASH-RELATED HEPATOCELLULAR CARCINOMA

Sara Torrecilla* 1, Roser Pinyol1, Huan Wang2, Carla Montironi1, 3, Carmen Andreu-Oller1, Miguel Torres-Martin3, Judit Peix1, Leow Wei-Qiang3, 4, Agrin Moeini1, Claudia P. Oliveira5, Venancio A. Alves5, Anja Lachenmayer6, Stephanie Roessler7, Mathias Heikenwälder8, 9, Arun J. Sanyal10, Beatriz Minguez11, Peter Schirmacher7, Paolo Boffetta3, Jean-François Dufour6, Swan N. Thung3, Helen L. Reeves12, 13, Andrew V. Uzilov2, Flair J. Carrilho5, Charissa Chang3, Scott L. Friedman3, Daniela Sia3, Josep M. Llovet1, 3, 14

1Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain, 2Sema4, a

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Mount Sinai venture, Stamford, CT, 3Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States, 4Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore, 5Departments of Gastroenterology and Pathology, University of São Paulo - School of Medicine, Sao Paulo, Brazil, 6Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, CH-3010, Bern, Switzerland, 7Institute of Pathology, University Hospital Heidelberg, 8Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, 9Institute for Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany, 10Divisions of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, VA, United States, 11Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d´Hebron, Vall d´Hebron Institut of Research (VHIR), CIBERehd, Universitat Autonoma de Barcelona, Barcelona, Catalonia, Spain, 12Northern Institute for Cancer Research, Paul O’Gorman Building, Newcastle University, Framlington Place, , Newcastle upon Tyne, NE2 4HH, 13Hepatopancreatobiliary Multidisciplinary Team, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN, United Kingdom, 14Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain

Introduction: Non-alcoholic steatohepatitis (NASH) is emerging as one of the leading risk factors for hepatocellular carcinoma (HCC), but its molecular pathogenesis is still ill-defined. This study aims to provide a comprehensive molecular characterization of NASH-HCC and to identify unique molecular traits that differentiate it from other HCC-aetiologies.

Methods: A total of 235 tissue samples were collected, including samples from 125 biopsied/transplanted NASH patients; and 110 resected/transplanted NASH-HCC patients. NASH was histologically confirmed using NAS score. Molecular characterization comprised expression array (n=63 NASH-HCC; n=74 NASH), whole exome sequencing (n=50 NASH-HCC), and targeted-sequencing (n=50 NASH-HCC). Publicly available data from viral/alcohol-related HCCs were used to identify NASH-HCC distinctive traits. A total of 18 tumour samples from 3 different mouse models of NASH-HCC (WD+CCL4, WDSD in S129 background and CD-HFD) have been analysed with RNA-Seq/expression array and targeted-exome sequencing.

Results: NASH-HCC patients were predominantly male (82% vs 42%, p<0.001), and older (67 years vs 54, p<0.01), compared to NASH non-HCC patients, with a higher incidence of diabetes (72% vs 50%, p=0.004), hypertension (80% vs 52%, p<0.01) and cirrhosis (69% vs 29%, p<0.001). Transcriptomic analysis of signalling pathways in NASH-HCC tumours showed upregulation of hallmarks of proliferation, PI3K-Akt-mTor and oxidative stress pathways when compared to non-tumoral adjacent tissue. Unsupervised clustering of NASH-HCC together with viral/alcohol-related HCC showed that a similar distribution of liver molecular classes in NASH compared to other risk factors. Mutational profiling of NASH-HCC tumours identified mutations in 82 driver genes from which 4 presented mutations in ≥10% of cases: TERT (54%), CTNNB1 (28%), TP53 (18%) and the TGFß-receptor ACVR2A (10%). Interestingly, mutations in ACVR2A were significantly more prevalent in NASH-HCC than in viral/alcohol-related HCC (2.6%, p<0.05). Unsupervised clustering of mutational signatures showed that NASH-HCC tumours are clustered in 2 groups, enriched in liver-cancer signatures #16 (44%) and #5 (22%). A third cluster (15%) was enriched in signature #3, which is novel in liver cancer, and might indicate a specific genotoxic agent. In contrast, mutational profiles from viral/alcohol-related HCCs did not show a cluster enriched in signature#3. Average mutational tumour burden (MTB) in NASH–HCC was of 38 non-silent somatic mutations (53 in non-cirrhotic NASH-HCC vs 17 in cirrhotic-NASH HCC, p<0.0001). Higher MTB was significantly associated with higher immune infiltration. The transcriptomic study of NASH-HCC non-tumoral adjacent livers presented enrichment of poor prognosis signatures and hallmark signatures related to epithelial-mesenchymal transition, apoptosis, hypoxia and immunity, when compared to livers from NASH patients (FDR<0.05). Comparative analysis of the molecular data of human and mouse models of NASH-HCC to identify similarities is ongoing.

Conclusions: NASH-HCC tumors present specific molecular traits compared with non-NASH-related HCCs: higher frequency of mutations in ACVR2A (10%), and a unique mutational signature #3 (15%), which might reflect genotoxic factors specifically associated to this entity. In addition, non-cirrhotic NASH-HCC characteristically showed higher MTB and higher immune infiltrate.


O-10 CHARACTERIZATION OF HEPATITIS B VIRUS-RELATED INSERTIONAL MUTAGENESIS IN HEPATOCELLULAR CARCINOMAS FROM EUROPEAN AND AFRICAN PATIENTS

Camille Peneau* 1, 2, Sandrine Imbeaud1, 2, Tiziana La Bella1, 2, Iadh Mami1, 2, Jessica Zucman-Rossi1, 2, 3

1UMRS-1138, Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, 2Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, 3European Hospital Georges Pompidou, AP-HP, Paris, France

Introduction: Hepatitis B virus (HBV) infection remains the leading cause of hepatocellular carcinoma (HCC) occurrence worldwide, and not only in the setting of cirrhosis, underlying that the virus has its own oncogenic properties. The risk for HCC development persists for the patients receiving antiviral therapies with undetectable HBV DNA in serum. HBV is a 3.2 kb enveloped DNA virus that could integrate in human genome and induce liver carcinogenesis by altering the expression of endogenous genes or generating chromosomal instability. Next-generation sequencing data enabled to characterize more precisely the role of HBV insertion as a cancer driver alteration in large cohorts of HCC, by identifying cancer-related genes as recurrent integration sites associated with distinct biological and clinical outcomes. However, up to now, such identifications of HBV insertions in HCC have been mainly performed in Asian populations. Our project deciphered the landscape of HBV-related insertional mutagenesis in HCC and non-tumor liver tissues from European and African patients.

Methods: The presence of HBV DNA was screened by quantitative PCR in tumor and non-tumor liver tissues from 750 patients (95% with a European or African origin) and we selected 220 HCC and their normal liver counterparts from 180 HBV-positive patients to perform viral capture. In silico analyses were set up to characterize the HBV genotypes and reconstruct the integrated viral sequences in each tissue. Episomal and viral active forms were identified using a DNase/TaqMan based assay and quantitative RT-PCR.

Results: The number of copies of HBV DNA was quantified in the whole series of tumor and non-tumor liver tissues. Based on the bi-Gaussian distribution observed, we identified 180 patients whose liver tissues were highly positive for HBV DNA, and 8% of them had a negative AgHbs in serum. In most of the cases, several viral DNA forms were actually coexisting in the liver. On one part, we investigated the HBV-related insertional mutagenesis. 493 integration events were classified as clonal or sub-clonal, distributed among 182 samples, and 97% of these events were observed in tumors. The only gene found as a recurrent integration site among tumors was the TERT promoter region (in 46 tumors), but HBV insertions were also frequently observed in centromeric and telomeric regions (respectively in 12 and 28 tumors). Moreover 74% of the HBV-integrated tumors had more than one clonal or sub-clonal insertion site. In-silico reconstruction of integrated sequences revealed the existence of frequent structural rearrangements in the viral sequence as in the human genome around the integration breakpoints. Copy-number variations were also significantly modified at integration sites. In another part, we assessed the presence of HBV covalently closed circular DNA, an episomal replicative form maintaining chronic infection, and we confirmed that it is significantly less present in tumors than in non-tumor liver tissues.

Conclusions: This study described HBV integrated sequences and episomal DNA in HBV-related HCC from European and African populations. We confirmed the strong enrichment of integrations in the TERT promoter as in Asian populations. Besides our data suggest that HBV integration occurs multiple times in the same cellular clone and may cause or derive from chromosomal instability. The characterization of these HBV genomes according to the genetic and clinical features of the patients will help to define potential groups of HBV-infected patients, considering their serological status, with an increased risk to develop HCC.


O-11 DIFFERENTIAL ROLE OF HIPPO CASCADE IN C-MET/ß-CATENIN AND C-MET/SGAXIN1 DRIVEN MOUSE HCC

Binyong Liang1, Haichuan Wang* 1, Xin Chen1

1Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States

Introduction: Mutations in CTNNB1 and AXIN1 genes are frequently observed in human HCC samples. The HIPPO tumor suppressor pathway, especially its downstream transcriptional co-activators YAP and TAZ, have been implicated in HCC pathogenies. Recent studies suggest that AXIN1 mutant HCCs demonstrate high YAP oncogenic gene expression signature. However, how the HIPPO/YAP/TAZ functions to regulate HCCs with CTNNB1 or AXIN1 mutants has not been well-characterized.

Methods: We generated two clinically relevant mouse HCC models: CRISPR/Cas9 based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met (c-Met/sgAxin1); or transposon-based co-expression of activated ΔN90-ß-Catenin and c-Met (c-Met/ΔN90-ß-Catenin). The role of the Hippo signaling was investigated in c-Met/sgAxin1 and c-Met/ΔN90-ß-Catenin via co-expression of Lats2, dominant negative form of Tead2 (dnTead2) or the application of Yapf/f, Tazf/f as well as Yapf/fTazf/f mice.

Results: Decreased expression of Lats2 as well as increased activation and nuclear localization of Yap and Taz were found in c-Met/sgAxin1 mouse HCC. In c-Met/ΔN90-ß-Catenin mouse HCC, increased nuclear localized Yap, but not Taz was observed. In c-Met/ΔN90-ß-Catenin mouse HCC model, co-expression of Lats2 or dnTead2 led to mild delayed HCC formation. Similarly, ablation of Yap, but not Taz mild delayed c-Met/ΔN90-ß-Catenin tumor development. In striking contrast, in c-Met/sgAxin1 mouse HCC model, overexpression of Lats2, which activates Hippo, strongly delayed hepatocarcinogenesis. Intriguingly, overexpression of the dnTead2, which blocks Yap/Taz mediated transcriptional regulation, did not affect hepatocarcinogenesis. While conditional knockout of either Yap or Taz alone did not affect c-Met/sgAxin1 driven hepatocarcinogenesis, concurrent knockout of both Yap and Taz significantly delayed c-Met/sgAxin1 HCC formation, recapitulating the phenotype when Lats2 was overexpressed.

Conclusions: Altogether, our results support that Hippo/Yap/Taz cascade has limited roles in c-Met/ΔN90-ß-Catenin driven hepatocarcinogenesis. However, this cascade has major functional significance during c-Met/sgAxin1 induced HCC development. Mechanistically, it likely functions via non-transcriptional activities of Yap and Taz. Targeting HIPPO/YAP/TAZ may represent effective therapeutics against AXIN1 mutant human HCCs.


O-12 A NOVEL IMMUNOGENIC MOUSE MODEL OF HEPATOCELLULAR CARCINOMA FOR STUDYING MECHANISMS OF IMMUNE ESCAPE AND RESPONSE TO IMMUNOTHERAPIES

Marina Ruiz de Galarreta1, Erin Bresnahan1, Pedro Molina-Sanchez1, Katherine Lindblad1, Daniela Sia2, Josep Maria Llovet2, Amaia Lujambio* 1

1Oncological Sciences, 2Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, United States

Introduction: Hepatocellular carcinoma (HCC) represents a major health problem, causing more than 700,000 deaths annually worldwide (1). Recently, nivolumab and pembrolizumab, two PD-1 (programmed cell death 1) immune checkpoint inhibitors, were approved by the FDA for second line HCC treatment (2), after showing unprecedented results in phase II clinical trials. However, not all HCC patients are sensitive, indicating the existence of mechanisms of resistance to anti-PD-1 therapy and highlighting the urgent need to identify biomarkers for optimal patient selection.

Methods: In order to identify oncogenic signaling pathways in HCC that promote immune escape and affect response to anti-PD-1 therapy, we created a novel non-germline genetically-engineered mouse model of HCC that allows interrogating how genetic alterations relevant to human disease affect immune surveillance and response to immunotherapies. The model is based on the hydrodynamic tail vein delivery of genetic elements to overexpress oncogenes (with transposon-based vectors), delete tumor suppressor genes (with CRISPR vectors), and modulate immunogenicity (with model tumor antigens) specifically in hepatocytes. The effect of the expression of model tumor antigens in liver tumor formation was tested in several independent models of HCC. Transcriptional analysis and immune profiling of the resulting tumors was performed. Finally, response to anti-PD1 therapy is been assessed in all the models.

Results: We have previously shown that expression of tumor antigens in the context of oncogene MYC overexpression and loss of p53 (MYC;p53-/-) in liver cancer cells leads to T cell infiltration and subsequent immune surveillance, with a decrease in tumor formation and increased survival. In contrast, expression of tumor antigens in the context of oncogene MYC overexpression and ß-catenin activation (MYC;CTNNB1) in liver cancer cells lead to immune escape, T cell exclusion, and resistance to immunotherapy (Ruiz de Galarreta, in revision in Cancer Discovery), a finding that was validated in HCC patient samples (3). Following a similar pipeline, we have now identified novel mechanisms of immune escape and resistance to immunotherapies that are highly relevant for HCC patients. As an example, PD-L1 overexpression by HCC tumor cells induces immune escape and originates HCC tumors that could respond to anti-PD-1 therapies. Novel unpublished examples validated in in vivo experiments and in HCC samples will be provided.

Conclusions: Our novel mouse model can be used to identify novel mechanisms of immune escape and resistance to anti-PD-1 therapies that are relevant in HCC patients. The novel mouse model is also being used to test novel combination therapies that can restore sensitivity to anti-PD-1.

References: 1. Llovet, J.M., et al. Hepatocellular carcinoma. Nature reviews. Disease primers 2, 16018 (2016).2. El-Khoueiry, A.B., et al. Nivolumab in patients with advanced hepatocellular carcinoma

(CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet (2017).

3. Sia, D., et al. Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on Molecular Features. Gastroenterology (2017).


General Session 2: Clinical Trials

O-13 SAFETY PROFILE OF NIVOLUMAB (NIVO) PLUS IPILIMUMAB (IPI) COMBINATION THERAPY IN PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR CARCINOMA (HCC) IN THE CHECKMATE 040 STUDY

Anthony B. El-Khoueiry* 1, Chiun Hsu2, Yoon-Koo Kang3, Tae-You Kim4, Armando Santoro5, Bruno Sangro6, Ignacio Melero7, Masatoshi Kudo8, Ming-Mo Hou9, Ana Matilla10, Francesco Tovoli11, Jennifer J. Knox12, Aiwu Ruth He13, Bassel El-Rayes14, Mirelis Acosta-Rivera15, Jaclyn Neely16, Yun Shen16, Jeffrey Anderson16, Thomas Yau17

1USC Norris Comprehensive Cancer Center, Los Angeles, United States, 2National Taiwan University Hospital, Taipei, Taiwan, Province of China, 3Asan Medical Center, University of Ulsan, 4Seoul National University, Seoul, Korea, Democratic People's Republic Of, 5Istituto Clinico Humanitas, Rozzano,

Italy, 6Clinica Universidad de Navarra and CIBEREHD, 7Universidad de Navarra, Pamplona, Spain, 8Kindai University Faculty of Medicine, Osaka, Japan, 9Chang Gung Memorial Hospital, Taipei, Taiwan, Province of China, 10Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 11Department of Medical & Surgical Sciences, University of Bologna, Bologna, Italy, 12Princess Margaret Cancer Centre, Toronto, Canada, 13Georgetown University Hospital, Washington DC, 14Emory University Winship Center, Atlanta, United States, 15Fundacion de Investigacion, San Juan, Puerto Rico, 16Bristol-Myers Squibb, Princeton, United States, 17University of Hong Kong, Hong Kong, China

Introduction: NIVO monotherapy is approved in several countries, including the United States, for sorafenib (SOR)-treated pts with HCC based on data from the CheckMate 040 study (NCT01658878), which reported an objective response rate (ORR) of 14% and median overall survival (OS) of 16 months.1 Here we report results for NIVO plus IPI combination in SOR-treated pts with advanced HCC, with a focus on hepatic safety.

Methods: SOR-treated pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety and tolerability. Key secondary endpoints included ORR (BICR per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS. Data cutoff was 25 Sep 2018. Safety was assessed by the investigator using the NCI CTCAE v4.0.

Results: Overall, 148 SOR-treated pts were randomized. The minimum follow-up for OS from the date of last pt randomization data cutoff was 24 months. Overall, ORR was 31% with a median DOR of 17 months; DCR was 49%. The 24-month OS rate was 40%. NIVO plus IPI was well tolerated; 37% of pts had a grade 3–4 treatment-related adverse event (TRAE). Grade 3–4 TRAEs leading to discontinuation were reported in 5% of patients. Any grade serious TRAEs were reported in 18% of patients. The most common any grade select TRAEs were in skin (50%), hepatic (23%), and gastrointestinal (19%) categories and included pruritus (35%), rash (23%), aspartate aminotransferase increased (18%), and diarrhea (18%). Detailed safety results will be presented.

Conclusions: The combination of NIVO plus IPI led to clinically meaningful responses in SOR-treated pts, with an ORR twice that reported for NIVO monotherapy. NIVO plus IPI had a manageable safety profile in this patient population with advanced HCC.

References: El-Khoueiry AB, et al. Lancet 2017;389:2492–2502.

Disclosure of Interest: A. El-Khoueiry Conflict with: Research/Education grant - AstraZeneca, Astex Pharmaceuticals, Conflict with: Honoraria - Bayer, Novartis, Bristol-Myers Squibb, Roche/Genentech, EMD Serono, EISAI, Merck, Conflict with: Advisory Board - CytomX Therapeutics, Bristol-Myers Squibb, AstraZeneca, Bayer, Eisai, Roche, EMD Serono, Merck, Exelixis, Pieris Pharmaceuticals, Agenus, Conflict with: Consulting - CytomX Therapeutics, Bristol-Myers Squibb, AstraZeneca, Bayer, Eisai, Roche, EMD Serono, Merck, Exelixis, Pieris Pharmaceuticals, Agenus, C. Hsu Conflict with: Honoraria - TTY Biopharm, Bayer Schering Pharma, MSG Oncology, Bristol-Myers Squibb, Y.-K. Kang Conflict with: Research/Education grant - LSK Biopharma, DAW HWA Pharmaceutical, Conflict with: Advisory Board - Lilly/ImClone, Taiho Pharmaceutical, Ono Pharmaceutical, Roche/Genentech, Meck Serono, DAE HWA Pharmaceutical, Bristol-Myers Squibb, Conflict with: Consulting - Lilly/ImClone, Taiho Pharmaceutical, Ono Pharmaceutical, Roche/Genentech, Meck Serono, DAE HWA Pharmaceutical, Bristol-Myers Squibb, T.-Y. Kim: None Declared, A. Santoro Conflict with: Research/Education grant - Takeda, Roche, Abbvie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Conflict with: Advisory Board - Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Conflict with: Consulting - Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, B. Sangro Conflict with: Research/Education grant - Bristol-Myers Squibb, Sirtex Medical, Conflict with: Advisory Board - Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, Conflict with: Consulting - Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, I. Melero Conflict with: Research/Education grant - Alligator Bioscience, Bristol-Myers Squibb, Roche/Genentech, Alligator Bioscience, Pfizer, Conflict with: Honoraria - Bristol-Myers Squibb, Roche/Genentech, Alligator Bioscience, Lilly, AZ-MEDIMMUNE, Bayer, Tusk Therapeutics, Conflict with: Advisory Board - Alligator Bioscience, Bristol-Myers Squibb, CytomX Therapeutics, EMD Serono, F-Star, Genmab, Roche, Lilly, AZ-MEDIMMUNE, Tusk Therapeutics, Conflict with: Consulting - Alligator Bioscience, Bristol-Myers Squibb, CytomX Therapeutics, EMD Serono, F-Star, Genmab, Roche, Lilly, AZ-MEDIMMUNE, Tusk Therapeutics, M. Kudo Conflict with: Research/Education grant - Chugai Pharma, Otsuka, Taiho Pharmaceutical, Daiichi Sankyo, Abbvie, Astellas Pharma, Bristol-Myers Squibb Japan, Conflict with: Honoraria - Bayer, Eisai, Novartis, MSD, EA Pharma, Bristol-Myers Squibb Japan, Abbvie, Taiho Pharmaceutical, Pfizer, Gilead Sciences, Merck Serono, Otsuka, Daiichi Sankyo, Astellas Pharma, Chugai Pharma, Conflict with: Advisory Board - MSD, Bristol-Myers Squibb, Bayer, Eisai, Conflict with: Consulting - MSD, Bristol-Myers Squibb, Bayer, Eisai, M.-M. Hou: None Declared, A. Matilla Conflict with: Advisory Board - Bayer, Conflict with: Consulting - Bayer, F. Tovoli Conflict with: Advisory Board - Bayer AG, Conflict with: Consulting - Bayer AG, J. Knox Conflict with: Research/Education grant - AstraZeneca, Merck, Conflict with: Honoraria - Novartis, Conflict with: Advisory Board - Lilly, Merck, Conflict with: Consulting - Lilly, Merck, A. Ruth He Conflict with: Research/Education grant - Merck, Conflict with: Honoraria - Bristol-Myers Squibb, Merck, Eisai, Bayer, Lilly, Conflict with: Advisory Board - Bristol-Myers Squibb, Merck, Bayer, Genentech, Eisai, Conflict with: Consulting - Bristol-Myers Squibb, Merck, Bayer, Genentech, Eisai, B. El-Rayes Conflict with: Research/Education grant - AVEO, Boston Biomedical, Boston Biomedical,

Oral Communications

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 1 5

Oral Communications

I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S1 4

Friday, 20 September 2019Friday, 20 September 2019

Boston Biomedical, Bristol-Myers Squibb, Cleave Biosciences, Five Prime Therapeutics, Genentech, Hoosier Cancer Research Network, ICON Clinical Research, Merck, Novartis, Pfizer, PPD, Taiho Pharmaceutical, Conflict with: Honoraria - Bayer, Lexicon, RTI Health Solutions, Conflict with: Advisory Board - Bayer, BTG, Loxo, Merrimack, RTI Health Solutions, Conflict with: Consulting - Bayer, BTG, Loxo, Merrimack, RTI Health Solutions, M. Acosta-Rivera: None Declared, J. Neely Conflict with: Stocks - Bristol-Myers Squibb, Y. Shen Conflict with: Stocks - Bristol-Myers Squibb, J. Anderson Conflict with: Stocks - Bristol-Myers Squibb, T. Yau Conflict with: Honoraria - Bristol-Myers Squibb, Conflict with: Advisory Board - Bristol-Myers Squibb, Conflict with: Consulting - Bristol-Myers Squibb

O-14 ALPHA-FETOPROTEIN (AFP) RESPONSE AND EFFICACY OUTCOMES IN THE PHASE 3 CELESTIAL TRIAL OF CABOZANTINIB VERSUS PLACEBO IN ADVANCED HEPATOCELLULAR CARCINOMA (HCC)

Robin K. Kelley* 1, Lorenza Rimassa2, Baek-Yeol Ryoo3, Joong-Won Park4, Jean-Frederic Blanc5, Stephen L. Chan6, Vincenzo Dadduzio7, Thomas Yau8, Suvajit Sen9, David W. Markby9, Rajesh Kaldate9, Anthony B. El-Khoueiry10, Ann-Lii Cheng11, Tim Meyer12, Ghassan K. Abou-Alfa13

1UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States, 2Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Milan, Italy, 3Asan Medical Center, University of Ulsan College of Medicine, Seoul, 4National Cancer Center, Goyang, Korea, Republic Of, 5Hôpital Haut-Lévêque, Bordeaux, France, 6The Chinese University of Hong Kong, Hong Kong, China, 7Medical Oncology Unit 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy, 8Queen Mary Hospital, Hong Kong, China, 9Exelixis, Inc., Alameda, 10USC Norris Comprehensive Cancer Center, Los Angeles, United States, 11National Taiwan University College of Medicine, Taipei, Taiwan, Province of China, 12Royal Free Hospital, London, United Kingdom, 13Memorial Sloan Kettering Cancer Center, New York, United States

Introduction: High baseline serum levels of AFP have been associated with poor prognosis in HCC. AFP response, defined as a decrease in AFP levels after therapy, may be associated with improved survival of patients with HCC treated with locoregional or systemic therapy. In the phase 3 CELESTIAL trial (NCT01908426), cabozantinib, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) versus placebo in patients with previously treated advanced HCC (Abou-Alfa 2018). Here, we evaluate clinical outcomes with cabozantinib in CELESTIAL based on AFP response or progression on treatment.

Methods: 707 patients were randomized 2:1 to receive cabozantinib (60 mg daily) or placebo. Eligible patients had a pathologic diagnosis of HCC, Child-Pugh class A, and ECOG PS ≤1. Patients received prior sorafenib and ≤2 lines of prior systemic therapy for HCC. Serum AFP levels were measured centrally at baseline and every 8 weeks thereafter. Outcomes were evaluated for patients with baseline AFP ≥20 ng/mL based on AFP response (≥20% decrease from baseline) or progression (≥20% increase from baseline) at Week 8. This definition of AFP response has been used in previous studies but requires further validation in large prospective studies.

Results: Overall, 331 patients (70%) in the cabozantinib arm and 160 (68%) in the placebo arm had baseline AFP ≥20 ng/mL; among these patients, 236 (71%) and 111 (69%), respectively, were evaluable for AFP response at Week 8. Among evaluable patients, 117 patients (50%) in the cabozantinib arm versus 14 (13%) in the placebo arm had an AFP response, and 72 (31%) versus 75 (68%) had AFP progression. Median OS with cabozantinib was 16.1 mo for patients with an AFP response versus 9.1 mo for patients without a response (HR 0.61, 95% CI 0.45-0.84), and median PFS with cabozantinib was 7.3 mo versus 4.0 mo (HR 0.55, 95% CI 0.41-0.74). For patients with AFP progression, median OS with cabozantinib was 8.1 mo, and median PFS with cabozantinib was 3.6 mo.

Conclusions: The AFP response rate was higher with cabozantinib versus placebo, and AFP response was associated with longer OS and PFS with cabozantinib for patients with previously treated advanced HCC. On-treatment AFP changes warrant further evaluation as a biomarker of response.

References: Abou-Alfa GK, et al. N Engl J Med. 2018;379(14):54-63.

Disclosure of Interest: R. Kelley Conflict with: Research/Education grant - Adaptimmune, Agios, Astra Zeneca, Bayer, Bristol Myers Squibb, Celgene, Exelixis, Eli Lilly, Medimmune, Merck, Novartis, Regeneron, Sanofi, Taiho, Target Pharma Solutions, Tekmira (institution), Conflict with: Consulting - Genentech for IDMC (self); Bayer, BMS, Astra Zeneca, DebioPharm, Agios (institution), L. Rimassa Conflict with: Honoraria - AstraZeneca, AbbVie, Gilead, Roche, Conflict with: Advisory Board - Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Celgene, Incyte, Eisai, Conflict with: Consulting - Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Celgene, Incyte, Eisai, B.-Y. Ryoo: None Declared, J.-W. Park Conflict with: Research/Education grant - Ono-BMS, AstraZeneca, Blueprint, Roche, Eisai, Exelixis, Kowa, Conflict with: Honoraria - Bayer, Eisai, Ono, Conflict with: Advisory Board - BMS, Ono, Bayer, Eisai, Midatech, Conflict with: Consulting - Ono, Eisai, Bayer, Roche-Genetech, J.-F. Blanc Conflict with: Honoraria - IPSEN, BAYER, Conflict with: Advisory Board - Bayer SP, ESAI, IPSEN, Conflict with: Consulting - IPSEN, S. Chan: None Declared, V. Dadduzio Conflict with: Advisory Board - IPSEN, Conflict with: Consulting - Bayer, T. Yau Conflict with: Advisory Board - BMS, MSD, Exelixis and Ipsen, S. Sen Conflict with: Stocks - Exelixis Employment/Stock, D. Markby Conflict with: Stocks

- Exelixis Employment/Stock, R. Kaldate Conflict with: Stocks - Former Exelixis Employee, A. El-Khoueiry Conflict with: Research/Education grant - Astrazeneca, Astex, Conflict with: Honoraria - BMS, Bayer, Exelixis, EMD Serono, EISAI, Roche, Cytomx , Merck , Conflict with: Consulting - BMS, Bayer, A.-L. Cheng Conflict with: Honoraria - Bayer Yakuhin, AstraZeneca, Genentech/Roche, Eli Lilly, Conflict with: Advisory Board - Bristol-Myers Squibb, Bayer Schering Pharma, Novartis, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, CSR Pharma Group, Inc., MSD, BeiGene, Ltd., Conflict with: Consulting - Bristol-Myers Squibb, Bayer Schering Pharma, Novartis, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, CSR Pharma Group, Inc., MSD, BeiGene, Ltd., T. Meyer Conflict with: Research/Education grant - Bayer BTG, Conflict with: Advisory Board - BMS, Astra Zeneca, Beigene, BTG, MSD, Eisai, G. Abou-Alfa Conflict with: Research/Education grant - ActaBiologica, Agios, Array, Astra Zeneca, Bayer, Beigene, BMS, Casi, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, Mabvax, Novartis, OncoQuest, Polaris Puma, QED, Roche, Conflict with: Consulting - 3DMedcare, Agios, Alignmed, Amgen, Antengene, Aptus, Aslan, Astellas, Astra Zeneca, Bayer, Beigene, Bioline, BMS, Boston Scientifc, Bridgebio, Carsgen, Celgene, Casi, Cipla, CytomX, Daiichi, Debio, Delcath, Eisai, Exelixis, Genoscience, Halozyme, Hengrui, Incyte, Inovio, Ipsen, Jazz, Jansen, Kyowa Kirin, LAM, Lilly, Loxo, Merck, Mina, Novella, Onxeo, PCI Biotech, Pfizer, Pieris, QED, Redhill, Sanofi, Servier, Silenseed, Sillajen, Sobi, Targovax, Tekmira, Twoxar, Vicus, Yakult, Yiviva

O-15 MULTICENTRIC PROSPETTIVE STUDY OF VALIDATION OF ANGIOGENESIS-RELATED GENE POLYMORPHISMS IN HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH SORAFENIB: FINAL RESULTS OF INNOVATE STUDY

Andrea Casadei Gardini* 1, Giorgia Marisi2, Vincenzo Dadduzio3, Luca Faloppi4, Luca Ielasi5, Caterina Vivaldi 6, Mario Domenico Rizzato3, Lorenzo Fornaro6, Sara Lonardi3, Laura Gramantieri5, Irene Pecora5, Giuseppe Francesco Foschi7, Nicola Silvestris8, Francesca Fornari5, Giulia Orsi1, Giulia Rovesti1, Daniele Santini9, Vittorina Zagonel3, Stefano Cascinu1, Mario Scartozzi4

1University of Modena, 2IRST-IRCCS, Modena, 3IOV Veneto, Padva, 4University of Cagliari, Cagliari, 5University of Bologna, Bologna, 6University of Pisa, Pisa, 7ASL Romagna, Faenza, 8IRCCS-Giovanni Paolo II, Bari, 9UNICAMPUS, Roma, Italy

Introduction: In two retrospective studies we analyzed endothelial-derived nitric oxide synthase (eNOS)1and angiopoietin-2 (ANGPT2) polymorphisms and at univariate analysis, patients with eNOS-786TTgenotype and ANGPT2rs55633437 TT/GT genotypes had significantly shorter median Progression Free Survival (PFS) and Overall Survival (OS) compared to those with other genotypes. On the basis of these preliminary results, our aim is to validate in a prospective study these data in patients with HCC treated with sorafenib (NCT02786342)2.

Methods: 182 patients were enrolled in the study and they were treated with Sorafenib between March 2015 and June 2018, 17 did not fulfil the inclusion criteria and they were considered screening failure. Out of the 165 patients who met the selection criteria, 114 patients were dead and 127 had progressed after a median follow-up time of 25.9 months at the time of database lock in February 2019. We analyzed eNOS-786T>C and ANGPT2rs55633437 G>T by Real Time PCR method or by direct sequencing in relation to the primary end point (OS). Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test.

Results: The main characteristics of these patients are: Child–Pugh (CP) class-A was the most represented (91.9%), 65.7% had BCLC-C stage disease and 24.1% of patients had alpha-fetoprotein (AFP) level >400 ng/ml. The most common underlying aetiology was hepatitis infections from C virus (39.3%) and others aetiologies (23.3%). Median OS was 13.1 months (95% CI 10.4-15.7) and median PFS was 4.2 months (95% CI 3.2-5.3).At univariate analysis, we confirmed that eNOS-786 TT genotype was significantly associated with a lower median OS (8.6 vs 15.7 months, HR 2.67, 95% CI 1.67-4.28 p<0.0001) and PFS (3.7 vs4.5 months, HR 1.79, 95% CI 1.13-2.83p=0.0126) than the other genotypes.At univariate analysis, we not confirmed that ANGPT2rs55633437 TT+GT genotypes were significantly associated with a lower median OS (15.1 vs13.0 months, HR 2.68, 95% CI 1.67-4.29 p=0.55) and PFS (2.0 vs4.5 months, HR 1.73, 95% CI 0.84-3.58 p=0.1339) than the other genotype.Regarding baseline patient characteristicsthe univariate analysis identified Portal Vein Thrombosis Yes (vsNo; p=0.0017), Child Pugh B (vsA; p=0.0491), LDH > normal value (vs< normal value; p=0.0429), albumin < 35 (vs>35;p=0.0111) and as a continue variable (p=0.0025), AST > normal value (vs< normal value; p=0.0341) and a decrease of sodium (p=0.0291) and platelets (p=0.0150) as a negative prognostic factor of OS. No significant association was found between the main clinical-pathologic patients characteristics and eNOSpolymorphisms.Following adjustment for clinical covariates (Gender, Child Pugh, Portal Vein Thrombosis, LDH, aetiology and eNOS), multivariate analysis confirmed eNOSas only independent prognostic factor predicting OS (HR 3.38, 95% CI 1.39–8.23 p=0.0072).

Conclusions: Our Italian multicenter, prospective study confirmed that eNOS-786 TT genotype may be capable of identifying a subset of HCC patients who have a lower median OS and PFS than the other genotypes. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study

References: 1. Casadei Gardini A et al. eNOS polymorphisms and clinical outcome in advanced HCC patients

receiving sorafenib: final results of the ePHAS study.Oncotarget. 2016 May 10;7(19):27988-99. doi: 10.18632/oncotarget.8569.

2. Casadei Gardini A. et al Multicenter Prospective Study of Angiogenesis Polymorphism Validation in HCC Patients Treated with Sorafenib. An INNOVATE Study Protocol. Tumori. 2017 Dec 1:tj5000704.


O-16 ECONOMIC ANALYSIS OF OPEN VERSUS MINIMALLY-INVASIVE HEPATECTOMY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Ioannis A. Ziogas* 1, 2, Alexandros P. Evangeliou1, 2, Konstantinos S. Mylonas2, 3, Dimitrios I. Athanasiadis2, 4, Panagiotis Cherouveim2, 5, David A. Geller6, Sophoclis P. Alexopoulos7, Georgios Tsoulfas4

1Medical School, Aristotle University of Thessaloniki, Thessaloniki, 2Surgery Working Group, Society of Junior Doctors, 3Medical School, National and Kapodistrian University of Athens, Athens, 4First Department of Surgery, Aristotle University of Thessaloniki, Thessaloniki, 5Medical School, University of Ioannina, Ioannina, Greece, 6Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, University of Pittsburgh Medical Center, Pittsburgh, 7Division of Hepatobiliary Surgery and Liver Transplantation, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, United States

Introduction: Following the publication of landmark international consensuses (Louisville 2008 & Morioka 2015), minimally-invasive hepatectomy became widely accepted as a legitimate alternative to open surgery. Although equal in safety and efficacy, the difference in economic burden between these approaches remains unclear.

Methods: We performed a systematic literature review and evidence quality assessment (end-of-search date: 03/16/2019) with respect to the PRISMA statement. Meta-analysis was performed using fixed-effect or random-effect models depending on the heterogeneity of the included studies. Funnel plots and Begg's tests were utilized to detect publication bias.

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Results: The search yielded 27 eligible studies (2 randomized 25 non-randomized), reporting on a total of 2464 patients (1130 open [OLS], 1080 laparoscopic [LLS], and 254 robotic liver surgery [RLS]) patients. The average modified Jadad and Newcastle-Ottawa scale scores were 4.5±2.1 and 7.8±0.7, respectively. Mean patient age was 57.7±10.5 years for OLS, 57.1±13.6 years for LLS, and 53.7±14.6 years for RLS. Underlying pathology was malignancy in 78.4% (OLS: n=859/1096; 95% CI: 75.8–80.7), 64.9% (LLS: n=690/1063; 95% CI: 62.0–67.7), and 67.2% (RLS: n=170/253; 95% CI: 61.2–72.7) of the cases, respectively. Mean operative time was OLS: 241±67.5, LLS: 214.5±58.9, and RLS: 299.3±133 minutes, respectively, mean blood loss was OLS: 758.8±562.9, LLS: 414±323, and RLS: 367.2±643.9 mL, respectively, and mean hospital stay was OLS: 10.5±5.2, LLS: 7.1±3.5, and RLS: 5.1±3.7 days, respectively. Blood transfusion was required in OLS: 23.8% (n=199/837; 95% CI: 21.4–26.3), LLS: 12.7% (n=96/759; 95% CI: 10.5–15.2), and RLS: 10.9% (n=25/229; 95% CI: 7.5–15.7), respectively. Death was reported in 1.5% (n=17/1127; 95% CI: 0.9–2.4) of the OLS patients, 0.9% (n=10/1076; 95% CI: 0.5–1.7) in the laparoscopic group, and in no patients treated robotically. The operative costs of OLS were significantly lower than those of LLS (WMD: -1.16, 95% CI: -1.88 to -0.43, p=0.002), while subgroup analysis also showed lower costs in favor of OLS for major hepatectomy (WMD: -2.13, 95% CI: -2.58 to -1.68, p<0.00001) and for combined major-minor series (WMD: -0.39, 95% CI: -0.59 to -0.19, p=0.0001), but no statistically significant difference for minor hepatectomy (WMD: 0.00, 95% CI: -0.71 to 0.72, p=0.99). Hospitalization costs were significantly lower in the LLS group (WMD: 0.46, 95% CI: 0.20 to 0.72, p = 0.0005), with subgroup analysis indicating lower costs for laparoscopic major (WMD: 0.43, 95% CI: 0.23 to 0.63, p<0.0001) and minor hepatectomy (WMD: 0.69, 95% CI: 0.04 to 1.33,

p=0.04), but no significant difference in the combined major-minor series (WMD: 0.21, 95% CI: -0.27 to 0.69, p=0.39). Total costs were significantly lower in the laparoscopic cohort (WMD: 0.29, 95% CI: 0.02 to 0.56, p = 0.04), while subgroup analysis showed lower costs in the laparoscopic minor hepatectomy subgroup (WMD: 0.71, 95% CI: 0.23 to 1.20, p=0.004), but no difference in the major (WMD: -0.09, 95% CI: -0.44 to 0.26, p=0.61) and combined major-minor series (WMD: -0.05, 95% CI: -0.24 to 0.14, p=0.57). The paucity of economic data regarding RLS precluded us from including this approach in the economic meta-analysis.

Conclusions: LLS has similar safety and efficacy with OLS but is overall less expensive, especially in minor hepatectomy series.


O-17 A MULTI-NATIONAL, MULTI-INSTITUTIONAL STUDY OF COMPARING AN EFFICACY OF STEREOTACTIC BODY RADIATION THERAPY AND RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA

Jinsil Seong* 1, Nalee Kim1, Jason C.-H. Cheng2, Wen-Yen Huang3, Tomoki Kimura4, Zhao-Chong Zeng5, Chul-Seung Kay6, Victor H. Lee7

1Yonsei Cancer Center, Seoul, Korea, Republic Of, 2Taiwan University Hospital, 3Tri-Service General Hospital, Taipei, Taiwan, Province of China, 4Hiroshima University, Hiroshima, Japan, 5Fudan University, Sanghai City, China, 6Incheon St. Mary Hospital, Incheon, Korea, Republic Of, 7The university of Hong Kong, Hong Kong, Hong Kong

Introduction: Several non-surgical, locoregional treatments are available for localized HCC regarding stereotactic body radiation therapy (SBRT), radiofrequency ablation (RFA), percutaneous ethanol injection, and transarterial chemoembolization. Until now, limited evidence has been available for determining the efficacy of SBRT in comparison to RFA. Our early reports of single-institutional retrospective analysis revealed that SBRT and RFA could achieve tolerable local control (LC). However, tumors located in subphrenic region and larger than 2 cm could be appropriate candidates for SBRT. In the present study, we underwent a thorough analysis for comparing the effectiveness of SBRT to RFA in patients treated at 7 tertiary-referral hospitals.

Methods: Patients treated for HCC in 7 tertiary-referral hospitals were retrospectively reviewed. Among these, 1607 patients who underwent RFA of 1758 tumors and 505 patients who underwent SBRT of 519 tumors were included. Median prescribed total dose and fractional dose for SBRT were 48 (interquartile range, IQR, 40-54) Gy and 10 (IQR, 8-12) Gy, respectively. SBRT was delivered using CyberKnife (Accuray, Sunnyvale, CA) (n=158; 30.4%), Tomotherapy (Accuray, Madison, WI) (n=135; 26.0%), 3-dimensional conformal radiotherapy (n=112; 21.6%), and volumetric modulated arc therapy (Elekta, Stockholm, Sweden) (n=114; 22.0%). Patients were assessed after the completion of treatment at first month, every 3-6 months thereafter with CT or MRI, liver function tests, and tumor markers. Radiologic responses were evaluated using modified Response Evaluation Criteria in Solid Tumors to assess LC. Using propensity score matching (PSM) to adjust for clinical factors, 232 tumors were selected from each treatment arm.

Results: At baseline, SBRT-treated tumors were in more advanced BCLC stage (B-C, 64.3% vs. 15.7%, p<0.001), larger (median, 3.0 cm vs. 1.8 cm; p < 0.001), and had a higher incidence of prior liver-directed treatments (median, 2 times vs. treatment naïve; p < 0.001) than RFA-treated tumors. The median follow-up period for the entire cohort was 31.4 (IQR, 14.1-45.7) months. The 3-year LC rates were 63.9% for tumors treated with SBRT and 66.6% for tumors treated with RFA, respectively (p=0.031). In the univariate analysis for LC, tumor size, advanced stage (B or C), and serum AFP levels were attributed to local progression. However, treatment modality was significantly correlated with LC favoring SBRT (HR 0.74, 95% CI 0.59-0.92, p<0.001). Other independent factors included age, tumor size, advanced stage and serum AFP level in the multivariate analysis. After PSM, 3-year LC rates were 83.6% for tumors treated with SBRT and 61.3% for tumors treated with RFA, respectively (p<0.001). The Cox proportional hazards model in matched cohort also revealed that the treatment modality was significantly correlated with LC favoring SBRT (HR 0.29, 95% CI 0.18-0.45, p<0.001).

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Saturday, 21 September 2019Friday, 20 September 2019

Conclusions: Although SBRT-treatment tumors had more negative prognostic factors at baseline, SBRT provided comparable LC rates to RFA in this multicenter retrospective analysis. Overall, SBRT was associated with a better LC rate than RFA in not only the entire cohort after adjusting clinical factors but also the matched cohort.


O-32 PHASE IB STUDY RESULTS: SAFETY AND EFFICACY OF ATEZOLIZUMAB + BEVACIZUMAB VERSUS ATEZOLIZUMAB IN PATIENTS WITH PREVIOUSLY UNTREATED, UNRESECTABLE OR ADVANCED HEPATOCELLULAR CARCINOMA

Kyung-Hun Lee* 1, Baek-Yeol Ryoo2, Chih-Hung Hsu3, Kazushi Numata4, Stacey Stein5, Wendy Verret6, Steve Hack6, Jessica Spahn6, Bo Liu6, Heba Abdullah6, Aiwu Ruth He7, Michael S. Lee8

1Seoul National University Hospital, 2Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic Of, 3National Taiwan University Hospital, Taipei, Taiwan, Province of China, 4Yokohama City University Medical Center, Yokohama, Japan, 5Yale School of Medicine, New Haven, CT, 6Genentech, Inc., South San Francisco, CA, 7Georgetown University Medical Center, Washington, DC, 8UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Introduction: Unresectable or advanced HCC is a lethal disease with limited treatment options. In addition to its anti-angiogenic activity, bevacizumab (anti-VEGF) has immunomodulatory effects that alter the tumour microenvironment and may therefore augment anti-tumour immune responses mediated by atezolizumab (anti–PD-L1). Here we report results from a Phase Ib study evaluating the safety and efficacy of atezolizumab + bevacizumab vs atezolizumab monotherapy in a cohort of patients with unresectable or advanced HCC (Arm F).

Methods: Arm F is an open-label, randomised arm of the Phase Ib study GO30140 (NCT02715531) and enrolled patients with unresectable or advanced HCC who were naive to systemic treatment. Patients were randomised 1:1 to receive atezolizumab 1200 mg + bevacizumab 15 mg/kg IV q3w (Group F1) or atezolizumab 1200 mg IV q3w (Group F2) until unacceptable toxicity or loss of clinical benefit. Randomisation was stratified by geographic region (Asia excluding Japan vs rest of world), macrovascular invasion and/or extrahepatic spread (presence vs absence), and baseline alpha fetoprotein (AFP) levels (< 400 vs ≥ 400 ng/mL). For patients in Group F2, crossover from atezolizumab monotherapy to atezolizumab + bevacizumab combination therapy was allowed upon investigator (INV)-assessed disease progression if patients still met eligibility criteria. Primary endpoints were safety and progression-free survival (PFS) per independent review facility (IRF)-assessed RECIST 1.1. Secondary endpoints included PFS per INV-assessed RECIST 1.1, objective response rate (ORR) and duration of response (DOR) per INV-assessed RECIST 1.1 and per IRF-assessed RECIST 1.1 and HCC mRECIST, as well as overall survival (OS).

Results: Enrolment (n = 119) was completed in March 2019. At the time of clinical data cutoff for the safety and efficacy results to be presented, approximately 60% of patients will have experienced a PFS event. Results will be available in August 2019.

Conclusions: N/A

Disclosure of Interest: K.-H. Lee Conflict with: Honoraria - Roche, AstraZeneca, Conflict with: Advisory Board - Bayer, Ono pharmaceutical, Samsung bioepis, Roche, Eisai, AstraZeneca , B.-Y. Ryoo: None Declared, C.-H. Hsu Conflict with: Research/Education grant - MSD (research grant), Conflict with: Honoraria - BMS, Ono Pharmaceutical, MSD, Conflict with: Advisory Board - BMS, Ono Pharmaceutical, Conflict with: Consulting - Eli Lilly, Astra Zeneca, Roche, K. Numata: None Declared, S. Stein Conflict with: Advisory Board - Genentech, BMS, Eisai, Bayer, Exelixis, W. Verret Conflict with: Consulting - Employee of Roche/Genentech, S. Hack Conflict with: Consulting - Employee of Roche/Genentech, J. Spahn Conflict with: Stocks - Roche/Genentech, B. Liu Conflict with: Consulting - Employee of Roche/Genentech, H. Abdullah Conflict with: Consulting - Employee of Roche/Genentech, A. R. He Conflict with: Research/Education grant - Merck, Conflict with: Advisory Board - AstraZeneca, Merck; Bayer; Bristol-Myers Squibb; Eisai Inc.; and Exelixis, Inc., M. Lee Conflict with: Research/Education grant - Amgen (Self) Bristol-Myers Squibb (Self) Pfizer (Self) EMD Serono (Self) Genentech/Roche (Self)

Presidential Session

O-01 RESULTS OF A PHASE 3 STUDY OF PEMBROLIZUMAB VERSUS BEST SUPPORTIVE CARE FOR SECOND-LINE THERAPY IN ADVANCED HEPATOCELLULAR CARCINOMA: KEYNOTE-240

Richard S. Finn* 1, Baek-Yeol Ryoo2, Philippe Merle3, Masatoshi Kudo4, Mohamed Bouattour5, Ho-Yeong Lim6, Valeriy Breder7, Julien Edeline8, Yee Chao9, Sadahisa Ogasawara10, Thomas Yau11, Marcelo Garrido12, Stephen L. Chan13, Jennifer Knox14, Bruno Daniele15, Scot W. Ebbinghaus16, Erluo Chen16, Abby B. Siegel16, Andrew X. Zhu17, Ann-Lii Cheng18 and for the KEYNOTE-240 Investigators

1University of Callifornia, Los Angeles, Los Angeles, United States, 2Asan Medical Center University of Ulsan College of Medicine, Seoul, Korea, Republic Of, 3Hepatology Unit, Lyon North Hospital, Lyon, France, 4Kindai University Faculty of Medicine, Osaka, Japan, 5Beaujon University Hospital, APHP, Clichy, France, 6Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic Of, 7NN Blokhin National Medical Research Center of Oncology of MoH, Moscow, Russian Federation, 8Centre Eugène Marquis, Rennes, France, 9 Taipei Veterans General Hospital, Taipai, Taiwan, Province of China, 10Chiba University Graduate School of Medicine, Chiba, Japan, 11The University of Hong Kong, Hong Kong, Hong Kong, 12Pontificia Universidad Catolica de Chile, Santiago, Chile, 13State Key Laboratory of Translation Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Shatin, Hong Kong, 14Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada, 15Ospedale del Mare, Napoli, Italy, 16Merck & Co., Inc., Kenilworth, 17Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, United States, 18National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan, Province of China

Introduction: Pembrolizumab (Pembro) received accelerated approval based on results of KEYNOTE-224, a phase 2 trial in pts with advanced hepatocellular carcinoma (HCC) in the second-line setting. KEYNOTE-240 (NCT02702401) is a randomized, placebo controlled, phase 3 study designed to confirm the efficacy and safety of pembrolizumab plus best supportive care (BSC) versus placebo plus BSC in patients with previously-treated advanced HCC.

Methods: Eligible pts had a radiographic or pathologic diagnosis of HCC, radiographic progression on or intolerance to sorafenib, Child-Pugh A disease and ECOG PS 0-1. Pts were randomized 2:1 to receive Pembro 200 mg plus BSC or placebo plus BSC IV every 3 weeks, stratified by geographic region, macrovascular invasion and ：-fetoprotein levels for ≤35 cycles or until confirmed PD/unacceptable toxicity. Response was assessed every 6 weeks per RECIST v1.1 by central imaging review. Co-primary endpoints were OS and PFS. Secondary endpoints included ORR, DOR and safety. Pre-specified efficacy boundaries were p=0.0174 for overall survival (final analysis, Jan 2, 2019) and p=0.002 for progression-free survival (first interim analysis, Mar 26, 2018). Data are presented from final analysis for OS, and both first interim and final analyses for PFS.

Results: 413 patients were randomized; 278 to Pembro and 135 to placebo. After a median follow up of 13.8 mo, 10.1% of pts remained on Pembro and 3.0% on placebo. Pembro improved OS (HR: 0.781, 95% CI 0.611−0.998; one-sided p=0.0238) and PFS (HR: 0.781, 95% CI 0.614−0.993; p=0.0209 [first interim] and 0.729; 95% CI 0.580−0.917; p=0.0031 [final analysis]) versus placebo; the differences in OS (final analysis) and PFS (first interim analysis) did not meet significance per the prespecified statistical plan. ORR was 18.3% (95% CI, 14.0−23.4%) for Pembro and 4.4% (95% CI, 1.6−9.4% p=0.00007) for placebo at final analysis; responses on Pembro were durable (median DOR: 13.8 mo [1.5+ – 23.6+]). Off study, subsequent anticancer use was 42% for Pembro and 47% for placebo. The safety profile including incidence of hepatitis and other immune-mediated events was generally consistent with that previously reported in Pembro studies; no cases of HBV/HCV flare were identified.

Conclusions: Pembro reduced the risk of death by 22% and improved PFS over placebo in pts with advanced HCC, although significance was not reached per the prespecified statistical criteria. ORR in the Pembro arm was consistent with that of KEYNOTE-224. Subsequent anticancer therapy in the placebo arm likely impacted the OS results. The safety profile was comparable to that established for Pembro monotherapy. These results support the use of Pembro in this HCC population.

Disclosure of Interest: R. Finn Conflict with: Research/Education grant - Pfizer (Inst); Bayer (Inst); Novartis (Inst); Eisai (Inst); Lilly (Inst); Merck (Inst); Bristol-Myers Squibb (Inst); Roche/Genentech (Inst), Conflict with: Consulting - Pfizer; Bayer; Novartis; Bristol-Myers Squibb; Merck; Eisai; Lilly; Genentech/Roche; AstraZeneca; Exelixis, B.-Y. Ryoo: None Declared, P. Merle Conflict with: Consulting - Bayer; Ipsen; BMS; MSD; Onxeo; Roche, M. Kudo Conflict with: Research/Education grant - Chugai Pharma (Inst); Otsuka (Inst); Taiho Pharmaceutical (Inst); Daiichi Sankyo (Inst); Abbvie (Inst); Astellas Pharma (Inst); Bristol-Myers Squibb Japan (Inst), Conflict with: Honoraria - MSD; Abbvie; Taiho Pharmaceutical; Gilead Sciences; Otsuka; Daiichi Sankyo; Chugai Pharma; EA Pharma; Astellas Pharma; Eisai, Conflict with: Consulting - MSD; Bayer; Eisai, M. Bouattour Conflict with: Honoraria - Bayer Schering Pharma, Conflict with: Consulting - Bayer; Bristol-Myers Squibb; Sirtex Medical; Eisai; Ipsen, H.-Y. Lim: None Declared, V. Breder Conflict with: Honoraria - MSD Oncology; Roche; Bristol-Myers Squibb; Bayer; Eisai; Takeda; Boehringer Ingelheim; BioCad, Conflict with: Consulting - Bristol-Myers Squibb; Bayer; Roche; MSD Oncology; Eisai; Boehringer Ingelheim; BioCad, J. Edeline Conflict with: Research/Education grant - Bristol-Myers Squibb (Inst), Conflict with: Consulting - BTG, Bristol-Myers Squibb; AstraZeneca; Bayer; Ipsen; AstraZeneca, Y.

Chao: None Declared, S. Ogasawara Conflict with: Research/Education grant - Bayer; Eisai, Conflict with: Honoraria - Bayer; Eisai, Conflict with: Consulting - MSD; AstraZeneca, T. Yau Conflict with: Honoraria - Bristol-Myers Squibb, Conflict with: Consulting - Bristol-Myers Squibb, M. Garrido Conflict with: Research/Education grant - Novartis; Pfizer, S. Chan Conflict with: Research/Education grant - Novartis; Sirtex Medical, Conflict with: Honoraria - Bayer, Conflict with: Consulting - Novartis; AstraZeneca/MedImmune; MSD Oncology, J. Knox Conflict with: Research/Education grant - AstraZeneca; Merck, Conflict with: Honoraria - Novartis, Conflict with: Consulting - Lilly; Merck, B. Daniele Conflict with: Honoraria - Bayer; Eisai; Lilly; Ipsen, Conflict with: Consulting - Ipsen; Eisai; Incyte; MSD, S. Ebbinghaus Conflict with: Stocks - Merck & Co., Inc., E. Chen Conflict with: Stocks - Merck & Co., Inc., A. Siegel Conflict with: Stocks - Merck & Co., Inc., A. Zhu Conflict with: Research/Education grant - Lilly (Inst); Bayer (Inst); Bristol-Myers Squibb (Inst); Merck (Inst); Novartis (Inst), Conflict with: Consulting - Eisai; Bristol-Myers Squibb; Merck; Novartis; AstraZeneca; Bayer; Exelixis; Lilly; Roche/Genentech, A.-L. Cheng Conflict with: Honoraria - Bayer Yakuhin; AstraZeneca; Eisai; Genentech/Roche; Lilly, Conflict with: Consulting - Bristol-Myers Squibb; Bayer Schering Pharma; Novartis; Eisai; Ono Pharmaceutical; AstraZeneca; Genentech/Roche; CSR Pharma; MSD; BeiGene

O-02 RANDOMIZED, OPEN-LABEL, PERIOPERATIVE PHASE II STUDY EVALUATING NIVOLUMAB ALONE OR NIVOLUMAB PLUS IPILIMUMAB IN PATIENTS WITH RESECTABLE HCC

Ahmed O. Kaseb 1, Roberto Carmagnani1, Luis M. Vence2, Jorge M. Blando2, Shalini Singh2, Naruhiko Ikoma3, Kanwal Raghav1, Divya Sakamuri1, Lauren Girard1, Tan Dongfeng4, Jean Vauthey3, Ching-Wei D. Tzeng3, Yehia I. Abugabal1, Thomas A. Aloia5, Yun Shin Chun3, James Yao1, Robert A. Wolff1, James P. Allison2, Padmanee Sharma6 , Yehia Mihammed*

1Department of Gastrointestinal Medical Oncology, 2Department of Immunology, 3Department of Surgical Oncology, 4Department of pathology, 5The University of Texas MD Anderson Cancer Center, Houston, United States, 6Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, United States

Introduction: In HCC, surgical resection is associated with high recurrence rate, and no effective neoadjuvant or adjuvant therapies currently exist. On the basis of of previous reports on the efficacy and safety of anti–PD-1 (nivolumab) and anti–CTLA-4 (ipilimumab) antibodies against HCC, we initiated a randomized pilot trial of perioperative immunotherapy for resectable HCC.

Methods: This is a randomized, phase II pilot trial of nivolumab (Arm A) or nivolumab + ipilimumab (Arm B) as pre-operative treatment for patients (pt) with HCC who are eligible for surgical resection. Pt are given nivolumab 240 mg every 2 weeks (wk) for a total of 6 wk. Pt in Arm B are treated concurrently with ipilimumab 1 mg/kg every 6 wk. Surgical resection occurs within 4 weeks after last cycle of therapy. Pt continue adjuvant immunotherapy for up to 2 years after resection. Primary objective is the safety and tolerability of nivolumab +/- ipilimumab. Secondary objectives include overall response rate, complete response rate and time to progression. Exploratory objectives include evaluating the pre- and post-treatment immunological changes in tumor tissues and peripheral blood.

Results: 17 pt were enrolled at the time of interim analysis (8 in Arm A, 9 in Arm B) and 14 were evaluable. Most pt (53%) were 60-70yo, and males (70%). 6 pt were HCV-positive and 4 had chronic hepatitis B. 14 pt proceeded with resection as planned; surgery was aborted for 2 pt (1 for frozen abdomen and 1 for development of contralateral liver nodule). One is still receiving preoperative therapy. Pathologic complete response (pCR) was observed in 4/14 evaluable pt – 2 in Arm A and 2 Arm B (29% pCR rate). 4 pt in Arm B and 1 in Arm A experienced grade 3 or higher toxicity prior to surgery.

Conclusions: We report a pCR rate of 29% in an interim analysis of a phase II pilot trial of perioperative immunotherapy for resectable HCC. Treatment was safe and surgical resection was not delayed. The study is ongoing and results may contribute to a paradigm shift in the perioperative treatment of HCC.


O-03 PROFILING OF ROUTINE SERUM PARAMETERS AND APP EVOLUTION IN CIRRHOSIS FOLLOWING HCV ERADICATION FOR STRATIFICATION OF HCC RISK: A TRAJECTORY CLUSTERING ANALYSIS FROM THE ANRS CO12 CIRVIR COHORT

Pierre Nahon* 1, Thomas Diot2, Richard Layese2, Carole Cagnot3, Stanislas Pol4, Patrick Marcellin5, Etienne Audureau2 and ANRS CO12 CirVir group

1Hôpital Jean Verdier, Bondy, 2APHP Henri Mondor, Créteil, 3ANRS, 4APHP Cochin, 5APHP Beaujon, Paris, France

Introduction: HCC surveillance following HCV eradication in patients with cirrhosis needs to be refined to tailor personalized management and increase cost-effectiveness. Our study aimed to identify specific longitudinal profiles of routine serum parameters (RSP) and AFP evolution before and after HCV eradication in patients with cirrhosis which could be associated with higher risk of HCC occurrence.

Saturday, 21 September 2019Saturday, 21 September 2019

Methods: Data were driven from the French ANRS CirVir multicenter prospective cohort of patients with biopsy-proven viral compensated cirrhosis included in semi-annual HCC surveillance programs. Serum AFP and RSP (ALT, AST, GGT, PT, albumin, bilirubin, platelets) were assessed every 6 months. For the present analysis, only patients with at least 3 available AFP and RSP repeated measurements per trajectory analysis (i) no/before SVR, ii) after SVR achievement) were included. Trajectory analysis was based on a k-means approach for clustering individuals with similar trajectories of AFP and RSP over time.

Results: After a median follow-up of 74.2 months, 717 patients with active HCV replication at baseline and 413 achieving SVR during follow-up were included, of whom 142 and 47 patients developed HCC, respectively. Before SVR achievement, trajectory analysis identified 3 clusters of patients with common AFP and RSP evolution, with profiles characterized by increasing AFP and the highest GGT/ALT/AST levels (cluster A, n=190; HCC incidence during follow-up 25.3%), a globally worsening liver function (cluster B, n=198; HCC 26.8%), or overall more favorable and stable levels over time (Cluster C, n=329; HCC 12.5%, p<0.0001). In the 413 patients who achieved SVR, trajectory analysis then revealed 3 post-SVR patients clusters (Figure), all demonstrating a global trend towards AST, ALT, GGT and AFP normalization, particularly in Cluster A (n=228; HCC 7.5%). Of note, the two other clusters were associated with higher HCC incidence rates despite SVR achievement, being characterized either by persisting impaired liver function (cluster B, n=109; HCC 15.6%) or elevated biochemical parameters (Cluster C, n=95; HCC 13.7%).

Image:

Conclusion: Liver function impairment (“liver failure cluster”) or persistent elevated biochemical parameters (“inflammatory cluster”) despite SVR achievement in cirrhosis define two different profiles of patients in whom the residual risk of HCC following HCV eradication is increased. These analyses based on novel statistical approaches suggest that HCC surveillance in these patients could be refined and improved according to the longitudinal evolution of these parameters over time.


O-04 MRI RADIOMICS FEATURES PREDICT IMMUNO-ONCOLOGICAL CHARACTERISTICS AND RECURRENCE OF HEPATOCELLULAR CARCINOMA

Stefanie Hectors* 1, Sara Lewis1, Cecilia Besa1, Michael King1, Daniela Said1, Juan Putra1, Stephen Ward1, Takaaki Higashi1, Swang Thung1, Shen Yao1, Ilaria Laface1, Myron Schwartz1, Sacha Gnjatic1, Miriam Merad1, Yujin Hoshida2, Bachir Taouli1

1Icahn School of Medicine at Mount Sinai, New York, 2UT Southwestern, Dallas, United States

Introduction: Pathological and genomics evaluation of hepatocellular carcinoma (HCC) plays an important role for prediction of prognosis and treatment response. However, these techniques require tissue sampling, which is invasive and rarely clinically indicated in HCC. Surrogate measurements of HCC pathological and genomics characteristics using MRI would be of major clinical interest, because MRI is noninvasive and covers the entire lesion [1]. The objective of our study was to assess the value of qualitative and quantitative radiomics features measured with MRI for noninvasive prediction of histopathologic and genomics characteristics, as well as outcomes of HCC.

Methods: This retrospective study was approved by the Institutional Review Board and the requirement of informed consent was waived. Forty-eight patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI were included. Qualitative imaging traits, quantitative non-texture related and texture features were

assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. Advanced histopathological analysis was performed using multiplex immunohistochemistry [2]. Gene expression analysis was performed on paraffin-embedded tissue blocks of the index HCC lesions. The association of imaging features with histopathologic and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyze the association of radiomics, histopathologic and genomics features with radiological recurrence of HCC at 12 months.

Results: Qualitative (correlation coefficient r=-0.41–0.40, P<0.042) and quantitative (r=-0.52–0.45, P<0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68), and endothelial cells (CD31). MRI radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r=0.41-0.47, P<0.029) as well as PD1 and CTLA4 at mRNA expression level (r=-0.48–0.47, P<0.037). Follow-up imaging data up to at least 1 year after surgery was available for 43 patients, of whom 10 patients showed HCC recurrence within 1 year after surgery. Several radiomics features showed significant association with HCC recurrence (highest AUC =0.80, odds ratio=5.51, P<0.028), while histopathologic and genomics features did not (P>0.098).

Conclusions: We observed significant associations of MRI radiomics features with HCC histopathological and genomics characteristics and recurrence. These results suggest that MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumor recurrence, providing potentially valuable information regarding tumor aggressiveness to enable optimized treatment planning. We are currently validating these results in a prospective study.

References: 1. Taouli B, Hoshida Y, Kakite S, Chen X, Tan PS, Sun X, Kihira S, Kojima K, Toffanin S, Fiel MI,

Hirschfield H, Wagner M, Llovet JM. Imaging-based surrogate markers of transcriptome subclasses and signatures in hepatocellular carcinoma: preliminary results. European radiology. 2017. doi: 10.1007/s00330-017-4844-6. PubMed PMID: 28439654; PMCID: 5654702.

2. Remark R, Merghoub T, Grabe N, Litjens G, Damotte D, Wolchok JD, Merad M, Gnjatic S. In-depth tissue profiling using multiplexed immunohistochemical consecutive staining on single slide. Sci Immunol. 2016;1(1):aaf6925. doi: 10.1126/sciimmunol.aaf6925. PubMed PMID: 28783673.


O-05 IDENTIFICATION OF A PAN-GAMMA-SECRETASE INHIBITOR RESPONSE SIGNATURE FOR NOTCH-DRIVEN CHOLANGIOCARCINOMA

Colm J. O Rourke* 1, Matthias S. Matter2, Chirag Nepal1, Rui Caetano-Oliveira3, Phuongnga T. Ton4, Valentina M. Factor5, Jesper B. Andersen1

1Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen N, Denmark, 2Institute of Pathology, University Hospital Basel, Basel, Switzerland, 3CHUC Pathology Department, iCBR, University of Coimbra, Coimbra, Portugal, 4Molecular Imaging Program, 5Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, United States

Introduction: Cholangiocarcinoma (CCA) mortality rates are increasing. NOTCH pathway reactivation has been reported in CCA to conflicting degrees, hindering prioritization of therapeutic targets and identification of candidate responder patients for NOTCH-directed therapies. As 40% of NOTCH-directed clinical trials in cancer have been terminated or withdrawn, thorough guidelines for patient selection are clearly required. Here, we identified a transcriptomic signature capable of predicting pan-gamma-secretase inhibitor (GSi) response across multiple patient cohorts and CCA models, as well as diverse cancer types.

Methods: Transcriptomes were analyzed from 341 CCA patients. Models of GSi-sensitivity and -resistance were initially identified from 13 CCA cell lines in vitro, followed by subcutaneous CCA xenograft models. The responder signature was developed by transcriptome profiling of murine tumors and tested for enrichment across diverse hydrodynamic models and patient subgroups. Pan-cancer analysis of this signature was also pursued in 9409 patient tissues (31 cancer types) and 60 cancer cell lines.

Results: A NOTCH1high CCA patient subgroup was identified, characterized by distinct stromal infiltration and lymph node metastasis. Extensive NOTCH network imbalance, including multiple ligand and receptor usage, identified the g-secretase (GS) complex as an optimal therapeutic target. Treatment using two GSi classified HuCCT-1 and WITT as models of sensitivity and resistance, respectively. Subcutaneous transplantation of sensitive and resistant CCA cell lines pre-treated with a GSi cocktail demonstrated anti-neoplastic effects in the sensitive model only and led to development of a 225-gene responder signature. This signature was enriched in intrahepatic tumors developed by hydrodynamic injections of activated NOTCH as compared to AKT-RAS-driven tumors (P<0.001), as well as in a subgroup of CCA patients (P=0.0232). Candidate GSi-responder patients were characterized by grossly unique intra-tumoral stromal reaction and signaling pathways, as well as metastasis (P=0.0078) and cancer stemness (P=0.0142) signatures. Furthermore, GSi-responder tumors were characterized by unique intra-tumoral immune landscapes, in particular significant elevation of infiltrative CD8+ cytotoxic T cells which display transcriptomic profiles indicative of T

cell exhaustion. Pan-cancer analysis identified 41.9% cancers to harbor prospective GSi-responder patients. This GSi-responder signature was further refined to a 20-gene sub-signature which was capable of discriminating nanomolar versus micromolar GSi-sensitivity of 60 tumor lines with an AUC of 1 (versus AUC:0-50.61 for NOTCH receptor expression).

Conclusions: Identification of this pan-GSi-responder signature may facilitate precision medicine application of NOTCH-directed therapy in CCA, as well as prospectively across diverse malignancies. Consequently, application of this theranostic signature may be supportive of basket trial approaches.


O-06 GENOMIC ANALYSIS OF HEPATOCELLULAR CARCINOMA WITH ACTIVE HEPATITIS B VIRUS REPLICATION

Huat Chye Lim* 1, John Gordan2

1Division of Hospital Medicine, 2Division of Medical Oncology, University of California, San Francisco, San Francisco, United States

Introduction: Hepatitis B virus (HBV) replication contributes to hepatocellular carcinoma (HCC) initiation and is associated with worse patient outcomes. Prior tumor genomic studies of HCC associated with HBV infection have used detection of HBV surface antigen (HBsAg) in serum to annotate HBV infection status. However, a substantial proportion of HBsAg+ patients lack HBV replication in tumor, suggesting a potentially distinct patient subset. In this study, we determined HBV status by measuring tumor HBV RNA, a proxy for active replication. We then investigated HBV RNA+/- association with several tumor genomic characteristics.

Methods: RNA-Seq and somatic mutation data for 439 HCC tumors were obtained from TCGA (n = 371) and ICGC (n = 68). Tumors were classified as HBV RNA+ if they harbored more than 1 HBV RNA read per million human reads, as measured using GATK PathSeq software. For all tumors, we investigated the association between HBV RNA status and nonsynonymous somatic mutations. Additionally, for TCGA tumors, for which RNA-Seq expression level data were available, we investigated whether HBV RNA status was associated with gene set expression, mutational signatures, homologous recombination deficiency (HRD) score and tumor mutation burden (TMB). HRD score was calculated as the sum of 3 independent HRD measures: large-scale state transitions, loss of heterozygosity and telomeric allelic imbalance.

Results: In all tumors, HBV RNA+ status was associated with a higher rate of nonsynonymous somatic mutations in multiple genes, including the tumor suppressors TP53, CDKN2A and CHD5 (p < 0.004 for all), while HBV RNA- status was associated with a higher rate of nonsynonymous mutations in the tumor suppressor BAP1 and the chromatin remodeler CHD9 (p < 0.04 for both). In TCGA tumors, for which normalized RNA-Seq expression level read counts were available, gene set enrichment analysis of this data showed that HBV RNA+ status was associated with increased transcription of genes upregulated by MYC and mTORC1, genes overexpressed in Hoshida molecular subclass S2 HCC, and genes involved in multiple DNA damage repair pathways, including mismatch, base excision and nucleotide excision repair (FDR < 0.03 for all). Consistent with this, mutational signature analysis showed that COSMIC mutational signatures 6, 15, 20 and 26, all associated with mismatch repair deficiency, were enriched or had a trend toward enrichment in HBV RNA- tumors in TCGA (p < 0.06 for all). Finally, HBV RNA status was associated with HRD score in TCGA tumors (22.19 for HBV RNA+ vs. 15.97 for HBV RNA-, p = 1e-6), but not with TMB. A majority of HBV RNA+ patients (61/100) were not annotated as HBsAg+ in the TCGA clinical database, while HBsAg annotation was not available in the ICGC clinical database.

Conclusions: HBV status based on tumor HBV RNA detection identifies a genetically distinct subset within all HCC patients with a history of HBV infection that is associated with a distinct pattern of nonsynonymous somatic mutations in several genes and differential transcription of gene sets, some of which have not been previously reported. HBV RNA status is also associated with differences in HRD score and mutational signatures associated with DNA damage repair. These findings suggest that HCC with active HBV replication may represent a molecularly distinct subset within all HCC, with the potential for differential responsiveness to targeted therapies.


General Session 3: Epidemiology, Diagnosis, Staging

O-18 EVALUATION OF THE PROGNOSTIC AND PREDICTIVE SIGNIFICANCE OF HEPATOCELLULAR CARCINOMA CIRCULATING TUMOR CELLS EXPRESSING PROGRAMMED DEATH-LIGAND 1 (PD-L1)

Pin Jung Chen1, Paul Winograd2, Shuang Hou2, Colin Court2, Saeed Sadeghi3, Richard Finn3, Yazhen Zhu1, Fady Kaldas2, Ronald Busuttil2, James Tomlinson2, Hsian-Rong Tseng1, Vatche G. Agopian* 2

1Molecular and Medical Pharmacology, 2Surgery, 3Division of Hematology/Oncology; Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, United States

Introduction: Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide with limited therapeutic options. Immunotherapies employing checkpoint inhibition between programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown promise in treating advanced HCC, but lack biomarkers that predict response. While enumeration of HCC circulating tumor cells (CTCs) expressing cytokeratin (CK) has been associated with prognosis, data on HCC CTCs expressing PD-L1 have not been reported. We sought to detect PD-L1-expressing HCC CTCs, and investigate its role as a prognostic/predictive biomarker.

Methods: We utilized a microfluidic, antibody-based platform to enumerate and phenotype CTCs from 4mL of peripheral blood in a prospective cohort of 107 patients (87 had HCC, 12 had non-malignant liver disease, and 8 healthy controls). Immunocytochemical staining identified total HCC CTCs (DAPI+/CK+/CD45-) and a subpopulation expressing PD-L1 (DAPI+/CK+/PD-L1+/CD45-). CTC number and phenotype were correlated with clinicopathologic data.

Results: CK+ CTCs were detected in 96.6% of HCC patients (median = 6, range = 0-27), and discriminated HCC and non-HCC patients (AUROC = 0.93, sensitivity = 92%, specificity = 85%, p < 0.0001). The presence of PDL1+ CTCs discriminated HCC patients with early stage (4/49 had PD-L1+ CTCs) and advanced/metastatic disease (27/48 had PD-L1+ CTCs; AUROC = 0.81, sensitivity = 71.1%, specificity = 94.2%, p < 0.0001). PD-L1+ CTCs remained an independent predictor of overall survival (HR 3.74, P=0.01) in multivariate analysis controlling for tumor stage, AFP, and MELD score. Of 10 patients receiving anti-PD1 therapy, the 5 demonstrating response all had PD-L1+ CTCs, compared to only 1 of 5 non-responders (Figure 1).

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Conclusions: To our knowledge, this is the first report evaluating PD-L1+ CTCs in HCC, which discriminate early and advanced stage HCC, and are associated with response to immunotherapy. Further validation in a larger patient cohort are required to determine if PDL1 CTC phenotype may help guide selection of patients likely to benefit from immune checkpoint inhibitors.


O-19 ADDITION OF 18F-FLUORODEOXYGLUCOSE (FDG) PET-CT TO CROSS SECTIONAL IMAGING IMPROVES STAGING AND ALTERS MANAGEMENT IN PATIENTS WITH HCC- RESULTS FROM A NORTH AMERICAN PROSPECTIVE STUDY

Binu John* 1, Sean Aubuchon2, Bassam Dahman2, Yangyang Deng2, Venkata Rajesh Konjeti2, Latha Sundaram3, Eleanor Love2, Smitha John3, Michael Chang3, James Tatum3

1Gastroenterology and Hepatology, 2Virginia Commonwealth University, 3Mcguire VA Medical Center, Richmond, United States

Saturday, 21 September 2019Saturday, 21 September 2019

Introduction: Staging of hepatocellular carcinoma (HCC) relies on cross-sectional imaging such as contrast-enhanced CT and MRI. PET-CT is not being used in the staging of HCC in North America, because up to a third of lesions do not take up 18F-flurodeoxyglucose (FDG). However, data from Europe and Asia have shown that PET-CTs have a role in the superior detection of extra hepatic metastasis and may help to change staging. The aim of this study is to prospectively characterize the role of FDG PET-CT in the staging and management of patients with HCC in North American population.

Methods: 148 patients diagnosed to have HCC based on pathology or LIRADS imaging criteria underwent 181 PET-CT studies and were prospectively enrolled in an IRB approved protocol between 02/2011 and 01/2018. Of these 101 underwent PET-CT prior to and 80 during the course of treatment. All patients underwent Barcelona Clinic Liver Cancer (BCLC) and TNM staging based on results of contrast MRI or CT. They then underwent PET-CTs which were interpreted independently by a single Nuclear Radiologist for the purpose of this study. Patients were then restaged based on PET-CT findings. New lesions identified on PET-CT that were not seen on concurrent cross-sectional imaging were confirmed to be primary or metastatic HCC if proven by biopsy, demonstration of interval growth or LIRADS 5 criteria on a follow up contrast CT or MRI. It was determined if PET-CT findings change the management, from curative (surgery, ablation or transplantation) to palliative (Loco-regional or systemic). if new lesions were found on PET CT but patient remained a candidate for transplantation or surgical resection, it was documented that PET CT changed staging but not management.

Results: Adjuvant PET-CT changed BCLC staging in 13.3% and TNM staging in 19.3% of studies. PET-CT detected new liver lesions in 7.73% , extrahepatic metastasis in 13.26% and disease recurrence post-treatment in 18.75% . PET-CT was relaibly able to distinguish HCC recurrence near ablation margins from post-treatment changes earlier than cross sectional imaging. PET-CT was also able to reliably identify metastatic lymphadenopathy before cross sectional imaging. 24 patients were found to have extrahepatic metastasis based on PET CT. These included 19 with metastatic lymphadenopathy and 5 with other extrahepatic sites (lung, adrenal, kidney and vertebral body).PET-CT changed management in 16%. This included additional locoregional therapy in 10, change of focus of care to systemic therapy (Sorafenib) in 11 and to best supportive care in 5 patients.

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Conclusion: In a prospective study of North American patients with HCC, PET-CT helped to accurately change BCLC and TNM staging by identifying additional hepatic and extrahepatic lesions that resulted in the change in management of one in six patients.


O-20 HEPATOCELLULAR CARCINOMA INCIDENCE IS DECREASING AMONG YOUNG AND MIDDLE-AGED ADULTS IN THE UNITED STATES

Nicole E. Rich* 1, Adam C. Yopp2, Amit G. Singal1, 3, Caitlin C. Murphy1, 3

1Internal Medicine, 2Surgery, 3Population and Data Sciences, UT Southwestern, Dallas, United States

Introduction: Hepatocellular carcinoma (HCC) incidence rates have increased dramatically in the United States since the 1990s. While recent data suggests rates may have plateaued or begun to decline in other industrialized countries, it is unclear if and when a similar trend will be observed in the U.S. Our aim was to examine temporal trends in HCC incidence rates in the U.S. by age, sex, and race/ethnicity.

Methods: We calculated age-adjusted HCC incidence rates among adults ages 20-85+ years using data from the Surveillance, Epidemiology and End Results (SEER) program of cancer registries from 1992 to 2015. We estimated incidence rates by 10-year age group and used joinpoint regression to quantify the magnitude and direction of trends, overall and by sex and race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic and Asian/Pacific Islander).

Results: Overall, HCC incidence increased by 4.8% per year from 1992 to 2010 from 4.1 per 100,000 to 9.5 per 100,000, but then started to plateau (annual percent change [APC] -0.7, 95% CI -2.0, 0.7). With the exception of Asian/Pacific Islanders age 70-79 years, incidence rates continued to increase after 2010 among older (age ≥ 60 years) adults across all racial/ethnic groups. In contrast, incidence rates declined in younger and middle-aged adults beginning in the mid-2000s, in both men and women and persons of all races/ethnicities. Rates decreased by 6.2% per year in 40-49 year-olds and by 10.3% per year in 50-59 year-olds. Specifically, rates decreased from 3.5

per 100,0000 in 2006 to 2.0 per 100,000 in 2015 among the 40-49 year age group (incidence rate ratio [IRR] 0.57, 95% CI 0.45, 0.93). The 50-59 year age group experienced a similar decrease during this time period but of larger magnitude (from 15.1 to 12.7 per 100,000; IRR 0.84, 95% CI 0.76, 0.93). Annual decreases in incidence were larger among middle-aged blacks (17.2% decrease per year since 2012) compared to adults of the same age in other racial/ethnic groups. We noted a similar pattern by sex, whereby incidence rates decreased among both men and women in the 40-49 year age group starting in the mid-2000s. The rate of decline appeared similar in the two groups (men: APC -6.7, 95% CI -8.7, -4.6; women: APC -8.3, 95% CI -14.8, -1.3). Rates decreased by 10.7% per year among 50-59 year-old men starting in 2012. While there was not a statistically significant decline seen among women of this age group, the APC (-6.3, 95% CI -17.6, 6.5) estimate was consistent with declining rates from 2011 to 2015.

Conclusions: HCC incidence is declining among younger and middle-aged adults in the U.S. across both sexes and all racial/ethnic groups, in contrast to continued increases observed among adults over the age of 60 years. It is unclear whether current declines in incidence among younger and middle-aged adults will translate to lower disease burden of HCC in the future.


O-21 ASSOCIATIONS BETWEEN PREDIAGNOSTIC CONCENTRATIONS OF CIRCULATING SEX STEROID HORMONES AND PRIMARY LIVER CANCER AMONG WOMEN

Jessica L. Petrick* 1, Andrea R. Florio1, Xuehong Zhang2, Peter T. Campbell3, Katherine A. McGlynn1 and The Liver Cancer Pooling Project

1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 2Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, 3Epidemiology Research Program, American Cancer Society, Atlanta, United States

Introduction: Male predominance in primary liver cancer has been noted worldwide, with rates among males being 2-3-times higher than rates among females. However, these rates are largely determined by the dominant histologic type of liver cancer, hepatocellular carcinoma (HCC), which accounts for approximately 75% of cases. The second most common histologic type of primary liver cancer, intrahepatic cholangiocarcinoma (ICC), accounts for approximately 12% of cases and has a male:female ratio of 1.4. Established risk factors that vary in prevalence by sex, including hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol consumption, smoking, and obesity, cannot fully explain the male predominance of liver cancer. Sex steroid hormones have been proposed as an explanation of the sex differences. This hypothesis is supported by animal models, in which dosing with estrogen or castration of male rodents reduces liver cancer development in male rodents while dosing with testosterone or ovariectomizing female rodents increases liver cancer development. Several small studies have investigated circulating hormones, primarily testosterone or estradiol, in relation to HCC risk in men. These studies have reported that testosterone levels are higher in HCC cases compared to controls. Only one study, in Europe, has examined this hypothesis in the population that included women, concluding that sex hormone binding globulin (SHBG), but not testosterone, was associated with increased HCC risk. However, the study was not powered to examine the associations separately for men (n=85 cases) and women (n=40 cases). No prospective study has examined other sex steroid hormones and no study has examined the relationship between hormone levels and ICC. Thus, we investigated whether circulating sex steroid hormone concentrations were associated with risk of liver cancer.

Methods: In a pooled analysis of five prospective cohort studies: Nurses’ Health Study; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Women’s Health Initiative; Kaiser Multiphasic Health Checkup Study; and New York University Women’s Health Study, we used gas chromatography-mass spectrometry (GC-MS) and competitive electrochemiluminescence immunoassay to quantitate sex steroid hormones and sex hormone binding globulin, respectively, in serum from 191 post-menopausal female liver cancer cases (HCC n=83 and ICC n=56) and 426 controls, matched on study cohort, age, race/ethnicity, and date of baseline blood draw. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and liver cancer. As continuous hormone values were right skewed, values were log2 transformed, which corresponds to a doubling of circulating hormone per unit change.

Results: A doubling in the circulating concentration of 4-androstenedione was associated with a 50% decreased primary liver cancer risk (OR=0.50, 95% CI=0.30–0.82). For total liver cancer, there was no association with SHBG or other sex steroid hormones. However, a doubling in the circulating concentration of estradiol and free estradiol was associated with a 40% increased ICC risk (OR=1.40, 95% CI=1.05–1.89 and OR=1.43, 95% CI=1.04–1.95, respectively), but not HCC (OR=1.12, 95% CI=0.81–1.54 and OR=0.89, 95% CI=0.62–1.26, respectively).

Conclusions: This study provides the first evidence that higher levels of circulating 4-androstenedione in women may be associated with decreased liver cancer risk, while higher levels of circulating estradiol may be associated with increased ICC risk.


O-22 A GENE EXPRESSION SIGNATURE OF MICROVASCULAR INVASION IN HEPATOCELLULAR CARCINOMA IN FORMALIN FIXED-PARAFFIN EMBEDDED BIOPSIES

Aurélie Beaufrère* 1, 2, Stefano Caruso3, Gabrielle Couchy3, Jessica Zucman-Rossi3, Nicolas Poté2,4, Valérie Paradis1, 2

1Department of pathology, Hôpital Beaujon, APHP, 2INSERM UMR1149, INSERM, Clichy, 3INSERM UMR1162, INSERM, 4Department of pathology, Hôpital Bichat, APHP, Paris, France

Introduction: The presence of microvascular invasion (mVI) is a major risk factor of tumor recurrence after surgery and mortality in hepatocellular carcinoma (HCC). mVI is only detectable by microscopic examination of the surgical specimen (1). The absence of mVI status knowledge at the time of the diagnosis represents de facto a real lack for optimal management of patients with HCC eligible for curative treatments. Several gene expression signature associated with mVI has been already described in the literature. However, the reproducibility of this type of complex signature is often poor and none of them has been assessed on formalin fixed-paraffin embedded (FFPE) biopsies (2,3). The goal of our study was to define a gene expression signature associated with mVI in HCC, applicable on FFPE biopsies using a Nanostring approach.

Methods: A total of 108 FFPE archived HCC samples (1995-2017) were included, of which 69 preoperative biopsies were available with a paired surgical specimen. Various etiologies were represented including HCV, HBV, alcohol and NAFLD. All cases have been reviewed by two pathologists in order to assess the mVI status. Total FFPE mRNAs were extracted from samples. Gene expression was assessed using the nCounter® technology (Nanostring). Data obtained were normalized using VSN method. Genes differentially expressed between tumors with mVI and without mVI were selected based on adjusted p value<0.1 and log Fold change≥0.5. Prediction of mVI was realized thanks to k Nearest Neighbor analysis. In a training set of 69 HCC samples (39 surgical samples and 30 biopsies), we defined a gene expression signature associated with mVI based on expression of 200 genes. This mVI signature was validated in an independent set of 39 biopsies.

Results: Training and validation sets were similar for all clinico-pathological criteria particularly on mVI (52% vs 67%, p=0.14), tumor differentiation (poor differentiation: 9% vs 10%, p=0.79), tumor size (mean size: 6,4 cm vs 6,6 cm, p=0.88) and fibrosis in the non-tumoral liver (cirrhosis : 36% vs 36%, p=0.97). A 10 gene-signature (PIR, BUB1, TAF9, NRCAM, UGT2B7, NARF, TM6SF2, FGFR4, PGLS, PGC), strongly associated with mVI, was obtained in the training set. In the validation set, this signature predicted mVI with an accuracy of 82%. The sensitivity and the specificity were respectively of 0.92 and 0.62 (figure). Of note, there was an excellent correlation of gene expression between biopsies and corresponding surgical samples (14 paired specimens, mean correlation index = 0.92 [0.87-0.95]).

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Conclusion: This study provides a relevant surrogate signature of mVI in HCC, that may be applied in clinical practice on routine tumor biopsy, and then integrated into the therapeutic strategy of patients.

References: 1. Sumie S, Kuromatsu R, Okuda K, Ando E, Takata A, Fukushima N, et al. Microvascular invasion in

patients with hepatocellular carcinoma and its predictable clinicopathological factors. Ann Surg Oncol. 2008;15(5):1375–82.

2. Tanaka S, Mogushi K, Yasen M, Noguchi N, Kudo A, Nakamura N, et al. Gene-expression phenotypes for vascular invasiveness of hepatocellular carcinomas. Surgery. 2010 ;147(3):405–14.

3. Mínguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J Hepatol. 2011 ;55(6):1325–31.


O-33 VETC (VESSELS ENCAPSULATING TUMOR CLUSTERS) IS A POWERFUL PREDICTOR OF AGGRESSIVE HEPATOCELLULAR CARCINOMA.

Salvatore L. Renne1, Ha Y. Woo 2, Sarah Allegra1, Noemi Rudini1, Hirohisa Yano3, Matteo Donadon4, Luca Viganò4, Jun Akiba3, Hye S. Lee2, Young N. Park5, Massimo Roncalli4, 6, Luca Di Tommaso* 4, 6

1Anatomic Pathology, Humanitas Clinical and Research Center, Rozzano (MI), Italy, 2Yonsei University College of Medicine, Seoul, Korea, Republic Of, 3Kurume University School of Medicine, Pathology, Kurume, Japan, 4Humanitas Clinical and Research Center, Rozzano (MI), Italy, 5Yonsei University, Seoul, Korea, Republic Of, 6Humanitas University, Pieve Emanuele (MI), Italy

Introduction: We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the VETC (vessels that encapsulate tumor clusters), previously linked to HCC metastatic dissemination.

Methods: VETC was assessed in a large multi-institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as equal to or greater than 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small sized tissues of tissue microarray (Panel A).

Results: VETC-HCCs represented the 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated to several clinical and pathological features such as: high AFP level,tumor size >5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion (Panel B). VETC was associated with early recurrence [HR: 1.52 (1.06-2.19), p= 0.023], DFS [HR: 1.66 (1.21-2.27), p= 0.002] and OS [HR: 2.26 (1.37-3.72), p= 0.001] at multivariable analysis (Panel C). VETC impacted on survival in HCC patients stratified for etiology (HCV/HBV), vascular invasion and specific molecular phenotypes (ß-catenin/GS+). This distinct vascular pattern was enriched in the recently reported macro-trabecular massive HCC subtype, which was seen in 7.8% (42/541) and associated with high AFP levels, poor differentiation.

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Conclusion: n conclusion, the VETC pattern revealed to be easily detectable in a consistent fraction of HCC and to be a powerful pathological finding impacting on survival. This study also suggests that vascular heterogeneity could be helpful, in the future, for an individual treatment of HCC.

References: Aguirre-Ghiso JA. Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007;7:834-846.Calderaro J, Couchy G, Imbeaud S, Amaddeo G, Letouze E, Blanc JF, Laurent C, et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J Hepatol 2017;67:727-738.Fang JH, Zhou HC, Zhang C, Shang LR, Zhang L, Xu J, Zheng L, et al. A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial-mesenchymal transition-independent manner. Hepatology 2015;62:452-465.Fang JH, Xu L, Shang LR, Pan CZ, Ding J, Tang YQ, et al. Vessels that encapsulate tumor clusters (VETC) pattern is a predictor of sorafenib benefit in patients with hepatocellular carcinoma. Hepatology. 2018 [Epub ahead of print]Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, Villanueva A, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69(18):7385-92.

Oral Communications

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 2 3

Oral Communications

I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S2 2

Sunday, 22 September 2019Saturday, 21 September 2019

Naumov GN, Akslen LA, Folkman J. Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell Cycle 2006;5:1779-1787.Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D, Rautou PE. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol 2017;66:212-227.Qu B, Liu BR, DU YJ, Chen J, Cheng YQ, Xu W, Wang XH. Wnt/ß-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol Lett. 2014;7(4):1175-1178.Roncalli M, Roz E, Coggi G, Di Rocco MG, Bossi P, Minola E, Gambacorta M, et al. The vascular profile of regenerative and dysplastic nodules of the cirrhotic liver: implications for diagnosis and classification. Hepatology 1999;30:1174-1178.Rudini N, Novello C, Destro A, Riboldi E, Donadon M, Vigano L, Morenghi E, et al. Phenotypic and molecular changes in nodule-in-nodule hepatocellular carcinoma with pathogenetic implications. Histopathology 2018. 2018;73(4):601-611.Sciarra A, Di Tommaso L, Nakano M, Destro A, Torzilli G, Donadon M, Maggioni M, et al. Morphophenotypic changes in human multistep hepatocarcinogenesis with translational implications. J Hepatol 2016;64:87-93.Villa E, Critelli R, Lei B, Marzocchi G, Camma C, Giannelli G, Pontisso P, et al. Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study. Gut 2015;65:861-869.Ziol M, Pote N, Amaddeo G, Laurent A, Nault JC, Oberti F, Costentin C, et al. Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance. Hepatology 2018;68:103-112.


General Session 4: Novel Targets and Prognostics Markers

O-23 FIRST-IN-HUMAN, FIRST-IN-CLASS PHASE I TRIAL OF MTL-CEBPA, A RNA OLIGONUCLEOTIDE TARGETING THE TRANSCRIPTION FACTOR C/EBP-ALPHA, GIVEN AS A SINGLE AGENT OR IN COMBINATION WITH SORAFENIB, IN PATIENTS WITH ADVANCED HEPATOCELLULAR CANCER (HCC)

Debashis Sarker* 1, Elizabeth R. Plummer2, Bristi Basu3, Tim Meyer4, Kai-Wen Huang5, Jeffry Evans6, Mikael Sodergren7, Duncan Spalding7, Yuk-Ting Ma8, Daniel Palmer9, Cheng Chee10, Nagy Habib7

1King's College London, London, 2University of Newcastle, Newcastle, 3Addenbrooke's Hospital, Cambridge, 4University College London, London, United Kingdom, 5National Taiwan University Hospital, Taipei, Taiwan, Province of China, 6Beatson West of Scotland Cancer Centre, Glasgow, 7Imperial College, London, 8University of Birmingham, Birmingham, 9University of Liverpool, Liverpool, United Kingdom, 10National University Cancer Institute, Singapore, Singapore

Introduction: Transcription factor C/EBP-a (CCAAT/enhancer-binding protein alpha) is a leucine zipper protein which acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes including cell cycle control, proliferation and angiogenesis. We assessed the safety of MTL-CEBPA, a first-in-class small activating RNA (saRNA) oligonucleotide which up-regulates the C/EBP-a gene, in patients with advanced HCC.

Methods: Transcription factor C/EBP-a (CCAAT/enhancer-binding protein alpha) is a leucine zipper protein which acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes including cell cycle control, proliferation and angiogenesis. We assessed the safety of MTL-CEBPA, a first-in-class small activating RNA (saRNA) oligonucleotide which up-regulates the C/EBP-a gene, in patients with advanced HCC.

Results: 38 participants (31 HCC, 4 colorectal, 2 fibrolamellar, 1 ampullary) have been treated across 6 dose levels (28-160 mg/m2) and 3 dosing schedules: 29M/9F, median age 66 years (range 27 - 80), ECOG PS 0/1: 16/22.34 patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose and no maximum dose was reached across the 3 schedules evaluated. Grade 3 treatment related adverse events occurred in 9 (24%) patients. Treatment related serious adverse events were reported in 4 (11%) patients. Treatment-related adverse events (all grades) that occurred in more than 10% of patients were fatigue (23.7%), thrombocytopaenia (13.2%), anaemia (13.2%), elevated AST (13.2%), elevated ALP (10.5%), hypoalbuminaemia (10.5%), increased ALT (10.5%) and increased bilirubin (10.5%). Serum PK analysis shows a terminal half-life of > 24 hrs, with supra-proportional increase in Cmax and AUC. C/EBP-a mRNA levels increased by 1.5-fold consistently across all cohorts treated, providing evidence of target engagement. MTL-CEBPA also caused significant increase in WBC consistent with C/EBP-a dependent granulopoiesis, and decreased expression of adenosine, PD-1 and CXCR4 mRNA. In 24 HCC patients evaluable for efficacy, partial response (PR) was achieved in 1 (4%) and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven HCC patients were treated with tyrosine kinase inhibitors (TKI); 3/7 had complete response, 1/7 had PR and 2/7 SD by RECIST 1.1.

Conclusions: MTL-CEBPA is a first-in-class saRNA with a good safety profile and demonstrates promising clinical activity in HCC. These encouraging phase 1 data validate targeting of C/EBP-a and have prompted MTL-CEBPA + sorafenib combination studies in patients both naive and resistant to sorafenib; updated results will be presented at the meeting.

Disclosure of Interest: D. Sarker Conflict with: Honoraria - MiNA Therapeutics, E. Plummer: None Declared, B. Basu: None Declared, T. Meyer: None Declared, K.-W. Huang: None Declared, J. Evans: None Declared, M. Sodergren: None Declared, D. Spalding: None Declared, Y.-T. Ma: None Declared, D. Palmer: None Declared, C. Chee: None Declared, N. Habib Conflict with: Stocks - MiNA Therapeutics

O-24 INTEGRATED ANALYSIS OF THE CERNA NETWORK REVEALING A 4-GENE-BASED PROGNOSTIC SIGNATURE ASSOCIATED WITH OVERALL SURVIVAL IN HEPATOCELLULAR CARCINOMA

Yongcong Yan* 1, Kai Mao1, Qianlei Zhou1, Bingchao Shi1, Jie Wang1, Zhiyu Xiao1

1Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

Introduction: Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC. However, reliable molecular signatures predicting overall survival (OS) lacks of systematic research and validation. Our study was designed to investigate prognostic biomarkers that could function as auxiliary clinical indicators of HCC on integrated global transcriptome analysis.

Methods: A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA (ceRNA) network from The Cancer Genome Atlas (TCGA) database. The prognostic signature was established with the least absolute shrinkage and selection operator (LASSO) algorithm in the TCGA training set. Multivariate Cox regression analysis and subgroup analysis was used to screen for independent prognostic factors for HCC OS. A time-dependent receiver operating characteristic curve analysis was performed to compare predictive value of the prognostic signature. The robustness of the prognostic signature was validated in the internal validation set and two external validation cohorts.

Results: There were 39 differentially expressed mRNAs (DEmRNAs), 83 differentially expressed lncRNAs and 20 differentially expressed miRNAs involved in the ceRNA network. Twenty DEmRNAs were found to be significantly associated with OS. We identified a 4-gene signature (PBK, CBX2, CLSPN and CPEB3) using LASSO penalized regression in the training set. Patients in the high-risk group exhibited worse survival than those in the low-risk group (P = 0.0004), and median OS was significantly shorter in the high-risk group than in the low-risk group (1005 days versus 2456 days), and death was also more likely in the high-risk group (HR = 2.444, P < 0.001). The 4-gene signature was an independent prognostic factor in multivariate Cox regression and subgroup analysis, particularly for patients with serum AFP ≥ 20 ng/ml. The results were validated in internal validation set (P = 0.0057) and two external validation cohorts (HR = 1.305, P = 0.29 and HR = 2.626, P = 0.04). The signature (AUCs of one, two, three years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy in the complete TCGA cohort.

Image:

Conclusion: We constructed a novel lncRNA-miRNA-mRNA ceRNA network for HCC based on genome-wide analysis. Then we identified a 4-gene-based signature and effectively predicted OS in HCC patients based on the ceRNA network and survival analysis. Moreover, we validated the signature in the internal set and two external validation cohorts. Hence, we identified and validated a new candidate therapeutic decision marker that yields great promise in the prediction of HCC OS in the future.


O-25 DEVELOPMENT OF EFFICIENT COMBINATION IMMUNOTHERAPY FOR PRIMARY AND METASTATIC LIVER CANCER BY BOOSTING INNATE AND ADAPTIVE IMMUNITY SIMULTANEOUSLY

Gen-Sheng Feng* 1, Jin Lee1, Liang Wen1, Bing Xin1

1Pathology, University of California, San Diego, La Jolla, United States

Introduction: Immunotherapy by blocking inhibitory pathways in T lymphocytes, such as the PD-L1/PD-1 axis, is being widely tested in various solid tumors. Notably, this emerging therapeutic approach is already in clinical trials for advanced HCC, although the outcomes can be compounded by the unique immunotolerant microenvironment in the liver. Many combinations of immune checkpoint inhibitors or with other drugs are ongoing in clinical trials, without support by preclinical data. In previous experiments, we identified unexpectedly a robust liver tumor-preventive effect of a synthetic double-stranded RNA (dsRNA) polyinosinic-polycytidylic acid (polyIC) in mice. In this study, we tested a combination of polyIC with anti-PD-L1 Ab in treatment of HCC in mouse models.

Methods: In this study, we have used hepatocyte-specific gene deletion mouse lines, mouse HCC models driven by hydrodynamic tail vein injection (HTVi) of oncogenes, such as NRas, c-Myc, c-MET and b-catenin, and metastatic liver tumor models by splenic injection of tumor cells. polyIC, anti-

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PD-L1 or anti-CTLA4 antibodies were injected intraperitoneally into tumor-bearing mice. Tumor burdens were evaluated by the ratios of liver/body weights, numbers and maximal sizes of tumor nodules. Liver tumors and non-tumor liver tissues were dissected out for molecular and cellular analyses.

Results: polyIC given at the pre-cancer stage effectively prevented liver tumorigenesis by activation of NK cells and macrophages, with no inhibition on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced PD-L1 expression in liver sinusoid endothelial cells, which prompted us to test a combination treatment of polyIC and PD-L1 antibody. Although injecting PD-L1 antibody alone did not show significant therapeutic effect, polyIC sensitized hepatic response to PD-L1 blockade, resulting in sustained accumulation of active CD8 cytotoxic T cells, robust tumor suppression and survival advantage. Similar results have been obtained for other combinations. Therefore, a powerful combinatorial immunotherapy may shift the paradigm in liver cancer treatment by boosting multiple innate and adaptive immune functions simultaneously.

Conclusions: Conclusion. It is feasible to develop efficacious combination immunotherapies for primary and metastatic liver tumors by coordinated activation of innate and adaptive immunity.

References: Jin L, R Liao, G Wang, BH Yang, X Luo, NM Varki, SJ Qiu, B Ren, W Fu, and GS Feng. 2017. Preventive inhibition of liver tumorigenesis by systematic modulation of innate immunity. Cell Reports 21, 1870-1882, 2017. PMID 29141219, PMCIDWen L, B Xin, P Wu, CH Lin, C Peng, G Wang, J Lee, LF Lu, and GS Feng. 2019. An efficient combination immunotherapy for primary liver cancer by harmonized activation of innate and adaptive immunity. Hepatology Accepted.


O-26 AU-409: PRECLINICAL ACTIVITY OF A NOVEL ORAL DNA BINDING AGENT FOR HEPATOCELLULAR CARCINOMA

Anna Nowak1, Gregory R. Luedtke1, Rajaa Sukhun1, Ananya Paul2, James Hart1, Zhewei Shen1, Sidney Elmer1, Brent Louie1, W. David Wilson2, Pek Lum1, Andrew A. Protter* 1

1Auransa Inc., Palo Alto, 2Georgia State University, Atlanta, United States

Introduction: Limited effectiveness of current treatments for HCC highlights the need for therapeutics with distinct mechanisms of action that may be more effective. Gene expression profiles of HCC tumors suggested agents that bind to DNA would be effective. A unique small molecule AU-409 was developed to combine three features: DNA binding, antitumor activity in cell culture and in vivo and achieves pharmacologically significant liver exposure. The pharmacology profile of AU409 in vitro, in cell culture and in vivo is described.

Methods: DNA binding activity was measured by thermal denaturation using defined hairpin oligonucleotides. Tm measurements were made on with a Cary-300Bio spectrophotometer at 260nm wavelength in 1.0 cm reduced volume quartz cuvettes. A Tris-NaCl buffer at pH 7.4 was used. In vitro, viability was measured by CellTiter Glo (Promega) with a panel of HCC cell lines. In vivo, antitumor activity was measured in an liver orthotopic model with Hep3B2.1-7-Luc cells (ChemPartner, Shanghai, China) which express luciferase; 1.25x10^6 cells in matrigel were injected into the left lobe of the liver of female BAL/c nude mice. 13 days after tumor cell implantation, bioluminescence was measured using Xenogen IVIS imaging following luciferase administration and animals were randomized to each treatment group. Body weight and bioluminescence was measured every 3 or 4 days until day 28. Vehicle (saline) or AU-409 was administered by oral gavage at doses of 10 and 20 mg/kg twice a week for the first week and then once a day until the end of the study. On day 28, blood was processed for serum markers of liver damage and liver tissue processed to determine exposure of drug using MS.

Total Flux

Day 11

Total Flux

Day 281

Body weight (gr)1

ALT (U/L)2

AST (U/L)2

ALP (U/L)2

AU-409 liver

exposure (uM) 2,3

Vehicle 23 ± 5 1223 ± 350

21.17 ± 0.66

91 ±87

241 ± 120

87 ± 33

NT

AU-409 10mg/kg

23 ± 5 465 ± 129

22.16 ± 0.44

49 ±30

206 ± 115

84 ± 18

0.8 ± 0.3

AU-409 20mg/kg

23 ± 5 307 ± 92*

22.80 ±0.15**

45 ±16

150 ± 22

67 ± 9

2.3 ± 0.7

Values are mean ± standard error of the mean1 or mean ± standard deviation2

* p<0.05 by Kruskal-Wallis Test (Nonparametric ANOVA);** p<0.05 by Two-way ANOVA with Bonferoni post test NT not tested3 AU-409 concentration in the liver was derived from micromoles of drug/gram of tissue

Results: AU-409 was found to increase the thermal denaturation temperature of synthetic deoxyoligonucleotides, consistent with high affinity binding to DNA (estimated Kd 0.8 uM). In cell culture AU-409 inhibited viability of the liver HCC cell line Hep3B in a concentration-dependent manner with an IC50 of 0.18 uM. The viability of other liver cancer cell lines was also inhibited with IC50 values ranging from 0.31 uM to 9.65 uM. In vivo in an orthotopic HCC model oral AU-409 treatment was associated with a dose-dependent, statistically significant decrease in total flux, a marker for tumor burden 63% and 76% inhibition in the 10mg/kg and 20mg/kg groups, respectively. Treatment was well tolerated; there were no clinical observations associated with treatment and no animals died prematurely. Treatment with AU-409 was associated with a statistically significant increase in body weight and a decrease in liver enzymes associated with liver toxicity. Drug concentrations in the tumor-containing left lobe were dose dependent and consistent with concentrations required for anti-tumor effects in cell culture.

Conclusions: AU-409 is a unique orally active small molecule with efficacy in cell culture and in vivo models of liver cancer and appears to be well tolerated at pharmacological doses.

Disclosure of Interest: A. Nowak Conflict with: Stocks - Auransa Inc., G. Luedtke Conflict with: Stocks - Auransa Inc., R. Sukhun Conflict with: Stocks - Auransa Inc., A. Paul: None Declared, J. Hart Conflict with: Stocks - Auransa Inc., Z. Shen Conflict with: Stocks - Auransa Inc., S. Elmer Conflict with: Stocks - Auransa Inc., B. Louie Conflict with: Stocks - Auransa Inc., W. D. Wilson: None Declared, P. Lum Conflict with: Stocks - Auransa Inc., A. Protter Conflict with: Stocks - Auransa Inc.

O-27 THE SAFETY AND EFFICACY OF NAMODENOSON IN THE SECOND LINE TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA (HCC) PATIENTS WITH UNDERLYING CHILD-PUGH B (CPB) LIVER CIRRHOSIS: A PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED

Salomon Stemmer 1, Nebojsa Manojlovic2, Mihai V. Marinca3, Petar Petrov4, Nelly Cherciu5, Doina L. Groza6, Ioana A. Puscas7, Tudor-Eliade Ciuleanu8, Muhammad S. Beg9, William Purcell10, Adina E. Croitoru11, Rumyana N. Ilieva12, Sladjana Natoševic13, Amedeia L. Nita14, Zivit Harpaz15, Motti Farbstein15, Michael Silverman16, Pnina Fishman* 15, Josep Llovet17

1Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Israel, 2Military Medical Academy, Belgrade, Serbia, 3Institutul Regional de Oncologie Iasi – Sectia Oncologie Medical, Iasi, Romania, 4Complex Oncology Center–Plovdiv, Plovdiv, Bulgaria, 5Clinica Onco-Life, Craiova, 6Spitalul Judetean de Urgenta Sf. Pantelimon, Focsani, 7S.C. Pelican Impex S.R.L. - Sectia Oncologie Medicala, Oradea, 8Institute of Oncology/University of Medicine and Pharmacy, Cluj-Napoca, Romania, 9Simmons Cancer Center, University of Texas Southwestern Medical Center, 2201 Inwood Road, NB2.418, Dallas, 10University of Colorado Comprehensive Cancer Center, Aurora, United States, 11Fundeni Clinical Hospital, Bucharest, Romania, 12Multiprofile Hospital for Active Treatment Central Onco Hospital OOD Department of Medical Oncology, Plovdiv, Bulgaria, 13Zdravstveni Centar Kladovo Služba Onkologije, Kladovo, Serbia; County Hospital Pratova, Ploiesti, Romania, 14Sveta Marina University Hospital, Varna, Bulgaria, 15Can Fite BioPharma, Petach Tikva, Israel, 16Biostrategic Consulting Ltd, Boston, 17Mount Sinai School of Medicine, New York University, New York, United States

Introduction: Namodenoson, a highly selective Gi protein associated A3 adenosine receptor (A3AR) agonist, demonstrated anti-tumor effect in HCC experimental models. In a Phase I/II clinical study including Child-Pugh B class (CPB) patients, (NCT00790218) an improvement in median overall survival (OS) of 8.1 months took place. We here present the results of a double blind, randomized phase 2, placebo-controlled study (NCT02128958), assessing the efficacy and safety of namodenoson as a second-line therapy of patients with advanced HCC and CPB class.

Methods: Patients were randomized 2:1 to BID namodenoson (25 mg; n = 50) or placebo (n=28) in 15 centers globally. Primary endpoint was OS and secondary endpoints were safety, progression-free survival (PFS), objective response (OR) and disease control rate (DCR). Assessment of OS and PFS was done by log rank test at a one final analysis when 75 deaths had occurred. Response was assessed by RECIST (local investigator) and mRECIST (central review).

Results: The study did not meet the primary end point, with median OS 4.1 months (mo) for namodenoson vs. 4.3 mo for placebo (HR: 0.82). Pre-planned subgroup analysis of Child-Pugh 7 patients (n=56; namodenoson=34, placebo=21) showed median survival 6.8 mo vs 4.3 mo [HR: 0.77 (95% CI 0.49-1.40)]. Similarly, for this subgroup of patients PFS was 3.5 mo vs 1.9 (HR=0.87). In terms of objective response, 3/34 patients assessed achieved OR (9%) with namodenoson vs 0% for placebo. 32.0% of patients treated with Namodenoson completed at least 12 months of treatment vs 14.3% who were treated with placebo (p=0.058). Namodenoson was generally well-tolerated, with no treated patients being withdrawn for toxicity and no cases of treatment-related deaths. The most common adverse event (>10%) were anemia, abdominal pain, ascites, nausea, asthenia, fatigue, peripheral edema, and increased AST. Treatment-related grade 3 toxicities accounted for anemia, fatigue and hyponatremia.

Conclusions: Namodenoson has demonstrated favorable clinical safety profile in patients with advanced HCC and severe liver dysfunction. Although the primary end-point was not met, the subgroup analysis showed a positive signal of efficacy for OS in patients with Child-Pugh 7. Both safety and efficacy results warrant testing this drug in a phase III trial.

Disclosure of Interest: S. Stemmer: None Declared, N. Manojlovic: None Declared, M. Marinca: None Declared, P. Petrov: None Declared, N. Cherciu: None Declared, D. Groza: None Declared, I. Puscas: None Declared, T.-E. Ciuleanu: None Declared, M. Beg: None Declared, W. Purcell: None Declared, A. Croitoru: None Declared, R. Ilieva: None Declared, S. Natoševi：: None Declared, A. Nita: None Declared, Z. Harpaz Conflict with: Stocks - Stock in the company, M. Farbstein Conflict with: Stocks - Stock in the company, M. Silverman Conflict with: Stocks - Stock in the company, P. Fishman: None Declared, J. Llovet Conflict with: Consulting - Consulting with the company

O-34 DEVELOPMENT OF NOVEL CAR-T CELLS FOR IMMUNOTHERAPY OF HEPATOCELLULAR CARCINOMA

Yukai He* 1

1Georgia Cancer Center, Augusta University, Augusta, United States

Introduction: HCC is one of the deadly diseases due to the lack of effective therapies. In this study, we first developed human glypican 3 (hGPC3)-specific novel monoclonal antibodies (mAbs) and created chimeric antigen receptor (CAR) T cells (CAR-Ts) and tested their antitumor effects.

Methods: mAbs against human glypican 3, one of the HCC associated molecules were developed in mice and CAR-Ts were created. Human HCC xenografts were used to evaluate the antitumor efficacy of CAR-Ts

Results: The hGPC3-specific mAbs were obtained by immunizing BalB/C mice with hGPC3 protein. Out of 22 mAbs that bound to soluble hGPC3 by ELISA assay, 14 also bound the hGPC3 on hepatocellular carcinoma (HCC) tumor cell surface. Five of the mAbs were further characterized by immunohistochemical staining (IHC). Three of them could specifically stain human HCC tumor tissues but not the adjacent normal tissues. We obtained the cDNA sequences of these 3 antibodies and created recombinant antibodies. All 3 recombinant mAbs have affinity for hGPC3. The 6G11 mAb recognized and bound to the 25-39aa of hGPC3, whereas the 8F8 mAb bound the epitope 463-500aa of hGPC3. Next, we created 3 CAR-T cells. We found that all three CAR-Ts remain their recognition of hGPC3 and could be activated by HepG2 tumor cells. The in vitro study also showed that all 3 CAR-Ts are capable of killing HepG2 tumor cells with the 8F8 CARTs having the most potent activity. Our data also showed that soluble hGPC3 does not activate CAR-Ts. Conversely, the recognition of HepG2 tumor cells by CAR-Ts was not blocked by soluble hGPC3. Adoptive transfer of CART regress HepG2 tumor xenografts in NSG mice.

Conclusions: We conclude that we have developed a set of novel HCC hGPC3-specific mAbs and CAR-Ts, providing additional tools for HCC immunotherapy.

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induced dysbiosis and inflammation support the development and recruitment of IgA+IL10+PD-L1+ plasmocytes in NASH-afflicted human and mouse livers. These plasmocytes cause localized immunosuppression that fosters HCC development by attenuating activation of a protective, tumor-directed, cytotoxic T cell (CTL) response. Liver fibrosis is another outcome of chronic hepatitis, but its exact pro-tumorigenic function remains obscure. Moreover, the contribution of adaptive immunity to fibrosis and further HCC development has also been elusive.

Methods: MUP-uPA and STAM NASH/ASH-induced HCC models (alcohol and HFD feeding) were crossed to IgA, B cell, CD8 and CD4 deficient mice to analyze the effect of adaptive immune cells in fibrosis and HCC development, as described previously (Shalapour et al, Nature, 2017). We also conducted flow cytometry, RNA-seq and single cell RNA-seq of immune cells and HSC to understand the underlying mechanism of the immunogenic activity of HFD, alcohol, and anti-PD-(L1) therapy. Additionally, IHC, Sirius Red and Oil Red Oil staining were used to characterize NASH/ASH status.

Results: Here we show that consistent with the anti-fibrogenic effect of IFNY, CD8+T cell ablation enhanced liver fibrosis in MUP-uPA and STAM NASH-induced HCC models. Similar results were found in the MCD-fed NASH mouse model but not in CCl4-treated animals, whose collagen deposition pattern was different, suggesting that stromal cell types differ in their response to IFNY. Although HFD supports CD8+T cell infiltration in the liver, alcohol suppresses it. Analysis of the small fraction of HCC-bearing mice that did not respond to anti-PD-L1 treatment revealed immune excluded tumors that were encapsulated by stromal cells. Moreover, detailed analysis of stromal cells confirmed that they express distinct hepatic stellate cell (HSC) markers. Combination therapy with compounds that inhibit the induction of fibrosis restored the response to immune checkpoint blockade.

Conclusions: Our results indicate that the non-responsiveness to anti-PD-L1 treatment correlates with a fibrotic tumor stroma due to CTL exclusion in HCC. Our work provides new insights on how HFD and alcohol regulate adaptive immune cells and thereby affect fibrosis and the response to immunotherapy. Specifically, consumption of alcohol or HFD regulated the response to anti-PD(L)1 therapy in a different manner, namely due to their distinct ability to regulate CTL function and induction of dysbiosis. Combination therapy with compounds that inhibit the induction of fibrosis can be considered with anti-PD(L)1 therapy in HCC.

References: Shalapour S, Lin X, Bastian IN, Brain J, Burt AD, Aksenov AA, Vrbanac AF, Li W, Perkins A, Matsutani T, Zhong Z, Dhar D, Navas-Molina JA, Xu J, Loomba R, Downes M, Yu RT, Evans RM, Dorrestein PC, Knight R, Benner C, Anstee QM, Karin M*. Inflammation-induced IgA+cells dismantle anti-liver cancer immunity. Nature. 2017 Nov 16;551(7680):340-345.


P-003 THERAPEUTIC MODULATION OF THE DUCTULAR REACTION AS A CHEMOPREVENTATIVE STRATEGY AGAINST LIVER CANCER

Adiba I. Azad* 1, Steve Bronk1, Anuradha Krishnan1, Tomohiro Katsumi1, Maria E Guicciardi 1, Gregory Gores1

1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States

Introduction: Chronic inflammation and fibrosis mediate development of tumors in the liver. Ductular reaction is a complex response to liver injury characterized by aberrant proliferation of bile ducts consisting of reactive cholangiocytes, and is associated with progression of fibrosis and liver carcinogenesis1,2. There is a need for chemoprevention in chronic liver disease. Here, we demonstrate that ductular reactive cells are primed for cell death and therefore, these cells can be therapeutically manipulated to ameliorate liver injury and potentially reduce the risk of development of liver carcinogenesis.

Methods: We employed ATP binding cassette B4 (Abcb4) also known as multidrug resistance 2 (Mdr2) knock out mice which we named MKO, as a model of chronic cholestatic injury. Previously, we have demonstrated that double mutant (DKO) mice generated by knocking out Mdr2 and the receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) genes displayed a more severe degree of liver injury by increased ductular reaction and recruitment of inflammatory cells and more extensive fibrosis (unpublished results), when compared to MKO mice. We performed in vitro cell death experiments and single cell transcriptomics on cholangiocyte derived organoids from the aforementioned mouse models. Finally, we conducted in vivo treatment studies on DKO mice to determine treatment efficacy of MCL-1 inhibition on ductular reaction.

Results: Single cell transcriptomics on cholangiocyte derived organoids from wild type (WT) and DKO mice demonstrated gene expression of cytokeratin 7, cytokeratin 19, Epcam and Sox9, which are markers associated with cholangiocyte activation. Cluster analysis revealed unique gene expression profiles in subpopulations of cholangiocytes in the two samples. Protein expression of cholangiocyte markers on organoids was confirmed by immunofluorescence studies. To circumvent the issue of hepatotoxicity associated with exogenous administration of TRAIL, we utilized the BH3 mimetic S63845, which specifically inhibits the pro-survival myeloid cell leukemia 1(MCL-1 ) protein to induce apoptosis. Cell viability following treatment with S63845 was significantly more diminished in DKO organoids (23%) than in MKO (42%) and WT (62%) organoids, P < 0.05. 603B cholangiocytes treated with the ligand TNF related weak inducer of apoptosis (TWEAK) which is a

P-001 MECHANISMS OF IMMUNE-MEDIATED ANTITUMOR ACTIVITY OF COMBINED LENVATINIB AND PD-1 BLOCKADE IN MURINE MODELS OF HEPATOCELLULAR CARCINOMA

Jing H. Deng* 1 on behalf of Conceptualization;Data analysis and interpretation;Writing-original draft, Ning Lyu1, 2 on behalf of Data analysis and interpretation;Writing-original draft, Ming Zhao1, 2 on behalf of Conceptualization; Data analysis and interpretation;Writing-review and editing

1Minimally Invasive Interventional Division, Sun Yat Sen University Cancer Center, 2State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guang Zhou, China

Introduction: Combined immune checkpoint/lenvatinib has shown promising effectiveness in the treatment of hepatocellular carcinoma (HCC)[1]. Preclinical studies suggest lenvatinib has immunomodulatory activity that synergistically enhances anti-tumor activity when used in combination with anti-PD-1 antibodies[2] [3] [4]. However, the specific regulation of this treatment strategy on effector T cells is not well understood, and the immunomodulatory mechanisms of other immune cells in the microenvironment and their interaction with effector T cells are unclear. Therefore, we investigated the immunomodulatory action of lenvatinib in vitro and its anti-tumor effect in vivo in several murine models of HCC, with or without anti-PD-1 antibodies, to explore the potential synergic mechanisms of combination treatment.

Methods: We investigated the anti-tumor activity and mechanisms of combined therapy in vitro, ex vivo and in murine H22, Hepa1-6 competent and H22 nude models of HCC. We used multi-color flow, solid-phase protein microarray analysis and RNA-seq to analyze the state of immune activation and the mechanisms of combined therapy.

Results: Our results show that combined treatment with lenvatinib and anti-PD-1 antibodies significantly inhibited tumor growth in H22 and Hepa1-6 murine models of HCC. Combined treatment also led to the development of long-term immune memory, with unsuccessful re-inoculation of tumor cells in mice that experienced a complete response to treatment. Our ex vivo and in vitro results suggest that combined therapy leads to synergistic anti-tumor activity through three mechanisms. Firstly, combined treatment synergistically enhances the antiangiogenic action of lenvatinib, which may partially contribute to anti-tumor effect. Secondly, combined therapy mainly depends on modulating the function of effector T cells not their infiltration, leading to decreased expression of PD-1 on CD4+ and CD8+ T cells, and increasing T cell cytotoxicity. Finally, lenvatinib and the combined therapy extensively modulates the tumor microenvironment (TME) by regulating chemokines secretion, and anti-PD-1 therapy augments lenvatinib’s efficacy by decreasing the infiltration of neutrophils through inhibiting CXCL2 expression in TME.

Conclusions: Combined therapy with lenvatinib and anti-PD-1 antibodies exerts anti-tumor activity by synergistically modulating effector T cells function in TME and through mutual regulation of tumor vessel normalization.

References: 1. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, et al. Lenvatinib versus sorafenib in

first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-1173.

2. Kato Y. Abstract 4614: Upregulation of memory T cell population and enhancement of Th1 response by lenvatinib potentiate antitumor activity of PD-1 signaling blockade. Cancer Research 2017;77:4614-4614.

3. Kimura T, Kato Y, Ozawa Y, Kodama K, Ito J, Ichikawa K, Yamada K, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. Cancer Sci 2018;109:3993-4002.

4. Kato Y, Tabata K, Hori Y, Tachino S, Okamoto K, Matsui J. Abstract A92: Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors. Molecular Cancer Therapeutics 2015;14:A92-A92.


P-002 ADAPTIVE IMMUNITY REGULATES THE DEVELOPMENT OF NASH/ASH-RELATED FIBROSIS, THEREBY INFLUENCING THE PROGRESSION OF HCC AND ITS RESPONSE TO IMMUNOTHERAPY

Ingmar N. Bastian* 1, 2, Xue-jia Lin1, 2, Jian Y. Huang1, 2, Cristian Vera-Torres1, 2, Michael Karin1, 2, Shabnam Shalapour1, 2

1Medicine, 2Pharmacology, University of California, San Diego, La Jolla, United States

Introduction: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and a leading cause of cancer-related deaths. HCC is initiated by chronic liver inflammation driven by hepatitis virus B or C (HBV, HCV) infections, alcohol consumption or non-alcoholic fatty liver disease (NAFLD). Despite major gains in fighting hepatitis viruses, the epidemic of liver disease continues to grow with clear links to obesity and alcohol abuse. We recently found that high-fat diet (HFD)-

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References: - Llovet, J. M et al. Nat. Rev. Clin. Oncol. 15, 599–616 (2018). - Davoli, T. et al. Science . 355, eaaf8399 (2017).- Taylor, A. M. et al. Cancer Cell 33, 676–689.e3 (2018).- Sia, D. et al. Gastroenterology 153, 812–826 (2017).- Chiang, D. Y. et al. Cancer Res. 68, 6779–88 (2008).

Disclosure of Interest: R. Esteban-Fabró: None Declared, L. Bassaganyas: None Declared, S. Torrecilla: None Declared, A. Moeini: None Declared, S. Franch-Expósito: None Declared, M. Vila-Casadesús: None Declared, F. Nadeu: None Declared, L. Torrens: None Declared, L. Cabellos: None Declared, D. Sia: None Declared, I. Salaverria: None Declared, R. Pinyol: None Declared, J. Camps: None Declared, V. Mazzaferro: None Declared, J. M. Llovet Conflict with: Research/Education grant - Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen, Conflict with: Consulting - Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech, Sprink Pharmaceuticals and Nucleix

P-007 DEVELOPMENT OF A PORCINE HEPATOCELLULAR CARCINOMA MODEL FOR TARGETED THERAPEUTIC TESTING

Lobna Elkhadragy* 1, Hanna Chen1, Eileena Giurini1, Sulalita Chaki2, Faith M. Thomas2, Aisha Qazi2, Grace Guzman3, Matthew C. Stewart4, Lawrence B. Schook1, Ron C. Gaba1, Kyle M. Schachtschneider1

1Department of Radiology, University of Illinois at Chicago, Chicago, 2Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, 3Department of Pathology, University of Illinois at Chicago, Chicago, 4College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, United States

Introduction: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, and predominantly presents at an advanced stage at which most patients are not candidates for curative surgery. Currently available therapeutic options yield an overall survival of advanced HCC patients not exceeding one year. Hence, there is a critical need to develop novel therapeutic strategies for HCC which necessitates the availability of effective animal models for preclinical assessments. As cancer treatments move toward targeted therapeutics based on genetic alterations in the tumor, modeling the role driver mutations play in tumorigenesis and therapeutic susceptibility is essential. Here, we aim to develop an integrated rapid approach for generating porcine HCC models representative of mutational profiles observed clinically. Pigs represent an ideal animal disease model due to their similar anatomy, physiology, metabolism, immunology, and genetics compared with humans. Importantly, in contrast to murine models, the size of the pigs permits utilization of devices and procedures used clinically in humans.

Methods: Porcine HCC cells were developed from an Oncopig Cancer Model (OCM), a transgenic pig that recapitulates human cancer through induced expression of TP53R167H and KRASG12D, as described previously [1,2]. Generated OCM HCC cells were autologously injected into 6 subcutaneous (SQ) sites in an Oncopig with alcohol-induced liver cirrhosis. Two weeks later, the SQ tumors were excised and engrafted intrahepatically in the same animal, and tumor progression was monitored by ultrasound and CT scan. To generate HCC tumors with different mutational profiles, the OCM HCC cells were subject to CRISPR-Cas9 mediated editing of several genes including KRASG12D, TP53R167H, and ARID1A, a tumor-suppressor gene mutated in 10-15% HCC. Gene editing was performed by transfection of a ribonucleoprotein (RNP) complex comprising a fluorescently-labeled gRNA targeting the gene of interest and recombinant Cas9 nuclease, and was analyzed by Illumina sequencing. Enrichment of edited cells was accomplished by sorting of transfected fluorescent cells by FACS and single cells were plated in 96-well plates.

Results: OCM HCC cells and SQ tumors recapitulated histopathological characteristics of human HCC similar to previously described [2]. Five of 6 SQ sites (>80%) developed 1-2 cm tumors within 2 weeks. Engraftment of SQ tumor fragments into the cirrhotic Oncopig liver resulted in a 1 cm tumor within 4 weeks, and was histologically characterized as HCC. CRISPR-Cas9 mediated gene-editing efficiencies ranged from 11.8-16.3% for KRASG12D, TP53R167H, and ARID1A, and comprised small insertions or deletions (INDELs) near predicted Cas9 cleavage sites. FACS increased the fraction of edited cells, as the RNP transfection efficiency into OCM HCC cells was 17-25%. Single cell clones were expanded and screened for gene editing by Sanger sequencing.

Conclusions: The OCM can be used for development of orthotopic autologous HCC tumors in a cirrhotic liver microenvironment, and represents a novel and promising large animal model for HCC. Successful editing of KRASG12D, TP53R167H and/or oncogenes or tumor suppressor genes in OCM HCC cells enables the generation of genetically-defined HCC tumors similar to those detected clinically. Hence, the OCM can be used as a versatile platform for generating HCC models that can serve as tools for testing innovative precision medicine approaches, and for investigating the contribution of distinct driver mutations on tumor progression and treatment susceptibility.

Introduction: Hepatocarcinoma (HCC) is the second-leading cause of cancer-related death worldwide and new treatments are required (1). Recently, a link between alterations in epigenetic modifiers that modulates histone post-translational modifications and carcinogenesis has been established, thus their inhibition could become a new therapeutic strategy for HCC (2). The aim of our work was to identify and target epigenetic modifiers (EM) that are deregulated in patients with HCC and to preclinically assess the therapeutic potential of their inhibition.

Methods: Clinical information, gene expression and mutations data were obtained from The Cancer Genome Atlas (TCGA) for tumors (n=365) and normal tissues (n=50) of HCC patients. Then TCGA data were analyzed for gene expression, mutation and prognosis correlation. For in vitro assays HCC cells were treated with epigenetic inhibitors (EI) and assayed by MTS, iodure propidium and Annexin V. For expression analysis, RNA-Seq was performed. For hierarchical Clustering our gene signature was used to segregate the TCGA and the GSE14520 cohorts of HCC patients using the ¨R¨ software.

Results: The TCGA data analysis show that 75% of patients with HCC present a somatic mutation in at least one of the EM studied (n=90). Analyzed by EM families, the frequency of patients with mutations is 20% for bromodomains (BRDs), 38% for histone acetyltransferases (HATs), 57% for lysine methyltransferases (KMTs), and 35% for lysine demethylases (KDMs). Additionally, comparison of the expression levels of the EM showed that 45% of them are up-regulated when compared tumor vs normal tissue. Then, we wondered whether the expression levels of these up-regulated genes correlate with clinical prognosis. This analysis showed that high tumoral expression levels of 12 of them correlates with a worst prognosis in patients with HCC. To test the potential survival dependence of HCC cells to the likely epigenetic targets, we tested the antiproliferative activity of a set of EI on HCC cell lines. High to moderate antiproliferative effect was observed for 7 of 19 of the EI tested including: inhibitors of Jumonji C family of KDMs (JmjCs) JIB-04, GSK-J4, SD-70 and ML324; the KMTs inhibitors BIX 1294 and LLY-507; and the BRD4 inhibitor JQ-1. In addition, these 7 EI induce cell cycle arrest and cell death. Even more, the pan-inhibitors of JmjC JIB-04 showed antitumoral effect in mice bearing orthotopic HCC. Then, we performed RNA-Seq analysis of HuH7 cells treated with JmjC inhibitors (JIB-04, GSK-J4 or SD-70) to identify the mechanisms involved in their antitumoral effect. Gene ontology analysis of genes modulated by JmjC inhibitors showed an induction of a transcription program related with inhibition of cell proliferation and induction of cell death on HCC cells. Even more, we found that several genes depleted by JmjC inhibitors are highly expressed in tumor vs non-tumor tissues and that their high expression correlates with a poor prognosis in HCC patients. Finally, we identified a gene signature based on CENPA, KIF20A, PLK1 and NCAPG gene expression that could be used for prognosis prediction and to define a group of high-risk patients that could be benefited by a therapy based on JmjC inhibitors (Figure).

Image:

Conclusions: Our work highlights the importance of epigenetic alterations in HCC development, in patient prognosis and supports the research on EM as therapeutic targets.Our work highlights the importance of epigenetic alterations in HCC development, in patient prognosis and supports the research on EM as therapeutic targets.

References: 1. Forner A, et al. Lancet 2018;391:1301-1314. 2. Bayo J, et al. Future Med Chem 2015;7:2243-2261


known inducer of ductular reaction in mice, also displayed a higher apoptotic response when treated with S63845, than cells that were not treated with TWEAK, P<0.05. To examine the dependence of reactive cholangiocytes on MCL-1, we performed immunoprecipitation experiments on mouse 603B cholangiocytes. Treatment with TWEAK resulted in greater binding of MCL-1 to its pro-apoptotic partner BAK, and MCL-1 inhibition with S63845 resulted in disruption of MCL-1’s interaction with BAK. Finally, in vivo studies on DKO mice treated with S63845 showed significantly reduced degree of ductular reaction (which comprises of reactive cholangiocytes), as measured by PANCK and SOX9 expression by immunohistochemistry, in contrast to controls treated with vehicle, P<0.05.

Conclusions: Collectively our findings indicate that reactive cholangiocytes are primed for cell death by MCL-1 inhibition. Importantly, MCL-1 inhibition in vivo results in attenuation of ductular reaction in a mouse model of chronic cholestatic liver injury. We conclude that apoptosis of ductular reactive cells in chronic cholestatic liver disease can serve as a potential target for intervention to protect against the development of hepatic fibrosis and liver cancer.

References: 1. Williams MJ, Clouston AD, Forbes SJ. Links between hepatic fibrosis, ductular reaction, and

progenitor cell expansion. Gastroenterology 2014;146:349-562. Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G. Ductular reaction in liver diseases:

pathological mechanisms and translational significances. Hepatology 2018


P-004 PRECLINICAL STUDIES OF CABOZANTINIB FOR HCC TREATMENT

Runze Shang* 1, 2, Pan Wang1, Meng Xu1, Xinyan Chen1, Xin Chen1

1 Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, United States, 2Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, China

Introduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with limited treatment options. Cabozantinib is an orally bioavailable multi-kinase inhibitor which targets c-Met, VEGFR2 and Axl. Recent clinical trials have demonstrated the effectively of Cabozantinib for HCC treatment. It is now approved by FDA for patients with HCC who have been previously treated with Sorafenib. However, the molecular mechanism by which Cabozantinib inhibits HCC progression is not fully understood.

Methods: The therapeutic efficacy of Cabozantinib was evaluated in a panel of 14 human HCC cell lines as well as 4 types of oncogene driven HCC mouse models (c-Met/ß-Catenin, Akt/c-Met, Akt/Ras and c-Myc). Statistical analyses were conducted using Student’s t-test, Tukey-Kramer test and linear regression analyses.

Results: We demonstrated that Cabozatintinib suppresses HCC cell growth with variable IC50 values. The sensitivities of Cabozatintinib correlated with p-Met, t-AXL and p-ERK expression in HCC cell lines. In addition, we found that Cabozatintinib treatment led to stable disease in c-Met/ß-Catenin and Akt/c-Met mouse HCC models, but it showed no efficacy towards AKT/Ras and c-Myc mouse HCCs. At the cellular levels, Cabozatintinib inhibited tumor cell proliferation in c-Met/ß-Catenin and Akt/c-Met HCC, but not in AKT/Ras and c-Myc HCC. Intriguingly, a strong inhibition of angiogenesis as illustrated as decreased vascular densities were observed regardless of the oncogenic drivers. Mechanistically, we demonstrate that Cabozatintinib effectively inhibited p-MET and p-ERK, and induced p21 expression, but did not affect p-AKT/mTOR signaling in HCC cells as well as in c-Met/ß-Catenin and Akt/c-Met mouse HCC. In all mouse HCC models, Cabozantinib also suppressed the p-VEGFR2, leading to decreased tumor angiogenesis.

Conclusions: We demonstrated that c-MET/ERK/p21 cascade as well as p-VEGFR2 mediated angiogenesis are the primary targets of Cabozantinib during HCC treatment. However, decreased angiogenesis has limited roles in inducing HCC regression. High levels of p-MET may be a useful biomarker to select patients who may respond to cabozantinib treatment.


P-005 LINKING EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA WITH CLINICAL PROGNOSIS AND NEW THERAPEUTIC TARGETS

Juan M. Bayo1, Esteban Fiore1, Manglio Rizzo1, Luciana Dominguez1, Alejandrina Real1, Agostina Onorato1, Marcelo Rodriguez1, Catalina Atorrasagasti1, Mariana Garcia1, Josepmaria Argemi* 2, Mariana Malvicini1, Guillermo Mazzolini1

1Instituto de Investigaciones en Medicina Traslacional, Universidad Austral-CONICET, Derqui-Pilar, Argentina, 2Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, United States

P-006 CHROMOSOMAL STABILITY CORRELATES WITH THE IMMUNE CLASS OF HEPATOCELLULAR CARCINOMA

Roger Esteban-Fabró* 1, Laia Bassaganyas1, Sara Torrecilla2, Agrin Moeini1, Sebastià Franch-Expósito3, Maria Vila-Casadesús4, 5, Ferran Nadeu5, 6, Laura Torrens1, 7, Laia Cabellos1, Daniela Sia7, Itziar Salaverria5, 8, Roser Pinyol1, Jordi Camps9, Vincenzo Mazzaferro10, Josep M Llovet7, 11, 12

1Liver Cancer Translational Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, 2Liver Cancer Translational Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 3Gastrointestinal and Pancreatic Oncology Group, Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERehd, 4Bioinformatics Platform, CIBERehd, Barcelona, 5Tumores Hematológicos, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, 6Lymphoid Neoplasms Program, Lymphoid Neoplasms Program, Barcelona, Spain, 7Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States, 8Lymphoid Neoplasms Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 9Gastrointestinal and Pancreatic Oncology Group, Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, 10Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 11Liver Cancer Translational Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Bacelona, 12Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

Introduction: Aneuploidy is a hallmark of cancer that includes broad somatic copy-number alterations (CNAs), being whole chromosome- or arm-level events, and also smaller focal CNAs. Pan-cancer studies suggest that distinctive molecular/clinical traits are linked to either broad or focal CNA genomic loads, with the first potentially interfering with tumor immune infiltration. We aimed at dissecting the impact of CNA genomic burdens on hepatocellular carcinoma (HCC) molecular profiles and immune features by proposing scores that distinguish focal and broad CNA loads and predict chromosomal instability.

Methods: The study includes 520 paired tumor/adjacent surgically resected HCC samples from 2 cohorts (training: HEPTROMIC, n=150; validation: TCGA, n=370). We extracted tumor ploidy and CNAs from SNP array data using ASCAT and SAASCNV. With the CNApp tool (http://bioinfo.ciberehd.org/CNApp), we generated a Broad CNA Score (BCS) to quantify broad CNA burdens per sample, and a Focal CNA Score (FCS) to determine focal CNA loads. These scores were based on CNA number, amplitude and length, setting ≥50% of a chromosome arm as the threshold for broad alterations as opposed to focal events. The scores were integrated with gene expression profiling, clinico-pathological data from tumors and their immune infiltrate characteristics –immune infiltrate levels and immunogenicity profiles-, which were determined using the tools ESTIMATE and Immunophenoscore.

Results: Low BCS tumors (25% Heptromic, 15% TCGA) were associated with the HCC immune class and upregulation of pro-inflammatory, active infiltrate signaling, antigen presentation and cytolytic activity-related genes (FDR<0.1, p<0.05). Conversely, high BCS samples (25% Heptromic, 45% TCGA) were linked to a lack of immune infiltration and immunogenicity, as well as polyploidy, TP53 dysfunction and signatures of DNA repair and proliferation. Additionally, high FCS tumors (25% Heptromic, 49% TCGA) were associated with TP53 loss of function and phenotypes of proliferation and progenitor cells, whereas low-intermediate FCS samples were linked to CTNNB1 activating mutations. Immunity features were not influenced by FCS.

Image:

Conclusions: Tumors with chromosomal stability, defined by low burdens of broad copy number alterations, are enriched in the immune class of HCC. Proposed Broad CNA Score (BCS) capturing chromosomal stability might enable to identify those patients responding to immune checkpoint inhibitors.

Results: A total of 232 patients (regorafenib, n=168; placebo, n=64) had baseline AFP ≥20 ng/mL and an AFP measurement at the start of Cycle 3. Of these, 46% (77/168) of patients who received regorafenib and 11% (7/64) of patients who received placebo had an AFP response. Among patients evaluable for an AFP response in both treatment groups (n=232), AFP response was observed in 67% (8/12) of patients with a partial tumor response, 40% (71/177) with stable disease, and 10% (4/42) with progressive disease (1 patient was not evaluable for tumor response). The median OS from randomization was 13.8 months in patients with an AFP response (n=84) versus 8.9 months in patients without an AFP response (n=148; Table). In a landmark analysis, the median OS from the start of Cycle 3 was 12.0 months in patients with an AFP response versus 7.0 months in patients without an AFP response.

Patients with ≥20% decrease in AFP from baseline*

Median OS (95% CI) from randomization, months 13.8 (11.8, 16.5) 8.9 (8.0, 9.7)

HR (95% CI) 0.57 (0.40, 0.82)

Landmark analysis of median OS (95% CI) from start of Cycle 3, months

12.0 (9.9, 14.6) 7.0 (6.2, 7.9)

HR (95% CI) 0.57 (0.40, 0.82)

*Among patients with baseline AFP ≥20 ng/mL and an AFP measurement at the start of Cycle 3.CI, confidence interval; HR, hazard ratio.

Conclusions: In RESORCE, the rate of AFP response was higher in patients treated with regorafenib than with placebo. AFP response was associated with a longer OS.

Disclosure of Interest: J. Bruix Conflict with: Research/Education grant - Bayer; BTG, Conflict with: Honoraria - Bayer; BTG; Ipsen; Eisai; Terumo; Sirtex, Conflict with: Consulting - Arqule; Bayer; Novartis; Bristol-Myers Squibb; BTG; Eisai; Kowa; Terumo; Gilead; Bio-Alliance; Roche; AbbVie; MSD; Sirtex; Ipsen; Astra-Medimmune; Incyte; Quirem; Adaptimmune; Lilly; Basilea; Nerviano; Sanofi Aventis, M. Reig Conflict with: Research/Education grant - Bayer, Conflict with: Honoraria - AstraZeneca; Bayer; Bristol-Myers Squibb; BTG; Ipsen; Lilly; Gilead, Conflict with: Advisory Board - AstraZeneca; Bayer; Bristol-Myers Squibb; Ipsen; Lilly, Conflict with: Consulting - AstraZeneca; Bayer; Bristol-Myers Squibb; Ipsen; Lilly; Roche, P. Merle Conflict with: Advisory Board - Bayer, Exelix, Ipsen, Onxeo, Bristol-Myers Squibb, MSD, AstraZeneca, Roche, Eisai, Conflict with: Consulting - Bayer, Ipsen, Onxeo, MSD, M. Kudo Conflict with: Research/Education grant - Daiichi Sankyo; Otsuka; Taiho; Astellas Pharma; Chugai; AbbVie; Bristol-Myers Squibb; EA Pharma; Takeda; Gilead; Eisai; Ono, Conflict with: Honoraria - Bayer; Eisai; MSD, Conflict with: Advisory Board - Bayer; Eisai; Ono; MSD; Bristol-Myers Squibb; Lilly, G. Meinhardt Conflict with: Stocks - Bayer, M. Zhang Conflict with: Stocks - Bayer , K. Ozgurdal: None Declared

P-014 PROVIDER ATTITUDES AND PRACTICE PATTERNS FOR DIRECT-ACTING ANTIVIRAL THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA IN THE UNITED STATES

Nicole E. Rich* 1, Ju Dong Yang2, Ponni V. Perumalswami3, Naim Alkhouri4, Whitney Jackson 5, Neehar D. Parikh6, Neil Mehta7, Reena Salgia8, Andres Duarte-Rojo9, Laura Kulik10, Mina Rakoski11, Adnan Said12, Omobonike Oloruntoba13, George N. Ioannou14, Maarouf A. Hoteit15, Andrew M. Moon16, Amol S. Rangnekar17, Sheila L. Eswaran18, Elizabeth Zheng19, Janice H. Jou20, James Hanje21, Anjana Pillai22, Ruben Hernaez23, Robert Wong24, Steven Scaglione25, Hrishikesh Samant26, Devika Kapuria27, Shaun Chandna28, Russell Rosenblatt29, Veeral Ajmera30, Catherine T. Frenette31, Sanjaya K. Satapathy32, Parvez Mantry33, Prasun Jalal23, Binu V. John34, Oren K. Fix35, Michael Leise36, Christina C. Lindenmeyer37, Avegail Flores38, Nayan Patel39, Z. Gordon Jiang40, Nyan Latt41, Renumathy Dhanasekaran42, Mobolaji Odewole1, Sofia Kagan1, Jorge A. Marrero1, Amit G. Singal1

1UT Southwestern Medical Center, Dallas, 2Cedars Sinai Medical Center, Los Angeles, 3Ichan School of Medicine at Mount Sinai, New York, 4University of Texas Health San Antonio, San Antonio, 5University of Colorado Denver School of Medicine, Denver, 6University of Michigan, Ann Arbor, 7University of California San Francisco, San Francisco, 8Henry Ford Hospital, Detroit, 9University of Pittsburgh Medical Center, Pittsburgh, 10Northwestern University, Chicago, 11Loma Linda University, Loma Linda, 12University of Wisconsin, Madison, 13Duke University, Durham, 14Veterans Affairs Puget Sound Healthcare System and University of Washington, Seattle, 15University of Pennsylvania, Philadelphia, 16University of North Carolina, Chapel Hill, 17Georgetown University, Washington, D.C., 18Rush Medical College, Chicago, 19Columbia University, New York, 20Oregon Health and Science University, Portland, 21The Ohio State University, Columbus, 22University of Chicago, Chicago, 23Baylor College of Medicine, Houston, 24Alameda Health System, Oakland, 25Loyola University Medical Center and Edward Hines Veterans Affairs, Chicago, 26Louisiana State University Health Sciences Center, Shreveport, 27University of New Mexico, Albuquerque, 28University of Utah, Salt Lake City, 29Weill Cornell Medicine – New York-Presbyterian Hospital, New York, 30University of California San Diego, San Diego, 31Scripps Green Hospital, La Jolla, 32Northwell Health, Northshore University Hospital, New York, 33Methodist Dallas, Dallas, 34McGuire VA Medical Center, Richmond, 35Swedish Medical Center, Seattle, 36Mayo Clinic, Rochester, 37Cleveland Clinic Foundation, Cleveland, 38Washington University, St. Louis, 39Banner University Medical Center, Phoenix, 40Beth Israel Deaconess Medical Center, Boston, 41Oschner Health System, New Orleans, 42Stanford University, Palo Alto, United States

We integrated this with previously reported methylation data of 12 normal liver and 227 HCC (Villanueva et al. Hepatology 2015) resulting in a total of 390 samples analyzed. We evaluated differentially methylated sites using an F-test. To detect novel epigenetic gatekeepers we defined hypermethylation as a B value higher than 0.5. We used unsupervised clustering using Euclidean distances, and correlation between DNA methylation and RNA expression (n= 361) was quantified with the Pearson’s coefficient.

Results: Patients were mostly male (76%), with a median age of 66, and with underlying liver disease mainly due to hepatitis C (43%) and B (23%) virus infection. There were 43 tumors below 2 cm in diameter defined as early HCC. A phylo-epigenetic tree including differentially DNA methylated sites (n=421,997) reveals a gradient of DNA methylation changes that spans normal, cirrhotic, dysplastic nodules and HCC. Epigenetic analysis confirmed closer proximity of dysplastic nodules to HCC than to cirrhotic tissue. We validated aberrant methylation of previously reported HCC epidrivers (e.g. EFBN2, TBX15). Focusing on CpG sites located in promoter regions (i.e., TSS200, TSS1500, 5’UTR, and 1st exon), we selected candidates hypermethylated in less than 1% of normal and cirrhotic tissue, in at least 25% of dysplastic nodules, and in more than 50% of early HCC (<2 cm). When we integrated DNA methylation and gene expression, we found a significant (all P<0.001) inverse correlation in TSPYL5 (r=-0.31), KCNA3 (r=-0.33), LDBH (r=-0.46) and SPINT2 (r=-0.43).

Conclusions: Whole-genome DNA methylation profiles accurately discriminate between different histological lesions along the human hepatocarcinogenesis spectrum. We report novel candidate epigenetic gatekeepers in the transition between dysplastic nodules and early HCC.


P-010 RNA-SEQUENCING OF PLASMA EXOSOMES REVEALS SPECIFIC TRANSCRIPTOMIC PROFILES IN PATIENTS WITH HEPATOCELLULAR CARCINOMA

Johann von Felden1, 2, Teresa García-Lezana1, Mehmet E. Ahsen3, Amanda Craig1, Ismail Labgaa1,4, Delia D’Avola1, 5, Gabriela Hernandez-Meza* 1, Kimaada Allette3, 6, Navneet Dogra3, Parissa Tabrizian7, Amon Asgharpour1, Douglas Dieterich1, Robert Sebra3, 6, 8, Gustavo Stolovitzky3, Myron Schwartz7, Bojan Losic3, 6, Augusto Villanueva1, 9

1Division of Liver Diseases, Department of Medicine, Icanh School of Medicine at Mount Sinai, New York, United States, 2I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 3Genetics and Genomic Sciences, Icanh School of Medicine at Mount Sinai, New York, United States, 4Department of Visceral Surgery, Lausanne University Hospital CHUV , Lausanne, Switzerland, 5CIBEREHD, Clínica Universidad de Navarra, Pamplona, Spain, 6Icahn Institute of Genomics and Multiscale Biology, 7Department of Surgery, Icanh School of Medicine at Mount Sinai, New York, 8Sema4, Mount Sinai venture, Stamford, 9Division of Hematology and Medical Oncology, Department of Medicine, Icanh School of Medicine at Mount Sinai, New York, United States

Introduction: Early detection of hepatocellular carcinoma (HCC) is key to improve survival. Standard surveillance tools (e.g., abdominal ultrasound plus serum AFP) have a sensitivity of 63% for the detection of early stage HCC. Exosomes are nanoparticles loaded with RNA, DNA and proteins involved in intercellular communication. The aims of this study are: 1) to establish a method to isolate exosomes from plasma of HCC patients, and 2) to evaluate de-regulated transcripts in exosomes as a potential novel early HCC detection tool.

Methods: In this pilot study we included 15 patients, n=10 HCC and n=5 controls at high-risk of HCC development (i.e. patients with cirrhosis and/or chronic hepatitis B). Plasma exosomes were isolated by differential ultracentrifugation. Presence of exosomes was confirmed by morphological assessment with electron microscopy, nanoparticle tracking analysis and immune-labeling of EV specific markers (CD9, CD63, CD81, and TSG101) with ExoView and Western Blotting. RNA from exosomes was extracted and quantified with Bioanalyzer. Library preparation was done with SMARTer smRNA-Seq kit and whole transcriptome sequencing was performed on an Illumina HiSeq2500 instrument. Differential gene expression was done with LIMMA and enrichment analyses (i.e., gene ontology) with Enrichr.

Results: HCC patients and controls were matched for age (median 67 vs. 63 yrs.), sex (70% vs. 67% males), and etiology (viral 70% vs. 67%). Average particle size of the isolate was 120.5 nm and immune-labeling confirmed strong positivity for CD9 and CD81 indicating the presence of exosomes in the isolate. Sequencing reads obtained from exosomes mapped to different RNA species including mRNA, lincRNA and small RNA, including miRNAs and Y-RNAs. Compartment ontology enrichment analysis of the top 250 expressed transcripts matched to exosomes and membrane-bounded vesicles (FDR<0.01). Genes from hepatic lineage were among the top expressed genes including ALB, BAAT, CRP, C3/5, FGA/B, CYP and APO family. This suggest the presence of liver-derived exosomes in human plasma. We identified 273 differentially expressed genes between HCC and controls (FDR<0.2), which accurately discriminated the two groups.

Conclusions: Whole transcriptomic analysis of plasma exosomes is feasible in patients with HCC. Our pilot study detects significant differences in the transcriptomic profiles of HCC patients compared to controls, including miRNAs and lincRNAs.


P-011 MELD EXCEPTION: THE EFFECT OF THE OCTOBER 2015 POLICY CHANGE

Ranya Selim* 1, Randeep Kaur2, Dilshan Dhillon2, Reena Salgia1

1Gastroenterology, 2Internal Medicine, Henry Ford Health System, Detroit, United States

Introduction: The Model for End-Stage Liver Disease (MELD) exception policy for liver transplant has been revised over the years since MELD allocation was initiated. The latest revision instituted in October 2015 involved a 6-month waiting period prior to allocation of exception points for patients with hepatocellular carcinoma (HCC). This was a change from the prior longstanding allocation of exception points upon listing for patients within Milan criteria. Theoretically, this new policy would serve as a way to select for those with less aggressive disease, thereby improving post-transplant outcomes. In this study, we will compare waitlist and transplant outcomes before and after this policy change.

Methods: This study was conducted at a high volume liver transplant program, and included patients who had an application for MELD exception points between 2012-2018. Patients were excluded if HCC was incidentally noted in the explant. Variables collected included standard demographics, etiology of liver disease, date of evaluation, listing, transplant or dropout, reason for dropout, receipt of MELD exception, peak alpha-fetoprotein (AFP) prior to listing, whether the explant tumor burden was within Milan criteria, and mortality. We then compared outcomes between those listed before (Group A) and those listed after (Group B) October 8th, 2015.

Results: A total of 179 patients listed for transplant had a UNOS MELD exception request for T2 HCC between 2012-2018. There were 100 patients in Group A and 79 patients in Group B. Of the 179 patients, 138 (77.1%) were male. 100 (55.9%) had hepatitis C cirrhosis, 21 (11.7%) had alcoholic cirrhosis, and 14 (7.8%) had non-alcoholic steatohepatitis. Peak AFP levels prior to transplant listing were 211.6 ± 973.6 vs 224.7 ± 711.5 ng/mL (P=0.514), and the rates of MELD exception allocation for HCC were 70.7% vs 54.4% (P=0.025) for Group A vs B, respectively. 81.0% vs 72.2% (P=0.162) of patients received transplants, and mean time from listing to transplant was 142.2 ± 201.7 vs 266.3 ± 134.5 days (P<0.001) in Group A vs B, respectively. 79.0% vs 77.2% (P=0.799) of explant livers were within Milan criteria for Group A vs B, respectively. The waitlist dropout rates were 19.0% and 25.3% (P=0.309) for group A and B respectively, with the majority of patients (42.1% and 60.0%, respectively) dropping out due to progression of their cancer (P=0.527). The time from transplant listing to dropout was 492.8 ± 619.3 vs 164.2 ± 110.7 days (P=0.342), and the overall mortality rates were 25.0% vs 19.0% (P=0.338) in Groups A vs B, respectively.

Conclusions: In conclusion, following the MELD policy changes in October 2015, there was a significant decrease in the number of patients receiving a MELD exception for HCC on the waitlist, and an increase in the time from listing to transplant. Importantly however, the rates of dropout, transplant, and mortality were not significantly different post-implementation of the new policy. In addition, the number of days from transplant listing to dropout and peak AFP values prior to transplant were also not significantly different. Our results suggest that despite efforts to select for those patients with less aggressive disease and thereby improve post-transplant outcomes, there does not appear to be a significant improvement in mortality or explant tumor burden. This finding is particularly important to consider in light of the new MELD allocation policies taking effect soon, which propose further restrictions on MELD exception and likely longer waitlist times for patients with HCC.


P-013 ALPHA-FETOPROTEIN (AFP) RESPONSE AND OUTCOMES IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH REGORAFENIB OR PLACEBO IN THE PHASE 3 RESORCE TRIAL

Jordi Bruix1, Maria Reig1, Philippe Merle2, Masatoshi Kudo3, Gerold Meinhardt4, Meizhuo Zhang4, Kirhan Ozgurdal4, Danielle Kopecky*

1BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain, 2Groupement Hospitalier Lyon Nord, Lyon, France, 3Kindai University Faculty of Medicine, Osaka, Japan, 4Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States

Introduction: Elevated levels of the tumor marker AFP are associated with a poor prognosis in patients with HCC. A decrease in AFP level during treatment has been reported to be associated with longer overall survival (OS). In the phase 3 RESORCE trial (NCT01774344), the multikinase inhibitor regorafenib significantly improved OS versus placebo in patients with HCC and disease progression on sorafenib. We analyzed patient outcomes by AFP response in RESORCE.

Methods: In RESORCE, 573 patients were randomized 2:1 to regorafenib 160 mg/day (n=379) or placebo (n=194) for Weeks 1–3 of each 4-week cycle. Eligible patients had Barcelona Clinic Liver Cancer stage B or C HCC, Child–Pugh A liver function, ECOG performance status 0−1, and documented radiologic progression on prior sorafenib. Tumor response was assessed by investigators using mRECIST criteria. Serum AFP levels were assessed at baseline, every 4 weeks during treatment, and at the end of treatment. Patients with baseline AFP ≥20 ng/mL were included in the analysis. AFP response (yes/no) was defined as a ≥20% decrease in AFP level from baseline at the start of Cycle 3. Outcomes by AFP response were evaluated.

References: [1] Schook LB, Collares TV, Hu W, Liang Y, Rodrigues FM, Rund LA, Schachtschneider KM, Seixas

FK, Singh K, Wells KD, Walters EM, Prather RS, Counter CM. A Genetic Porcine Model of Cancer. PLoS One 2015;10:e0128864.

[2] Schachtschneider KM, Schwind RM, Darfour-Oduro KA, De AK, Rund LA, Singh K, Principe DR, Guzman G, Ray CE Jr, Ozer H, Gaba RC, Schook LB. A validated, transitional and translational porcine model of hepatocellular carcinoma. Oncotarget 2017;8:63620-63634.


P-008 CHOLANGIOCARCINOMA (CCA) DERIVED EXTRACELLULAR VESICLES REPROGRAM HEPATIC MACROPHAGES TO A PD-L1+ PRO-TUMOR PHENOTYPE

Sumera Rizvi* 1, Emilien Loeuillard1, Jingchun Yang1, Gregory Gores1, Haidong Dong2

1Gastroenterology and Hepatology, 2Division of Urology, Mayo Clinic, Rochester, United States

Introduction: Cholangiocarcinoma (CCA) is characterized by a desmoplastic stroma with abundant tumor associated macrophages (TAMS). In a murine model of CCA (PMID: 29464042), we have recently identified TAMS as a potent source of the immune checkpoint programmed cell death 1 ligand 1 (PD-L1). However, neither the origin of the TAMS, resident Kupffer cells vs. bone marrow derived recruited macrophages, nor the mechanisms mediating TAM expression of PD-L1 are known. Yet, such information has treatment implications for CCA.

Methods: Because extracellular vesicles (EVs) often mediate cell-to-cell communication, bone marrow derived macrophages (BMDM) were incubated with EVs from murine CCA cells (SB cells) or exosome depleted medium. BMDM were harvested, macrophage phenotype (protumor vs. antitumor) and PD-L1 expression was assessed by flow cytometry. In vivo studies were conducted in wild type (WT) C57BL/6J and Ccr2-/- mice using a unique syngeneic orthotopic CCA murine model where murine CCA cells (SB cells) are implanted into the liver.

Results: We observed PD-L1 expression on CD206+ protumor macrophages in murine CCA tumors, including recruited macrophages (F4/80+/CD11b+/CCR2+) and resident Kupffer cells (F4/80+/CD11b+/Clec4f+). The ratio of resident Kupffer cells to recruited macrophages in murine CCA tumors was 1:3.6. Ccr2-/- mice, which have defective monocyte recruitment, underwent orthotopic implantation of SB cells in the liver. Interestingly, tumors weights from Ccr2-/- mice and WT mice were similar as the Ccr2-/- had an increase in myeloid-depressive suppressive cells (MDSCs) which appeared to compensate for the lack of recruited macrophages. Depletion of MDSCs with a Gr-1 neutralizing antibody resulted in a significant reduction in tumor burden of Ccr2-/- mice compared to vehicle treated Ccr2-/- mice. In vitro studies showed that SB cell derived EVs increase PD-L1 expression in isolated bone marrow derived macrophages.

Conclusions: In conclusion, we have shown that PD-L1+ macrophages, especially recruited macrophages, are an important source of PD-L1-positive TAMs in a murine model of CCA. CCA cell derived EVs appear to reprogram macrophages to a PD-L1+, protumor phenotype. Moreover, immune therapies targeting PD-L1 and immunosuppressive myeloid cell populations represent a promising therapeutic approach in CCA.


P-009 GENOME-WIDE DNA METHYLATION PROFILING REVEALS NOVEL CANDIDATE EPIGENETIC GATEKEEPERS IN HEPATOCARCINOGENESIS

Gabriela Hernandez Meza* 1, Johann von Felden1, Edgar Gonzalez-Kozlova1, Teresa Garcia-Lezana1, Amanda J. Craig1, Anna Portela2, Manel Esteller2, Myron Schwartz3, Vincenzo Mazzaferro4, Bojan Losic5, Josep M. Lovet6, Augusto Villanueva7

1Icahn School of Medicine at Mount Sinai, New York, United States, 2Institut d’Investigació Biomédica de Bellvitge, Barcelona, Spain, 3Surgery, Icahn School of Medicine at Mount Sinai, New York, United States, 4Istituto Nazionale dei Tumori, Milan, Italy, 5Department of Genetics and Genomic Sciences, Icahn School of Medicine, 6Division of Liver Diseases, Liver Cancer Program, Tish Cancer Institute, Icahn School of Medicine at Mount Sinai, 7Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States

Introduction: Besides mutations in TERT promoter, found in 20% of dysplastic nodules, little is known about the key molecular alterations driving early hepatocarcinogenesis. The aims of this study were: 1) to analyze DNA methylation changes during the transition from preneoplastic lesions to early hepatocellular carcinoma (HCC), and 2) to identify candidate epigenetic gatekeepers in the transition between dysplasia and early HCC.

Methods: We conducted DNA methylation profiling in 147 fresh-frozen samples from resection or liver transplant specimens including 139 cirrhosis, 8 dysplastic nodules (2 high and 6 low grade) using the Illumina HumanMethylation450 (485,000 CpG, 96% of known CpG islands).

Sankyo, Abbvie, Astellas Pharma, Bristol-Myers Squibb Japan, Conflict with: Honoraria - Bayer, Eisai, Novartis, MSD, EA Pharma, Bristol-Myers Squibb Japan, Abbvie, Taiho Pharmaceutical, Pfizer, Gilead Sciences, Merck Serono, Otsuka, Daiichi Sankyo, Astellas Pharma, Chugai Pharma, Conflict with: Advisory Board - MSD, Bristol-Myers Squibb, Bayer, Eisai, Conflict with: Consulting - MSD, Bristol-Myers Squibb, Bayer, Eisai

P-017 PERIOPERATIVE ANALGESIA WITH PARECOXIB SODIUM IMPROVES POSTOPERATIVE PAIN AND IMMUNE FUNCTION IN PATIENTS UNDERGOING HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA： A RANDOMIZED CONTROLLED TRIAL

Jia Weidong* 1

1Department of Liver Surgery, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China

Introduction: Acute postoperative pain can result in immune dysfunction, which can be partly mitigated by efficient pain management. Opioids that have been widely applied to analgesia have been shown to suppress immune function, which has a negative impact on the treatment of patients with cancer. This study investigated the effects of perioperative fentanyl analgesia alone or in combination with parecoxib sodium on postoperative pain, immune function and prognosis in patients undergoing hepatectomy of hepatocellular carcinoma (HCC).

Methods: A total of 80 patients scheduled for hepatectomy between October 2013 and August 2014 were included. Patients were randomly divided into two groups (n = 40) and allocated to receive parecoxib sodium 40 mg (Group P) or placebo (Group C) 30 min before induction of anaesthesia, followed by 40 mg every 12 h for 48 h after the operation. All patients had access to patient-controlled analgesia with intravenous fentanyl postoperatively. Venous blood samples were collected at the following time points: 30 minutes before induction of anesthesia (T0), the end of the surgery (T1), 24 h after surgery (T2) and 72 h after surgery (T3). The percentages of CD3+, CD4+, CD8+, CD4+/CD8+ T cells and CD3-CD16+CD56+ (NK) cells at these time points were quantified by flow cytometry (FCM). Visual analogue scale (VAS) scores, total fentanyl consumption, and adverse effects were recorded. The prognostic differences in overall survival (OS) and disease-free survival (DFS) between the two groups was also investigated

Results: For both groups, the percentages of CD3+, CD4+ T cells and the ratio of CD4+/CD8+ significantly decreased at T1 and T2 (P < 0.05). The percentages of CD3+ T cells were significantly lower in group C than that in group P at T2 (P < 0.05). In group C, the amount of CD3+ T cells was lower at T3 compared to T0 (P < 0.05). The percentages of NK cells significantly decreased at T1 in both groups (P < 0.05). The percentages of NK in group P were recovered nearly to baseline (T0) at T2, which was higher than that of group C (P < 0.05). In group C, the percentages of NK cells have not recovered nearly to baseline at T3 compared to T0 (P < 0.05). VAS scores at rest and on cough in group P were significantly lower than those in group C at 2 h, 6 h, 12 h and 24 h after operation (P < 0.05), and there were no significant differences in VAS scores between the two groups at 48 h after surgery (P > 0.05). There were no significant differences regarding the incidence of adverse effects between the two groups (P > 0.05). Kaplan-Meier analysis indicated that the disease-free survival (DFS) time in group P was significantly longer than in group C (19.0 months, 95% confidence interval[CI]: 9.8-28.2 vs 14.0 months, 95% CI: 8.1-19.9; P < 0.05). There was no significant difference in overall survival (OS) time (36.0 months, 95% CI, 13.4-58.9 vs 14.0 months, 95% CI 10.6-25.4; P > 0.05) between two groups

Conclusions: The present study indicated that perioperative analgesia of parecoxib sodium combined with patient-controlled analgesic fentanyl resulted in a better preserved immune function with enhancement of the analgesic efficacy to fentanyl alone of HCC patients undergoing hepatectomy and helped postpone postoperative tumor recurrence.


P-018 PHASE II CLINICAL TRIAL OF STEREOTACTIC BODY RADIATION THERAPY FOR SMALL (≤ 5 CM) HEPATOCELLULAR CARCINOMA NOT AMENABLE TO CURATIVE TREATMENT

Sang Min Yoon* 1, So Yeon Kim2, Young-Suk Lim3, Kang Mo Kim3, Ju Hyun Shim3, Danbi Lee3, Jihyun An4, Jinhong Jung1, Jong Hoon Kim1, Han Chu Lee3

1Radiation Oncology, 2Radiology, 3Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 4Gastroenterology, Hanyang University Guri Hospital, Guri, Korea, Republic Of

Introduction: With recent technological advances in radiation therapy, stereotactic body radiation therapy (SBRT) is regarded as an alternative local ablative treatment in hepatocellular carcinoma (HCC) that is not suitable for hepatic resection or local ablative therapy. The purpose of this prospective study was to evaluate the long-term efficacy of SBRT for small (≤ 5 cm) HCC.

Methods: Between 2013 and 2016, 50 patients with HCC were enrolled in this phase 2, single-arm, clinical trial at an academic tertiary care center. Planned SBRT dose was 45 Gy with the fraction size of 15-Gy over 3 consecutive days. The primary endpoint was 2-year local tumor control. Radiologic

for non-screening purposes (non-screening). Tumor characteristics included number of primary lesions, diameter of largest tumor, and whether HCC was within Milan criteria at time of diagnosis. Multivariate logistic regression methods (adjusted for age, sex, race/ethnicity, and potential clustering by site) were utilized to evaluate predictors of tumor stage at diagnosis (within Milan vs. outside Milan) and likelihood of receiving potentially curative therapy (liver transplantation, surgical resection, or radiofrequency ablation). Kaplan Meier methods and Cox proportional hazards models evaluated overall survival after HCC diagnosis.

Results: Among 605 adults with HCC (73.5% male, mean age 62.9 ± 9.0, 63.6% white, 30.9% black, 22.1% Hispanic), etiology of HCC was HCV in 45.2%, alcoholic cirrhosis 17.4%, combined HCV/alcohol 10.7%, NASH 10.7%, HBV 6.9%. Among patients with complete available data to assess all HCC outcomes (n=379), 54.7% of HCC patients were diagnosed via screening, 45.3% diagnosed via non-screening. Median number of primary tumors was 1.0 (IQR 1-2), median size of largest tumor was 4.0cm (IQR 2.5-7.1), and 42.6% were within Milan criteria at time of diagnosis. On multivariate regression, compared to patients with HCC detected via screening, patients diagnosed via non-screening had significantly lower odds of being within Milan criteria at time of diagnosis (27.0% vs. 57.5%, OR 0.26, 95% CI 0.20 -0.35, p<0.001), lower odds of receiving potentially curative therapy (23.2% vs. 37.9%, OR 0.65, 95% CI 0.65-1.00, p=0.05), and had significantly higher risk of death (HR 1.69, 95% CI 1.49-1.93, p<0.001). HCC patients within Milan criteria had significantly higher odds of receiving potentially curative therapy (47.2% vs. 18.3%, OR 3.70, 95% CI 2.27-6.05, p<0.001) and had significantly lower risk of death (HR 0.30, 95% CI 0.17-0.55, p<0.01). As expected, HCC patients who received potentially curative therapy also had significantly lower risk of death (HR 0.14, 95% CI 0.04-0.49, p<0.01).

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Conclusions: Among adults with HCC across five safety-net health systems, only 54.7% were diagnosed via screening, and these patients had earlier stage tumor, higher rates of potentially curative therapy, and higher overall survival, whereas patients diagnosed via non-screening had more advanced HCC at diagnosis, lower rates of potentially curative therapy, and lower overall survival. Better understanding the barriers to effective implementation of HCC screening – particularly among underserved safety-net populations – is needed to develop targeted interventions to improve early detection, treatment, and survival of HCC patients.

Disclosure of Interest: R. Wong Conflict with: Research/Education grant - Gilead Sciences, Abbvie, Conflict with: Honoraria - Gilead Sciences, Conflict with: Advisory Board - Gilead Sciences, Conflict with: Consulting - Gilead Sciences, A. Singal Conflict with: Research/Education grant - Gilead Sciences, Abbvie, Conflict with: Advisory Board - Gilead, Abbvie, Bayer, Eisai, Wako Diagnostics, Roche, and Exact Sciences, Conflict with: Consulting - Bayer, Eisai, Roche, and Glycotest, P. Jones: None Declared, H. Khallafi: None Declared, G. Therapondos Conflict with: Honoraria - Eisai, C. Murphy: None Declared, P. Pinheiro: None Declared, M. Thamer: None Declared

P-016 CHECKMATE 040: HEALTH-RELATED QUALITY OF LIFE (HRQOL) IN PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR CARCINOMA (AHCC) AND CHILD-PUGH B STATUS TREATED WITH NIVOLUMAB (NIVO)

Bruno Sangro* 1, Ana Matilla2, Armando Santoro3, Antonio Cubillo4, 5, Anthony B. El-Khoueiry6, Bassel El-Rayes7, Kazushi Numata8, Yoshito Itoh9, Fiona Taylor10, Gwilym Thompson11, Steven Blum12, Tami Wisniewski12, Jeffrey Anderson12, Masatoshi Kudo13

1Clinica Universidad de Navarra and CIBEREHD, Pamplona, 2Servicio de Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain, 3Istituto Clinico Humanitas, Rozzano, Italy, 4Hospital HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (HM-CIOCC), 5Departamento de Ciencias Médicas Clinicas Universidad San Pablo CEU, Madrid, Spain, 6USC Norris Comprehensive Cancer Center, Los Angeles, 7Emory University Winship Center, Atlanta, United States, 8Yokohama City University Medical Center, Yokohama, Japan, 9Kyoto Prefectural University of Medicine, Kyoto, Jersey, 10Adelphi Values, Boston, United States, 11Bristol-Myers Squibb, Uxbridge, United Kingdom, 12Bristol-Myers Squibb, Princeton, United States, 13Kindai University Faculty of Medicine, Osaka, Japan

Introduction: Pts with aHCC and Child-Pugh B liver status are often excluded from clinical trials of novel therapies due to their poor prognosis1. Historical overall survival (OS) for these pts when treated with sorafenib (SOR) has ranged ≈3–4 mo.2-4 Very limited information is available on the HRQoL of these pts. The PD-1 inhibitor NIVO is approved in the US, Canada, and elsewhere for SOR-treated pts with aHCC based on results from the CheckMate 040 study5. Here we report HRQoL data from the Child-Pugh B cohort of CheckMate 040, the first prospective study of immunotherapy in this pt group.

Methods: Pts with Child-Pugh B (B7–B8) aHCC (n=49) who were SOR naïve or experienced received NIVO 240 mg IV for 30 min Q2W (flat dose) until unacceptable toxicity or disease progression. EQ-5D-3L and Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) questionnaires were administered prior to clinical activities baseline on cycle 1 day 1 and every other cycle thereafter. FACT-Hep item responses range from 0 = Not at all to 4 = Very much. For HRQoL analyses, pts with baseline and at least 1 subsequent assessment were included. Mixed model with repeated measures (MMRM) analyses were conducted for the EQ-5D-3L and FACT-Hep using baseline patient-reported outcome (PRO) score and visit (as a repeated measure) as covariates. Median time to clinically meaningful deterioration (TTD) was calculated with corresponding 95% confidence intervals. Timepoints with at least 10 patients were considered evaluable. Clinically meaningful changes were pre-specified.6,7

Results: During a follow-up range of 6–18 mo, investigator-assessed ORR by RECIST 1.1 was 12.2% with 6 pts responding; disease control rate was 55.1%.8 Median (m) time to response was 2.7 mo and m duration of response was 9.9 mo. The mOS was 7.6 mo (mOS follow-up was 7.4 mo). NIVO safety profile in these pts appeared comparable to that in a cohort of pts with Child-Pugh A aHCC. HRQoL analysis population included 37 pts and with completion rates among expected >70% through week 36, for evaluable timepoints. MMRM results showed EQ-5D Visual Analogue Scale (LS means -3.2 [SE 2.6]) and utility index (LS means -.06 [SE .03]) scores remained stable over time relative to baseline, with no clinically meaningful decline observed through week 36 and 28, respectively. FACT-Hep demonstrated similar results through week 36, with no clinically meaningful declined observed in 29 of 33 (87.8%) evaluable timepoints across domains and hepatobiliary cancer sub-scale (HCS). Across all evaluable timepoints, mean scores on disease specific symptoms: discomfort/pain in stomach and presence of diarrhea, were not reported above 1 (“A little bit”) with scores on swelling/cramps in stomach decreasing week 16-28. TTD for HCS and FACT Hepatobiliary Symptom Index subscales was 2.9 and 4.7 months.

Conclusions: Durable responses were observed in pts with Child-Pugh B aHCC treated with NIVO. AEs in this cohort were manageable and HRQoL did not demonstrate clinically meaningful decline. NIVO may be a new treatment option that does not compromise HRQoL for this pt population with high unmet need.

References: 1. Greten Br J Cancer 2005; 2. Abou-Alfa Gastrointest Cancer Res 2011; 3. Da Fonseca Mol Clin Oncol 2015; 4. Pressiani Ann Oncol 2013; 5. NCT01658878; El-Khoueiry Lancet 2017; 6. Steel Ann Oncol. 2006; 7. Pickard Health Qual Life Outcomes. 2007; 8. Sangro B, et al. Poster pesentation at the EASL Congress, April 10-14, 2019; Vienna, Austria. Abstract #1492.

Disclosure of Interest: B. Sangro Conflict with: Research/Education grant - Bristol-Myers Squibb, Sirtex Medical, Conflict with: Advisory Board - Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, Conflict with: Consulting - Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Merck, Onxeo, Sirtex Medical, TERUMO, H3 Biomedicine, Ipsen, Lilly, A. Matilla Conflict with: Advisory Board - Bayer, Conflict with: Consulting - Bayer, A. Santoro Conflict with: Advisory Board - Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Conflict with: Consulting - Bristol-Myers Squibb, SERVIER, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, A. Cubillo: None Declared, A. El-Khoueiry Conflict with: Research/Education grant - AstraZeneca, Astex Pharmaceuticals, Conflict with: Honoraria - Bayer, Novartis, Bristol-Myers Squibb, Rocher/Genentech, EMD Serono, Eisai, Merck, Conflict with: Advisory Board - CytomX Therapeutics, Bristol-Myers Squibb, AstraZeneca, Bayer, Eisai, Roche, EMD Serono, Merck, Exelixis, Conflict with: Consulting - CytomX Therapeutics, Bristol-Myers Squibb, AstraZeneca, Bayer, Eisai, Roche, EMD Serono, Merck, Exelixis, B. El-Rayes Conflict with: Research/Education grant - AVEO, Boston Biomedical, Boston Biomedical, Boston Biomedical, Bristol-Myers Squibb, Bristol-Myers Squibb, Cleave Biosciences, Five Prime Therapeutics, Genentech, Hoosier Cancer Research Network, ICON Clinical Research, Merck, Novartis, Pfizer, PPD, Taiho Pharmaceutical, Conflict with: Honoraria - Bayer, Lexicon, RTI Health Solutions, Conflict with: Advisory Board - Bayer, BTG, Loxo, Merrimack, RTI Health Solutions, Conflict with: Consulting - Bayer, BTG, Loxo, Merrimack, RTI Health Solutions, K. Numata: None Declared, Y. Itoh Conflict with: Research/Education grant - Abbvie, Ajinomoto, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, Fujifilm, Gilead Sciences, GlaxoSmithKline, Kyorin, Merck Serono, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Nichinichi Pharmaceutical, Novo Nordisk, Ono Pharmaceutical, Otsuka, Sumitomo Dainippon, Takeda, Conflict with: Honoraria - Abbvie, Ajinomoto, Asahi Kasei, ASKA Pharmaceutical, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, Eisai, Fujifilm, Gilead Sciences, GlaxoSmithKline K.K., Janssen, Kowa, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mylan, Otsuka, Sanofi, Sumitomo Dainippon, Sysmex, Taiho Pharmaceutical, Taisho Toyama Pharma, Takeda, Tsumura & Co., Zeria Pharmaceutical, Conflict with: Advisory Board - Gilead Sciences, Conflict with: Consulting - Gilead Sciences, F. Taylor Conflict with: Consulting - Adelphi Values, G. Thompson Conflict with: Stocks - Bristol-Myers Squibb, S. Blum Conflict with: Stocks - Bristol-Myers Squibb, T. Wisniewski Conflict with: Stocks - Bristol-Myers Squibb, J. Anderson Conflict with: Stocks - Bristol-Myers Squibb, M. Kudo Conflict with: Research/Education grant - Chugai Pharma, Otsuka, Taiho Pharmaceutical, Daiichi

Introduction: Direct-acting antivirals (DAAs) are highly effective against hepatitis C virus (HCV) and sustained virologic response is associated with reduction in hepatocellular carcinoma (HCC) incidence. However, the use of DAAs in patients with active or treated HCC remains controversial, leading to uncertainty about optimal management of this patient population. Our aim was to characterize attitudes and practice patterns of hepatology practitioners in the United States (U.S.) regarding the use of DAAs in patients with HCC.

Methods: We conducted a web-based survey study of hepatology physicians and advanced practice providers (APPs) at 47 tertiary care centers across 25 states in the U.S. The primary outcome of interest was provider-reported practice patterns for DAA recommendations in patients with HCC based on responses to four clinical vignettes. Secondary outcomes included provider attitudes regarding use of DAAs in patients with HCC. We used Fisher’s exact and chi-square tests to identify factors associated with DAA therapy recommendations.

Results: We obtained 279 responses with a 58.6% (279 or 476) provider-level and 92.2% (47 of 51) institutional-level response rate. A majority of respondents were MD or DO providers, 50% were female and the sample was racially diverse. Most identified their primary practice location as a tertiary referral center with a transplant program (88.4%). Over 75% of providers had treated more than 50 total HCV patients with DAAs and 90% reported being directly involved in HCC management.Nearly 80% of providers believed DAAs reduced risk of incident (de novo) HCC in patients with cirrhosis. However, there was wider variation in provider beliefs surrounding risk of HCC recurrence after DAA therapy, with 48%, 36%, and 16% reporting DAAs reduce, do not change, and increase HCC recurrence risk, respectively. However, most providers believed DAAs are beneficial (97.5%) and likely reduce mortality (77.8%) in patients with complete response to HCC treatment. Accordingly, nearly all providers (94.9%) reported recommending DAA therapy in patients with early HCC who received curative treatment; however, fewer providers recommended DAA therapy in patients with intermediate (72.9%) or advanced (57.5%) HCC undergoing palliative therapies. Overall, timing of DAA initiation varied among providers based on HCC treatment modality; with 16.8% and 12.8% reporting they would initiate DAA therapy prior to treatment, 45.5% and 45.8% delaying DAA initiation between 3-12 months and 5.3% and 11.9% delaying DAA initiation >1 year for patients undergoing resection and transarterial chemoembolization (TACE), respectively. Nearly 40% of providers reported a willingness to treat advanced stage HCC patients if they had an objective response to treatment, and nearly 70% of providers said the treatment modality leading to HCC complete response would not impact their likelihood to recommend DAA therapy. MD and DO providers were significantly more likely than APPs to believe that DAAs reduce risk of incident HCC (84.5% vs. 66.3%, p=0.002); however, attitudes about HCC incidence or recurrence after DAAs did not otherwise differ by provider sex, race/ethnicity, years in practice, provider experience with HCV or HCC treatment, type of institution, or region of the U.S. in which they practiced.

Conclusions: There is variation in provider attitudes and practice patterns in the U.S. regarding use and timing of DAAs in patients with HCC, highlighting a need for further data characterizing the risks and benefits of DAA therapy in this patient population.


P-015 ADVANCED HEPATOCELLULAR CARCINOMA (HCC) TUMOR STAGE AT DIAGNOSIS AND POOR SURVIVAL REFLECT INEFFECTIVE IMPLEMENTATION OF HCC SCREENING AT FIVE UNDERSERVED, ETHNICALLY DIVERSE UNITED STATES SAFETY-NET HEALTH SYSTEMS

Robert Wong* 1, Amit Singal2, Patricia Jones3, Hicham Khallafi4, George Therapondos5, Caitlin Murphy6, Paulo Pinheiro7, Mae Thamer8

1Gastroenterology and Hepatology, Alameda Health System - Highland Hospital Campus, Oakland, 2Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, 3Division of Hepatology, Department of Medicine, University of Miami Miller School of Medicine, Miami, 4Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, 5Multi-Organ Transplant Institute, Ochsner Health System, New Orleans, 6Departments of Clinical Sciences and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 7Public Health Sciences, University of Miami Miller School of Medicine, Miami, 8Medical Technology and Practice Patterns Institute, Bethesda, United States

Introduction: Implementing routine hepatocellular carcinoma (HCC) screening among at risk individuals leads to earlier tumor stage at diagnosis and improves options for curative therapy and overall survival. Safety-net populations, which have high proportions of underserved ethnic minorities with low socioeconomic status, may face barriers to timely HCC screening, leading to more advanced HCC at diagnosis. We evaluated disparities in HCC outcomes across five safety-net health systems in the U.S. focusing on tumor stage at diagnosis, receipt of potentially curative therapy, and overall survival.

Methods: We retrospectively evaluated adults (age≥18 years) with HCC diagnosed from January 1, 2016 – December 31, 2016 across five safety-net health systems in the U.S. Methods of HCC diagnosis were categorized as via routine screening (screening) vs. patients who presented with symptoms or decompensation or were diagnosed via incidental findings on imaging performed

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Amgen, Antengene, Aptus Clinical, ASLAN Pharmaceuticals, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BioLineRx, Boston Scientific, BridgeBio Pharma, Bristol-Myers Squibb, CARsgen Therapeutics, CASI Pharmaceuticals, Celgene, Celsion, Cipla, Delcath Systems, Eisai, Eli Lilly, EMD Serono, Gilead Sciences, Genoscience Pharma, Halozyme, Hengrui Pharmaceutical, Ipsen, Janssen, Jazz Pharmaceuticals, Kyowa Hakko Kirin, LAM Therapeutics, Loxo, MedImmune, Merck Serono, Mina, NewLink Genetics, Novella Clinical, Onxeo, PCI Biotech, Pfizer, Pharmacyclics, PharmaCyte Biotech, Pieris Pharmaceuticals, QED, RedHill Biopharma, Roche, Sanofi, Servier, Silenseed, SillaJen, Sirtex Medical, Sobi, Targovax, Tekmira, twoXAR, Vicus Therapeutics, Yakult and Yiviva; travel/accommodation/expenses from Polaris

P-023 MIRNA-MRNA REGULATORY NETWORK AND FACTORS ASSOCIATED WITH PREDICTION OF PROGNOSIS IN HEPATOCELLULAR CARCINOMA

Bo Hu* 1, Pei-Yao Fu1, Qi-Man Sun1, Min-Cheng Yu1, Yang Xu1, Jian Zhou1, Jia Fan1

1Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

Introduction: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths in the world, accounting for approximately 662,000 deaths per year. Although etiological factors, including alcohol, hepatitis B/C virus, and aflatoxin B1, have been identified, the underlying comprehensive molecular pathogenesis of HCC carcinogenesis and prognosis is lacking.The aim of this study was to identify novel gene and miRNA biomarkers of risk and prognostic factors for hepatocarcinogenesis using systems biology methods. Differentially expressed genes (DEGs), miRNAs (DEmiRNAs), and lncRNAs were compared between hepatocellular carcinoma (HCC) tumour tissue and normal liver tissues in the Cancer Genome Atlas (TCGA) database.

Methods: Hepatocellular carcinoma data were downloaded from “TCGA-LIHC” project in the TCGA database (https://gdc-portal.nci.nih.gov/). Relations of lncRNA and mRNA were annotated as stated by the HUGO Gene Nomenclature Committee (HGNC) (http://www.genenames.org/). Weighted correlation network analysis (WGCNA) is a systems biology method used to identify clusters of highly correlated gene. miRTarBase (http://mirtarbase.mbc.nctu.edu.tw) and miRecords (http://c1.accurascience.com/miRecords/) databases contain extensive information about experimentally verified miRNA-target interactions. The prognosis-associated gene co-expression network, mRNA-miRNA, and mRNA-miRNA-lncRNA regulatory networks were constructed to identify biomarkers of risk for HCC through Cox survival analysis. Seven prognosis-associated gene co-expression modules were obtained by analysing these DEGs. Retrospective analysis was performed on 258 patients.

Results: An expression module including 120 genes significantly correlated with HCC patient survival. Combined with patient survival data, several mRNAs and miRNAs, including CHST4, SLC22A8, STC2, hsa-miR-326, and hsa-miR-21 were identified from the network to predict HCC patient prognosis. Clinical significance was investigated using tissue microarray analysis of samples from 258 patients with HCC. Functional annotation of hsa-miR-326 and hsa-miR-21-5p indicated specific associations with p53, FoxO and several other cancer-related signalling pathways.

Conclusions: The present study provides a bioinformatics method for biomarker screening, which led to the identification of an integrated mRNA-miRNA-lncRNA regulatory network and their co-expression in relation to predicting HCC patient survival. Five key molecules (CHST4, SLC22A8, STC2, hsa-miR-326, and hsa-miR-21) serve as potential markers of prognosis in HCC potentially through regulation of p53 and FoxO signalling. Further mechanistic studies focusing on these genes and miRNAs are needed to understand the underlying causes of hepatocarcinogenesis.


P-024 THE MECHANISM OF ITGB3/SRC FROM PLATELET-EXOSOMES ON REGULATING CD155+ CIRCULATING TUMOR CELLS TO PROMOTE IMMUNE ESCAPE AND ITS CLINICAL SIGNIFICANCE AS A NEW BIOMARKER IN HEPATOCELLULAR CARCINOMA

Yang Wenjing* 1

1Zhongshan Hospital, affiliated Fudan University, Shanghai, China

Introduction: Immune escape of circulating tumor cell (CTC) mediated by platelets is the basis for CTC survival, proliferation, and metastasis of tumor. However, the specific mechanism of platelet-mediated CTC immune escape in hepatocellular carcinoma has not been clarified. We investigated how platelets promote CTC immune escape.

Methods: the 156 of CTCs were analyzed by single-cell sequencing. Exosomes from tumor cell and platelet-tumor cell co-culture supernatants were performed protein chips analysis, respectively. This was used to screen changes in related immune checkpoints and to explore potential molecules that promoted CTC immune escape by platelets. Mass spectrometry and bioinformatics were used to analyze the specific molecular mechanisms by which platelets regulate CTC immune escape. The transgenic mouse models (Cre-Loxp models) were combined with immunofluorescence and flow cytometry to observe changes in immune escape phenotypes of CTC survival in blood vessels.

P-021 MATCHING-ADJUSTED INDIRECT COMPARISON OF CABOZANTINIB VERSUS REGORAFENIB IN ADVANCED HEPATOCELLULAR CARCINOMA

Robin Kate Kelley* 1, Patrick Mollon2, Jean-Frederic Blanc3, Bruno Daniele4, 5, Thomas Yau6, Ann-Lii Cheng7, Velichka Valcheva8, Antonio Remiro Azocar9, Gianluca Baio9, Yuxin Li10, Abou-Alfa K. Ghassan11

1UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States, 2Ipsen Pharma SAS, Boulogne-Billancourt, 3Hôpital Haut-Lévêque, Bordeaux, France, 4Azienda Ospedaliera G Rummo Benevento, Benevento, 5Ospedale del Mare, Naples, Italy, 6The University of Hong Kong, Hong Kong, Hong Kong, 7National Taiwan University Hospital and National Taiwan University Cancer Center, Taiwan, China, 8Ipsen, Boulogne-Billancourt, France, 9University College London, 10IQVIA World Publications Ltd, London, United Kingdom, 11Memorial Sloan Kettering Cancer Center, New York, United States

Introduction: Advanced hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. First-line therapy is either sorafenib or lenvatinib. Cabozantinib and regorafenib have demonstrated survival benefit in second-line treatment of advanced HCC. However, there is no head-to-head trial comparing these two treatment options. The aim of this matching-adjusted indirect comparison (MAIC) was to compare the safety and efficacy of cabozantinib and regorafenib for patients with HCC who have received sorafenib as the only prior systemic therapy.

Methods: The study used data from two pivotal trials with cabozantinib (CELESTIAL; N=707; NCT01908426) or regorafenib (RESORCE; N=573; NCT01774344) in patients with HCC who had progressed on prior sorafenib. In CELESTIAL, up to two previous systemic treatments were allowed. Using MAIC, individual-level data (ILD) from patients enrolled in CELESTIAL who had received sorafenib as the sole prior therapy (N=495) were adjusted to match the average baseline (BL) characteristics of the 573 patients enrolled in RESORCE, for which ILD are not available. Before matching, trial populations differed in several BL characteristics deemed potential effect modifiers by clinical experts. After MAIC, the selected BL characteristics were balanced across trials. To compare survival outcomes, ILD were simulated for regorafenib using the published Kaplan-Meier (KM) curves for the RESORCE trial. Parametric distributions were fitted to the ILD to model progression-free survival (PFS) and overall survival (OS). Grade 3/4 treatment-emergent drug-related adverse events (AEs) affecting >5% of patients in any arm of either CELESTIAL or RESORCE were compared. These AEs were: hypertension, aspartate aminotransferase increase, fatigue, diarrhea, palmar-plantar erythrodysesthesia and elevated bilirubin.

Results: After balancing BL characteristics, the weighted KM curves for patients receiving cabozantinib or regorafenib as the second-line treatment were associated with a median (95% Confidence Interval) PFS of 5.59 (4.90–7.26) months and 3.19 (2.78–4.14) months, respectively (p<0.05, log-rank test); median OS for cabozantinib and regorafenib were 11.37 (8.90–16.95) months and 10.79 (9.18–12.30) months, respectively (p>0.05, log-rank test). Upon fitting and extrapolating the selected models, cabozantinib treatment was associated with longer median PFS and OS than regorafenib. The median PFS estimate was 5.49 (4.92–6.13) months for cabozantinib vs 3.39 (3.05–3.78) months for regorafenib; median OS was 11.40 (10.01–12.96) months for cabozantinib vs 10.29 (9.15–11.56) months for regorafenib. Estimates for safety outcomes were affected by very small counts in the data, particularly in the placebo arms, giving rise to large confidence intervals. An unanchored estimate for the log odds ratio of diarrhea showed statistically significant differences at the 5% level. Regorafenib was associated with lower rates of diarrhea compared with patients receiving cabozantinib as the second-line treatment.

Conclusions: In patients who received second-line treatment after sorafenib and were matched for BL characteristics, cabozantinib was associated with prolonged median PFS and OS compared with regorafenib, whereas regorafenib was associated with lower rates of diarrhea than cabozantinib. However, even after matching, bias may still occur in MAIC due to imbalance in unobserved factors, and it cannot replace a head-to-head randomized control trial.

Disclosure of Interest: R. K. Kelley Conflict with: Research/Education grant - Adapttimmune, Agios, AstraZenica, Bayer, Bristol-Meyer Squibb, Celgene, Exelisix, Lilly, MedImmune, Merck Sharpe & Dohme Novartis, Regeneron, Sanfi, Tekmira, Taiho Pharmaceutical, Conflict with: Consulting - Agios, AstraZeneca, Bayer, Bristol-Myers Squibb, Debiopharm group, Genentech/Roche, TRGET pharmaSolutions, P. Mollon Conflict with: Consulting - Employee of Ipsen, J.-F. Blanc Conflict with: Consulting - Ipsen, Bayer, Lilly, Esai, B. Daniele Conflict with: Honoraria - Bayer, Eisai, Lilly, Ipsen, BMS, Conflict with: Consulting - Ipsen, Eisai, Incyte, MSD, T. Yau Conflict with: Honoraria - BMS, MSD, Eisai, Bayer, A.-L. Cheng Conflict with: Advisory Board - AstraZeneca, Bayer and Eli Lilly, Conflict with: Consulting - Acta Biologica, Agios, Array BioPharma, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, CASI Pharmaceuticals, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, MedImmune, Momenta Pharmaceuticals, Novartis, OncoMed, OncoQuest, Polaris, Puma Biotechnology, QED and Roche, V. Valcheva Conflict with: Consulting - Employee of Ipsen, A. Remiro Azocar Conflict with: Consulting - Iqvia, G. Baio Conflict with: Research/Education grant - University College London, Y. Li Conflict with: Consulting - Ipsen, A.-A. Ghassan Conflict with: Research/Education grant - Acta Biologica, Agios, Array BioPharma, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, CASI Pharmaceuticals, Celgene, Exelixis, Genentech, Halozyme, Incyte, Lilly, MabVax, MedImmune, Momenta Pharmaceuticals, Novartis, OncoMed, OncoQuest, Polaris, Puma Biotechnology, QED and Roche, Conflict with: Consulting - 3DMedcare, Agios, Alignmed,

1University of Glasgow, Glasgow, United Kingdom, 2Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan, 3Department of Internal Medicine and Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan, Province of China, 4Medical Oncology Department, 12 de Octubre University Hospital , Madrid, Spain, 5Ospedale del Mare, Napoli, Italy, 6Musashino Red Cross Hospital Musashino, Tokyo, 7Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, 8Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 9British Columbia Cancer Vancouver, Vancouver, Canada, 10Department of Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China, 11E-Da Cancer Hospital, Kaohsiung, Taiwan and Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, Province of China, 12Tampa General Hospital, Tampa, 13Eisai Inc., Woodcliff, 14Tisch Cancer Institute at Mount Sinai, Mount Sinai, United States

Introduction: LEN is a multityrosine kinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFR-alpha, RET, and KIT. It is approved for first-line use in patients with uHCC based on REFLECT, a multicenter, open-label, phase 3 trial that demonstrated a treatment effect on overall survival (OS) by statistical confirmation of noninferiority versus SOR. NLR, a subclinical marker of inflammation, is a strong prognostic marker for OS in patients with HCC. Previous analyses examined several covariates that may be predictive of the OS benefit in response to LEN; this study focuses on NLR.

Methods: To determine the effect of NLR in the REFLECT study, a post hoc analysis stratified by NLR was performed. Kaplan-Meier estimates of median progression-free survival (mPFS) and mOS per investigator assessment for patients in the LEN or SOR treatment groups with an NLR of ≤3 versus >3 were assessed.

Results: The median baseline NLR for the overall study population was 2.91, and 2.92 and 2.91 in the LEN and SOR arms, respectively. Hazard ratios (95% confidence intervals [CI]) indicated that mOS was better across all groups with NLR ≤3 vs NLR >3 (Table). In a subanalysis of patients who responded to therapy, the median NLR decreased by 14.6% with LEN compared with a decrease of 3.3% with SOR (change from baseline to 1-month posttreatment in responders; to median NLR=2.39 with LEN compared to median NLR=2.67 with SOR). Moreover, in a covariate analysis of treatment adjusted by baseline NLR (>3 and ≤3), the HR for treatment (LEN vs SOR) is 0.88 (95% CI: 0.76–1.03) for OS and 0.65 (95% CI: 0.55–0.76) for PFS.

LEN SOR

NLR ≤3(n=250)

NLR >3(n=225)

NLR ≤3 (n=216)

NLR >3(n=255)

mPFS, months 8.6 6.9 4.6 3.6

HR (95% CI) 0.88 (0.715-1.090) 0.80 (0.650-0.983)

mOS, months 16.2 11.2 16.0 9.3

HR (95% CI) 0.69 (0.555-0.847) 0.60 (0.484-0.740)

Conclusions: In this post hoc exploratory analysis of patients with uHCC from REFLECT, median NLR ≤3 was associated with better mOS compared with median NLR >3, regardless of treatment. LEN was associated with numerically higher mPFS, mOS, and a greater percent decrease in posttreatment NLR, compared with SOR.

Disclosure of Interest: T. J. Evans Conflict with: Research/Education grant - support from Eisai, Bristol-Myers Squibb, GlaxoSmithKIine, Roche, Genentech, Celgene, TC Biopharm, Merck, Novartis, e-Therapeutics, Vertex, Verastem, Daiichi, AstraZeneca, Basilea, Immunocore, Chugai for sponsored clinical trials (payable to the institution), Conflict with: Honoraria - reports honoraria from Eisai, Bristol-Myers Squibb, Bayer, GlaxoSmithKline, Roche/Genentech for advisory boards and speaker’s bureau (payable to his institution), Conflict with: Advisory Board - support to attend international scientific conferences from Bristol-Myers Squibb, Roche/Genentech, Bayer, Merck, Eisai, M. Kudo Conflict with: Research/Education grant - reports grants/research support from Bayer, Daiichi Sankyo, Chugai, Otsuka, Taiho, Sumitomo Dainippon, and Merck Sharp & Dohme Corp, Conflict with: Honoraria - received honoraria from Bayer, Eisai, Merck Sharp & Dohme Corp, BMS, and EA Pharma, Conflict with: Consulting - consulting/advisory role for Bayer and Eisai, A.-L. Cheng Conflict with: Consulting - reports personal fees for consulting/advisory role for BMS, Ono, Novartis, Bayer, Merck, and Merck Sharp & Dohme Corp., C. Gomez-Martin Conflict with: Consulting - consulting or advisory role for BMS, EISAI, ROCHE, B. Daniele Conflict with: Honoraria - from BMS, Bayer, Conflict with: Consulting - consulting or advisory role for MSD, Eisai, Bayer, Lilly, Ipsen, N. Izumi Conflict with: Honoraria - speaker bureau for Bayer, Eisai, T. Yamashita Conflict with: Honoraria - speaker bureau for Bayer, Eisai, R. Tateishi Conflict with: Research/Education grant - funded by Kyowa Hakko Kirin, Conflict with: Honoraria - speaker bureau for Eisai, Bayer, MSD, Sumitomo-Dainihon Phama, Conflict with: Consulting - consulting or advisory role for Eisai Co. Ltd., Bayer Yakuhin, H. Lim: None Declared, S. Chan: None Declared, K.-M. Rau Conflict with: Honoraria - speaker bureau for Eisai, A. Alsina Conflict with: Honoraria - speaker bureau for Eisai, Conflict with: Advisory Board - for Eisai, Conflict with: Consulting - for Eisai, S. Misir: None Declared, C. Dutcus: None Declared, M. Sung Conflict with: Consulting - Consulting or advisory role for Bayer, Eisai, Exelixis Conflict with: for Eisai, Conflict with: for Eisai, S. Misir: None Declared, C. Dutcus: None Declared, M. Sung Conflict with: Consulting or advisory role for Bayer, Eisai, Exelixis

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response was assessed by independent review according to both Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and modified RECIST.

Results: Patients were 41 to 74 years of age, and 80% were male. All patients had Child-Pugh class A hepatic function before SBRT. The median follow-up period of all patients was 47.8 months (range, 2.9 – 70.6), and the median tumor size was 1.3 cm (interquartile range, 1.0 – 1.7). The 2- and 5-year local control rates were 100% and 97.1%, respectively. The 5-year overall survival rate was 77.6%. A radiologic response was achieved in 44 (83%) lesions according to RECIST and in 49 (92.4%) according to modified RECIST at 6 months after SBRT. Any grade ≥3 acute or late adverse events were not observed in all patients. Two (4%) patients experienced elevation in the Child-Pugh score to ≥2.

Conclusions: SBRT was an excellent ablative treatment with acceptable toxicities for patients with small HCC. SBRT can be a good treatment option for HCC in both curative and salvage settings that is unsuitable for curative treatment.


P-019 INTRA-TUMOUR HETEROGENEITY IN THE REGULATION OF IMMUNE-TOLEROGENIC PATHWAYS IN PRIMARY AND METASTATIC HEPATOCELLULAR CARCINOMA.

David James Pinato* 1, Stephane Victor1, Paolo Spina1, Pritesh Trivedi2, Mario Pirisi3, Michela E. Burlone4, James Black1, Renzo Boldorini5, Francesco A. Mauri1, Rohini Sharma1

1Surgery and Cancer, Imperial College London, 2Histopathology, Imperial College NHS Trust, London, United Kingdom, 3Translational Medicine, Universita Piemonte Orientale, 4Department of Translational Medicine, Universitá degli Studi del Piemonte Orientale “A. Avogadro”, 5Histopathology, Universita Piemonte Orientale, Novara, Italy

Introduction: Immune-checkpoint inhibitors targeting the programmed-death (PD) pathway and its ligands (PD-Ls) have shown preliminary evidence of activity in hepatocellular carcinoma (HCC), with variable response rates. Whilst PD-L1 status is utilised as a stratifying biomarker in clinical trials, evidence from other solid tumours suggests heterogeneity in PD ligands expression across sampled sites, with implications in the development of immunotherapy.

Methods: We collected archival paraffin embedded samples from 77 patients across 2 institutions: 56 with surgically resected and 21 with intermediate/advanced HCC. In 15 cases a total of 20 matching metastatic deposits was available for analysis. Surgical samples were re-embedded in a tissue microarray including tumour tissue and surrounding cirrhotic background and were analysed for PD-L1 and PD-L2 expression by immunohistochemistry. Following total RNA extraction, we performed targeted transcriptomic analysis by Nanostring technology using a panel of 770 immune-related genes in 12 paired primary and metastatic HCC cores from 6 patients.

Results: Surgically resected cases were predominantly Child A (51/56, 91%), BCLC stage A (45/56, 80%). In resected tumour cores 11/56 (20%) were PD-L1 and 18/56 (32%) were PD-L2 positive. Surrounding cirrhotic liver revealed PD-L1 in the lymphocytic infiltrate in 8/56 samples (14%), whilst PD-L2 expression was found in the cirrhotic background in 29/56 cases (52%). PD-L2 expression in cirrhotic (p=0.03) but not in tumour cores (p=0.13) correlated with more advanced BCLC stage. In patients with intermediate-advanced HCC (n=21), the prevalence of tumour PD-Ls expression was 40% (8/21) for both markers. Concordance between PD-L1 positive primary and metastases was 33% and 85% in PD-L1 negative tumours. In contrast, there was universal concordance between in PD-L2 expression between primary and metastatic HCC (p<0.001). Targeted transcriptomic profiling revealed a subset of 40 genes involved in innate and adaptive immunity to be differentially regulated across primary and metastatic disease.

Conclusions: Intra-tumour heterogeneity in the expression of PD-L1 is common in HCC, whilst PD-L2 is homogeneously distributed in primary and metastatic deposits. Unsupervised transcriptomic profiling confirms differential activation of innate and adaptive immune-related pathways in the metastatic dissemination of liver cancer. This has profound implications in the clinical development of immune response biomarkers in HCC.

References: Challenges and opportunities in the clinical development of immune checkpoint inhibitors for hepatocellular carcinoma. Flynn MJ, Sayed AA, Sharma R, Siddique A, Pinato DJ. Hepatology. 2018 Nov 1.


P-020 A POST HOC ANALYSIS OF NEUTROPHIL-LYMPHOCYTE RATIOS (NLR) IN THE REFLECT STUDY: FIRST-LINE LENVATINIB (LEN) OR SORAFENIB (SOR) IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (UHCC).

TR Jeffry Evans* 1, Masatoshi Kudo2, Ann-Lii Cheng3, Carlos Gomez-Martin4, Bruno Daniele5, Namiki Izumi6, Tatsuya Yamashita7, Ryosuke Tateishi8, Howard J. Lim9, Stephan L. Chan10, Kun-Ming Rau11, Angel Alsina12, Soamnauth Misir13, Corina Dutcus13, Max W. Sung14

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B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 3 7I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S 3 6

2. Altekruse, S. F., McGlynn, K. A. & Reichman, M. E. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 27, 1485–1491 (2009).

3. Heimbach, J. K. et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 67, 358–380 (2018).

4. Vogel, A. et al. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 29, iv238-iv255 (2018).

5. Chen, M.-S. et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann. Surg. 243, 321–328 (2006).

6. N’Kontchou, G. et al. Radiofrequency ablation of hepatocellular carcinoma: long-term results and prognostic factors in 235 Western patients with cirrhosis. Hepatology 50, 1475–1483 (2009).

7. Tateishi, R. et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 103, 1201–1209 (2005).

8. Waki, K. et al. Percutaneous radiofrequency ablation as first-line treatment for small hepatocellular carcinoma: results and prognostic factors on long-term follow up. J. Gastroenterol. Hepatol. 25, 597–604 (2010).

9. Granata, V. et al. Surveillance of HCC Patients after Liver RFA: Role of MRI with Hepatospecific Contrast versus Three-Phase CT Scan-Experience of High Volume Oncologic Institute. Gastroenterol. Res. Pract. 2013, 469097 (2013).

10. Doyle, A. et al. Outcomes of Radiofrequency Ablation as First-Line Therapy for Hepatocellular Carcinoma less than 3 cm in Potentially Transplantable Patients. J. Hepatol. (2019). doi:10.1016/j.jhep.2018.12.027

11. Rossi, S. et al. Repeated radiofrequency ablation for management of patients with cirrhosis with small hepatocellular carcinomas: a long-term cohort study. Hepatology 53, 136–147 (2011).

12. Yokoyama, K. et al. Limitation of repeated radiofrequency ablation in hepatocellular carcinoma: proposal of a three (times) x 3 (years) index. J. Gastroenterol. Hepatol. 27, 1044–1050 (2012).

13. Wahl, D. R. et al. Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma. J. Clin. Oncol. 34, 452–459 (2016).

14. Feng, M. et al. Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage: A Phase 2 Clinical Trial. JAMA Oncol. 4, 40–47 (2018).

15. Rajyaguru, D. J. et al. Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database. J. Clin. Oncol. 36, 600–608 (2018).

16. Parikh, N. D. et al. Effectiveness and cost of radiofrequency ablation and stereotactic body radiotherapy for treatment of early-stage hepatocellular carcinoma: An analysis of SEER-medicare. J. Med. Imaging Radiat. Oncol. 62, 673–681 (2018).

17. Pollom, E. L. et al. Cost-effectiveness of Stereotactic Body Radiation Therapy versus Radiofrequency Ablation for Hepatocellular Carcinoma: A Markov Modeling Study. Radiology 283, 460–468 (2017).

18. Lencioni, R. & Llovet, J. M. Modified RECIST ( mRECIST ) Assessment for Hepatocellular Carcinoma. Semin. Liver Dis. 30, 52–60 (2010).

19. Peng, Z.-W. et al. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial. J. Clin. Oncol. 31, 426–432 (2013).

20. National Institute of Health. Common Terminology Criteria for Adverse Events ( CTCAE ). NIH Publ. 0, 0–71 (2010).

21. Yanaga, K. Central bisectionectomy (bisegmentectomy) of the liver (with video). J. Hepatobiliary. Pancreat. Sci. 19, 44–47 (2012).

22. Ripatti, S. & Palmgren, J. Estimation of multivariate frailty models using penalized partial likelihood. Biometrics 56, 1016–1022 (2000).

23. Song, K. D. et al. Repeated Hepatic Resection versus Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma after Hepatic Resection: A Propensity Score Matching Study. Radiology 000, 1–10 (2015).

24. Sapisochin, G. et al. Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis. J. Hepatol. 67, 92–99 (2017).

25. Moore, A. et al. Stereotactic body radiation therapy (SBRT) for definitive treatment and as a bridge to liver transplantation in early stage inoperable Hepatocellular carcinoma. Radiat. Oncol. 12, 163 (2017).

26. Takeda, A. et al. Stereotactic ablative body radiotherapy for previously untreated solitary hepatocellular carcinoma. J. Gastroenterol. Hepatol. 29, 372–379 (2014).

27. Seo, Y.-S. et al. Radiofrequency ablation versus stereotactic body radiotherapy for small hepatocellular carcinoma: a Markov model-based analysis. Cancer Med. 5, 3094–3101 (2016).

28. Lee, S. et al. Evaluation of Hepatic Toxicity after Repeated Stereotactic Body Radiation Therapy for Recurrent Hepatocellular Carcinoma using Deformable Image Registration. Sci. Rep. 8, 16224 (2018).

29. Chang, W.-T. et al. Hepatic resection can provide long-term survival of patients with non-early-stage hepatocellular carcinoma: extending the indication for resection? Surgery 152, 809–820 (2012).

30. Forner, A., Llovet, J. M. & Bruix, J. Hepatocellular carcinoma. Lancet (London, England) 379, 1245–1255 (2012).

31. KANG, J. et al. Stereotactic body radiotherapy combined with transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombosis. Mol. Clin. Oncol. 2, 43–50 (2014).

Results: Of 164 patients with HCV+ treated with DAAs, 40.2% and 59.8% were treated before and after transplantation, respectively. The most frequent genotype was 1b (28.7%), Sofosbuvir/ Daclatasvir was the most frequent DAAs regimen and overall sustained virological response was 89.8% (treated pre-LT 90.6% and post-LT 89.2%; P=0.78). Overall cumulative incidence of combined primary event in the entire cohort was 25.8% (CI 23.1%>28.7%); being significantly lower in HCV+ patients treated with DAAs 18.9% (CI 13.2%>25.7%) when compared to those HCV+ not treated with DAAs 32.7% (CI 27.7%>38.1%) and those patients HCV- 23.8% (CI 20.2%>27.8%). This effect remained statistically significant after adjusting for waiting list and explanted liver variables, as well as after adjusting for the propensity score matching of receiving/not receiving DAAs with a SHR of 0.68 (CI 0.46-1.02; P=0.06) with respect to those HCV- and significant with respect to those untreated HCV+ SHR of 0.41 (0.27;0.61; P<.0001).

Conclusions: The use of direct-acting antivirals for the treatment of HCV in patients with HCC listed for transplantation does not seem to be associated with an increased risk of tumor progression during the waiting list or recurrence after LT.


P-027 STEREOTACTIC BODY RADIOTHERAPY AS A SALVAGE THERAPY AFTER INCOMPLETE RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA: A RETROSPECTIVE PROPENSITY SCORE MATCHING STUDY

Yangxun Pan* 1, Yaojun Zhang1

1Hepatobiliary pancreatic surgery, Sun Yan-sen University Cancer Center, Guangdong, China

Introduction: Incomplete response after initial radiofrequency ablation (RFA), known as residual hepatocellular carcinoma (RHCC), is a critical risk factor for worse prognosis. Data guiding treatment allocation of RHCC is lacking. We therefore compared outcomes between stereotactic body radiotherapy (SBRT) and RFA for RHCC.

Methods: From 2008 to 2016, 139 patients reported RHCC after postoperative checkup among which 39 and 33 patients underwent RFA or SBRT as salvage treatments respectively. We applied propensity score matching (PSM) to adjust for imbalances in treatment assignment. Progression free survival (PFS), overall survival (OS) and treatment related side effects were retrospectively analyzed.

Results: RFA and SBRT groups were significant different regarding platelet (mean, 107.0 vs. 137.0 *109/L; P=0.038), tumor size (mean, 2.1 vs. 4.1 cm in maximum diameter; P<0.001) and tumor location (P=0.001). The SBRT group demonstrated significantly lower local disease progression rate (6/33 vs. 23/39; P=0.002), better PFS (the 1- and 3-year PFS were 41.5% and 22.3% in RFA group vs. 63.3% and 49.3% in SBRT group respectively, P=0.036), and comparable OS (the 1- and 3-year OS were 97.3% and 57.6% in RFA group vs. 85.4%, and 71.1% in SBRT group respectively, P=0.680). Similar results were observed after PSM. Tumor located central predicted worse OS [hazard ratio =2.79; P=0.032]. No acute grade 3+ toxicity was observed after SBRT.

Image:

Conclusions: SBRT achieved better local control and PFS, and comparable OS. SBRT could be the preferred treatment for RHCC patients who had larger tumor or abutting to major vessels, rather than repeated RFA.

References: 1. Njei, B., Rotman, Y., Ditah, I. & Lim, J. K. Emerging trends in hepatocellular carcinoma incidence

and mortality. Hepatology 61, 191–199 (2015).

P-026 TREATMENT WITH DIRECT-ACTING ANTIVIRALS DOES NEITHER INCREASE THE RISK OF HEPATOCELLULAR CARCINOMA PROGRESSION DURING WAITING LIST NOR RECURRENCE AFTER LIVER TRANSPLANTATION

Federico Piñero* 1, 2, Ilka Boin3, Aline Chagas4, Emilio Quiñonez5, Sebastián Marciano6, 7, Mario Vilatoba8, Adriana Varón9, Margarita Anders10, Sergio Hoyos Duque11, 12, Agnaldo Soares Lima13, Josemaría Menéndez14, Martín Padilla-Machaca15, Jaime Poniachik16, Rodrigo Zapata17, Martín Barrabino18, Ricardo Chong Menéndez19, Linda Muñoz Espinosa20, Pía Raffa21, Rodrigo Figueroa22, Martín Fauda1, Leticia Zanaga23, Claudia Maccali4, Rodrigo Vergara Sandoval5, Carla Bermúdez6, Oscar Beltrán9, Isabel Arenas11, Solange Gerona24, José Chaman15, Alexis Iracheta25, Alexandra Ginesta26, Adrian Gadano6, Juan Mattera5, Raquel Silveira Bello Stucchi23, Flair Carrilho4, Marcelo Silva1, 27

1Liver Unit, Hospital Universitario Austral, Pilar, 2Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina, 3Liver Transplantation, Hospital das Clínicas UNICAMP Campiñas, Campiñas, 4Hepatology and Gastroenterology, Hospital das Clínicas University of São Paulo School of Medicine, São Paulo, Brazil, 5Liver Transplantation and Hepatobiliary Surgery, Hospital El Cruce, Florencia Varela, 6Hepatology Section., 7Department of Clinical Research, Hospital Italiano, Buenos Aires, Argentina, 8Liver Transplantation and Hepatobiliary Surgery, Instituto de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico DF, Mexico, 9Hepatology and Gastroenterology, Fundación Cardioinfantil, Bogotá, Colombia, 10Liver Transplantation and Hepatobiliary Surgery, Hospital Alemán, Buenos Aires, Argentina, 11HPB and Liver Transplant Program, Hospital Pablo Tobón Uribe, 12Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia, 13Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas da UFMG, Minas Gerais, Brazil, 14Liver Transplantation and Hepatology, Hospital de Clínicas, Montevideo, Uruguay, 15Departamento de Trasplantes, Hospital Nacional Guillermo Almenara, Lima, Peru, 16Hepatology and Gastroenterology, Hospital de la Universidad de Chile, 17Hepatology and Gastroenterology, Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile, 18Hepatology and Gastroenterology, Hospital Privado, Córdoba, Argentina, 19Hepatology, Hospital Metropolitano, Quito, Ecuador, 20Hepatology, Hospital Universitario “Dr. José E. González”, Monterrey, Mexico, 21Liver Unit, Sanatorio Sagrado Corazón, Buenos Aires, 22Liver Transplantation and Hepatobiliary Surgery, Sanatorio Allende, Córdoba, Argentina, 23Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas UNICAMP Campiñas, Campiñas, Brazil, 24Liver Unit, Hospital de Clínicas, Montevideo, Uruguay, 25Hepatology and Gastroenterology, Hospital Clínico de la Universidad de Chile, 26Hepatology and Gastroenterology, Clinica Alemana, Santiago, Chile, 27Latin American Liver Research and Awareness Network, Buenos Aires, Argentina

Introduction: Uncertainty of treating or not treating hepatitis C virus (HCV) before or after liver transplantation in patients with hepatocellular carcinoma (HCC) with direct-acting antivirals (DAAs) has recently been established from observational studies due to an unexpected increased risk of tumor progression. Our objective was to evaluate the impact of treatment with DAAs in both, HCC tumor progression during waiting list and post-LT recurrence.

Methods: In this multicenter cohort study from Latin America, three cohorts of patients listed for LT with HCC between years 2011-2018 were compared: COHORT 1 without HCV (n=503), COHORT 2 HCV+ untreated with DAAs (n=327) and COHORT 3 HCV+ treated with DAAs (n=164). Primary end-point analysis was a composite end-point of HCC tumor progression by RECIST 1.1 (PD) and/or post LT recurrence evaluated with the intention-to-treat principle. A multivariable competing risks analysis was performed, with Sub-Hazard Ratios (SHR) and 95% confidence intervals (95% CI) calculations. Treatment effect with DAAs was adjusted by the probability of receiving or not receiving DAAs in the HCV+ population (propensity score matching).

Image:

Results: We found that high expression of CD155 on CTC surface is a key factor in protecting CTC from immune cell killing. Platelets have the ability to release exosomes, which are potential mediators of communication between platelets and circulating tumor cells. Platelets are delivered to the CTC by releasing exosomes containing ITGB3 and Src. As a adaptor protein of Src and CD155, ITGB3 promotes Src direct phosphorylation of CD155 in CTC, enhancing its protein stability and its function, thereby promoting CTC immune escape.

Conclusions: Upregulation of CD155 expression on CTC surface by platelets plays a key role in the immune escape of liver cancer. Future targeting of CD155 therapy is an effective measure to eliminate circulating CTC and reduce the risk of liver cancer metastasis and recurrence.


P-025 MAJOR IMPACT OF PERSONALIZED DOSIMETRY ON THE TARGETED TUMOR RESPONSE USING 90Y LOADED GLASS MICROSPHERES SIRT IN HCC: RESULTS OF A PROSPECTIVE AND MULTICENTRIC RANDOMIZED STUDY

Etienne Garin1, Lambros Tselikas2, Boris Guiu3, Julia Chalaye4, Julien Edeline* 5, Sophie Laffont1, Corentin Robert6, Thierry de Baère2, Christophe Cassinotto3, Vania Tacher7, M Terroir-Cassou-Mounat1, Fayçal Ben Bouallègue8, Giuliana Amaddeo9, Xavier Palard1, Boris Campillo-Gimenez10, Yan Rolland6

1Nuclear Medicine, Centre Eugene Marquis-Rennes, Rennes, 2Radiology, Gustave Roussy, Villejuif, 3Radiology, CHU Montpellier, Montpellier, 4Nuclear Medicine, AP-HP Henri Mondor, Créteil, 5Medical Oncology, 6Radiology, Centre Eugene Marquis-Rennes, Rennes, 7Radiology, AP-HP Henri Mondor, Créteil, 8Nuclear Medicine, CHU Montpellier, Montpellier, 9Hepatology, AP-HP Henri Mondor, Créteil, 10Methodology, Centre Eugene Marquis-Rennes, Rennes, France

Introduction: Previous retrospective studies suggested that in patients with Hepatocellular carcinoma (HCC) treated with Selective Internal Radiation Therapy (SIRT), also known as radioembolization, the tumor absorbed dose (TD) was associated with response. Specifically, with 90Y loaded glass microsphere, a threshold of 205Gy was defined (1). A personalized dosimetric approach was previously developed to increase the activity injected to reach the TD of 205Gy, in order to improve results (2).The goal of this randomized multicentric study was to demonstrate that this personalized dosimetric approach improved response rate (RR) over a standard dosimetric approach.

Methods: 56 HCC patients with at least one lesion larger than 7cm (index lesion) were included and treated by SIRT. Treatment arm was randomly assigned (1:1). In the standard dosimetric arm (SDA) the goal was to deliver 120±20Gy to the treated volume. In the personalized dosimetric arm (PDA) the goal was to deliver at least 205Gy to the index lesion, intensification with a dose >150Gy to the treated volume was allowed but without exceeding 120Gy to the healthy treated liver. Dosimetry was based on MAA SPECT/CT. Response of the index lesion was evaluated at 3 month using EASL criteria.

Results: 28 patients were included in each arm. Portal Vein Tumoral Thrombosis was present in 68% and 75%, mean size of the lesions were 10.5 and 10.9, mean liver involvement were 23.0% and 25.6%, in the PDA and SDA, respectively. RR was significantly increased in the PDA versus the SDA, respectively 71.4% and 35.7%, p=0.007. Results were confirmed by central review, respectively 78.6% vs 42.9%, p=0.006. Mean tumor dose (MTD) was significantly higher in the PDA versus the SDA, respectively 342±131Gy and 221±139Gy, p=0.003. MTD was significantly higher for responding lesions vs non responding ones, respectively 337±145Gy and 210±118Gy, p=0.002. These results were confirmed by centralized dosimetric review. RR was significantly higher for TD >205Gy vs TD<205 (irrespective of randomization arm), respectively 76.6% and 22.2%, p=0.0002. Two early deaths (occurring within 3m from SIRT) were reported in the SDA and none in the PDA. Survival results will be available with further follow-up of the study.

Conclusions: MAA SPECT/CT based personalized dosimetry with intensification is safe and significantly highly increases the response rate of large HCC. Results of previously reported phase 3 trials should be analyzed and interpreted according to adequate dosimetric evaluation. Personalized dosimetry has to be used in new RCT trials evaluating SIRT efficacy.

References: (1) Garin et al. Liver Int 2017 ; (2) Garin et al. Eur J Nucl Med 2013

Disclosure of Interest: E. Garin Conflict with: Research/Education grant - BTG, Conflict with: Honoraria - BTG, Conflict with: Advisory Board - BTG, L. Tselikas: None Declared, B. Guiu: None Declared, J. Chalaye: None Declared, J. Edeline Conflict with: Research/Education grant - BTG, Conflict with: Honoraria - BTG, S. Laffont: None Declared, C. Robert: None Declared, T. de Baère: None Declared, C. Cassinotto: None Declared, V. Tacher: None Declared, M. Terroir-Cassou-Mounat: None Declared, F. Ben Bouallègue: None Declared, G. Amaddeo: None Declared, X. Palard: None Declared, B. Campillo-Gimenez: None Declared, Y. Rolland Conflict with: Honoraria - BTG, Conflict with: Advisory Board - BTG

Posters Posters


Results: A total of 28 prospective cohort studies with 8,135,906 subjects were included in the final analysis. These included 22 studies with 6,059,561 subjects for cancer occurrence and 7 studies with 2,077,425 subjects for cancer-related mortality. In the meta-analysis, an increase in BMI was associated with the occurrence of primary liver cancer (pooled HR 1.69, 95% confidence interval [CI]: 1.50-1.90, I2 = 56%). A BMI-dependent occurrence of primary liver cancer was reported. HRs were 1.36 (95% CI: 1.02-1.81), 1.77 (95% CI: 1.56-2.01), and 3.08 (95% CI: 1.21-7.86) for BMI > 25 kg/m2, > 30 kg/m2, and > 35 kg/m2, respectively. Furthermore, increased BMI resulted in enhanced liver cancer-related mortality (HR 1.61, 95% CI: 1.14-2.27, I2 = 80%). In subgroup analyses, the HR for the occurrence of primary liver cancer was 1.42 (95% CI: 1.23-1.63, I2 = 37%) among Asian subjects. And, the HR for cancer occurrence was 1.76 (95% CI: 1.22-2.54, I2 = 66%) in patients with viral hepatitis (hepatitis B virus or hepatitis C virus).

Conclusions: High BMI increases liver cancer mortality and occurrence of primary liver cancer. Obesity is an independent risk factor for the occurrence of and mortality from primary liver cancer.


P-032 RISK OF HEPATOCELLULAR CARCINOMA IN DANISH OUTPATIENTS WITH ALCOHOLIC CIRRHOSIS

Peter Jepsen1, 2, Frederik Kraglund1, Joe West3, Gerda E. Villadsen* 1, Henrik T. Sørensen2, Hendrik Vilstrup1

1Department of Hepatology and Gastroenterology, 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark, 3Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom

Introduction: Accurate data on hepatocellular carcinoma (HCC) risk among patients with alcoholic cirrhosis are needed for patient counseling and decisions concerning HCC surveillance.

Methods: This was a nationwide historical cohort study using data from Danish healthcare registries. We first identified all patients with a first-time primary hospital diagnosis of alcoholic cirrhosis between 1 July 2002 and 30 June 2017. Then we restricted this cohort to patients who were alive and without an HCC diagnosis 6 months later. The six-month mark after the first primary diagnosis of alcoholic cirrhosis was defined as the date of study inclusion (index date). By study design, it fell between 1 January 2003 and 31 December 2017. To be included in the analyses, patients were required to fulfill five further criteria as of the index date: 1) Followed as outpatients with alcoholic cirrhosis as the primary or secondary diagnosis; 2) at least one ultrasound/CT/MR examination of the liver during the previous 9 months; 3) age under 80 years; 4) no cancer diagnoses in the past 5 years; and 5) no diagnoses of autoimmune liver disease or chronic viral hepatitis in the past 5 years.We followed the cohort through 2017 to ascertain HCC development. By our definition, all decedents who had been diagnosed with HCC died from HCC. For comparison we identified deaths less than 30 days after hospitalization for variceal bleeding or trauma. All others were categorized as dead from other causes. Among those who developed HCC, we compared median survival time between those who were treated with curative intent and those who were not. This difference was used as an estimate of the maximum number of life-years that could be gained through HCC surveillance.

Results: Among 4054 patients, 142 developed HCC and 2022 died. Median age was 62.1 years, 67% were men, and 14% had diabetes. At inclusion, 16% had no portal hypertension, 25% had silent portal hypertension, and the remaining 59% had manifest portal hypertension. The 1-year risk of HCC was 0.8% (95% confidence interval [CI] 0.6 to 1.1), and 5-year risk was 3.2% (95% CI 2.7 to 3.9). HCC risk increased with age and was much higher for men than for women. Portal hypertension did not affect HCC risk noticeably. After 10 years, only 5.4% of deaths in the cohort could be attributed to HCC, whereas 7.1% could be attributed to variceal bleeding, and 4.5% to trauma. We estimated that each patient who developed HCC would gain up to 1.8 life-years by being diagnosed through surveillance (and consequently treated with curative intent) as opposed to being diagnosed later (and consequently not treated with curative intent).

Conclusions: We followed a nationwide cohort of patients with alcoholic cirrhosis and showed that HCC risk in 2003–2017 was around 0.6% per year. Because of this low incidence, a large number of screening examinations and subsequent diagnostic examinations will be required for every HCC found through screening, and only a limited number of life-years can be gained. We conclude that interventions targeting other causes of death will likely be more cost-effective.


P-033 FINANCIAL BURDEN IS COMMON IN U.S. PATIENTS WITH CIRRHOSIS AND ASSOCIATED WITH LOWER HCC SURVEILLANCE RECEIPT

Amit Singal* 1, Nicole Rich1, Katharine McCallister1, Jennifer Kramer2, Cynthia Ortiz1, Anupama Vasudevan1, Ruben Hernaez2

1UT Southwestern Medical Center, Dallas, 2Baylor College of Medicine, Houston, United States

Introduction: Hepatocellular carcinoma (HCC) surveillance is underused in clinical practice; however, few studies have evaluated the impact of patient-level factors on surveillance receipt.

1Division of Gastroenterology and Hepatology, Department of Medicine, 2Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, 4Department of Radiology, 5Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Province of China

Introduction: Whether esophagogastric varices (EGV) can determine the outcome of patients with hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE) remains unknown. This study aimed to assess the impact of EGV on the prognosis of HCC patients after TACE.

Methods: From 2007 to 2012, we retrospectively enrolled 251 treatment-naïve HCC patients who underwent TACE and received esophagogastroduodenoscopy (EGD) when HCC was diagnosed. The HCC diagnosis was established based on the American Association for the Study of Liver Disease diagnostic criteria. The presence of EV was diagnosed by EGD and classified as follows: F1, small and straight varices; F2, moderately sized, tortuous varices; and F3, large, tumorous varices. The effect of TACE on the tumor was defined according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessment based on dynamic imaging studies one month after the first TACE. The prognostic factors were analyzed using a Cox proportional hazards model and propensity score-matching analysis.

Results: There were 120 (47.8%) patients with EGV. Compared to those without EGV, patients with EGV had worse liver functional reserve. After a median follow-up of 14.7 months (25th–75th

percentiles, 6.4–35.6 months), 152 patients died. The cumulative 5-year overall survival (OS) rates were 11.2% and 38.8% in patients with and without EGV, respectively (p<0.001). Multivariate analysis showed that presence of EGV, presence of ascites, tumor size >5 cm, serum alpha-fetoprotein >20 ng/mL, progressive disease by modified Response Evaluation Criteria in Solid Tumors, Assessment for Retreatment with TACE score ≥2.5, and higher albumin-bilirubin grades were the independent predictors of poor OS. Subgroup analysis also demonstrated that EGV was associated with poor OS in most of the subgroups. After propensity score matching, the EGV group still had a lower OS rate than their counterparts (p=0.004).

Image:

Conclusions: HCC patients with EGV had worse liver functional reserve compared to those without EGV. Moreover, EGV was an independent risk factor to predict poor prognosis in patients with HCC after TACE.

Disclosure of Interest: C.-Y. Wei: None Declared, C.-W. Su Conflict with: Advisory Board - Gilead Sciences, P.-H. Chen: None Declared, W.-Y. Kao: None Declared, R.-C. Lee: None Declared, Y.-H. Huang: None Declared, M.-C. Hou: None Declared, J.-C. Wu: None Declared

P-031 OBESITY AND THE RISK OF PRIMARY LIVER CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS

Won Sohn* 1, Hyun Woong Lee2, Sangheun Lee3, Jin Hong Lim2, Min Woo Lee4, Chan Hyuk Park5, Seung Kew Yoon6 and the Korean Liver Cancer Association (KLCA)

1Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 2Yonsei University College of Medicine, Seoul, 3Catholic Kwandong University College of Medicine, Incheon, 4Sungkyunkwan University School of Medicine, Seoul, 5Hanyang University College of Medicine, Guri, 6The Catholic University College of Medicine, Seoul, Korea, Republic Of

Introduction: In this systematic review and meta-analysis, we aimed to clarify the effect of obesity on the occurrence of and mortality from primary liver cancer.

Methods: This study was conducted using a systematic literature search on MEDLINE, EMBASE, and the Cochrane Library until November 2018 using the primary keywords “obesity,” “overweight,” “body mass index (BMI),” “body weight,” “liver,” “cancer,” “hepatocellular carcinoma,” “liver cancer,” “risk,” and “mortality.” Studies assessing the relationship between BMI and occurrence of or mortality from primary liver cancer including hepatocellular carcinoma in prospective cohorts and those reporting hazard ratios (HRs) or provided data to allow HR estimation were included.

Introduction: LEN is a multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRalpha, RET, and KIT. In a phase 3 trial (REFLECT), LEN demonstrated a treatment effect on overall survival (OS) by statistical confirmation of noninferiority vs sorafenib for first-line treatment of uHCC. Dosing by bw was implemented in REFLECT based on a phase 2 study of LEN in uHCC and PK modelling showing an exposure–response relationship with higher LEN AUC and lower bw resulting in earlier drug withdrawal or dose reduction. Cutoff values established were LEN 8 mg/d for bw <60 kg and 12 mg/d for bw ≥60 kg. This post hoc analysis of REFLECT assessed safety and efficacy of LEN in patients with bw >80 kg.

Methods: Details of REFLECT methodology are previously published. For this analysis, patients were stratified by baseline bw: <60 kg, ≥60 to ≤80kg, and >80 kg. Safety and efficacy outcomes by bw group were generated.

Results: Baseline demographics among the groups were similar, except that patients with bw >80 kg were more likely to be white, from western regions, and have higher body mass indexes. For bw <60 kg, bw ≥60 to ≤80 kg, and >80 kg: the median treatment durations (months) were 5.59, 6.29, and 6.54, respectively; mean LEN relative dose intensities were 87%, 86%, and 93%, respectively. Key safety and efficacy data are reported in the Table. Adjusted by treatment duration, AE rates (episodes/patient-year) were similar across bw groups. No adjustments were made for comorbidities by bw groups.

Table: Summary of Efficacy and AEs of Interest by bw

BW

<60 kg (n=153)

BW ≥60 to ≤80 kg

(n=234)

BW >80 kg (n=89)

Median OS, months 13.4 13.6 14.9

Median PFS, months 7.4 7.3 9.2

ORR (mRECIST by investigator), % 22 24 28

Hypertension, n (%) 66 (43) 97 (42) 38 (43)

Fatigue, n (%) 43 (28) 69 (30) 29 (33)

Palmar-plantar erythrodysesthesia, n (%) 37 (24) 65 (28) 26 (29)

Proteinuria, n (%) 38 (25) 59 (25) 20 (23)

Diarrhea, n (%) 54 (35) 91 (39) 39 (44)

Conclusions: In this post hoc analysis including patients of bw >80 kg receiving LEN 12 mg/d, efficacy and safety were similar to results in REFLECT. These results are consistent with the approved dose of 8 mg/d (bw <60 kg) and 12 mg/d (bw ≥60 kg) of LEN in uHCC.

Disclosure of Interest: A. Vogel: None Declared, M. Kudo Conflict with: Research/Education grant - Bayer, Daiichi Sankyo, Chugai, Otsuka, Taiho, Sumitomo Dainippon, and Merck Sharp & Dohme Corp, Conflict with: Honoraria - Bayer, Eisai, Merck Sharp & Dohme Corp, BMS, and EA Pharma, Conflict with: Consulting - Bayer, Eisai, A.-L. Cheng Conflict with: Honoraria - BMS, Ono, Novartis, Bayer, Merck, and Merck Sharpe & Dohme Corp., M. Sung Conflict with: Consulting - Eisai, Bayer, Exelixis, R. Finn Conflict with: Research/Education grant - Bayer, BMS, Novartis, Pfizer, Eisai, Eli Lilly, Merck, Conflict with: Consulting - AstraZeneca, Bayer, BMS, Eisai, Eli Lilly, Novartis, Merck, Pfizer, Roche/Genentech., A. Lin Conflict with: Consulting - Eisai, G. Abou-Alfa: None Declared, A. Alsina Conflict with: Honoraria - Vital Therapies, Eisai, Inc, Conflict with: Consulting - Vital Therapies, Eisai, Inc., V. Breder Conflict with: Honoraria - Roche, MSD, BMS, Bayer, Eisai, Takeda, Boehringer Ingelheim, Biocad, N. Tebbutt Conflict with: Research/Education grant - Amgen, Novartis, Conflict with: Honoraria - Amgen, P. Osterlund: None Declared, C. J. Yen: None Declared, M. Ren Conflict with: Research/Education grant - Eisai, Inc., S. Misir Conflict with: Research/Education grant - Eisai, Inc., C. Dutcus Conflict with: Research/Education grant - Eisai, Inc., D. Palmer Conflict with: Research/Education grant - BMS, Bayer, Sirtex, Nucana, AstraZeneca, Conflict with: Honoraria - BMS, Bayer, Eisai, Sirtex, Nucana, AstraZeneca, MSD, Conflict with: Consulting - BMS, Bayer, Eisai, Sirtex, Nucana, AstraZeneca, MSD, P. Merle Conflict with: Research/Education grant - Oxneo, Conflict with: Honoraria - Bayer, Oxneo, Ipsen, Merck, BMS, Roche, Conflict with: Consulting - Bayer, Oxneo, Ipsen, Merck, M. Pinter Conflict with: Honoraria - Bayer, BMS, Eisai, MSD, Conflict with: Consulting - Bayer, BMS, Eisai, Ipsen, Lilly, J. Evans Conflict with: Research/Education grant - Bristol-Myers Squibb, GlaxoSmithKIine, Roche / Genentech, Celgene, TC Biopharm, Merck, Novartis, e-Therapeutics, Vertex, Verastem, Daiichi, AstraZeneca, Basilea, Immunocore, Chugai, Conflict with: Honoraria - Eisai, BMS, Bayer, GlaxoSmithKline, Roche/Genetech, Celgene Karus Therapeutics, Baxalta, TC Biopharm, Immunova

P-030 ASSOCIATION BETWEEN ESOPHAGOGASTRIC VARICES IN HEPATOCELLULAR CARCINOMA AND POOR PROGNOSIS AFTER TRANSARTERIAL CHEMOEMBOLIZATION: A PROPENSITY SCORE MATCHING ANALYSIS

Cheng-Yi Wei* 1, Chien-Wei Su1, Ping-Hsien Chen2, Wei-Yu Kao3, Rheun-Chuan Lee4, Yi-Hsiang Huang1, Ming-Chih Hou1, Jaw-Ching Wu5

32. Bujold, A. et al. Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma. J. Clin. Oncol. 31, 1631–1639 (2013).

33. Livraghi, T. et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology 47, 82–89 (2008).

34. Groeschl, R. T. et al. Microwave ablation for hepatic malignancies: a multiinstitutional analysis. Ann. Surg. 259, 1195–1200 (2014).

35. Mazzaferro, V. et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann. Surg. 240, 900–909 (2004).


P-028 CLINICAL OUTCOMES OF STEREOTACTIC BODY RADIATION THERAPY FOR SINGLE VIABLE HEPATOCELLULAR CARCINOMA AT THE SITE OF INCOMPLETE TRANSARTERIAL CHEMOEMBOLIZATION

Jinhong Jung* 1, Hee Hyun Park1, So Yeon Kim2, Young-Suk Lim3, Han Chu Lee3, Jin-hong Park1, Jong Hoon Kim1, Sang Min Yoon1

1Department of Radiation Oncology, 2Department of Radiology, 3Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic Of

Introduction: Transarterial chemoembolization (TACE) is performed in the majority of patients with hepatocellular carcinoma (HCC). However, TACE shows unsatisfactory local control rate, with some “incomplete TACE” cases showing viable HCCs at 1–3 months after multiple consecutive TACE procedures. No study to date has provided clear recommendation on effective local treatment option for residual viable HCC at the site of incomplete TACE. Therefore, we evaluated the clinical outcomes of patients who received stereotactic body radiation therapy (SBRT) for single viable HCC at the site of incomplete TACE.

Methods: A total of 313 patients were treated with SBRT for single viable HCC after incomplete TACE between March 2012 and July 2017 at Asan Medical Center (Seoul, Korea). Doses of 10–15 Gy per fraction were given over 3–4 consecutive days using a respiratory-gated volumetric-modulated arc therapy technique, resulting in a total dose of 30–60 Gy. Incomplete TACE was defined as evidence of viable HCC at the site of TACE on response evaluation images at 1–3 months following two or more consecutive TACE procedures. Treatment-related adverse events were evaluated according to the common terminology criteria for adverse events (CTCAE, version 4.03).

Results: The median follow-up period was 32.9 months (interquartile range [IQR], 23.6–41.4) and the median tumor size was 2.0 cm (IQR, 1.5¬–2.5). The majority of the patients were male (77.0%), and almost all patients had ECOG performance status of 0 (93.3%). The median radiation dose was 45 Gy with a median fraction size of 15 Gy. The local control rate at 3 years was 91.5%. The overall survival, out-of-field intrahepatic recurrence-free survival, and distant metastasis-free survival rates at 3 years were 72.5%, 35.8%, and 82.7%, respectively. Elevations in the level of transaminases or bilirubin of CTCAE grade ≥ 2, which may be related to SBRT without progression of intrahepatic HCC, were observed in 8 patients (2.5%). Worsening of Child-Pugh score ≥ 2 was observed in 6 patients (1.9%). No patients experienced late gastroduodenal bleeding within the radiation field.

Conclusions: SBRT showed excellent clinical outcomes in terms of local control, survival, and adverse events when used as an ablative treatment modality for residual single viable HCC at the site of incomplete TACE. SBRT may be considered as a treatment option for viable HCC after incomplete TACE.


P-029 SAFETY AND EFFICACY OF 12 MG/D LENVATINIB (LEN) IN PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA (UHCC) AND BODYWEIGHT (BW) >80 KG IN REFLECT

Arndt Vogel* 1, Masatoshi Kudo2, Ann-Lii Cheng3, Max W. Sung4, Richard S. Finn5, Albert Y. Lin6, Ghassan K. Abou-Alfa7, Angel Alsina8, Valeriy Breder9, Niall Tebbutt10, Pia Osterlund11, Chia Jui Yen12, Min Ren13, Soamnauth Misir13, Corina E. Dutcus13, Daniel Palmer14, Phillippe Merle15, Matthias Pinter16, Jeffry Evans17

1Hannover Medical School, Hannover, Germany, 2Kindai University School of Medicine, Osakasayama, Japan, 3National Taiwan University Hospital, Taipei, Taiwan, Province of China, 4Tisch Cancer Institute at Mount Sinai, New York, 5Geffen School of Medicine, UCLA Medical Center, Santa Monica, 6VA Palo Alto Health Care System, Palo Alto, 7Memorial Sloan Kettering Cancer Center, New York, 8Tampa General Hospital, Tampa, United States, 9N.N. Blokhin Russian Cancer Research Center, Ministry of Health of the Russian Federation, Moscow, Russian Federation, 10Olivia Newton-John Cancer Centre, Victoria, Australia, 11Tampere University & Central Hospital, Tampere, Finland, 12National Cheng Kung University Hospital, Tainan, Taiwan, Province of China, 13Eisai Inc., Woodcliff Lake, United States, 14University of Liverpool, Liverpool, United Kingdom, 15CHU de Lyon -Hospital La Croix-Rousse, Lyon, France, 16Medical University of Vienna, Vienna, Austria, 17University of Glasgow, Glasgow, United Kingdom

Posters Posters


However, patients treated in a period less than or equal to 12 months after the complete response of HCC treatment showed a significantly higher recurrence than those treated at least 1 year after obtaining the complete response in HCC

References: Reig, M., Mariño, Z., Perelló, C. et al, Unexpected early tumor recurrence in patients with hepatitis C virus-related hepatocellular carcinoma undergoing interferon-free therapy: a note of caution. J Hepatol. 2016;65:719–726.F. Conti. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.G. Cabbibo. Is aearly recurrence of hepatocelular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study. Alimentary Pharmacology and Therapeutics, Otc 2017.N. Saraiya. Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy. Alimentary Pharmacology and Therapeutics, May 2018.AG Singal. Direct-Acting Antiviral Therapy not Associated with Recurrence of Hepatocellular Carcinoma in a Multicenter North American Cohort Study. Gastroenterology Jan 2019.

Disclosure of Interest: C. Perelló: None Declared, E. Llop: None Declared, I. Fernandez: None Declared, A. Matilla: None Declared, F. Gea: None Declared, J. Garcia-Samaniego Conflict with: Consulting - Gilead, Abbvie, A. Martin: None Declared, A. Garcia-Sanchez: None Declared, R. Bañares: None Declared, A. Albillos Conflict with: Advisory Board - Gilead, Abbvie, Gore, Griffols, Intercept, Pfizer and Merck, J. L. Calleja Conflict with: Advisory Board - Gilead, Abbvie, MSD

P-037 RETROSPECTIVE, EXPLORATORY ANALYSIS OF THE OPTIMIS STUDY IN A SUBGROUP OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH TRANSARTERIAL CHEMOEMBOLIZATION (TACE) WHO RECEIVED SORAFENIB

Ann-Lii Cheng* 1, Jean-Luc Raoul2, Markus Peck-Radosavljevic3, 4, Han Chu Lee5, Keiko Nakajima6, Inga Bayh7, Masatoshi Kudo8

1National Taiwan University Hospital, Taipei, Taiwan, 2Institut de Cancérologie de l’Ouest, Nantes, France, 3Medical University of Vienna, Vienna, 4Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria, 5Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea 6Bayer HealthCare Pharmaceuticals, Whippany, NJ, United States, 7Bayer AG, Wuppertal, Germany, 8Kindai University Faculty of Medicine, Osaka, Japan

Introduction: There is no global consensus on the use of TACE in patients with unresectable HCC. Using TACE outside of recommended guidelines may delay or prevent patients from receiving subsequent systemic therapies, such as sorafenib. Here we report results from a retrospective, exploratory analysis of the OPTIMIS study in the subgroup of patients who received sorafenib.

Methods: OPTIMIS was an international, prospective, non-interventional study evaluating patients with HCC for whom a decision to treat with TACE was made at study entry. This retrospective, exploratory analysis included all patients who received sorafenib at any time during the study. Patients were assigned to 2 groups: the early sorafenib (ES) group initiated sorafenib prior to or within 30 days after TACE ineligibility, whereas the late sorafenib (LS) group started sorafenib more than 30 days after TACE ineligibility. TACE ineligibility was determined from collected data using study protocol-specified criteria according to international guidelines and expert consensus.

Results: Of the 1650 patients who received TACE, 511 received sorafenib treatment; 260 were in the ES group and 251 were in the LS group. At the time of first TACE, a higher proportion of patients in the ES group were Barcelona Clinic Liver Cancer (BCLC) stage B compared with the LS group (61% vs 43%, respectively) and a lower proportion of patients in the ES group were BCLC stage C (33% vs 52%, respectively). Most patients had an initial sorafenib dose of 800 mg/day (65% ES, 57% LS). The median duration of sorafenib treatment and the median average daily dose were higher in the ES group (5.5 months and 761 mg) compared with the LS group (3.6 months and 606 mg). The main reasons for discontinuing sorafenib treatment were adverse events (AEs; 20% ES, 35% LS) and disease progression (20% ES, 27% LS). Median overall survival (OS) from the time of first TACE was 24.5 months (95% CI 19.2, 31.8) in the ES group and 20.7 months (95% CI 17.7, 25.7) in the LS group. From the time of sorafenib initiation, median OS was 15.1 months (95% CI 11.9, 18.9) in the ES group and 9.7 months (95% CI 8.6, 11.7) in the LS group.

Conclusions: These data suggest that in clinical practice, patients who initiated sorafenib before or soon after TACE ineligibility generally had more favorable disease characteristics at baseline, lower rates of treatment discontinuation due to AEs and disease progression, and better outcomes (as measured from the time of first TACE and the time of sorafenib initiation) compared with those who initiated sorafenib at a later time.

Disclosure of Interest: A.-L. Cheng Conflict with: Honoraria - Bayer, Eisai, Merck Sharp & Dohme, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche, and IQVIA, Conflict with: Advisory Board - Bayer, Bristol-Myers Squibb, Eisai, Merck Serono, Novartis, Ono Pharmaceutical, Exelixis, Nucleix Ltd., Roche, and IQVIA, Conflict with: Consulting - Novartis, Onxeo, Eisai, Exelixis, Merck Serono, and Ono Pharmaceutical, J.-L. Raoul Conflict with: Honoraria - Bayer, Conflict with:

One patient experienced non-classic RILD with acute toxicity at 2 month after SABR.

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Conclusions: The high-dose SABR for HCC ≤ 5 cm is and effective as evidenced by the high rates of tumor control, overall survival, and acceptable treatment-related toxicity.


P-036 RECURRENCE OF HEPATOCELLULAR CARCINOMA IN PATIENTS WITH COMPLETE RESPONSE TREATED WITH DIRECT-ACTING ANTIVIRALS IN CLINICAL PRACTICE

Christie Perelló* 1, Elba Llop1, Inmaculada Fernandez2, Ana Matilla3, Francisco Gea4, Javier Garcia-Samaniego5, Ana Martin2, Araceli Garcia-Sanchez5, Rafael Bañares3, Agustin Albillos4, Jose Luis Calleja1

1Gastroenterology and hepatology, University Hospital Puerta de Hierro, 2Gastroenterology and hepatology, University Hospital 12 de Octubre, 3Gastroenterology and hepatology, University Hospital Gregorio Marañón, 4Gastroenterology and hepatology, University Hospital Ramon y Cajal, 5Gastroenterology and hepatology, University Hospital La Paz, Madrid, Spain

Introduction: Direct-Acting Antivirals (DAA) have revolutionized the treatment of hepatitis C in terms of sustained viral response.There is still controversy about the effect of DAA on the early recurrence of Hepatocellular Carcinoma (HCC) in patients with complete response.The objective was to analyze the recurrence rate in patients with HCC who have received DAA and compare it with a control group who did not received antiviral treatment

Methods: Retrospective, observational and multicentric study in 5 tertiary hospital in Madrid.Patients were selected from the HCV Community of Madrid Registry from November 2015-April 2016 all patients with HCC treated with surgery or ablation in complete response with at least 1-year of follow-up from the beginning of the DAA (Cohort A) and was compared with a consecutive historical group in the same centers that did not received antiviral treatment (Cohort B). Clinical, radiological baseline and follow-up data were collected during DAA treatment until the last visit.

Results: We analyzed 665 patients treated with selected DAA from the HCV Community of Madrid Registry. 57 patients were included in Cohort A with a mean age of 64 years (SD9.4), males 61.4%, HIV infection 7.8% (n=4), diabetes mellitus 28.1% (n=16). Child-Pugh A: 81%. BCLC 0: 29.8% (n=17), A: 63.1% (n=38), B: 7% (n=2). In the control group, 57 patients who did not received antiviral treatment were included. Mean age 65 (SD12.8), males 73.7% (n=42), HIV infection 16% (n=4), diabetes mellitus 31.6% (n=18), child-pugh A:94% (n=45). BCLC 0: 12.3% (n=7), A: 82.5% (n=47), B 5.3% (n=3).The median follow up from the beginning of DAA was 15 months (6-120) and 25 months (3-157) in the control group.The global recurrence in DAA was 25/100 people-year (CI95% 14-36) and in the control group: 32/100 people-year (CI95% 23-42) Graph 1. There were no significant differences in the recurrence rate in Cohort A an B at 6,12 and 24 months: 14%, 23.1% and 37.5% and Cohort B: 20%, 30% and 56.5% respectively, despite the fact that the majority of patients in Cohort A on¡btained the sustained viral response.In Cohort A, a greater recurrence was observed in patients treated in the first 12 months after HCC treatment compared with those who were treated later (85.2% vs 24.5%) p=<0.001. The cumulative probability of recurrence among those who started treatment in less than or equal to 12 months was 34/100 person-years (CI95% 15-55) vs those who started after 12 months 17/100 recurrence persons-years (CI95% 5-30) and in the control group was 32/100 persons-years (CI95% 23-42) Graph 2. A propensity score matching was perfomed not observing changes in the previously obtained results.

Conclusions: There was no significant differences in terms of recurrence between patients treated with DAA and untreated.

Methods: Tumors and paired non-tumor (NT) tissues of 32 HB patients were used in this study. The transcriptomic, genomic and epigenomic features of HB tumors were assessed using RNA-seq (HiSeq 2000), SNP array (CytoScan HD) and methylation array (EPIC) respectively. The main targetable driver in HB was identified by gene co-expression network analysis (GCN) and its overexpression was confirmed by qRT-PCR. The antitumor potential of targeted inhibition of the HB driver was assessed in vitro in HepG2 and HuH6 HB cells by MTS and colony formation assay.

Results: RNA-seq and GCN analysis identified IGF2 signaling and TGF-ß-related immune response among the top deregulated pathways in HB tumors (FDR<0.001). IGF2 was further explored as a potential targetable alteration and its overexpression was detected in 71% of the HB samples (fold change>4 vs NT samples). IGF2-high HB tumors showed an enrichment in CTNNB1 mutations and gene signatures characteristic of progenitor and proliferative phenotypes, while IGF2-low tumors presented signatures of immune cell infiltration and high TGF-ß expression levels. HB patients with high IGF2 also showed worse recurrence-free survival compared to IGF2-low patients (median RFS: 34 months (0–86) vs NR (NE–NE); p<0.05). Potential mechanisms of IGF2 overexpression were investigated using methylation and SNP data. IGF2-high HB tumors presented hypomethylation of the IGF2 fetal P3 promoter and overexpression of the fetal IGF2 isoform compared to IGF2-low tumors. In addition, loss of heterozygosity (LOH) in the 11p15 chromosomal region, containing the IGF2 gene, was identified in 45% of the HB tumors. This allelic imbalance was significantly enriched in tumors with high IGF2 compared to IGF2-low tumors (12/21 IGF2-high vs 1/9 IHG2-low, p<0.05). The altered fetal methylation pattern and LOH were able to explain IGF2 overexpression in 75% of the IGF2-high HB samples analyzed. IGF2 inhibition using the monoclonal antibody xentuzumab reduced proliferation and clonogenic capacity in HB cells overexpressing IGF2 (HepG2) compared to IGF2-low HB cells (HuH6). The antitumor efficacy of IGF2 blockage is currently being tested in xenograft and patient-derived xenograft (PDX) models.

Conclusions: Increased IGF2 signaling is the main targetable alteration in HB tumors. Our results indicate that IGF2 overexpression in HB could be explained by hypomethylation of its fetal promoters and LOH in 11p15. IGF2 inhibition with xentuzumab could be an effective therapy for HB patients with IGF2 overexpression.

Disclosure of Interest: L. Torrens: None Declared, C. Montironi: None Declared, P. Haber: None Declared, O. Kuchuk: None Declared, N. Akers: None Declared, M. Simon-Coma: None Declared, I. Martinez-Quetglas: None Declared, L. Nonell: None Declared, M. Mallo: None Declared, J. Carrillo-Reixach: None Declared, S. Cairo: None Declared, M. Buendia: None Declared, L. Royo: None Declared, M. Sala: None Declared, M. R. Sarrias: None Declared, V. Mazzaferro: None Declared, B. Losic: None Declared, D. Sia: None Declared, C. Armengol: None Declared, J. Llovet Conflict with: Research/Education grant - Incyte, Bayer, BMS, EISAI, Conflict with: Honoraria - Incyte, Bayer, BMS, EISAI, Lilly, Celsion, Glycotest, IPSEN, Merck, Exelixis, Conflict with: Advisory Board - Incyte, Bayer, BMS, EISAI, Lilly, Celsion, Glycotest, IPSEN, Merck, Exelixis, Conflict with: Consulting - Incyte, Bayer, BMS, EISAI, Lilly, Celsion, Glycotest, IPSEN, Merck, Exelixis

P-035 MULTICENTER PHASE II STUDY OF STEREOTACTIC ABLATIVE RADIOTHERAPY FOR HEPATOCELLULAR CARCINOMA ≤ 5 CM (KROG 12-02)

Wonil Jang* 1, Mi-Sook Kim1, Eun Kyung Paik1, Chul Won Choi2, Ah Ram Chang3, Young Hee Park3, Eun Seog Kim4, Sunmi Jo5, Woochul Kim6, Sun Hyun Bae7, Hae Jin Park8 and Korean Radiation Oncology Group (KROG)

1Radiation Oncology, Korea Institute of Radiological & Medical Scineces, Seoul, 2Radiation Oncology, Dongnam Institute of Radiological & Medical Scineces, Busan, 3Radiation Oncology, Soonchunhyang University Seoul Hospital, Seoul, 4Radiation Oncology, Soonchunhyang University Cheonan Hospital, Cheonan, 5Radiation Oncology, Haeundae Paik Hospital, Busan, 6Radiation Oncology, Inha University Hospital, Incheon, 7Radiation Oncology, Soonchunhyang University Bucheon Hospital, Bucheon, 8Radiation Oncology, Hanyang University Hospital, Seoul, Korea, Republic Of

Introduction: The purpose of this study is to evaluate the efficacy of stereotactic ablative radiotherapy (SABR) for hepatocellular carcinoma (HCC) ≤ 5 cm.

Methods: A total of 54 patients with unresectable HCC showing an incomplete response after 1-5 sessions of transarterial chemoembolization were enrolled in a phase II clinical trial of SABR from 6 institutions between July 2012 and June 2015. SABR was delivered with a total dose of 60 Gy in 3 fractions within 14 days, with ≥ 48 hour-intervals between each fraction. The treatment response was evaluated using the Modified Response Evaluation Criteria in Solid Tumors (mRECIST). Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Radiation-induced liver disease (RILD) was analyzed at 2 months. Survival outcomes were analyzed with the Kaplan-Meier method. This trial is registered with Clinical Trials.gov, number NCT01825824.

Results: Forty-eight patients were evaluable with a median follow-up of 41 months (range, 2?61 months). The median tumor size was 2.0 cm (range, 1.0?4.5 cm) and most patients (89.6%) had a single lesion. Thirty-six patients (75%) received TACE ≤ 2 times. Local control rate at 2 and 5 years were 97.4% and 94.7%, respectively. Overall survival rate at 2 and 5 years were 90.9% and 78.3%, respectively. Progression-free survival rate at 2 and 5 years were 50.3% and 27.0%, respectively.

Therefore, we characterized the association between patient knowledge, attitudes, and barriers and HCC surveillance receipt in a large cohort of patients with cirrhosis.

Methods: We conducted a telephone-based survey study among patients with cirrhosis followed at two large U.S. health systems between April and December 2018. Eligible patients were initially identified using ICD-10 codes and lab data, with cirrhosis diagnosis confirmed by characteristic imaging or histology per chart review. Patients were required to have at least one primary care visit in the year prior to baseline to demonstrate the health system was their medical home. HCC surveillance receipt was assessed by the presence of an abdominal ultrasound for each 6-month period in the year prior to survey administration and classified as consistent (2 of 2), inconsistent (1 of 2), or none (0 of 2). Logistic regression analysis was performed to identify factors associated with HCC surveillance receipt.

Results: We obtained a response rate of 36.6% (784/2141). The cohort was 55% male, racially diverse (26% non-Hispanic white, 40% Hispanic white, 30% Black), and socioeconomically disadvantaged (58.9% with annual income <$25,000). Most had Child Pugh A cirrhosis (73%), and 46% were followed in Hepatology clinic. Overall, patients demonstrated high levels of HCC knowledge about HCC risk and need for HCC surveillance (median score 83.3%); however 43.7% believed HCC surveillance was not necessary with a normal physical exam and/or lack of clinical symptoms and 22.7% did not know curative options existed if HCC were detected at an early stage. Patients expressed worry about developing HCC, with 78.1% reporting they were at least somewhat likely to develop HCC during their lifetime and 43.3% expressing fear of dying from HCC. Accordingly, 89% of patients reported HCC surveillance to be “very important”. However, patients reported various barriers to receiving HCC surveillance including cost of surveillance testing (34.6%), difficulty with the scheduling process (26.8%), uncertainty where to complete the ultrasound (20.7%), and transportation difficulties (19.6%). Financial burden of medical care (including cost of HCC surveillance) resulted in 11.7% delaying care, 12.9% needing to borrow money or go into debt, 28.8% being unable to cover co-pays or deductibles, and 47.8% expressing worry about the ability to pay medical bills. Most patients received HCC surveillance in the year prior to survey administration (22.3% consistent and 43.9% inconsistent), but 33.8% had no surveillance. Receipt of consistent surveillance was associated with male gender (p=0.04), presence of documented cirrhosis (p=0.003), number of primary care visits (p<0.001), and receipt of hepatology care (p<0.001). We did not observe differences in surveillance receipt by level of patients knowledge, fear of developing HCC, or perceived importance of HCC surveillance; however, patients receiving consistent surveillance were significantly more likely to report financial distress delaying medical care than those with inconsistent or no surveillance (13.9% vs. 4.0%, p<0.001).

Conclusions: Patients with cirrhosis are knowledgeable and recognize the benefits of HCC surveillance; however, financial barriers are associated with lower surveillance rates in clinical practice and may represent an intervention target to improve HCC surveillance effectiveness in the U.S.

Disclosure of Interest: A. Singal Conflict with: Advisory Board - Bayer, Eisai, BMS, Wako, Exact Sciences, Glycotest, Conflict with: Consulting - Bayer, Eisai, Exelixis, BMS, Exact Sciences, Glycotest, N. Rich: None Declared, K. McCallister: None Declared, J. Kramer: None Declared, C. Ortiz: None Declared, A. Vasudevan: None Declared, R. Hernaez: None Declared

P-034 IDENTIFICATION OF IGF2 AS GENOMIC DRIVER AND THERAPEUTIC TARGET IN HEPATOBLASTOMA

Laura Torrens* 1, 2, Carla Montironi1, 2, Philipp Haber2, Olga Kuchuk2, 3, Nicholas Akers2, 4, Marina Simon-Coma5, 6, Iris Martinez-Quetglas1, 2, Lara Nonell7, Mar Mallo8, Juan Carrillo-Reixach6, Stefano Cairo9, Marie A. Buendia10, Laura Royo6, Margarita Sala5, 6, 11, Maria Rosa Sarrias5, 12, Vincenzo Mazzaferro3, Bojan Losic2, 4, Daniela Sia2, Carolina Armengol5, 6, Josep M. Llovet1, 2, 13

1Translational Research in Hepatic Oncology, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat de Barcelona, Barcelona, Spain, 2Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States, 3Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy, 4Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States, 5CIBERehd, Barcelona, 6Childhood Liver Oncology Group (c-LOG), Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, 7Microarray Analysis Service, Institute of Medical Research (IMIM), 8Affymetrix Microarrays Platform and MDS Group, Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain, 9XenTech, Evry, 10Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France, 11Gastroenterology Department, Universitary Hospital Germans Trias i Pujol (HGTiP), 12Innate Immunity Response Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, 13Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain

Introduction: Hepatoblastoma (HB) is the most frequent pediatric liver cancer, with limited therapeutic options for patients with aggressive tumors. The identification of novel molecular targets for HB is crucial to generate novel targeted therapies for those patients whose tumors are refractory to standard perioperative chemotherapy regimens. Here, we aimed at defining the most prevalent targetable drivers in HB and assessing the antitumor potential of their inhibition.

Posters Posters


3. Irtan S, Barbier L, Francoz C, Dondero F, Durand F, Belghiti J. Liver transplantation for hepatocellular carcinoma: is zero recurrence theoretically possible? Hepatobiliary & pancreatic diseases international : HBPD INT. 2016;15(2):147-51.

4. Heckman JT, Devera MB, Marsh JW, Fontes P, Amesur NB, Holloway SE, et al. Bridging locoregional therapy for hepatocellular carcinoma prior to liver transplantation. Ann Surg Oncol. 2008;15(11):3169-77.

5. Agopian VG, Harlander-Locke MP, Ruiz RM, Klintmalm GB, Senguttuvan S, Florman SS, et al. Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium. Ann Surg. 2017;266(3):525-35.


P-045 BREATH METABOLOMICS ACCURATELY CLASSIFIES PATIENTS WITH CHRONIC LIVER DISEASE, PRIMARY, AND SECONDARY LIVER CANCERS

Galen Miller-Atkins* 1, Lou-Anne Acevedo-Moreno2, Mark Brown3, David Grove4, Raed Dweik5, Daniela Allende6, Daniel M. Rotroff1, Federico Aucejo2

1Department of Quantitative Health Sciences, 2Department of General Surgery, 3Department of Cellular and Molecular Medicine, 4Department of Inflammation and Immunity, 5Respiratory Institute, 6Department of Pathology, Cleveland Clinic, Cleveland, United States

Introduction: Primary and secondary liver tumors remain non-curative diseases in a large subset of patients1. Surgery is the mainstay therapy, however challenges in early tumor detection prevent better outcomes for many patients. Current diagnostic biomarkers such as alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) have low sensitivity resulting in many false negative diagnoses2,3. Therefore, it is critical to develop accurate tools to diagnose these diseases early and track their progression and response to therapy. Breath-based metabolomics may be uniquely situated to address these issues due to its non-invasiveness and ability to detect biochemical changes in response to disease. Here, we present a predictive model utilizing breath metabolomics data from patients classified as either healthy, having pulmonary hypertension, cirrhosis, hepatocellular carcinoma (HCC), or colorectal cancer liver metastases (CRLM).

Methods: Breath samples were collected from 274 patients seen at the Cleveland Clinic Liver Tumor Clinic. Eligible participants were > 18 years of age and categorized as either healthy controls (N=49) or individuals with cirrhosis (N=28), HCC (N=100), CRLM (N=48), or pulmonary hypertension (N=49). A random forest model was developed using age, sex, and 22 volatile organic compounds (VOCs) to accurately classify patients by disease status. A grid search was performed to find the optimal hyper-parameter values, and leave-one-out cross-validation was used to protect against model over fitting. The final model was evaluated using mean classification accuracy, sensitivity, specificity, and balanced accuracy (BA). Mean decrease Gini estimates were used to gauge the importance of each VOC.

Results: The best performing model, using both VOCs and demographic variables, had a BA of 76% across all groups. Healthy controls had the highest BA of 90%, with 84% sensitivity and 96% specificity. Pulmonary hypertension had the second highest BA (77%), followed by HCC (76%), CRLM (71%), and cirrhosis (67%). In contrast, AFP had a BA of 70%, with 53% sensitivity and 88% specificity for detecting HCC with a threshold of 11 ng/mL. CEA (3 ng/mL) performed equivalent to breath VOCs with 50% sensitivity. (E)-2-nonene and acetaldehyde were the VOCs with highest Gini estimates.

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Conclusions: Liver malignancies are serious burden in global cancer-related deaths. Improving early detection and identifying new biomarkers is crucial to curbing HCC and other liver-related disease and mortality rates. Machine learning is a potential approach to leverage the metabolome, identify important patterns, and predict disease. Our model is more accurate than standard biomarkers and exhibited higher sensitivity for detecting individuals with HCC than AFP. Breath metabolomics may be a valuable screening tool for chronic liver disease and liver cancers.

related to adverse events. The number of cases of postoperative ambulation in the trial group was significantly more than the control group. Additionally, the time of flatus and defecation, as well as hospital stay in the trial group were significantly shorter than those in the control group.

Conclusions: Parecoxib sodium combined with the TAP block effectively alleviates postoperative pain from hepatectomy without additional adverse effects and demonstrates benefits for early ambulation, facilitates the recovery of the gastrointestinal function, and shortens the hospitalization time after surgery in HCC patients.


P-042 INCREASED NEED OF LOCOREGIONAL THERAPIES IS A SURROGATE OF TUMOR BIOLOGY IN PATIENTS UNDERGOING LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA

Andre Gorgen1, Phillipe Abreu* 1, Sydney McCluskey2, Samantha McCluskey2, Mary Zhu2, Bettina Hansen2, Anand Ghanekar1, Les Lilly1, Mark Cattral1, Zita Galvin2, Markus Selzner1, Mamatha Bhat2, Nazia Selzner2, Ian McGilvray1, Paul D. Greig1, David R. Grant1, Gonzalo Sapisochin1 and Liver Cancer Research Group

1Department of Surgery, 2University of Toronto, Toronto, Canada

Introduction: We hypothesized that an increased need for locoregional therapies (LRT) during the waiting time would be an independent predictor of cancer recurrence and poor survival after liver transplantation (LT) for hepatocellular carcinoma (HCC).

Methods: Patients with HCC listed for LT between 2000-2016 were included in an intention-to-treat analysis (ITT). Patients were divided according to the number of LRT prior to LT: 1, 2 or ≥3. Patients who did not receive LRT were excluded. Overall survival (OS) and the cumulative recurrence incidence (CRI) were assessed by the Kaplan-Meier method and compared with the log-rank test. Multivariable Cox regression with competing-risks was applied to identify predictors of post-LT HCC recurrence. The increased need of LRT was included in validated prediction scores and compared by Harrell’s c-statistics. The median follow-up was 3.2 (IQR 1.6-7.1) years.

Results: 1,005 patients with HCC were listed during the study period of which 621 (61.5%) were treated with LRT. The three groups had similar profiles. OS was higher for patients who underwent only 1-LRT (Figure 1-A). In a multivariable regression model, undergoing 2-LRT [HR=1.54 (95%CI 1.16-2.04) and ≥3-LRT [HR=2.28 (95%CI 1.62-3.20)] was predictive of death on an ITT basis. Among the 481 patients who underwent LT, the actuarial 5-year CRI was 13.8%, 24.2% and 29.8% for patients with 1, 2 and ≥3-LRT, respectively (p=0.003) (Figure 1-B). The risk of recurrence was higher for patients who underwent 2-LRT [HR=1.67 (95%CI 1.03-2.72) or ≥3-LRT [HR=1.95 (95%CI 1.12-3.37)]. Other predictors of recurrence were serum AFP>100ng/mL and pre-transplant maximum tumor size. The AFP score’s accuracy was 0.66 (95%CI 0.60-0.72) and the accuracy of Metroticket 2.0 was 0.65 (95%CI 0.58-0.72). The accuracy of both scores increased [0.69 (95%CI 0.63-0.75), p=0.03, and 0.67 (95%CI 0.61-0.74), p=0.004, respectively] after including the number of LRTs.

Image:

Conclusions: The increased need of LRT prior to LT is correlated with a and a poorer prognosis after LT independently from size and number of tumors.

References: 1. Rayar M, Levi Sandri GB, Houssel-Debry P, Camus C, Sulpice L, Boudjema K. Multimodal Therapy

including Yttrium-90 Radioembolization as a Bridging Therapy to Liver Transplantation for a Huge and Locally Advanced Intrahepatic Cholangiocarcinoma. Journal of gastrointestinal and liver diseases: JGLD. 2016;25(3):401-4.

2. Mittler J, Heinrich S, Lang H. [Indications for transplantation and bridging procedures for primary hepatobiliary malignancies]. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen. 2018.

Introduction: Positive results of the phase III REFLECT trial in terms of survival for the third tyrosine kinase inhibitor (TKI), lenvatinib, offer a new first-line option for investigating advanced hepatocellular carcinoma (HCC)[1]. However, in practice, lenvatinib serves not only as the first-line option, but also subsequent treatment (second-line, or third-line) systemic therapy for patients with advanced HCC. Though patients in the REFLECT trial who had massive intrahepatic lesions (>50% of intrahepatic tumor burden), major portal vein or/and bile duct invasion, or who were Child-Pugh B, were excluded, real-world clinical practice necessitated their inclusion for therapy. Clinical outcomes of lenvatinib in this patient population are lacking, and therefore the aim of this study was to assess the safety and efficacy of lenvatinib in Japanese patients with advanced HCC, particularly focusing on those who were excluded from the REFLECT trial, reflecting real-world clinical practices.

Methods: Between March 2018 and October 2018, 105 patients were administered lenvatinib for advanced HCC. A retrospective analysis of medical records from these 105 patients, obtained from seven Japanese institutions, was performed in this study. Radiological assessments were evaluated according to both Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). CTCAE version 4.0 was used for assessment of adverse events (AEs).

Results: In this retrospective analysis, 62 patients [59%] used lenvatinib as first-line treatment, while 43 patients [41%] used this drug as subsequent therapy. Objective Response Rates (ORR) of first-line and subsequent line was 40% and 40%, respectively. Median Progression Free Survival (PFS) of first-line and subsequent line was 4.6 months (95% CI: 3.8–5.5) and 5.1 months (95% CI; 4.3–5.9), respectively. Of the 105 patients, 20% discontinued lenvatinib due to AEs. At baseline, 16 patients (15%) were Child-Pugh B and their ORR was 38%; however, of these 16 patients, 8 (50%) discontinued lenvatinib due to AEs. ORR of major portal vein or/and bile duct invasion (10 patients) and massive intrahepatic lesions (8 patients) were 50% and 25%, respectively. Rates of treatment discontinuation due to AEs were 20% in patients with major portal vein or/and bile duct invasion and 38% in patients with massive intrahepatic lesions.

Conclusions: Data from this study indicated that both TKI naïve patients and those with pre-exposure to TKI potentially achieved similar responses to lenvatinib. Despite the limitation with small number of patients with portal vein or/and bile duct invasion and massive intrahepatic lesions, the ORR of this subgroup of patients was similar to that of other patients.

References: 1. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163-1173.

Disclosure of Interest: S. Maruta: None Declared, S. Ogasawara Conflict with: Research/Education grant - Bayer, Eisai, Conflict with: Honoraria - Bayer, Eisai, Eli Lilly, Conflict with: Advisory Board - Bayer, Eisai, Eli Lilly, Conflict with: Consulting - Bayer, Eisai, Eli Lilly, Y. Ooka: None Declared, M. Inoue: None Declared, M. Obu: None Declared, N. Itokawa: None Declared, A. Seki: None Declared, Y. Haga: None Declared, S. Okabe: None Declared, E. Itobayashi: None Declared, N. Kanogawa: None Declared, R. Azemoto: None Declared, M. Atsukawa: None Declared, H. Mizumoto: None Declared, N. Sugiura: None Declared, H. Kanzaki: None Declared, K. Kanayama: None Declared, T. Maeda: None Declared, Y. Kusakabe: None Declared, K. Kobayashi: None Declared, S. Kiyono: None Declared, M. Nakamura: None Declared, T. Kondo: None Declared, T. Saito: None Declared, E. Suzuki: None Declared, S. Nakamoto: None Declared, S. Yasui: None Declared, A. Tawada: None Declared, T. Chiba: None Declared, M. Arai: None Declared, T. Kanda: None Declared, H. Maruyama: None Declared, N. Kato Conflict with: Research/Education grant - Bayer, Eisai, Conflict with: Honoraria - Bayer, Eisai, Conflict with: Advisory Board - Bayer, Eisai, Conflict with: Consulting - Bayer, Eisai

P-041 EFFECTIVENESS OF PARECOXIB SODIUM COMBINED WITH TRANSVERSUS ABDOMINIS PLANE BLOCK FOR PAIN MANAGEMENT AFTER HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA: A RANDOMIZED CONTROLLED STUDY

Jia Weidong* 1

1Department of Liver Surgery, Affiliated Provincial Hospital, Anhui Medical University, hefei, China

Introduction: This study aimed to investigate the effect of perioperative parecoxib sodium combined with transversus abdominis plane (TAP) block on pain management for hepatocellular carcinoma (HCC) patients after hepatectomy

Methods: One hundred and twenty HCC patients who underwent hepatectomy were randomized into a trial group and control group. Trial group received 40 mg of parecoxib sodium 30 minutes before anesthetic induction, and 150 mg of 0.375% ropivacaine with 5 mg dexamethasone were administrated, as TAP inhibitors, before closing abdomen. The control group received 40 mg of placebo 30 minutes before anesthetic induction, without TAP block. Postoperatively, all patients received patient-controlled intravenous analgesia (PICA) as well as an evaluation with pain scores. Data on adverse events, postoperative ambulation (>6 hours/day), time of flatus and defecation, as well as hospitalization time were recorded

Results: The pain scores of trial group were significantly lower than those in the control group on the first three postoperative days. No significant differences were found between the two groups

Advisory Board - Genoscience Pharma, Bayer, BTG plc, Bristol-Myers Squibb, and Ipsen, M. Peck-Radosavljevic Conflict with: Research/Education grant - AbbVie, ArQule, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, ImClone Systems, Lilly, Merck Sharp & Dohme, Novartis, and Roche, Conflict with: Honoraria - Bayer and Ipsen, Conflict with: Advisory Board - AbbVie, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, Merck Sharp & Dohme, and Roche, Conflict with: Consulting - Bayer, H. C. Lee Conflict with: Research/Education grant - Sillajen, Bayer, Ono Pharmaceutical, Merck Sharp & Dohme, and AstraZeneca, Conflict with: Advisory Board - Bayer, K. Nakajima Conflict with: Stocks - Bayer, I. Bayh Conflict with: Stocks - Fresenius Medical Care Deutschland GmbH, M. Kudo Conflict with: Research/Education grant - AbbVie, Bayer, Chugai Pharma, Daiichi Sankyo, Eisai, Merck Sharp & Dohme, Otsuka, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, and Takeda, Gilead, and EA Pharma, Conflict with: Honoraria - Bayer, Eisai, and Merck Sharp & Dohme, Conflict with: Advisory Board - Bayer, Bristol-Myers Squibb, Chugai Pharma, Merck Sharp & Dohme, Eisai, and Ono Pharmaceutical

P-038 A DECISION-MAKING ALGORITHM FOR REPEATED TRANSARTERIAL CHEMOEMBOLIZATION OF INTERMEDIATE-STAGE HEPATOCELLULAR CARCINOMA: A MULTI-COHORT STUDY

Hwi Young Kim* 1, Jun Sik Yoon2, Dong-Hyun Sinn3, Jeong-Hoon Lee4, Cheol-Hyung Lee4, Sun Woong Kim4, Hyo Young Lee4, Jun Yeol Nam1, Young Chang4, Yun Bin Lee4, Eun Ju Cho4, Su Jong Yu4, Hyo-Cheol Kim5, Jin Wook Chung5, Yoon Jun Kim4, Jung-Hwan Yoon4

1Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, 2Department of Internal Medicine, Inje University College of Medicine, Busan, 3Department of Internal Medicine, Samsung Medical Center, 4Department of Internal Medicine and Liver Research Institute, 5Department of Radiology, Seoul National University College of Medicine, Seoul, Korea, Republic Of

Introduction: For patients with intermediate-stage hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might be candidate for systemic therapy, is still controversial. The aim was To derive and validate a tumor marker-based objective algorithm to guide the retreatment of intermediate-stage HCC with TACE.

Methods: The multiple study cohorts comprised a total of 482 consecutive patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using pre- and post-TACE MoRAL score (i.e., MoRAL score=11×√ protein induced by vitamin K absence-II [PIVKA-II] + 2×√alpha-fetoprotein [AFP]), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in explant liver, from the training cohort (n=193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n=140) and a Korean National Cancer Registry sample cohort (n=149). The predictive performance of tumor marker-based algorithm on OS, which can discriminate TACE-refractory patients with poor expected OS

Results: Multivariable analyses indicated that the changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio [HR]=2.18, 95% confidence interval [CI]=1.37–3.46, P=0.001). The MoRAL-increase patients showed significantly shorter OS than the MoRAL-non-increase patients (HR=1.96, 95% CI=1.24–3.09, P=0.003; median OS=18.8 vs. 37.8 months). In a subgroup of patients with high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR=3.68, 95% CI=1.54–8.76, P<0.001; median OS=9.9 vs. 37.4 months). These results were reproduced in the two external validation cohorts.

Conclusions: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefit in cases of MoRAL-increase after the first TACE in patients with high baseline MoRAL score (≥89.5) who might be candidates for systemic therapy.


P-039 REAL-WORLD APPROACHES TO TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA WITH LENVATINIB IN JAPANESE PATIENTS: COMPLEMENTARY DATA FROM THE REFLECT TRIAL

Susumu Maruta* 1, Sadahisa Ogasawara1, Yoshihiko Ooka1, Masanori Inoue2, Masamichi Obu3, Norio Itokawa4, Atsuyoshi Seki5, Yuki Haga6, Shinichiro Okabe7, Ei Itobayashi2, Naoya Kanogawa3, Ryosaku Azemoto3, Masanori Atsukawa4, Hideaki Mizumoto5, Nobuyuki Sugiura6, Hiroaki Kanzaki1, Kengo Kanayama1, Takahiro Maeda1, Yuko Kusakabe1, Kazufumi Kobayashi1, Soichiro Kiyono1, Masato Nakamura1, Takayuki Kondo1, Tomoko Saito1, Eiichiro Suzuki1, Shingo Nakamoto1, Shin Yasui1, Akinobu Tawada1, Tetsuhiro Chiba1, Makoto Arai1, Tatsuo Kanda1, Hitoshi Maruyama1, Naoya Kato1

1Chiba University, Graduate School of Medicine, 2Asahi General Hospital, 3Kimitsu Chuo Hospital, 4Nippon Medical School, Chiba Hokusoh Hospital, 5Funabashi Municipal Medical Center, 6National Hospital Organization Chiba Medical Center, 7Matsudo City General Hospital, Chiba, Japan

Posters Posters


Methods: This multicenter and multinational cohort study conducted in Latin America included adult patients listed for LT with HCC between the years 2011-2018. Development of HCC tumor progression by RECIST 1.1 (PD) and/or post LT recurrence was evaluated as a combined primary event. A multivariable competing risk regression analysis was performed (competitive event = death or withdrawal from other causes), with Sub-Hazard Ratios (SHR) and respective 95% confidence intervals (CI 95%) calculations.

Results: Of 994 patients with HCC listed for liver transplantation, 81.9% were within Milan criteria (n=814). Among patients within Milan, 91.6% and 8.4% had an AFP score ≤2 and >2 points, respectively. While in those beyond Milan at enrollment (n=180), 50.3% and 47.9% had an AFP score of ≤2 and >2 points, respectively. Locoregional treatment on the waiting list was carried out in 54.8% of the total cohort. After last radiological re-evaluation during waiting list in which the change on the AFP score was compared, the risk of developing the combined primary event was 21.8% for those patients with an AFP score ≤2 points at LISTING/≤2 points at LAST evaluation, similar to those with AFP score >2 points LISTING/≤2 points LAST (21.2%) adjusted SHR 0.65 (CI 0.32-1.34; P=0.25), and lower than those with an AFP score ≤2 points LISTING/>2 points LAST (38.5%) adjusted SHR 1.54 (CI 1.13-2.08; P=0.006) and with an AFP score >points LISTING/>2 points LAST (42.3%) adjusted SHR 1.77 (CI 1.21-2.59, P=0.003).

Image:

Conclusions: The AFP score has been shown to be effective in categorizing the risk of post-transplant recurrence, as well as the risk of tumor progression on the waiting list.

Disclosure of Interest: F. Piñero Conflict with: Research/Education grant - National Institute of Cancer, Argentina, Conflict with: Honoraria - Bayer, Conflict with: Advisory Board - Bayer, Conflict with: Consulting - Bayer, C. Duvoux: None Declared, I. Boin: None Declared, A. Chagas: None Declared, E. Quiñonez: None Declared, S. Marciano: None Declared, M. Vilatoba: None Declared, A. Varón: None Declared, L. McCormack: None Declared, S. Hoyos Duque: None Declared, A. Soares Lima: None Declared, J. Menéndez: None Declared, M. Padilla-Machaca: None Declared, J. Poniachik: None Declared, R. Zapata: None Declared, M. Maraschio: None Declared, R. Chong Menéndez: None Declared, L. Muñoz Espinosa: None Declared, J. Menna: None Declared, R. Figueroa: None Declared, M. Fauda: None Declared, M. Chaim Correia: None Declared, C. Maccali: None Declared, R. Vergara Sandoval: None Declared, C. Bermúdez: None Declared, L. Santos: None Declared, M. Anders: None Declared, I. Arenas: None Declared, L. de Navarro Armando: None Declared, S. Gerona: None Declared, J. Chaman: None Declared, V. Henriquez: None Declared, A. Ginesta: None Declared, A. Gadano: None Declared, J. Mattera: None Declared, E. de Ataide: None Declared, F. Carrilho: None Declared, M. Silva: None Declared

P-049 RESPONSE TO SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA: PREDICTIVE ANALYTICS USING MACHINE LEARNING WITH A NEIGHBORHOOD-GROUP DETECTION METHOD

Jun Hyuk Kang* 1, Joong-Won Park1, Minjong Lee2, Bo Hyun Kim1

1Center for Liver Cancer, National Cancer Center, Goyang, 2Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea, Republic Of

Introduction: Global guidelines indicate that sorafenib is the treatment of choice for patients with advanced hepatocellular carcinoma (HCC). However, only a few clinical markers have been suggested as predictors of the response to sorafenib. Owing to the nonlinear distribution characteristics of clinical variables, it is difficult to identify predictors by using conventional statistical analysis. To address this nonlinearity, we developed a neighborhood-group (N-group) detection method and investigated the predictors of the response to sorafenib treatment.

(56%) even if using iRECIST definitions. However, after initial assessment the evolution of the tumor may reflect antitumor activity. Ultimately, a relevant number of patients may present complete response (4%) or be classified as hyperprogressors (11.5%). These results indicate an urgent need to develop accurate criteria to evaluate treatment efficacy for these novel and highly promising therapeutic agents.

References: 1. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with

advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet.2017;389:2492–2502.

2. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 ;18(3):e143-e152

Disclosure of Interest: J. Rimola Conflict with: Honoraria - Bayer, L. Da Fonseca Conflict with: Honoraria - Bayer, Ipsen, V. Sapena Conflict with: Research/Education grant - Bayer, C. Perelló: None Declared, A. Guerrero-Garcia: None Declared, M. Torner Simó: None Declared, M. Pons: None Declared, M. De La Torre Conflict with: Honoraria - Bayer, L. Márquez Conflict with: Honoraria - Bayer, Gilead, Abbvie, J. L. Calleja Conflict with: Honoraria - Gilead science, Abbvie, MSD, J. L. Lledó Conflict with: Honoraria - Bayer, M. Varela Conflict with: Honoraria - Bayer, IPSEN, Sirtex, BMS, BTG, B. Mínguez Conflict with: Research/Education grant - Proyecto de investigación en Salud AES 2018 (PI18/00961) Instituto de Salud Carlos III. Ministerio de Ciencia Innovación y Universidades, Conflict with: Honoraria - Bayer, Gilead, B. Sangro Conflict with: Honoraria - Terumo, Conflict with: Advisory Board - Adapt immune, Astra-Zeneca, Bayer, BMS, BTG, Eisai, Eli Lilly, Ipsen, Onxeo, Roche, Sirtex, Conflict with: Consulting - Novartis, Sirtex, Astra-Zeneca, Bayer, BMS , A. Matilla Conflict with: Honoraria - Bayer, F. Torres Conflict with: Honoraria - ImClone, Daiichi-Sankyo Pharma Development, ArQuleRovi, Bayer, C. Ayuso Conflict with: Honoraria - Bayer, J. Bruix Conflict with: Research/Education grant - Bayer and BTG, Conflict with: Honoraria - Bayer, BTG- Biocompatibles, Eisai, Terumo, Sirtex, Ipsen, Conflict with: Consulting - Arqule, Bayer, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, Merck, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, M. Reig Conflict with: Research/Education grant - Bayer, Conflict with: Honoraria - Bayer, BMS, Gilead, and Lilly, Conflict with: Consulting - Bayer, BMS, Roche, Ipsen, AstraZeneca and Lilly

P-048 EVALUATION OF THE AFP SCORE IN HEPATOCELLULAR CARCINOMA PROGRESSION DURING WAITING LIST AND RECURRENCE AFTER LIVER TRANSPLANTATION

Federico Piñero* 1, 2, Christophe Duvoux3, Ilka Boin4, Aline Chagas5, Emilio Quiñonez6, Sebastián Marciano7, 8, Mario Vilatoba9, Adriana Varón10, Lucas McCormack11, Sergio Hoyos Duque12, 13, Agnaldo Soares Lima14, Josemaría Menéndez15, Martín Padilla-Machaca16, Jaime Poniachik17, Rodrigo Zapata18, Martín Maraschio19, Ricardo Chong Menéndez20, Linda Muñoz Espinosa21, Jose L. Menna22, Rodrigo Figueroa23, Martín Fauda1, Maria F. Chaim Correia24, Claudia Maccali5, Rodrigo Vergara Sandoval6, Carla Bermúdez7, Luisa Santos10, Margarita Anders11, Isabel Arenas12, Leandro R. de Navarro Armando14, Solange Gerona15, José Chaman16, Victor Henriquez17, Alexandra Ginesta25, Adrian Gadano7, Juan Mattera6, Elaine C. de Ataide24, Flair Carrilho5, Marcelo Silva1, 26

1Liver Unit, Hospital Universitario Austral, Pilar, 2Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina, 3Hepatology, Hospital Henri Mondor, University of Paris-Est, Creteil, , Paris, France, 4Liver Transplantation, Hospital das Clínicas UNICAMP Campiñas, Campiñas, 5Hepatology and Gastroenterology, Hospital das Clínicas University of São Paulo School of Medicine, São Paulo, Brazil, 6Liver Transplantation and Hepatobiliary Surgery, Hospital El Cruce, Florencia Varela, 7Hepatology Section., 8Department of Clinical Research, Hospital Italiano, Buenos Aires, Argentina, 9Liver Transplantation and Hepatobiliary Surgery, Instituto de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico DF, Mexico, 10Hepatology and Gastroenterology, Fundación Cardioinfantil, Bogotá, Colombia, 11Liver Transplantation and Hepatobiliary Surgery, Hospital Alemán, Buenos Aires, Argentina, 12HPB and Liver Transplant Program, Hospital Pablo Tobón Uribe, 13Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia, 14Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas da UFMG, Minas Gerais, Brazil, 15Liver Transplantation and Hepatology, Hospital de Clínicas, Montevideo, Uruguay, 16Departamento de Trasplantes, Hospital Nacional Guillermo Almenara, Lima, Peru, 17Hepatology and Gastroenterology, Hospital Clínico de la Universidad de Chile, 18Hepatology and Gastroenterology, Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile, 19Hepatology and Gastroenterology, Hospital Privado, Córdoba, Argentina, 20Hepatology, Hospital Metropolitano, Quito, Ecuador, 21Hepatology, Hospital Universitario “Dr. José E. González”, Monterrey, Mexico, 22Liver Unit, Sanatorio Sagrado Corazón, Buenos Aires, 23Liver Transplantation and Hepatobiliary Surgery, Sanatorio Allende, Córdoba, Argentina, 24Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas UNICAMP Campiñas, Campiñas, Brazil, 25Hepatology and Gastroenterology, Clinica Alemana, Santiago, Chile, 26Latin American Liver Research and Awareness Network, Buenos Aires, Argentina

Introduction: The French AFP selection model has been shown to be superior in the prediction of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) when compared to the Milan criteria. It has been widely validated, even in a Latin American cohort. Our objective was to evaluate the AFP score in the prediction of tumor progression during the waiting list and HCC recurrence after LT.

1Barcelona Clinic Liver Cancer (BCLC) Group, Servicio de Radiodiagnostico, Hospital Clınic of Barcelona, 2Barcelona Clínic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic of Barcelona. IDIBAPS. CIBERehd, Barcelona, 3Servicio de Digestivo. Unidad de Hepatología, Hospital Universitario Puerta de Hierro. IDIPHISA. CIBERehd, 4Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal. CIBERehd, Madrid, 5Sección de Hepatología. Servicio de Digestivo., Hospital Universitario Central de Asturias. IUOPA. FINBA, Oviedo, 6Servicio de MI-Hepatología, Hospital Universitario Vall d'Hebron. Vall d'Hebron Institut of Research (VHIR). CIBERehd. Universidad Autónoma de Barcelona, Barcelona, 7Liver Unit, Clinica Universidad de Navarra, 8Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, 9Liver Unit, Clinica Universidad de Navarra-IDISNA, CIBERehd, Pamplona, 10Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón. CIBERehd, Madrid, 11Medical Statistics core facility, IDIBAPS, Hospital Clinic Barcelona & Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, 12Barcelona Clinic Liver Cancer (BCLC) Group, Servicio de Radiodiagnostico, Hospital Clinic of Barcelona, Barcelona, Spain

Introduction: Immune-checkpoint inhibitors have emerged as an effective treatment option for a variety of advanced cancers. However, there is scarce information regarding the radiological response and overall survival on advanced hepatocellular carcinoma (HCC) outside industry sponsored trials. The goal of this study was to describe the radiological response in a retrospective cohort of HCC patients treated with nivolumab in referral centers in Spain. Secondary aim was to analyze the evolution according to the tumor response at 1st radiological assessment (FRA) after treatment initiation.

Methods: Five Spanish centers submitted radiological studies (either CT or MR) including pre and post treatment assessments of HCC patients treated with nivolumab. These studies were centrally read by an expert radiologist blinded to clinical information. Radiological evaluation was assessed according to iRECIST and RECIST 1.0 (that includes higher number of lesions) criteria. Hyperprogressions (defined as increase in tumor burden ≥40% or ≥20% together with presence of new lesions) and pseudo-progression (defined as ≥20% increase in tumor burden and/or presence of new lesion that was not confirmed at next assessment) were also analyzed.

Results: A total of 118 patients were treated with nivolumab. 42 outside clinical trials were included in the multicenter study, and the CT/MR of 26 patients were sent for central reading (20 Child-Pugh A and 18 BCLC-C). Median follow-up and cycles of nivolumab were 5.13 months [IQR: 2.99-7.96] and 2.5 [IQR: 2-3.75]. The median time to first radiological evaluation after treatment initiation was 5 [IQR: 4 – 7] weeks. Twenty-five patients had measurable lesions and 22 had the FRA within 2 months after Nivolumab initiation. We observed disagreements on target lesions’ response when assessed per iRECIST vs. per RECIST 1.0 (5 patients showing progressive disease per iRECIST vs. 3 patients per RECIST; and 7 patients showing partial response as per iRECIST vs. 5 patients per RECIST). Six patients (24%) presented new lesions during follow-up. All new lesions appeared during the first two radiological assessments after treatment initiation. In 3 of them, the detection of a new lesion was associated to further progressions in size; in 2 patients it was followed by stability, and in 1 to a decrease in tumor burden. There were 3 pseudo-progressions, all of them detected during the first two radiology assessments.After the first cycle of nivolumab (n=22), we observed an heterogeneous evolutionary pattern in tumor burden: a) 4 subjects presented decrease in tumor burden, although 1 patients finally died due to disease progression; b) tumor burden increased in 12 subjects, but in 3 of them tumor burden decreased thereafter; c) 5 patients presented a <5% size change (Table 1).

Image:

Conclusions: Our data expose the challenge of response evaluation in patients treated with immune-oncology agents. The most frequent radiology assessment registers disease progression

References: [1] Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA. Cancer J. Clin. 68, 7–30

(2018).[2] Chaiteerakij, R. et al. Update on Biomarkers of Hepatocellular Carcinoma. Clinical Gastroenterology

and Hepatology 13(2), 237-245 (2015).[3] Sorensen, C.G. et al. The diagnostic accuracy of carcinoembryonic antigen to detect colorectal

cancer recurrence-A systematic review. International Journal of Surgery 25, 134-144 (2016).[4] Hackl C.et al. A population-based analysis on the rate and surgical management of colorectal

liver metastases in southern Germany. Int J Colorectal Dis 26:1475–1481 (2011).


P-046 RELATIONSHIP BETWEEN PRE-SARCOPENIA AND EVENT OCCURRENCE IN PATIENTS WITH PRIMARY HEPATOCELLULAR CARCINOMA

Hitomi Komiyama* 1, Tetsuya Okuwaki1, Naoto Imagawa1, Naruki Shimamura1, Makoto Kadokura1, Fumitake Amemiya1, Nobuyuki Enomoto2

1Gastroenterology and Hepatology, Municipal Hospital of Kofu, Yamanashi, Japan, Kofu, 2First Department of Internal Medicine, University of Yamanashi, Chuo, Japan

Introduction: Pre-sarcopenia is a prognostic factor for patients with liver disease. The Japan Integrated Staging Score (JIS score) is a prognostic score for liver cancer patients which combines the Child-Turcotte-Pugh classification and tumor-node-metastasis staging (TNM classification), and was published by Kudo et al. in 2003. The aim of this study is to clarify the relationship between pre-sarcopenia, JIS score, and event occurrence in patients with primary hepatocellular carcinoma.

Methods: This was a retrospective cohort study of 153 primary hepatocellular carcinoma(HCC) patients who were hospitalized from October 2011 to March 2018 at our hospital. We calculated Psoas Muscle Mass Index (PMI) (cm2/m2), and diagnosed low skeletal muscle mass as pre-sarcopenia. PMI is the value obtained by dividing the sum of the product of the long axis and the short axis of the intestinal psoas muscles on both sides of the L3 vertebra by the square of body height using CT images. Event-free survival was calculated starting from the date of hospitalization, with the event occurrence date required hospital care or the last follow-up date as the end point.

Results: The mean age was 73±9.2 years. Male patients were 114 (75%). Ninety-five patients (62%) were Child-Pugh grade A, 45 patients (29%) were grade B, and 13 patients (9%) were grade C. For TNM classification of HCC, 26 patients (17%) were stage 1, 62 patients (41%) stage 2, 32 patients (21%) were stage 3, and 33 patients (21%) stage 4. For JIS score, 15 patients (10%) were 0 point, 56 patients (37%) 1 point, 34 patients (22%) were 2 points, 25 patients (16%) 3 points, 17 patients (11%) 4 points, and 6 patients (5%) 5 points. Pre-sarcopenia was confirmed in 43 cases (28%).The events occurred in 79 cases (52%). Event-free survival of cases with pre-sarcopenia (n=43) was significantly poorer than cases without pre-sarcopenia (n=110); the median event-free survival was 12.0 months (5.1-29.6) and 34.1 months (24.1- 41.2) (p<0.05). Event-free survival of cases with Child-Pugh grade C was significantly poorer than that of Child-Pugh grade A or B; the median event-free survival was 1.1 months, 41.1 and 11.4 months (p<0.05). The median event-free survival for Stage 1, 2, 3 and 4 was 58.6), 35.1, 17.4, and 2.0 months (p<0.05). The event-free survival of cases with JIS score of 3 or more (n=48) was significantly poorer than cases with JIS score of 2 or less (n=105); the median was 2.7 (1.4-6.8) vs. 41.2 (29.2- 60.4) months (p<0.05). In univariate analysis, the following factors were significant: presence of pre-sarcopenia, JIS score of 3 or more, Y-GTP 100 IU/L or more, AFP 200 ng/ml or more, and PIVKA-II 200 mAU/ml or more. In multivariate analysis, presence of pre-sarcopenia (Hazard ratio 1.9), JIS score of 3 or more (HR 6.0), AFP 200 ng/ml or more (HR 2.3), and PIVKA-II 200 mAU/ml or more (HR 2.1) were significant factors. In cases with a JIS score of 3 or more, there was no difference in event rate with or without pre-sarcopenia (p=0.96). In cases with JIS score of 2 or less, the event free-survival of cases with pre-sarcopenia was significantly shorter compared with those without; the median was 19.1 vs. 49.2 months (p =0.05).

Conclusions: In patients with primary hepatocellular carcinoma, low skeletal muscle mass is an independent factor related to event occurrence. In the patients with JIS score 3 or more, there was no difference in the event rate regardless of pre-sarcopenia, whereas in patients with JIS score 2 points or less, the event rate was significantly higher in the pre-sarconia group than in the non-pre-sarconia group.


P-047 RADIOLOGICAL RESPONSE OF HEPATOCELLULAR CARCINOMA PATIENTS TREATED WITH NIVOLUMAB IN REAL LIFE. MULTICENTRIC ANALYSIS FROM REFERRAL CENTERS IN SPAIN

Jordi Rimola* 1, Leonardo G. Da Fonseca2, Victor Sapena2, Christie Perelló3, Antonio Guerrero-Garcia4, Maria Torner Simó5, Monica Pons6, Manuel De La Torre7, Laura Márquez8, José Luis Calleja3, José Luis Lledó4, Maria Varela5, Beatriz Mínguez6, Bruno Sangro9, Ana Matilla10, Ferrán Torres11, Carmen Ayuso12, Jordi Bruix2, Maria Reig2

Posters Posters


Introduction: Polyploidy refers to cells with whole genome duplications. In cancer cells, polyploidy is seen as a precarious precursor to genome instability. Surprisingly, polyploidy is a normal state in organisms such as plants and fish. In mammals, more than 50% of hepatocytes are tetraploid, octaploid, or greater, but putative liver stem cell populations are thought to be diploid. The functional implications and fates of polyploid hepatocytes are still unclear.

Methods: We have tested several genetic pathways to interrogate roles for polyploidy, which have remained obscure. Knocking down E2f8, a transcription factor required for polyploidization, or Anillin, a cytoskeletal protein required for cytokinesis, can decrease or increase ploidy, respectively. We developed a dox-inducible shRNA mouse against Anillin that permits reversible knockdown and massive polyploidization without permanent disruption of Anillin.

Results: These super-polyploid mice were potently protected from tumorigenesis induced by a single mutagen dose. However, it is unknown how polyploids react to chronic proliferative demands, which are characteristic of clinically relevant chronic diseases. What if damaged polyploids that divide result in chromosomally unstable daughter cells? Thus, we used persistent chemical injuries to induce damage and proliferation. Surprisingly, super-polyploid mice were again protected from cancer. We tested if tumor protection could be caused by gene expression changes, but RNA-seq showed no differences between ploidy states. Moreover, diploid and polyploids showed no differences in tissue damage as measured by serum tests, histology, and fibrosis. We also detected no significant differences in mitosis frequency between diploid and polyploid livers.

Conclusions: In summary, polyploid hepatocytes readily divide and regenerate while being buffered from tumor suppressor loss of heterozygosity and tumorigenesis. Our work implies that therapeutic polyploidization could protect livers from cancer while preserving the astounding regenerative capacity of this organ.


P-056 ADVANCES IN THE ETIOLOGY AND THERAPEUTICS OF A LETHAL CHILDHOOD CANCER, FIBROLAMELLAR HEPATOCELLULAR CARCINOMA

Gadi Lalazar1, Melissa Jarmel1, Michael Tomasini1, Sanford M. Simon* 1

1Cellular Biophysics, Rockefeller University, New York, United States

Introduction: Fibrolamellar hepatocellular carcinoma (FLC) is a liver cancer affecting adolescents and young adults without underlying liver disease. Patients with FLC are often diagnosed with advanced stage disease and have a poor 5-year survival. Recently we have made advances in both understanding the etiology of FLC as well as developing therapeutics. Etiology: We have found that the bulk of the genome is clear of recurrent single nucleotide or structural variants (inversions, amplifications) with the exception of a deletion in one copy of chromosome 19. This results in a fusion of the first exon of the heat shock protein, DNAJB1, with the 2nd through 10th exons of PRKACA, the catalytic subunit of protein kinase A (1-3). Expression of this fusion in the livers of mice, either by CRISPR or transposon, is sufficient to phenocopy the disease and the kinase activity of the fusion protein is essential for transformation (4, 5).

Methods: Etiology: We have tested the ability of the native kinase and fusion oncokinase to phosphorylate potential substrates in human liver. Therapeutics: A high-throughput screen as been used to find inhibitors of the fusion oncokinase.

Results: Etiology: We have found a discrete set of substrates that are phosphorylated in human liver for which we are now testing which are critical for the pathogenesis of this cancer.Therapeutics: We have developed several “never-in-plastic” patient derived xenograft (PDX) models that retain expression of the driver, histology, transcriptome and proteome of the original human tumor. We have found inhibitors in the nanomolar range for which we are using structural analysis to inform our medicinal chemistry (6). Additionally, we have screened for compounds that induce tumor cell death and tumor regression in FLC PDXs.

Conclusions: Subtle changes in the kinase substrate profile of the fusion kinase provides new leads for therapeutics for FLC. The ability to find inhibitors of the kinase in the nanomolar range, as well as the ability to screen for inhibitors of the PDX offer the first hope for patients from this lethal tumor.

References: 1. Darcy DG, Chiaroni-Clarke R, Murphy JM, Honeyman JN, Bhanot U, LaQuaglia MP, Simon SM.

The genomic landscape of fibrolamellar hepatocellular carcinoma: whole genome sequencing of ten patients. Oncotarget. 2015;6(2):755-70..

2. Honeyman JN, Simon EP, Robine N, Chiaroni-Clarke R, Darcy DG, Lim, II, Gleason CE, Murphy JM, Rosenberg BR, Teegan L, Takacs CN, Botero S, Belote R, Germer S, Emde AK, Vacic V, Bhanot U, LaQuaglia MP, Simon SM. Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science. 2014;343(6174):1010-4.

3. Simon EP, Freije CA, Farber BA, Lalazar G, Darcy DG, Honeyman JN, Chiaroni-Clarke R, Dill BD, Molina H, Bhanot UK, La Quaglia MP, Rosenberg BR, Simon SM. Transcriptomic characterization of fibrolamellar hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(44):E5916-25..

P-053 ROLE OF RPS6KA3 GENE INACTIVATION IN HEPATOCELLULAR CARCINOMA

Anna-Line Calatayud* 1, 2, Samantha Schaeffer1, 2, Barkha Gupta1, 2, Julien Calderaro3, Jessica Zucman-Rossi1, 2, 4, Sandra Rebouissou1, 2

1Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, F-75006 Paris, France, 2Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, F-75000 Paris, France, INSERM, Paris, 3Anathomopathology Department, Henri Mondor Hospital, Créteil; University of Paris Est Créteil, Inserm U955, Team 18, Mondor Institute of Biomedical Research, France, Creteil, 4European Hospital Georges Pompidou, AP-HP, F-75015, Paris, APHP, Paris, France

Introduction: Hepatocellular carcinoma (HCC) is a very aggressive cancer for which treatment options are still limited at advanced stages. Therefore, a better understanding of the molecular pathogenicity of HCC may help to improve patient care.Our laboratory has identified for the first time inactivating mutations in the RPS6KA3 gene, encoding for the RSK2 protein, in 6-9% of HCCs with frequent co-occurring mutations inactivating the AXIN1 gene involved in the Wnt/ß-catenin pathway. RSK2 is a serine/threonine kinase that acts at the distal end of the Ras-MAPK signaling pathway, however the role of its inactivation in liver carcinogenesis remains unknown. We showed previously that RSK2 inactivation in HCC cell lines leads to an aberrant activation of the RAS-MAPK pathway. Here, our goals were to demonstrate the tumor suppressor role of RSK2 in the liver, to study the functional consequences of its inactivation and to identify specific therapeutic targets for RSK2 inactivated HCCs.

Methods: RPS6KA3 mutational spectrum was investigated in a collection of more than 1000 human HCC and 50 other types of cancers from public datasets and co-occurring mutations with other HCC driver genes were searched.In vivo, different mouse models were generated: one model with a constitutive Knockout (KO) of Rps6ka31 alone and two other models were developed to test potential cooperation between Rsk2 inactivation and activation of the ß-catenin pathway. Mice were either treated with Diethylnitrosamine (DEN) and phenobarbital known to induce ß-catenin activating mutations2 or mice have both Rps6ka3 inactivation and Axin1 inactivation induced in the liver by ß-naphtoflavone3.In vitro, RPS6KA3 was reintroduced by lentiviral transduction in the Hep3B cell line displaying a homozygous deletion. Activation of the RAS-MAPK pathway following RSK2 modulation was assessed by western blot both in vivo and in vitro and glutamine-synthetase was analysed by immunohistochemistry in mice tumors to assess ß-catenin activation.

Results: RPS6KA3 mutational spectrum in human HCC was typical of tumor suppressor gene inactivation with 60% of truncating mutations while mutations in other cancer types were rare and more likely passenger events occurring in genetically instable cancers. RPS6KA3 mutations were significantly associated with AXIN1 mutations and a co-occurrence tendency was also observed with ß-catenin mutations.Rps6ka3 KO mice did not show spontaneous liver tumor development. However, in DEN/phenobarbital treated model, 12 months after DEN injection Rps6ka3 KO mice showed a significantly higher tumors incidence than wild-type (WT) (respectively 100% (n=8) versus 40% (n=10), P=0.01) and tumors were activated for ß-catenin. Also, Rps6ka3/Axin1 KO mice (n=8) showed spontaneous tumors appearance in a significantly higher rate (63%) than simple Axin1 KO (9%) or WT (0%) (P=0.002). Moreover, non-tumor liver of mice inactivated for Rps6ka3 showed an aberrant activation of the Ras-MAPK pathway.In the Hep3B cell line, re-expression of RSK2 inhibited cell proliferation (P=0.0004) and RAS-MAPK pathway activity (P=0.03) and reversed sensitivity to trametinib a MEK1/2 inhibitor.

Conclusions: We demonstrated that RPS6KA3 is a HCC specific tumor suppressor and that its inactivation cooperates either with AXIN1 inactivation or ß-catenin activation to promote hepatic carcinogenesis. Moreover, this work identified the RAS-MAPK pathway as a promising target to treat RPS6KA3 mutated HCC.

References: 1. Yang et al., ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology;

implication for Coffin-Lowry Syndrome. Cell, 20042. Aydinlik et al., Selective pressure during tumor promotion by phenobarbital leads to clonal

outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene, 20013. Feng et al., Conditional disruption of Axin1 leads to development of liver tumors in mice.

Gastroenterology, 2012


P-054 POLYPLOID HEPATOCYTES CONTRIBUTE TO REGENERATION BUT ARE PROTECTED FROM CANCER EVEN AFTER CHRONIC LIVER INJURY

Hao Zhu* 1, Yu-Hsuan Lin1

1Children's Research Institute, UT Southwestern, Dallas, United States

molecular understanding of the disease and patient stratification for advancing clinical intervention is limited. Recent whole exome sequencing (WES) studies have made efforts to understand the molecular basis of GBC by analyzing somatic mutations that contribute to the development of GBC. Yet, none of these studies have proposed a molecular stratification to classify different subtypes of GBC with pathobiological and clinical characteristics. This gap is partly due to small sample size and a focus exclusively on somatic mutation-centric characterization, emphasizing the urgency for understanding the molecular heterogeneity of the disease to prompt patient stratification and advance therapeutic options.

Methods: To comprehensively characterize the genomic landscape of GBC, we analyzed WES on a total of 92 GBCs and adjacent normal tissues, together with RNA-sequencing, DNA methylation, global SNP array and genotyping on 47 patients. We performed an integrative analysis of somatic mutations, dysregulated transcriptomes, DNA methylomes and copy number alterations to understand the association between activated perturbation mechanisms, genome clusters and unique pathological subtypes of GBC.

Results: In the most comprehensive annotation of somatic landscapes in GBC, we found the mutational load ranged from 9-566 deleterious mutations per patient. Significantly mutated genes included TP53, ELF3, ERBB2, KIR2DL4, TGFBR2, KIR2DL3 and PIK3CA. Mutations were enriched in pathways broadly associated with apoptosis, cell cycle, Wnt pathway and immune signaling. Systematic analysis of dysregulated GBC transcriptomes revealed three distinct clusters (C1-C3). The C1 cluster was characterized by low mutational burden, non-CpG island hypermethylation, higher expression levels of immune checkpoint genes (PDCD1 and CTLA4), and multiple pathways related to immune response (immune subtype). This group was preferentially represented by low-grade tumors showing an intestinal to biliary pathology. In contrast, the C3 cluster was characterized by high mutational burden and was significantly enriched in TP53, DNA repair and mismatch pathway gene mutations; hypermethylation of CpG-island ; and augmented expression of proliferation and cell cycle control genes. Additionally, C3 was highlighted by APOBEC signatures (ABOPEC3B subtype). Sixty-seven percent of patients in this subgroup had high-grade tumors with a predominant biliary-type pathology and severe inflammation. The C2 included patients with a mixed genotype that were characterized by both low-grade biliary and intestinal adenocarcinoma, moderate infiltration and the worst overall survival (P=0.002).

Conclusions: Our results provide a detailed molecular classification of GBC. The immune-type and APOBEC3B-type clusters appear to represent distinct subtypes of GBC that exhibit disparate histopathologic features and oncogenic programs. These findings highlight the potency of genomics-based approaches for patient stratification.


P-052 INTRA-HEPATIC IMMUNE CHANGES AFTER HEPATITIS C VIRUS ERADICATION BY DIRECT-ACTING ANTIVIRAL THERAPY

Giuliana Amaddeo* 1, Cong Trung Nguyen1, Pascale Maille1, Sebastien Mulé1, Alain Luciani1, Camilia Machou1, Aurélie Rodrigues2, Hélène Regnault3, Ariane Mallat4, Alexis Laurent3, Fouad Lafdil1, Christophe Hézode3, Jean Michel Pawlotsky1, Julien Calderaro1

1INSERM, Créteil, France, 2INSERM, Créteil, Côte d'Ivoire, 3Henri Mondor Hospital, 4Henri Mondor Hopsital, Créteil, France

Introduction: The recent approval of direct acting anti-virals (DAA) has dramatically changed the landscape of hepatitis C virus (HCV) therapy. Whether viral clearance could promote liver carcinogenesis is debated. It has been hypothesized that changes in intra-hepatic immune surveillance following viral cure could favor tumor growth. This study aimed at characterizing the intra-hepatic immune changes induced by HCV cure following DAA therapy.

Methods: Patients with compensated cirrhosis who underwent surgical resection for hepatocellular carcinoma (HCC) after a sustained virological response (SVR) to DAA therapy in our institution were included. A control group of untreated HCV-infected patients with compensated cirrhosis was selected. RNA was extracted from tumor and non-tumoral tissues and analyzed using the Nanostring Immuno-Oncology-360 panel. Immune cells were quantified by immunohistochemistry.

Results: Twenty patients were included: 10 patients with a DAA-induced SVR and 10 untreated controls. All of them had a de novo BCLC 0/A HCC. Non-tumoral tissue profiling showed down-regulation of interferon-related genes (including MX1, ISG15, and IFIT1) after DAA therapy. No other differences in immune profiles/immune cell densities were identified between the two groups. The intra-tumoral immune profiles of HCCs that occurred after DAA therapy were not qualitatively or quantitatively different from those of tumors occurring in untreated patients.

Conclusions: Removal of HCV infection after DAA-based therapy results only in a down-regulation of interferon-stimulated genes in non-tumoral tissues from patients with cirrhosis who develop HCC. These minor changes in the liver immune microenvironment are unlikely to favor HCC occurrence or recurrence after DAA-induced SVR.


Methods: A previous cohort of patients that had been subjected to conventional statistical analysis (Lee M, et al. ILCA 2018 p-101; n=709) was re-analyzed. The analyses comprised: (1) calculation of the distance between all patient pairs; (2) defining N-groups based on an appropriate threshold distance and the minimum number of patients that should be included in the group; and (3) survival analysis of all N-groups. Subsequently, the clinical features of the N-groups were examined in detail to reveal the predictors related to survival differences.

Results: In total, 139 N-groups with distinct clinical features were found. In the survival analyses for all 9591 pairs of N-groups, 661 pairs of nearby N-groups were found to have significant differences in overall survival. According to the clinical characteristics of each N-group pair, various factors associated with the differences in survival were observed. The presence of portal vein thrombosis (PVT) and the absence of hand-foot syndrome (HFS) were commonly associated with poor survival. In N-group pairs without significant differences in PVT and HFS, the presence of extrahepatic metastasis and non-viral etiology was consistently associated with poor survival.

Conclusions: Through the use of an N-group detection method, we were able to identify predictors of the response to sorafenib that were consistent with the conventional analysis and additional factors. This new analytical method will provide a novel perspective for clinical analysis.


P-050 DIETARY FAT INTAKE AND RISK OF HEPATOCELLULAR CARCINOMA IN TWO LARGE PROSPECTIVE COHORT STUDIES

Wanshui Yang1, Jing Sui1, Yanan Ma1, Tracey Simon2, Jessica Petrick3, Michelle Lai4, Katherine McGlynn3, Peter Campbell5, Edward Giovannucci6, Andrew Chan2, Xuehong Zhang* 7

1Brigham and Women's Hospital, 2Massachusetts General Hospital, Boston, 3National Cancer Institute, Washington DC, 4Beth Israel Deaconess Medical Center, Boston, 5American Cancer Society, Atlanta, 6Harvard T. H. Chan School of Public Health, 7Brigham and Women's Hospital and Harvard Medical School, Boston, United States

Introduction: Epidemiological evidence of an association between dietary fat intake and hepatocellular carcinoma (HCC) risk is limited and inconclusive, particularly from prospective studies.

Methods: We prospectively examined intake of total and specific fats and major sources of dietary fats in relation to HCC risk within the Nurses’ Health Study and the Health Professionals Follow-up Study. Dietary fats were measured at baseline and updated every 4 years using validated food frequency questionnaires. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders.

Results: After an average follow-up of 28 years, 160 incident HCC cases were documented. We found a non-significant association between total fat intake and HCC (the highest vs. lowest quartile, HR=0.76, 95% CI: 0.47-1.24, Ptrend=0.46). According to food sources, there was a significant inverse association between vegetable fat intake and HCC risk (HR=0.61, 95% CI: 0.39-0.96, Ptrend=0.02), but a suggestive positive association with animal and dairy fat intake. Replacing animal or dairy fats with an equivalent amount of vegetable fat was associated with a lower HCC risk (HR per 1-SD=0.79, 95% CI: 0.65-0.97). According to fat subtypes, both monounsaturated and polyunsaturated fatty acids (PUFAs) including omega-3 (the highest vs. lowest quartile, HR=0.63, 95% CI: 0.41-0.96, Ptrend=0.14) and omega-6 PUFAs (HR=0.54, 95% CI: 0.34-0.86, Ptrend=0.02) were inversely associated with risk of developing HCC. Higher monounsaturated or polyunsaturated fat to saturated fat ratios were all statistically inversely associated with HCC risk (all Ptrend≤0.02). In addition, when replacing saturated fats with monounsaturated or polyunsaturated fats, the HR per 1-SD was 0.77 (95% CI: 0.64-0.92).

Conclusions: Higher intake of vegetable fats and PUFAs could be associated with lower HCC risk. Replacing animal or dairy fats with vegetable fats, or replacing saturated fats with monounsaturated or polyunsaturated fats was associated with reduced risk of HCC among US adults.


P-051 INTEGRATED MOLECULAR PROFILING REVEALS ETIOLOGICALLY DISTINCT LANDSCAPES OF GALLBLADDER CANCER

Chirag Nepal* 1, Bin Zhu2, Colm J. O’Rourke1, Deepak K. Bhatt1, Donghyuk Lee2, Song Lei2, Difei Wang2, Alison V. Dyke2, Hyoyoung Choo-Wosoba2, Allan Hildesheim2, Alisa Goldstein2, Michael Dean2, Zhiwei Liu2, Ludmila Prokunina-Olsson2, Ann W. Hsing3, Yu-Tang Gao3, Catterina Ferreccio4, Juan C. Roa4, Justo L. Bermejo5, Stephen J. Chanock2, Juan C. Araya6, Jesper B. Andersen1, Jill Koshiol2

1BRIC, University of Copenhagen, copenhagen, Denmark, 2Division of Cancer Epidemiology and Genetics, NIH, Maryland, 3CPIC, Stanford University, Stanford, United States, 4Pontificia Universidad, Pontificia Universidad, Católica, Chile, 5Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany, 6Temuco Hospital , Universidad del la Frontera, Temuco, Chile

Introduction: Gallbladder carcinoma (GBC) is an aggressive biliary tract malignancy that is a notoriously intractable disease with dismal prognosis and designated an orphan cancer. Detailed

Posters Posters


EFNA3 was upregulated in multiple HCC cell lines upon hypoxia treatment, and this upregulation was abolished upon knockdown of HIF1A or HIF2A. Knockdown of EFNA3 significantly reduced proliferative, migratory and self-renewal ability of HCC cells in normoxia and hypoxia in vitro. Orthotopic liver implantation of EFNA3 knockdown cells in nude mice resulted in lower tumor incidence rate, smaller primary tumor size and fewer lung metastases in vivo. Sorted cells from HCC PDTX model with positive/high expression of liver cancer stemness markers (EpCAM, CD13, CD24, CD44, CD47, and CD133) consistently demonstrated a higher expression of EFNA3. In fact, human HCC samples enriched for CD47 high population showed a consistently higher expression of EFNA3 compared to the corresponding CD47 low population (n=15). Moreover, knockdown of EFNA3 significantly reduced the expression of CD47 in HCC cells. In search for the mechanistic basis and downstream targets, evaluation of relative phosphorylation levels of Eph receptors using human RTK phosphorylation antibody array upon knockdown of EFNA3 in various HCC cell lines revealed consistent inactivation of multiple candidate Eph receptors, suggesting they may play a critical role in disease progression of HCC.

Conclusions: EFNA3 was identified as a hypoxia-inducible gene which is frequently overexpressed in human HCC. Our findings suggests it may play a critical role in hypoxia driven tumor progression, metastasis and cancer stemness in HCC.


P-061 COMPARISON OF SURVIVAL OUTCOMES FOR ADVANCED HEPATOCELLULAR CARCINOMA BEFORE AND DURING THE FIRST AND SECOND ERAS OF TYROSINE KINASE INHIBITORS

Sadahisa Ogasawara* 1, Yoshihiko Ooka1, Kazufumi Kobayashi1, Miyuki Sensui1, Susumu Maruta1, Hiroaki Kanzaki1, Kengo Kanayama1, Takahiro Maeda1, Yuko Kusakabe1, Soichiro Kiyono1, Masato Nakamura1, Naoya Kanogawa1, Tomoko Saito1, Takayuki Kondo1, Eiichiro Suzuki1, Shingo Nakamoto1, Shin Yasui1, Akinobu Tawada1, Tetsuhiro Chiba1, Makoto Arai1, Hitoshi Maruyama1, Naoya Kato1

1Chiba University, Graduate School of Medicine, Chiba, Japan

Introduction: A phase III study of advanced hepatocellular carcinoma (HCC) showed positive results with four tyrosine kinase inhibitors (TKIs) and one anti-body drug. Of these, sorafenib, regorafenib, and lenvatinib are available for use for patients with advanced HCC. The aim of this study was to investigate the survival impact of tyrosine kinase inhibitors (TKIs) for advanced stage HCC in clinical practice in Japan.

Methods: We reviewed data for patients with advanced stage HCC (defined as either macrovascular invasion or extrahepatic metastasis) at Chiba University Hospital, Japan, between 2003 and 2017, dividing them into three groups bases on the date the advanced stage HCC was diagnose: the pre-TKI group (2003–2008), the first-term TKI group (2009–2013), and the second-term TKI group (2014–2017). Overall survival (OS) was calculated from the date of diagnosis of advanced stage HCC to either death from any cause or the date of the last follow-up.

Results: Of 2,034 patients treated for HCC, 587 were diagnosed with advanced stage HCC during their clinical course (pre-TKI group, 116 patients; first-term TKI group, 236 patients; second-term TKI group, 235 patients). The median [95% confidence interval (CI)] values for the OS and observation periods were 9.7 [8.1–11.4] months and 7.0 [5.9–8.0] months, respectively. Rates of hepatitis C virus infection decreased with the later groups (pre-TKI group, 65.6%; first-term TKI group, 50.9%; and second-term TKI group, 41.6%). Median OS was shorter for patients who started TKI before being diagnosed with advanced stage HCC (8.9 [4.6–13.2] months) than for those who started TKI after the diagnosis (12.1 [8.3–15.8] months; P = 0.004). We therefore excluded from the survival analyses 56 patients who started TKI before the diagnosis of advanced stage HCC. The median [95% CI] OS values for the three groups were as follows: pre-TKI group, 9.1 [7.1–11.1] months; first-term TKI group, 8.9 [6.8–10.9] months; second-term TKI group, 14.3 [9.0–19.6] months. These differences were significant (P = 0.007). The administration rates of TKIs for the three groups were 2.6%, 61.8%, and 55.0%, respectively, and the median [95% CI] durations of receiving the TKIs were 0.7 [0.0–1.4] months, 2.5 [2.2–2.9] months, and 4.4 [2.4–6.4] months, respectively (P <0.001).

Conclusions: Patients diagnosed with advanced stage HCC during the second term of TKI showed better survival outcomes than those diagnosed before and during the first term of TKIs. Multiple lines of TKI seem to markedly prolong OS for patients with advanced stage HCC.

Disclosure of Interest: S. Ogasawara Conflict with: Research/Education grant - Bayer, Eisai, Conflict with: Honoraria - Bayer, Eisai, Eli Lilly, Conflict with: Advisory Board - Bayer, Eisai, Eli Lilly, Conflict with: Consulting - Bayer, Eisai, Y. Ooka: None Declared, K. Kobayashi: None Declared, M. Sensui: None Declared, S. Maruta: None Declared, H. Kanzaki: None Declared, K. Kanayama: None Declared, T. Maeda: None Declared, Y. Kusakabe: None Declared, S. Kiyono: None Declared, M. Nakamura: None Declared, N. Kanogawa: None Declared, T. Saito: None Declared, T. Kondo: None Declared, E. Suzuki: None Declared, S. Nakamoto: None Declared, S. Yasui: None Declared, A. Tawada: None Declared, T. Chiba: None Declared, M. Arai: None Declared, H. Maruyama: None Declared, N. Kato Conflict with: Research/Education grant - Bayer, Eisai, Conflict with: Honoraria - Bayer, Eisai, Conflict with: Advisory Board - Bayer, Eisai, Conflict with: Consulting - Bayer, Eisai.

Conclusions: CD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immuosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.


P-059 A NOVEL LIQUID BIOPSY USING A HIGHLY SENSITIVE METHYLATED SEPT9 ASSAY TO DIAGNOSE HEPATOCELLULAR CARCINOMA

Yurika Kotoh* 1, Issei Saeki1, Yutaka Suehiro2, Tomomi Hoshida2, Masaki Maeda1, Takuya Iwamoto1, Toshihiko Matsumoto2, Taro Takami1, Isao Sakaida1, Takahiro Yamasaki2

1Gastroenterology and Hepatology, 2Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan

Introduction: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide, and its diagnose at an early stage is important. Alpha-fetoprotein (AFP) has been widely used as a tumor marker; however, its usefulness for diagnosis is restrictive. There have been no liquid biopsies in practical use for HCC, whereas Epi proColon (Epigenomics AG, Berlin, Germany) is the first commercial blood-based test for colorectal cancer screening consisting of DNA testing of methylated SEPT9. However, Epi proColon has some problems, which include a large amount of blood plasma (greater than 3.5 mL), degeneration and loss of DNA by bisulfite treatment, lack of quantitative performance, and expensive cost. Therefore, we have developed a novel liquid biopsy test that enables the counting of even one copy of methylated SEPT9 in a small amount of DNA sample without DNA bisulfite treatment. We evaluated the potential application of this assay to diagnose HCC.

Methods: The subjects comprised 80 healthy volunteers: 45 patients with chronic liver disease without HCC and 136 with HCC (Stages I, 13; II, 57; III, 31; IV A, 23; IV B, 12; according to the criteria of the Liver Cancer Study Group of Japan). For this assay, DNA was treated via a two-step treatment with methylation-sensitive restriction enzymes, followed by multiplex droplet digital PCR.

Results: The median copy numbers of methylated SEPT9 were 0.0, 2.0, and 6.4 in the healthy control group, chronic liver disease group, and HCC group, respectively, with significant differences among each group. The sensitivity and specificity were 62.5% and 83.2%, respectively (cut-off value, 4.8 copies), whereas the positive rate of AFP detection using a cut-off value of 20 ng/mL was 38.5% (52/136). Both positive rates, a positive rate of AFP alone, and a positive rate of methylated SEPT9 alone were 27.2% (37/136), 11.0% (15/136), and 35.3% (48/136), respectively. The combination of AFP detection and this assay resulted in a 73.5% sensitivity (100/136). The positive rate of methylated SEPT9 increased with HCC progression (stage I, 38.5%; stage II, 54.4%; stage III, 67.7%; stage IV A, 78.3%; stage IV B, 83.3%).

Conclusions: As the sensitivity of AFP detection is low, our novel liquid biopsy can complement this weak point. A highly sensitive methylated SEPT9 assay might be a potential liquid biopsy test to diagnose HCC.


P-060 EPHRIN-A3 (EFNA3) IS A KEY PLAYER IN HYPOXIC MICROENVIRONMENT OF HEPATOCELLULAR CARCINOMA

Abdullah Husain* 1, 2, Elley Y. T. Chiu1, 2, Daniel W. H. Ho1, 2, Karen M. F. Sze1, 2, Lo-Kong Chan1, 2, Yu-Man Tsui1, 2, Carmen C. L. Wong1, 2, Irene O. L. Ng1, 2

1State Key Laboratory for Liver Research , 2Department of Pathology, The University of Hong Kong, Hong Kong, Hong Kong

Introduction: Intra-tumoral hypoxia has been recognized as a critical driver of disease progression in hepatocellular carcinoma (HCC). However, mechanistic understanding of this phenomena is still lacking.

Methods: Integrative analysis of transcriptomic profiles of HCC patients in our in-house cohort, TCGA-LIHC cohort, and HCC cells treated with hypoxia or normoxia was performed to identify clinically relevant genes upregulated by hypoxia. Short hairpin RNA based stable EFNA3 knockdown HCC cell models were generated to evaluate its functional role and semi-quantitatively determine the phosphorylation levels of Eph receptors using human RTK phosphorylation antibody array. Sorted cells from HCC PDTX model and clinical samples with positive/high expression of liver cancer stemness markers were analysed for expression of EFNA3.

Results: Our integrative analysis identified Ephrin-A3 (EFNA3) as a potential hypoxia-regulated gene target related to disease progression in HCC. EFNA3 encodes Ephrin-A3, a membrane bound ligand for multiple members of the Eph receptor family. In human HCC samples, EFNA3 was significantly overexpressed in tumors as compared to their corresponding non-tumorous liver tissues (n=97, p<0.0001). Clinicopathological correlation analysis revealed significant association of EFNA3 overexpression with advanced tumor stage and presence of venous invasion. Functionally,

Conclusions: Analysis of mutations in cfDNA by massive sequencing identifies most of the tumor somatic mutations of HCC patients; moreover, there were other mutations detected in cfDNA that were not present in the tumor, suggesting cfDNA could overcome the problem of tumor heterogeneity. Its detection could have relevant implications in early diagnosis and its follow-up over time, could have prognostic implications in early detection of recurrence, optimizing clinical management of HCC.


P-058 CD73 PROMOTES HEPATOCELLULAR CARCINOMA PROGRESSION AND METASTASIS VIA ACTIVATING PI3K/AKT SIGNALING BY INDUCING RAP1-MEDIATED MEMBRANE LOCALIZATION OF P110ß AND PREDICTS POOR PROGNOSIS

Xiaolu Ma* 1

1Laboratory of Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China

Introduction: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidences show that CD73-expressing tumor cell is implicated in development of several types of cancer. However, role of CD73 in HCC cell has not been systematically investigated and its underlying mechanism remains elusive.

Methods: CD73 expression in HCC cell was determined by RT-PCR, western blot and immunohistochemistry staining. Clinical significance of CD73 was evaluated by Cox regression analysis. Cell counting kit-8 and colony formation assays were used for proliferation evaluation. Transwell assays were used for motility evaluations. Co-immunoprecipitation, cytosolic and plasma membrane fractionation separation, and ELISA were applied for evaluating membrane localization of P110ß and its catalytic activity. NOD/SCID/Yc(null) (NOG) mice model was used to investigate the in vivo functions of CD73.

Results: In present study, we demonstrate that CD73 was crucial for epithelial-mesenchymal-transition (EMT), progression and metastasis in HCC. CD73 expression is increased in HCC cells and correlated with aggressive clinicopathological characteristics. Clinically, CD73 is identified as an independent poor prognostic indicator for both time-to-recurrence and overall survival. CD73 knockdown dramatically inhibits HCC cells proliferation, migration, invasion, and EMT in vitro, and hinders tumor growth and metastasis in vivo. Opposite results could be observed when CD73 is overexpressed. Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor (A2AR) and activates Rap1, which recruits P110ß to the plasma membrane and triggers PIP3 production, thereby promoting AKT phosphorylation in HCC cells. Notably, combination of anti-CD73 and -A2AR achieves synergistic depression effects on HCC growth and metastasis than single agent alone.

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4. Engelholm LH, Riaz A, Serra D, Dagnaes-Hansen F, Johansen JV, Santoni-Rugiu E, Hansen SH, Niola F, Frodin M. CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion is Sufficient to Induce Tumors Resembling Fibrolamellar Hepatocellular Carcinoma. Gastroenterology. 2017.

5. Kastenhuber ER, Lalazar G, Houlihan SL, Tschaharganeh DF, Baslan T, Chen CC, Requena D, Tian S, Bosbach B, Wilkinson JE, Simon SM, Lowe SW. DNAJB1-PRKACA fusion kinase interacts with beta-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(50):13076-84..

6. Tomasini MD, Wang Y, Karamafrooz A, Li G, Beuming T, Gao J, Taylor SS, Veglia G, Simon SM. Conformational Landscape of the PRKACA-DNAJB1 Chimeric Kinase, the Driver for Fibrolamellar Hepatocellular Carcinoma. Scientific reports. 2018;8(1):720..


P-057 LIQUID BIOPSY FOR HEPATOCELLULAR CARCINOMA: POTENTIAL USEFULNESS OF MASSIVE SEQUENCING OF CIRCULATING DNA AS A TOOL FOR DIAGNOSIS AND FOLLOW-UP OF HCC PATIENTS

Monica Higuera1, Elena Vargas-Accarino1, Maria E. Soria1, Josep Gregori1, 2, 3, Maria Torrens1, Maria T. Salcedo4, Itxarone Bilbao5, Francisco Rodríguez-Frías1, 2, 6, Josep Quer1, 2, Beatriz Mínguez* 1, 2, 7

1Liver diseases research group, Vall d'Hebron Institute of Research, VHIR, Barcelona, 2CIBERehd, Instituto Carlos III, Madrid, 3Roche Diagnostics S.L, Sant Cugat del Vallés, 4Pathology Department, 5General and Digestive Surgery Department, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, 6Biochemistry and Microbiology Department, Hospital Universitario Vall d'Hebron, Barcelona , 7Liver Unit. Department of Internal Medicine, Hospital Universitario Vall d´Hebron. Universidad Autónoma de Barcelona, Barcelona, Spain

Introduction: Tumor biopsy is the usual source of molecular information in cancerThe analysis of plasma cell free DNA (cfDNA) could be an interesting non invasive tool, with clinical applications in terms of diagnosis and prognostic estimation in patients with hepatocellular carcinoma (HCC). Our aim is to evaluate the presence of cfDNA mutations in patients with HCC, evaluate their correlation with the mutations detected in HCC tissue and assess the prognostic value of their changes along follow up of patients.

Methods: Patients undergoing surgical resection for HCC in our center were prospectively included in the study. Four samples were analyzed on each patient: 1) fresh frozen tumor tissue (HCC), 2) adjacent non-tumoral tissue (NT), 3) peripheral blood mononuclear cells (PBMC) and 4) plasma. cfDNA was extracted from 1ml of plasma using the MagMAX Cell-Free DNA Isolation kit from Thermo fisher. Samples were subjected to high-depth sequencing for the detection of mutations in 5 of the most relevant/prevalent genes in HCC on the Illumina MiSeq platform. Only sequences with coverage of more than 10,000 readings were analyzed and only mutations with at least 1% of frequency were taken into account.

Results: 16 patients have been analyzed to date. 81% men (13/16), average age of 63 years. 100% had single HCC, median size of 4.05 cm. 44% (7/16) were HCV positive. 21 mutations were detected in HCC tissue distributed in: TERT (12/16), TP53 (4/16) and CTNNB1 (5/16) and 23 mutations in the cfDNA: TERT (10/16), TP53 (10/16) and Axin1 (3/16). 13/21 mutations detected in HCC, were detected in the corresponding sample of cfDNA, (62% agreement). 8 mutations detected in cfDNA were not present in their corresponding tumor tissue, suggesting that cfDNA could capture information that it is not obtained by conventional biopsy due to tumor heterogeneity. We have evaluated evolutive changes of cfDNA mutations in patients undergoing surgery. After 20 months from resection in 2 patients with no evidence of recurrence, we did not detect mutations in cfDNA. On the other side, analysis of samples collected 10 months before HCC diagnosis in one patient, detected a TERT mutation at 8% of frequency and in at 10% at the time of resection, suggesting it could be a tool for early diagnosis.

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P-066 EFFECT OF RAMUCIRUMAB ON ALBUMIN-BILIRUBIN GRADE DURING TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND ELEVATED ALPHA-FETOPROTEIN FOLLOWING SORAFENIB: OUTCOMES FROM TWO RANDOMIZED PHASE 3 STUDIES (REACH, REACH-2)

Masatoshi Kudo* 1, Peter R. Galle2, Giovanni Brandi3, Yoon-Koo Kang4, Chia-Jui Yen5, Richard S. Finn6, Josep M. Llovet7, Eric Assenat8, Philippe Merle9, Jean-Baptiste Hiriart10, Stephen L. Chan11, Daniel Palmer12, Chunxiao Wang13, Ryan Widau13, Yanzhi Hsu14, William Schelman13, Andrew X. Zhu15

1Kindai University, Osaka-Sayama, Japan, 2University Medical Center, Mainz, Germany, 3University Hospital S. Orsola, Bologna, Italy, 4Asan Medical Center, University of Ulsan, Seoul, Korea, Republic Of, 5National Cheng Kung University Hospital, Tainan, Taiwan, Province of China, 6Geffen School of Medicine at UCLA, Los Angeles, 7Icahn School of Medicine at Mount Sinai, New York, United States, 8CHU de Montpellier, Montpellier, 9Hôpital de la Croix Rousse, Lille, 10CHU de Bordeaux, Pessac, France, 11State Key Laboratory of Translational Oncology, Chinese University of Hong Kong, Hong Kong, China, 12Clatterbridge Cancer Centre, University of Liverpool, Bennington, United Kingdom, 13Eli Lilly and Company, Indianapolis, 14Eli Lilly and Company, New York, 15Massachusetts General Hospital Cancer Center, Harvard Medical Center, Boston, United States

Introduction: Patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) have a poorer prognosis compared to the general HCC population. REACH-2 (NCT02435433) and REACH (NCT01140347) studied ramucirumab (anti-VEGFR2 monoclonal antibody) in patients with advanced HCC following sorafenib, with REACH-2 only enrolling patients with baseline AFP ≥400 ng/mL. REACH-2 (NCT02435433) met its primary endpoint: ramucirumab improved overall survival (OS; HR 0.710, p=0.0199) and progression-free survival (PFS; HR 0.452, p<0.0001) compared to placebo in patients with HCC and elevated AFP without significant toxicity or compromise in patient-reported outcomes.1 Albumin-bilirubin (ALBI) grade has been proposed as an alternative approach to the Child-Pugh score to assess liver function and is based solely on serum bilirubin and albumin levels. Our previous analyses have suggested that baseline ALBI grade has prognostic utility in advanced HCC patients with elevated AFP.3

Methods: Patients with advanced HCC, Child-Pugh A, ECOG PS 0-1, with progression or intolerance to sorafenib, were randomized in REACH (1:1) or REACH-2 (2:1) to receive ramucirumab 8 mg/kg or placebo Q2W. Serum albumin and bilirubin levels were measured within 14 days prior to randomization and before administration of study drug at each cycle (every 14 days). A pooled population of patients from REACH-2 and REACH (AFP ≥400 ng/mL) were assigned to 1 of 3 prognostic groups (ALBI grade 1, 2, or 3) by applying cut-points to a calculated linear predictor.2 In this post hoc analysis, changes in ALBI grade over the course of study treatment were measured. OS and PFS by ALBI baseline grade were evaluated by the Kaplan-Meier method, and HR were estimated using Cox models.

Results: Baseline demographics and disease characteristics were generally balanced between treatment arms. Over the course of study treatment, ALBI grade remained consistent among patients receiving ramucirumab (n=313) or placebo (n=221) (Figure). Similar results were observed when patients were grouped according to those who had ALBI grade 1 (n=231), 2 (n=296), or 3 (n=7) at baseline. Ramucirumab improved PFS in patients with ALBI Grade 1 (median PFS: 2.83 vs 1.45 months; HR=0.425) and ALBI Grade 2 (median PFS: 2.60 vs 2.00 months; HR=0.730), at baseline compared with placebo. OS was also improved with ramucirumab in both ALBI Grade 1 (median OS: 11.40 vs 6.60 months; HR=0.605) and ALBI Grade 2 (median OS: 5.75 vs 4.21 months; HR=0.830) baseline groups. ALBI grade over the course of study treatment was not altered by patients’ best overall response to study treatment (complete response/partial response/stable disease compared to progressive disease). An increase in ALBI grade at baseline was associated with increased incidence of liver AESIs and discontinuation rate due to AEs in both treatment arms.

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Methods: Approximately 888 patients will be randomized 1:1:1 to either Arm A (durvalumab + bevacizumab), Arm B (durvalumab + placebo), or Arm C (placebo + placebo) following hepatic resection or ablation. Patients will be stratified based upon evidence of pathological microvascular invasion (assessed at study entry) and geographic region. Eligible patients must have confirmed HCC and successfully completed curative therapy (resection or ablation) with imaging to confirm disease-free status ≤28 days prior to randomization, ECOG 0-1, and Child-Pugh score of 5 or 6. Patients will not be included in the study if they have known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC, any evidence of metastatic, macrovascular invasion, or co-existing malignant disease on baseline imaging. Any patients with evidence of portal vein thrombosis or those on a waiting list for liver transplantation will be excluded. Prior systemic anticancer therapy for HCC is not allowed. Patients with hepatitis virus B or C (HBV, HCV) alone may be enrolled, but HBV+ patients must have adequately controlled viral suppression prior to enrollment and HBV/HCV replication will be monitored during the study and treated if appropriate.The primary endpoint is RFS as assessed by blinded independent central radiology review using RECIST v1.1. Secondary endpoints include 2- and 3-year RFS, time to recurrence, overall survival, health-related quality of life measures, and safety.

Results: N/A

Conclusions: N/A

Disclosure of Interest: J. Knox Conflict with: Research/Education grant - AstraZeneca, Conflict with: Honoraria - Novartis, Conflict with: Advisory Board - Lilly; Merck, Conflict with: Consulting - Lilly; Merck, A.-L. Cheng Conflict with: Honoraria - AstraZeneca; Bayer Yakuhin; Eisai; Genentech/Roche, Conflict with: Consulting - AstraZeneca; Bayer Schering Pharma; Bristol-Myers Squibb; CSR Pharma Group, Inc.; Eisai; Genentech/Roche; MSD; Novartis; Ono Pharmaceutical, S. Cleary : None Declared, P. Galle Conflict with: Research/Education grant - Bayer, Conflict with: Honoraria - AstraZeneca; Bayer; Blueprint Medicines; Bristol-Myers Squibb; Lilly; Merck Sharp & Dohme; Sirtex Medical, Conflict with: Consulting - AstraZeneca; Bayer; Bristol-Myers Squibb; Lilly, N. Kokudo: None Declared, R. Lencioni Conflict with: Research/Education grant - BTG, Conflict with: Consulting - Bayer; BTG; Eisai; Guerbet, J.-W. Park Conflict with: Honoraria - Bayer; Bristol-Myers Squibb, Conflict with: Consulting - AstraZeneca; Bayer; Bristol-Myers Squibb; Eisai; Exelixis; Merck; Ono Pharmaceutical, J. Zhou: None Declared, H. Mann Conflict with: Stocks - AstraZeneca, S. Morgan Conflict with: Stocks - AstraZeneca, X. Liu Conflict with: Stocks - AstraZeneca, S. Chin Conflict with: Stocks - AstraZeneca, G. Vlahovic Conflict with: Stocks - AstraZeneca, J. Fan : None Declared

P-065 OUTCOME AND SAFETY OF SECOND OR THIRD-LINE NIVOLUMAB TREATMENT IN REAL LIFE: A SINGLE CENTER EXPERIENCE

Soo Jeong Koh* 1, Ji Hee Park1, Joong-Won Park1, Bo Hyun Kim1, Ju Hee Lee1, Young Hwan Koh1, Chang-Min Kim1

1Center for Liver Cancer and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea, Seoul, Korea, Republic Of

Introduction: Nivolumab is an immune checkpoint inhibitor approved for the second-line therapy for advanced HCC. The aim of this study is to describe our experience with nivolumab in patients who have progressed on or been intolerant of prior sorafenib.

Methods: Forty-two patients with advanced HCC receiving nivolumab (3mg/kg intravenously every 2 weeks) were enrolled between October 2017 and November 2018. Assessment of response was based on the Immune-Modified Response Evaluation Criteria In Solid Tumors (iRECIST) and RECIST version 1.1 every 8 weeks.

Results: The median age of patients was 61 years. Portal vein invasion and extrahepatic spread was present in 38% and 76%, respectively.The median duration of nivolumab treatment was 76 days. Six out of 42 patients are on treatment, while 36 patients stopped treatment because of disease progression, serious toxicity, treatment refusal and discontinuance after achieving a complete response (CR).For evaluating tumor response, one showed CR; 7 (16.7%) partial response; 9 (21.4%) stable response; 1 immune unconfirmed progression and 24 (57.1%) immune confirmed progression. Three patients were continued to receive nivolumab after first response of progression due to a possibility of pseudo-progression and finally confirmed as progressed disease.Median duration of response was 80 days. The 3- and 6-month disease control rate were 47.0% and 23.5%, respectively. Median OS was 242 days and median progression free survival (PFS) was 108 days. Survival rate and PFS rate at 6 months were 55.6% and 29.0%, respectively. Common adverse reactions included abdominal discomfort (29%), skin eruption or pruritus (24%), general weakness (14%), fatigue (10%). The grade 3 adverse events included hepatotoxicity, azotemia, hematochezia, hyperbilirubinemia, hypercalcemia, and pneumonitis.

Conclusions: In real life practice of a single center, nivolumab as an above second-line therapy appears to have meaningful efficacy and acceptable tolerability in patients with advanced HCC. Further follow-up studies are warranted.


cross-sectional imaging (CSI) for nodules greater than 1 centimeter or for indeterminate findings. For certain patient groups, such as those listed for transplant, our practice has been to screen for HCC with CSI rather than US every 6 months, however there is no literature to support this practice. In this study, we examine those patients diagnosed with HCC amongst a group of cirrhotic patients to determine whether their initial lesions were detected with US or CSI (either MRI or CT), stage at diagnosis, and rate of other incidental findings noted on US vs CSI.

Methods: A retrospective chart review of cirrhotic patients being followed in the outpatient setting by Hepatology providers between 2013-2018 was performed using ICD-9 code 571.5 and ICD10 code K74.60 for cirrhosis of the liver. Patients for whom there was a lack of documentation regarding details of screening for or diagnosis of HCC were excluded. Data collected included patient demographics, etiology of liver disease, presence of HCC, modality of imaging demonstrating initial HCC lesion, Barcelona Clinic Liver Cancer (BCLC) stage at diagnosis, whether AFP was used for screening, and whether other incidental findings were noted.

Results: A total of 518 patients with cirrhosis were being followed in clinic by our Hepatology providers between 2013-2018. Of those, 286 (55.2%) were male. 40 patients (7.7%) were found to have HCC. Regarding the patients with HCC, 20 (50.0%) had hepatitis C, 9 (22.5%) had alcoholic cirrhosis, 7 (17.5%) had non-alcoholic steatohepatitis. AFP was performed for surveillance in 92.4% of patients. 45.5% of initial lesions were detected on US, with the remaining 54.5% detected on CSI. 72.2% of patients at diagnosis were BCLC stage A, 11.1% were BCLC stage B, and 16.7% were BCLC stage C. In the US vs CSI groups, 83.3% vs 70.4% were diagnosed at BCLC stage A, 0% vs 11.1% were diagnosed at BCLC stage B, and 16.7% vs 18.5% were diagnosed at BCLC stage C (P=1.000). AFP was routinely used for surveillance in 100% vs 87.9% in the US vs CSI groups (P=1.000), respectively. Incidental findings were noted in 36.7% vs 26.7% of US vs CSI groups, respectively (P=0.292).

Conclusions: Our results demonstrate no significant differences in modality of imaging detecting the initial HCC lesions, or the number of incidental findings noted using either modality. In addition, there was no significant difference in stage at diagnosis between US and CSI screening, with most patients undergoing screening with either modality being diagnosed with early stage HCC (BCLC A). The majority of our patients underwent screening with routine AFP levels. These findings support that US is likely comparable to CT for screening for HCC. This is perhaps augmented by the routine use in this study of AFP in conjunction with imaging for screening. Further large-scale studies are needed to determine patient factors that may influence the modality of screening.


P-064 A PHASE 3 STUDY OF DURVALUMAB WITH OR WITHOUT BEVACIZUMAB AS ADJUVANT THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA AT HIGH RISK OF RECURRENCE AFTER CURATIVE HEPATIC RESECTION OR ABLATION: EMERALD-2

Jennifer Knox* 1, Ann-Lii Cheng2, Sean Cleary3, Peter Galle4, Norihiro Kokudo5, Riccardo Lencioni6, Joong-Won Park7, Jian Zhou8, Helen Mann9, Shethah Morgan9, Xuan Liu10, Steve Chin11, Gordana Vlahovic11, Jia Fan 8

1Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada, 2National Taiwan University, Taipei City 100, Taiwan, Province of China, 3Mayo Clinic, Rochester, Rochester, United States, 4University Medical Center Mainz, Mainz, Germany, 5National Center for Global Health and Medicine, Tokyo, Japan, 6University of Pisa School of Medicine, Italy, Pisa PI, Italy, 7Seoul National Cancer Center, Gyeonggi-do, Korea, Republic Of, 8Zhongshan Hospital, Fudan University, Shanghai, China, 9AstraZeneca, Cambridge, United Kingdom, 10AstraZeneca, Beijing, China, 11AstraZeneca, Gaithersburg, United States

Introduction: Many patients with early-stage hepatocellular carcinoma (HCC) undergo hepatic resection and ablation as standard of care, but while potentially curative, the risk of cancer recurrence following resection is as high as 44-79% at 5 years (Bruix and Sherman 2005; Imamura, et al. 2003; Kianmanesh et al. 2003). Effective adjuvant therapy has not been demonstrated to date and the prevention and/or delay of recurrence of HCC after curative treatment presents a high unmet medical need.Adjuvant therapy given after resection or ablation has the potential to reduce the risk of relapse and is an effective therapeutic approach in the treatment of many solid tumors. There is encouraging evidence that adjuvant therapy involving agents that engage the immune response, including immunotherapy such as durvalumab (an anti-PD-L1 antibody), can prolong recurrence-free survival (RFS) in patients with early-stage HCC (Yin et al. 2013; Huang et al. 2015; Xu et al. 2015; Lee et al. 2015). Other evidence shows that inhibiting the VEGF pathway may enhance activity of PD-L1 blockade in patients with more advanced HCC (Pishvaian et al. 2018; Ikeda et al. 2018).EMERALD-2 (NCT03847428) is a Phase 3 randomized, double-blind, placebo-controlled study that will evaluate the efficacy and safety of durvalumab monotherapy and durvalumab combined with bevacizumab as adjuvant therapy in patients with HCC after curative resection or ablation who are at high risk of recurrence.

P-062 MULTICENTER RETROSPECTIVE ANALYSIS OF THE EFFICACY OF REGORAFENIB AFTER PROGRESSION ON SORAFENIB WITH HEPATOCELLULAR CARCINOMA

Minjin Lee* 1, Sung Won Chang1, Ha Seok Lee1, Sehwa Kim1, Young-Sun Lee1, Young Kul Jung1, Sang Jun Suh1, Ji Hoon Kim1, Yeon Seok Seo1, Hyung Joon Yim1, Jong Eun Yeon1, Kwan Soo Byun1

1Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea, Republic Of

Introduction: Regorafenib has been proved as 2nd line systemic therapy for hepatocellular carcinoma (HCC) patients with progression after sorafenib through 3 phase trial improving survival compared to placebo. Nevertheless, real-world data are needed to assess clinical outcomes in the practice. We analyzed the real-world data to assess clinical outcomes in the practice.

Methods: This study was a multicenter, non-comparative, retrospective cohort study. Between July 2017 and November 2018, patients with HCC who had evidence of disease progression on sorafenib were eligible for inclusion in this study. A total of 51 Patients who received at least one dose of regroafenib were included in this analysis. Tumor response was assessed according to modified RECIST criteria. Kaplan - Meier method and Cox regression were used for survival analysis.

Results: Their median age was 62 years, and most patients (n=43, 84%) were male. Hepatitis B virus infection was the most common etiology of HCC. (n=35, 71.4%) Except for 6 patients (11.8%) with Child-Pugh B(n=6), all patients were classified as Child-Pugh A at the time of initiation of regorafenib. Forty-six patients (90.2%) had extrahepatic metastasis, with the most common metastatic site being the lungs (n=36, 70.5%), followed by the bones (n=11, 21.5%), adrenal glands (n=9, 17.6%) and vascular invasion (n=12, 23.5%). We assessed a best response for 38 patients with at least one follow up imaging studies. Three patients (7.8%) achieved PR, whereas none achieved a complete response. SD and PD were the best responses in 10(26.3%), and 25(65.7%) patients, respectively. The disease control rate was was 34.1%. The median OS was 7.4 months, and the median PFS was 2.9 months. Five out of 9 variables were indentified statistically significant in univariate logistic regression analysis.These 5 significant variables(Portal vein thrombosis, Child-pugh score, HCC extent >50%, AFP >400ng/mL, Time to progression(TTP) of Sorafenib) entered multivariate logistic regression analysis.As a result ,Child-pugh score was associated with an increased risk for overall survival [OR(95% CI) = 3.487(1.123-10.825), p= 0.031], and TTP of sorafenib was associated with an decreased risk for progression-free survival[OR(95% CI) = 0.404(0.176-0.923), p= 0.032].

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Conclusions: Regorafenib was effective in patients with advanced HCC who progressed on first-line sorafenib in real-life setting consistent with the efficacy of the previous controlled clinical trial. Child pugh score and Sorafenib TTP were independent predictor of the prognosis for regorafenib.

References: Bruix J et el, Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389


P-063 HCC SCREENING: ULTRASOUND VERSUS CROSS-SECTIONAL IMAGING

Ranya Selim* 1, Rawan A. Hammoudeh2, Ivan M. C. Morales2, Taha Ashraf2, Reena Salgia1


Introduction: Currently, AASLD guidelines for hepatocellular carcinoma (HCC) screening involve ultrasound (US) imaging at 6-month intervals with or without alpha fetoprotein (AFP) levels, with

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lobes in 7 pts (35%). Eleven LAEs were reported in 10 pts (50% of all pts). LAEs consisted in elevations in AST, ALT or GGT (4), increased bilirubin (4), worsening liver function (1), malignant biliary obstruction (1) and upper GI bleeding (1). Five LAEs (45%) were G1, 3 (27%) were G2 and 3 (27%) were G3. There were no G4 or G5 LAEs. LAEs resolved by the end of cycle 2 in 5 patients while 4 of the remaining 6 pts had tumor progression after cycle 1. Most LAEs were not related to SIRT or Nivolumab. Five LAEs lead to a temporary delay in Nivolumab dosing. Nivolumab was permanently discontinued because of tumor biliary obstruction in one pt. Corticosteroids were not used to treat any LAE. Three LAEs were also LSAEs, including increased bilirubin, malignant biliary obstruction, and upper GI hemorrhage.

Table:

Pt AECTC Grade

Resolved before C2D42

Tumor Progression at C2D42

Nivolumab action taken

Relation to SIRT or Nivo. likely

1 Increas.GGTP 2 No Yes No No

23

Increas.ASTIncreas.AST

11

NoYes

YesNo

NoNo

NoYes

4 Increas.AST/ALT 1 No Yes No Yes

5678

Increas. Bil.Increas. Bil.Increase. Bil.Increase. Bil.

1223

NoYesNoYes

YesNoNoNo

NoDelayedDelayedDelayed

NoYesYesYes

9Worsening Liver Function

1 Yes No Delayed No

10Tumor Biliary Obstruction

3 No Yes Discontinued No

11 Upper GI Bleeding 3 Yes No Delayed No

Conclusions: In this interim analysis of patients treated with SIRT and Nivolumab, the frequency of liver AEs and SAEs were within the expected range and no sign of synergistic liver toxicity was observed.

Disclosure of Interest: M. De La Torre Conflict with: Research/Education grant - Bayer, A. Matilla Conflict with: Advisory Board - Bayer, Conflict with: Consulting - Bayer, M. Varela Conflict with: Advisory Board - Bayer, Bristol, Meyers Squibb, Conflict with: Consulting - Bayer, Bristol, Meyers Squibb, M. Iñarrairaegui: None Declared, M. Reig Conflict with: Research/Education grant - Baer, Ipsen, Conflict with: Honoraria - Bayer, Ipsen, BMS, Lilly, BTG, Gilead, Conflict with: Advisory Board - Bayer, BMS, Ipsen, Lilly, Conflict with: Consulting - Bayer, BMS, Ipsen, Lilly, J. L. Lledó Conflict with: Research/Education grant - Bayer, Conflict with: Advisory Board - Bayer, Conflict with: Consulting - Bayer, J. I. Arenas Conflict with: Advisory Board - Intercept, Conflict with: Consulting - Intercept, S. Lorente: None Declared, M. Testillano: None Declared, C. Gomez Conflict with: Advisory Board - BMS, ESAI, Roche, Conflict with: Consulting - BMS, ESAI, Roche, L. Márquez Conflict with: Research/Education grant - Bayer, Gilead, abbvie, L. Gomez-Da fonseca Conflict with: Honoraria - Bayer, J. I. Bilbao Conflict with: Research/Education grant - Sirtex, Terumo, Conflict with: Advisory Board - Sirtex, Boston Scientific, Terumo, Conflict with: Consulting - Sirtex, Boston Scientific, Terumo, B. Sangro Conflict with: Advisory Board - Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Onxeo, Sirtex and Terumo, Conflict with: Consulting - Adaptimmune, AstraZeneca, Bayer, Bristol-Myers Squibb, BTG, Onxeo, Sirtex and Terumo

P-071 TRANS-ARTERIAL CHEMOEMBOLIZATION (TACE) AS A LOCO-REGIONAL INDUCER OF IMMUNOGENIC CELL DEATH IN HEPATOCELLULAR CARCINOMA

David James Pinato* 1, Robert D. Goldin1, Takashi Mineo1, Abdul Siddique1, Ayse U. Akarca2, Teresa Marafioti2, Claudio Avellini3, Pierluigi Toniutto3, Ching N. Wong4, Francesco Mauri4, Rohini Sharma4

1Imperial College London, 2University College London, Gower Street, University College London, London, United Kingdom, 3Universita di Udine, Udine, Italy, 4Du Cane Road, Imperial College London, London, United Kingdom

Introduction: Modulation of adaptive immunity is postulated to underscore the efficacy of TACE. We evaluated the influence of TACE on T-cell function by assessing the phenotypic characteristics of lymphocyte populations from archival liver explants of patients who underwent orthotopic liver transplantation (OLT) with (T+) or without (T-) prior-TACE treatment using multi-parameter immunohistochemistry and targeted transcriptomics.

Methods: We profiled tumoural and non-tumoural cirrhotic background tissue to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD1+ T-cells in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163. Expression of candidate biomarkers was compared across T+ and T-

1Functional Genomics of Solid Tumors, Centre de Recherche des Cordeliers, INSERM UMRS-1138, Paris, France, 2Division of Gastroenterology and Hepatology, Clinic of Internal, Medicine III, Medical University of Vienna, Vienna, Austria, 3RPPA platform, Curie Institute, Paris, 4Bariton, Inserm UMR-1053, Bordeaux, 5Anathomopathology Department, University of Paris Est Créteil, Inserm U955, Créteil, France

Introduction: HCC is a highly heterogeneous malignancy with poor prognosis in patients with advanced disease. Due to this molecular diversity, most of the new agents tested in clinical trials provided only limited benefit in terms of survival. Here, we integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines to assess their clinical relevance as HCC preclinical models and identify new attractive therapies and biomarkers of their sensitivity.

Methods: Multi-omic analysis including whole-exome, RNA and microRNA sequencing and quantification of 126 proteins across 34 liver cancer cell lines coupled with a screening of 31 anti-cancer agents were performed. Elastic net regression and correlation analysis were used to identify molecular features associated with drug response. Molecular profiles of liver cancer cell lines and HCC primary tumors were compared.

Results: The 34 liver cancer cell lines recapitulated the most common genetic alterations identified in the most aggressive HCCs. Unsupervised consensus classification identified three robust transcriptomic subgroups of cell lines related to the differentiation status and associated with the global drug response rate, with the most differentiated CL1 subgroup showing the highest drug sensitivity. Genomic alterations of the RAS-MAPK pathway correlated with trametinib sensitivity with higher effect than anti-FGFR4 in tumor cells addicted to FGF19/FGFR4 pathway. Interestingly, FGF19 amplification solely was not sufficient to predict sensitivity to both trametinib and FGFR4 inhibitors but the expression of a full pathway modulated by the context of differentiation is required. Finally, we identified other drugs that could target HCCs with specific molecular features such as inactivating mutations in TSC1/TSC2 and TP53 associated with higher sensitivity to the mTOR inhibitor rapamycin and the AURKA inhibitor alisertib.

Conclusions: Liver cancer cell lines represent prominent preclinical biological models for drug-biomarker discovery in HCC which allow the identification of specific molecular contexts associated with distinct drug responses that may be crucial to stratify patients during clinical development. Moreover, this study is the first to provide a comprehensive molecular characterization of the most widely used liver cancer cell lines with all the data freely accessible to the scientific community (www.zucmanlab.com, available from September 2019).


P-070 A PRELIMINARY ANALYSIS OF EARLY LIVER ADVERSE EVENTS (LAE) IN PATIENTS WITH HEPATOCELLULAR CARCINOMA TREATED WITH SELECTIVE INTERNAL RADIATION THERAPY (SIRT) AND NIVOLUMAB

Manuel De La Torre* 1, Ana Matilla2, Maria Varela3, Mercedes Iñarrairaegui4, Maria Reig5, Jose Luis Lledó6, Juan Ignacio Arenas7, Sara Lorente8, Milagros Testillano9, Carlos Gomez10, Laura Márquez2, Leonardo Gomez-Da fonseca5, Jose Ignacio Bilbao11, Bruno Sangro12

1Liver unit, Clinica Universidad de Navarra, 2Liver unit, Hospital Gregorio Marañon, Madrid, 3Liver unit, Hospital central de Asturias, Oviedo, 4Liver unit, Clinica Universidad de Navarra. IDISNA and CIBEREHD., Pamplona, 5BCLC group. , Hospital Clinic de Barcelona. IDIBAPS. CIBEREHD., Barcelona, 6Liver unit, Hospital universitario Ramón y Cajal, Madrid, 7Liver unit, Hospital Universitario de Donostia, San Sebastian, 8Liver unit, Hospital clinico Lozano Blesa, Zaragoza, 9Liver unit, Hospital Universitario de Cruces, Bilbao, 10Liver unit, Hospital Universitario 12 de Octubre, Madrid, 11Interventional Radiology, 12Liver unit, Clinica Universidad de Navarra, Pamplona, Spain

Introduction: The NASIR-HCC phase II clinical trial is testing the combination of SIRT using yttrium 90-loaded resin microspheres and the anti-PD-1 antibody nivolumab. Since liver toxicity of the combination has not yet been defined, the aim of this study was to evaluate early LAE in order to identify any sign of synergistic liver toxicity.

Methods: NASIR-HCC will recruit 40 patients (pts) with non-metastatic HCC in Child-Pugh (CP) class A who are not amenable for resection, transplantation or ablation and are not considered good candidates to TACE because they have a) single tumors > 5 cm; b) multiple tumors that cannot be targeted superselectively and are within the BCLC-B2 substage; or c) unilobar tumors with segmental or lobar PVI. SIRT is followed 3 weeks later by nivolumab (240 mg IV every 2 weeks; 1 cycle consisting in 3 doses). An interim analysis of liver toxicity was performed in the first 20 pts followed for 2 cycles of Nivolumab (minimum follow-up of 15 weeks). Treatment-emergent LAEs and liver serious adverse events (LSAE) were identified. CTCAE v 4.0 was used to define the grade (G) of LSAEs. This study is suported by reserch grants from Bristol-Myers Squibb and Sirtex Medical.

Results: Twelve of the 20 pts (60%) were cirrhotics. Regarding reduced liver functional reserve at baseline, 5 of the 20 pts (25%) had a CP score of 6, and 10 patients (50%) had an ALBI (albumin-bilirubin) grade 2. Pts were in BCLC stages A (15%), B (65%) or C (20%). SIRT targeted both liver

Globally, 19 of 109 patients (17%) stopped Sorafenib due to intolerance/adverse events; they had a median survival of 7 months (95% CI 2.734-11.266), IQR 3-15 months; by contrast 4 of 29 patients (7.2%) stopped regorafenib due to adverse events. Their median survival from beginning of SOR was not reached, mean survival 32 months (95% CI 22.398-41.902), and the median duration of REGO before stopping it because of SAE was 11 months (IQR 7.5-22).

Conclusions: In this observational study in real life, a statistically significant survival advantage was observed in patients who, at the time of radiological progression, switched to REGO. Only 7.2% of patients stopped REGO due to adverse events, that appear late in time. In most cases REGO was prolonged until clinical progression, demonstrating their efficacy and safety in this population.

Disclosure of Interest: A. Castaño-García Conflict with: Research/Education grant - no, Conflict with: Honoraria - no, Conflict with: Stocks - no, Conflict with: Advisory Board - no, Conflict with: Consulting - no, P. Florez Conflict with: Research/Education grant - no, Conflict with: Honoraria - no, Conflict with: Stocks - no, Conflict with: Advisory Board - no, Conflict with: Consulting - no, A. Mesa Conflict with: Research/Education grant - no, Conflict with: Honoraria - no, Conflict with: Stocks - no, Conflict with: Advisory Board - no, Conflict with: Consulting - no, M. Fraile-López: None Declared, M. L. González-Diéguez Conflict with: Research/Education grant - NO, Conflict with: Honoraria - NO, Conflict with: Stocks - NO, Conflict with: Advisory Board - Gilead, Abbvie, Novartis, Conflict with: Consulting - Gilead, C. Álvarez-Navascués Conflict with: Advisory Board - Gilead, Abbvie, Intercept, Conflict with: Consulting - Gilead, V. Cadahía Conflict with: Research/Education grant - none, Conflict with: Honoraria - none, Conflict with: Stocks - none, Conflict with: Advisory Board - none, Conflict with: Consulting - none, M. Rodríguez Conflict with: Advisory Board - Intercept, Abbvie, Gilead, MSD, Conflict with: Consulting - Intercept, Abbvie, Gilead, MSD, M. Varela Conflict with: Advisory Board - Bayer, Sirtex, BTG, BMS, Conflict with: Consulting - Bayer

P-068 DOWNSTAGING WITH RADIOEMBOLIZATION OR CHEMOTHERAPY FOR INITIALLY UNRESECTABLE INTRAHEPATIC CHOLANGIOCARCINOMA

Julien Edeline* 1, Diane Riby1, Alessandro Mazzotta2, Lucas Verdure2, Laurent Sulpice2, Damien Bergeat2, Héloïse Bourien1, Samuel Le Sourd1, Yan Rolland3, Etienne Garin4, Astrid Lièvre5, Karim Boudjema2

1Medical Oncology, Centre Eugene Marquis-Rennes, 2Hepatobiliary Surgery, CHU Pontchaillou, 3Radiology, 4Nuclear Medicine, Centre Eugene Marquis-Rennes, 5Gastroenterology, CHU Pontchaillou, Rennes, France

Introduction: This study compared outcomes of patients resected for intrahepatic cholangio-carcinoma (ICC) whether surgery was performed upfront or after downstaging treatment.

Methods: We retrospectively analyzed data from patients resected for ICC in our center. Patients were divided into two groups: upfront resection or resection after downstaging using either chemotherapy alone, or selective internal radiation therapy (SIRT), combined with chemotherapy. We compared Overall Survival (OS) from the date of surgery between these groups, with the use of Kaplan-Meier method and univariable and multivariable Cox regression models.

Results: Between January 1997 and November 2017, 169 patients were resected for an ICC in our institution. 137 underwent primary surgery and 32 received downstaging treatment first. Downstaged patients had higher baseline tumor load. Median OS was not different between the 2 groups: 32.3 [95% CI: 23.9-40.7] months with primary surgery versus 45.9 [95% CI: 32.3-59.4] months with downstaging treatment (p=0.54, log-rank test). In multivariable analysis, when downstaging treatment was entered in the model along with variable associated with OS in univariable analysis, downstaging treatment was not associated with better or worse prognosis. However, delivery of SIRT as a downstaging treatment was associated with a significant benefit in multivariable analysis, [95%CI: 0.14-0.84, HR=0.34] (p=0.019).

Conclusions: The overall survival of patients resected after downstaging treatment is not different from overall survival of patients resected upfront. Moreover, our results suggest that neoadjuvant SIRT might be an option to improve surgical results. Our results lead to the hypothesis that SIRT may be an efficient neoadjuvant therapy in patient with resectable ICC.

Disclosure of Interest: J. Edeline Conflict with: Research/Education grant - BTG, Conflict with: Honoraria - BTG, D. Riby: None Declared, A. Mazzotta: None Declared, L. Verdure: None Declared, L. Sulpice: None Declared, D. Bergeat: None Declared, H. Bourien: None Declared, S. Le Sourd Conflict with: Honoraria - BTG, Y. Rolland Conflict with: Research/Education grant - BTG, Conflict with: Honoraria - BTG, Conflict with: Advisory Board - BTG, Conflict with: Consulting - BTG, E. Garin: None Declared, A. Lièvre: None Declared, K. Boudjema: None Declared

P-069 LIVER CANCER CELL LINES AS PHARMACOGENOMICS MODELS TO PREDICT DRUG SENSITIVITY IN HEPATOCELLULAR CARCINOMA

Stefano Caruso* 1, Anna-Line Calatayud1, Jill Pilet1, Tiziana La Bella1, Samia Rekik1, Sandrine Imbeaud1, Eric Letouzé1, Léa Meunier1, Quentin Bayard1, Nataliya Rohr-Udilova2, Camille Péneau1, Bettina Grasl-Kraupp2, Leanne de Koning3, Bérengère Ouine3, Paulette Bioulac-Sage4, Gabrielle Couchy1, Julien Calderaro5, Jean-Charles Nault1, Jessica Zucman-Rossi1, Sandra Rebouissou1

Conclusions: Ramucirumab does not alter ALBI grade over the course of study treatment when compared to placebo. Regardless of baseline ALBI grade, a consistent benefit in survival outcomes was observed in patients treated with ramucirumab compared to placebo.

References: 1. Zhu AX et al. Lancet Oncol. 2019;20(2):282-96. 2. Johnson PJ et al. J Clin Oncol. 2015;33(6):550-8. 3. Brandi G et al. Presentation at the EASL HCC Summit 2019; 14-16 Feb, 2019; Lisbon, Portugal:

OP-07.

Disclosure of Interest: M. Kudo Conflict with: Research/Education grant - Daiichi Sankyo, Otsuka, Taiho, Astellas Pharma, Chugai, AbbVie, BMS, EA Pharma, Takeda, Gilead, Eisai, Ono, Conflict with: Honoraria - Bayer, Eisai, MSD, Conflict with: Advisory Board - Bayer, Eisai, Ono, MSD, BMS, Eli Lilly, P. Galle Conflict with: Advisory Board - Bayer, BMS, MSD, Merck, SIRTEX, AstraZeneca, Sillajen, Eli Lilly and Company, G. Brandi: None Declared, Y.-K. Kang Conflict with: Consulting - ONO, BMS, Eli Lilly and Company, Roche, Daehwa, Taiho, C.-J. Yen: None Declared, R. Finn Conflict with: Consulting - Astra Zeneca, Bayer, BMS, Eli Lilly and Company, Pfizer, Merck, Novartis, Roche/Genentech, Eisai, J. Llovet Conflict with: Research/Education grant - Bayer, Eisai Inc, BMS, IPSEN, Blueprint, Incyte, Eli Lilly and Company, Celsion Corp, Elelixis, Merck, Glycotest, Navigant, Leerink Swann LLC, Midatech Ltd, Fortress Biotech Inc, Spring Bank Pharmaceuticals, E. Assenat: None Declared, P. Merle Conflict with: Research/Education grant - Onxeo, Conflict with: Advisory Board - Bayer, Ipsen/Exelixis, BMS, Onxeo, MSD, AZ, Eisai, Roche, J.-B. Hiriart Conflict with: Consulting - Gilead, AbbVie, Intercept, Bayer, BMS, Astellas, Chiesi, Biotest, S. Chan: None Declared, D. Palmer Conflict with: Research/Education grant - Bayer, Eisai, BMS, Sirtex, C. Wang Conflict with: Research/Education grant - Employed by Eli Lilly and Company, Conflict with: Stocks - Stocks held in Eli Lilly and Company, R. Widau Conflict with: Research/Education grant - Employed by Eli Lilly and Company, Conflict with: Stocks - Stocks held in Eli Lilly and Company, Y. Hsu Conflict with: Research/Education grant - Employed by Eli Lilly and Company, Conflict with: Stocks - Stocks held in Eli Lilly and Company, W. Schelman Conflict with: Research/Education grant - Employed by Eli Lilly and Company, Conflict with: Stocks - Stocks held in Eli Lilly and Company, A. Zhu Conflict with: Research/Education grant - Eisai, BMS, Merck, Novartis, Sanofi, AZ, Bayer, Eli Lilly and Company, Exelixis, Conflict with: Consulting - Merck, Novartis, BMS, Bayer, Eli Lilly and Company

P-067 ANALYSIS OF EFFICACY AND SAFETY IN A REAL LIFE COHORT OF HEPATOCELLULAR CARCINOMA TREATED WITH SORAFENIB-REGORAFENIB

Andrés Castaño-García1, Pablo Florez1, Alicia Mesa2, Miguel Fraile-López1, Maria Luisa González-Diéguez1, Carmen Álvarez-Navascués1, Valle Cadahía1, Manuel Rodríguez1, Maria Varela* 1 and Multidisciplinary team of HCC of Hospital Universitario Central de Asturias

1Liver Unit, 2Radiology, Hospital Universitario Central de Asturias, Oviedo, Spain

Introduction: According to RESORCE trial, Regorafenib (REGO) improves survival versus placebo in patients with hepatocellular carcinoma (HCC) that progressed to sorafenib (SOR). However, there are scarce data regarding its safety and efficacy in the real-life.

Aim: To analyze if the introduction of REGO supposes a real life advantage in patients with HCC that progress to SOR.

Materials and Methods: Unicentric study of consecutive HCC patients treated with SOR that switched to REGO at the time of radiological progression if 1) tolerance to SOR, 2) compensated liver disease and 3) ECOG PS 0-1. The pre-SOR baseline characteristics, adverse events to SOR, characteristics at the moment of progression and adverse events to REGO were prospectively collected and analyzed. Clinical and analytical evaluations were performed at week 2, 4, 8, 12 and every 2 months thereafter from the beginning of SOR/REGO, while radiological assessments were performed at week 12 and every 16 weeks after that. In addition, unscheduled visits and email/phone contacts were performed on demand.

Results: From Jan 1st 2016 to DEC 5th 2018 109 consecutive patients with compensated liver disease and ECOG PS 0-1 initiated SOR at our site. Follow-up until MAR 29th 2019. All patients had the opportunity to receive REGO at the moment of radiological progression.

Description of the cohort: Median age 66 years (IQR 59-71); 96 males (88%); 12 HCC upon normal liver, 9 chronic hepatitis, 88 liver cirrhosis. The most common etiology alcohol (52%), hepatitis C (30%), alcohol-hepatitis C (9%). 65 patients had received prior therapy for HCC (TACE 42%, surgical resection 17%), while SOR was the first therapy for 44 patients. At the moment of beginning SOR: 53 vascular invasion, 31 extrahepatic disease, 32 BCLC A-B, 77 BCLC-C; 78 asymptomatic, 31 minor symptoms. Median AFP 22.65 ng/mL, bilirubin 1 mg/dL, albumin 40 g/dL, INR 1.15, Platelets 130x10^9/mL. Median survival from starting SOR (n=109) was 15 months (95% CI 8.502 – 21.498) (IQR 6-37). Median duration of SOR was 6 months (IQR 3-10). Only 29 of 72 patients with radiological progression to SOR started REGO. Median overall survival from radiological progression was 5 months, 3 months (95% CI 2.636-3.364) in those who continued on SOR (n=43) vs 13 months (95% CI 3.718 – 22.282) in those who started REGO, p=0.012. The main causes of not starting REGO were clinical progression (33%) and cirrhosis decompensation (21%). Median survival from starting REGO was 12 months (95% CI 9.605-14.395) (IQR 9-26) and median duration of REGO 8 months (IQR 6-13). The median survival from starting SOR in the cohort SOR-REGO (n=29) was 28 months (95% CI 13.255-42.745) (IQR 18-not reached).

Posters Posters


single HCC ≤ 5 cm, with less invasive perioperative outcomes. However, HR would be recommended for HCC with tumor size > 3cm or DCP >100 mAu/mL when patients have good liver function.


P-079 DOWNSTAGING HEPATOCELLULAR CARCINOMA: ARE OUTCOMES EQUIVALENT?

Ranya Selim* 1, Randeep Kaur2, Reena Salgia1


Introduction: Multiple studies have demonstrated equivalent survival for patients with hepatocellular carcinoma (HCC) down-staged to Milan criteria prior to transplant as compared to those originally within the criteria. This has therefore increasingly become the standard of practice for select patients who respond successfully to treatment to sufficiently downsize their tumor burden. In this study, we investigate the effect of downstaging on the rates of transplant, waitlist dropout, explant tumors within Milan criteria, and mortality.

Methods: This study included patients listed for transplant between 2012-2018 at a tertiary care high volume transplant center. Patients were excluded if HCC was incidentally noted in the explant. Data collected included standard demographics and whether patients underwent downstaging of their tumor burden prior to listing. Outcomes measured included whether patients were transplanted or dropped out of the list, whether explants tumors were within Milan criteria, and mortality. These outcomes were then compared between patients down-staged and those not down-staged prior to transplant listing.

Results: A total of 179 patients with HCC were listed for transplant between 2012-2018. Of those, 138 (77.1%) were male. 100 (55.9%) had hepatitis C cirrhosis, 21 (11.7%) had alcoholic cirrhosis, and 14 (7.8%) had non-alcoholic steatohepatitis. For patients down-staged prior to transplant listing vs those who were not, transplant rates were 73.2% vs 78.7% (P=0.421), waitlist dropout rates were 26.8% vs 19.7% (P=0.287), 78.0% vs 78.1% (P=0.992) of explant livers were within Milan criteria, and overall mortality rates were 33.9 vs 17.2% (P=0.013), respectively.

Conclusions: Our results demonstrate a statistically significant increase in overall mortality for patients undergoing downstaging prior to transplant listing, with an insignificant difference in rates of transplant, waitlist dropout rates, and explant tumor burden within Milan criteria. This suggests that downstaging is effective in getting patients to transplant and markedly reducing tumor burden in their explants. Overall mortality, although likely lower in this group than it would be without downstaging and transplant, is still considerably higher for these patients as compared to those not requiring downstaging based on our results. This should perhaps be considered in the selection of these patients as candidates for transplant, given the limited organ supply and the need for careful selection of organ recipients.


P-080 THE EFFECT OF UREA CREAM ON SORAFENIB-ASSOCIATED HAND-FOOT SKIN REACTION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA: MULTICENTER, PROSPECTIVE RANDOMIZED DOUBLE-BLIND CONTROLLED STUDY

Young-Sun Lee* 1, Ji Hoon Kim1, Do Young Kim2, Moon Young Kim3, Hyung Joon Kim4, Yeon Seok Seo1, Ki Tae Yoon5, Jeong-Hoon Lee6, Hyun Woong Lee7, Young Kul Jung8, Hyung Joon Yim8, Byoung Kuk Jang9, Eun Sun Jang10, Jae Young Jang11, Sung Bum Cho12, Sang Youn Hwang13

1Department of Internal Medicine, Korea University College of Medicine, 22Yonsei Liver Center, Severance Hospital, Seoul, 3Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju Severance Christan Hospital, Wonju, 4Chung-Ang university hospital, Seoul, 5Department of internal medicine, Pusan National University school of Medicine, Pusan National University Yangsan Hospital, Pusan, 6Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 7Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 8Department of Internal Medicine, Korea University College of Medicine, Ansan, 9Department of Internal Medicine, Keimyung University School of Medicine, Daegu, 10Department of Intetnal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, Gyeonggi, 11Division of Gastroenterology and Hepatology, Department of Internal Medicine, Soonchunhyang University School of Medicine, Seoul, 12Department of internal medicine, Chonnam National University Medical School, Chonnam, 13Department of Internal Medicine, Dongnam Institute of Radiological & Medical Sciences, Pusan, Korea, Republic Of

Introduction: Sorafenib has recommended as first line treatment in patients with advanced hepatocellular carcinoma (HCC) patients. Although sorafenib increase overall survival in patients with HCC, it has many side effects such as fatigue, diarrhea, vomitting, nausea, pruritus, depilation, Hand-Foot Skin Reaction (HFSR). Among them, HFRS is the most common side effect and it is main reason for dose de-escalation or discontinuation of sorafenib in patients with HCC. In this study, we aimed that investigate the role of urea cream in preventing the occurrence of HFRS or ameliorating severity of HFRS.

Methods: 102 patients with HCC treated with TARE between 2012 and 2017, were reviewed retrospectively. Treatment response after TARE was evaluated at one, three, and six months by mRECIST and RECIST 1.1. Responders were defined as patients with complete or partial responses.

Results: The median age of 83 men and 19 women was 64.3 years. The median maximal tumor size was 8.3 cm, and multiple tumors were observed in 36 (35.3%) patients. During the follow-up period (median 20.7 months), 21 patients (20.6%) died, with a mean survival of 55.5 months. The cumulative survival rate was 96.1% at six months and 89.3% at 12 months. Responders defined by mRECIST showed better survival than non-responders (hazard ratio [HR]=5.736, P=0.008 at 1 month; HR=3.145, P=0.022 at 3 months, and HR=2.887, P=0.061 at 6 months). The survival rates were similar between the responders and non-responders defined by RECIST 1.1 (all P>0.05).

Conclusions: Response evaluations that use mRECIST provide more accurate prognoses than RECIST 1.1 in HCC patients treated with TARE.

References: McGlynn KA, Petrick JL, London WT (2015) Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis 19(2): 223-238


P-078 COMPARISON OF SURGICAL MICROWAVE ABLATION AND HEPATIC RESECTION FOR SINGLE HEPATOCELLULAR CARCINOMA ≤ 5CM: A PROPENSITY SCORE-MATCHED ANALYSIS

Yuko Takami* 1, Tomoki Ryu1, Takanobu Hara1, Yoshiyuki Wada1

1Department of Hepato-Billiary-Pancreatic Surgery & Clinical Research Institute, National Hospital Organization Kyushu Medical Cent, Fukuoka, Japan

Introduction: We have only a little evidence regarding the perioperative and oncological benefits of microwave ablation for HCC. The aim of this study was to compare the efficacy of hepatic resection (HR) and surgical microwave ablation (microwave coagulo-necrotic therapy [MCN]) for single hepatocellular carcinoma (HCC) ≤ 5 cm.

Methods: Between 1994 and 2015, a total of 551 patients with single HCC ≤ 5 cm were treated in our institution (HR: n=128; MCN; n=423). We compared perioperative outcomes, overall survival (OS) and recurrence-free survival (RFS) between HR and MCN. Propensity score matching (PSM) analysis identified 94 matched pairs of patients to compare outcomes.

Results: After PSM, baseline variables including liver function and tumor size were well-balanced between the two groups. MCN resulted in significantly shorter operation time (P < 0.001), less blood loss (P < 0.001), and shorter postoperative hospital stay (P < 0.001) vs. HR. The 5- and 10-year OS rates were 76% and 47% for HR, and 77% and 48% for MCN, respectively (P = 0.865). The 5- and 10-year RFS rates were 55% and 41% for HR, and 47% and 32% for MCN, respectively (P = 0.377). In the subgroup analysis, patients with tumor size > 3cm or DCP >100 mAu/mL had significantly worse RFS than patients with tumor size ≤ 3cm or DCP ≤ 100 mAu/mL in the MCN group (P < 0.001, and P = 0.003, respectively). In contrast, patients with tumor size > 3cm or DCP >100 mAu/mL had similar RFS compared with patients with tumor size ≤ 3cm or DCP ≤ 100 mAu/mL in the HR group (P = 0.664, and P = 0.136, respectively).

Conclusions: Our PSM study confirmed no significant differences in both OS and RFS between HR and MCN for single HCC ≤ 5 cm. MCN provided almost equivalent oncological outcomes to HR for

References: Abou-Alfa GK, et al. N Engl J Med. 2018(14);379:54-63.Agarwal N, et al. Ann Oncol. 2018;29(suppl 8): Abstr 872P.Pishvaian MJ, et al. Ann Oncol. 2018;29(suppl 8): Abstr LBA26.

Disclosure of Interest: R. Kelley Conflict with: Research/Education grant - Adaptimmune, Agios, Astra Zeneca, Bayer, Bristol Myers Squibb, Celgene, Exelixis, Eli Lilly, Medimmune, Merck, Novartis, Regeneron, Sanofi, Taiho, Target Pharma Solutions, Tekmira (institution), Conflict with: Consulting - Genentech for IDMC (self); Bayer, BMS, Astra Zeneca, DebioPharm, Agios (institution), A.-L. Cheng Conflict with: Honoraria - Bayer Yakuhin, AstraZeneca, Genentech/Roche, Eli Lilly, Conflict with: Consulting - Bristol-Myers Squibb, Bayer Schering Pharma, Novartis, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, CSR Pharma Group, Inc., MSD, BeiGene, Ltd., F. Braiteh Conflict with: Honoraria - Abbott Nutrition; Amgen; ARIAD; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Genentech/Roche; HERON; Incyte; Insys Therapeutics; Insys Therapeutics; Ipsen; Lexicon; Lilly; Taiho Pharmaceutical, Conflict with: Stocks - Agios; Bristol-Myers Squibb; Clovis Oncology; Insys Therapeutics; Tesaro, Conflict with: Advisory Board - Amgen; AstraZeneca; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Genentech/Roche; Incyte; Insys Therapeutics; Ipsen; Lilly; Merck; Merck; Merrimack; Pfizer; Taiho Pharmaceutical, Conflict with: Consulting - Ambry Genetics; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol-Myers Squibb; Celgene; Clovis Oncology; Genentech/Roche; Incyte; Insys Therapeutics; Ipsen; Ipsen; Lexicon; Lilly; Merck; Merrimack; Pfizer; Regeneron; Sanofi, A. Chaudhry: None Declared, F. Benzaghou Conflict with: Stocks - Stocks and employment: Ipsen pharma , S. Milwee Conflict with: Stocks - Exelixis employment/Stock holder, A. Borgman Conflict with: Stocks - Exelixis employment/Stock holder, R. Sinha: None Declared, Z. Kayali: None Declared, A. Zhu Conflict with: Research/Education grant - Bayer (Inst); Bristol-Myers Squibb (Inst); Lilly (Inst); Merck (Inst); Novartis (Inst), Conflict with: Consulting - AstraZeneca; Bayer; Bristol-Myers Squibb; eisai; Exelixis; Lilly; Merck; Novartis; Sanofi, L. Rimassa Conflict with: Advisory Board - Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Celgene, Incyte, Eisai, Conflict with: Consulting - Lilly, Bayer, Sirtex Medical, Italfarmaco, Sanofi, ArQule, Baxter, Ipsen, Exelixis, Amgen, Celgene, Incyte, Eisai

P-073 WHICH CURATIVE TREATMENT FOR STAGES 0-A HEPATOCELLULAR CARCINOMA IN HIV-INFECTED PATIENTS ? AN INTENTION-TO-TREAT ANALYSIS

Nicolas Golse1, Pablo Duarte1, Andrea Fontana1, Cristiane Bundchen1, Vincent Karam1, Antonio Sa Cunha1, Denis Castaing1, Didier Samuel1, Jean Charles Duclos Vallee1, Daniel Cherqui1, Rene Adam1, Eric Vibert* 1

1Paul Brousse Hospital, Paris, France

Introduction: Liver transplantation (LT) has become a consensual treatment for hepatocellular carcinoma (HCC) in human immunodeficiency virus (HIV)-carriers. However, high drop-out rates question the role of alternative treatments. Our aim was to address the results of resection in this setting and to compare them against survival after LT in an intention-to-treat analysis.

Methods: Records from all patients with HIV and HCC listed for LT (liver transplant candidates = LTc+) or resection (LR+) between 2000 and 2017 in our centre were analysed and compared for overall survival (OS) and disease-free survival (DFS).

Results: The LTc+ group (n=43) presented with higher MELD scores and more advanced portal hypertension and HCC stages than LR+ group (n=15), with no differences in epidemiological or co-infection rates. One-, 3- and 5-year intention-to-treat survival rates were: 81%, 60% and 44%, versus 86%, 58% and 58% in the LTc+ and LR+ groups, respectively (p=0.746). Eleven LTc+ patients dropped out. After LT, OS was 81%, 68% and 59% (no difference with LR+ group; p=0.844). There tended to be better DFS after LT, reaching 78%, 68% and 56% versus 53%, 33% and 33% in the LR+ group (p=0.062). Time-to-recurrence was significantly longer in the LT+ group (p=0.001).

Conclusions: This was the largest series of resections for HCC in HIV+ patients and the first intention-to-treat analysis. Although LT and resection do not always concern the same population, they enable equivalent survival. At the price of higher recurrence rate, resection could be integrated in the global armoury of liver surgeons.


P-074 BETTER PREDICTION OF OUTCOMES BY RESPONSE EVALUATION USING THE MODIFIED RECIST COMPARED WITH THE RECIST 1.1 IN PATIENTS WITH HCC TREATED WITH YTTRIUM-90 RADIOEMBOLISATION

Hong Jun Choi* 1, Jae Seung Lee1, Beom Kyung Kim1, Jun Yong Park1, Do Young Kim1, Sang Hoon Ahn1, Kwang-Hyub Han1, Seung Up Kim1

1Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea, Republic Of

Introduction: The RECIST 1.1 and mRECIST criteria have been used to assess treatment responses for hepatocellular carcinoma (HCC). We investigated which criteria provide better survival predictions in HCC patients treated with trans-arterial radioembolization (TARE)

patients and correlated with clinico-pathologic characteristics. We utilised Nanostring PanCancer Immune profiling to broadly characterise the differential enrichment of 770 immune-related transcripts across T+ versus T-.

Results: We analysed archival samples from 20 OLT recipients (T+ n=11, T- n=9), 80% males, 75% with HCV-cirrhosis. Median tumour size was 2.3 cm, 75% of patients had T1-T2 tumours, 85% were within Milan criteria, 70% grade 2 with micro-vascular invasion in 35%. Median percentage of necrosis post TACE was 30% (range 0-90%). T+ and T- groups were similar by size, stage, grade, etiology of cirrhosis and MVI (p>0.05). T+ specimens had evidence of significantly lower density of CD8+/PD1+ immune-exhausted T-cells within the tumour (9 versus 21 cells/mm2, p=0.03) but higher CD4+/FOXP3+ density of T-regs in cirrhosis (7.5 versus 0 cells/mm2, p=0.01). We found no significant difference in the expression of a number of drivers of T-cell exhaustion including PD-L1, IDO-1, Lag-3, Tim-3 or CD163 across T+ versus T- samples. Targeted transcriptomic profiling revealed differential regulation of genes reflective of adaptive and innate anti-cancer immune responses across T+ versus T-.

Conclusions: Pre-treatment with TACE is associated by lower density of immune-exhausted intra-tumoural T-cells and stronger T-reg infiltration in the peri-tumoural infiltrate. This highlights the pleiotropic effects of TACE in modulating the tumour microenvironment and strengthens the rationale for developing immunotherapy alongside TACE to improve clinical outcomes of patients with HCC.

References: Review article: delivering precision oncology in intermediate-stage liver cancer.Pinato DJ, Howell J, Ramaswami R, Sharma R.Aliment Pharmacol Ther. 2017 Jun;45(12):1514-1523.


P-072 PHASE 3 (COSMIC-312) STUDY OF CABOZANTINIB IN COMBINATION WITH ATEZOLIZUMAB VS SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA (AHCC) WHO HAVE NOT RECEIVED PREVIOUS SYSTEMIC ANTICANCER THERAPY

Robin K. Kelley* 1, Ann-Lii Cheng2, Fadi Braiteh3, Arvind Chaudhry4, Fawzi Benzaghou5, Steven Milwee6, Anne Borgman6, Rajni Sinha7, Zeid K. Kayali8, Andrew X. Zhu9, Lorenza Rimassa10

1UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, United States, 2National Taiwan University College of Medicine, Taipei, Taiwan, Province of China, 3Comprehensive Cancer Centers of Nevada, Las Vegas, 4Summit Cancer Centers, Spokane, United States, 5Ipsen Innovation, Les Ulis, France, 6Exelixis, Inc., Alameda, 7Piedmont Cancer Institute, Atlanta, 8Riverside Community Hospital, Rialto, 9Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States, 10Humanitas Cancer Center, Humanitas Clinical and Research Center, IRCCS, Milan, Italy

Introduction: Cabozantinib inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER). Cabozantinib is approved in the United States and Europe for treatment of aHCC after prior sorafenib based on improved overall survival versus placebo in the phase 3 CELESTIAL trial (Abou-Alfa 2018). VEGFR tyrosine kinase inhibitors sorafenib or lenvatinib are considered standard of care in first-line aHCC, while phase 3 trials of immune checkpoint inhibitors (ICIs) in first- and second- line aHCC are ongoing. Cabozantinib may promote an immune-permissive tumor environment, which could enhance response to ICIs. Cabozantinib is being evaluated in combination with the anti-PD-L1 antibody atezolizumab in multiple tumor types including HCC in a phase 1 study; the recommended dose, preliminary clinical activity, and safety of the combination have been established in advanced renal cell carcinoma (Agarwal 2018). Atezolizumab in combination with bevacizumab, an anti-VEGF antibody, has shown preliminary clinical activity in first-line aHCC (Pishvaian 2018). Here, we present the study design of a phase 3 trial of cabozantinib + atezolizumab versus sorafenib in patients with aHCC who have not received prior systemic therapy.

Trial Design: This international, randomized, open-label phase 3 trial (NCT03755791) is evaluating the efficacy and safety of cabozantinib + atezolizumab versus sorafenib as first-line treatment for aHCC. Eligibility criteria include age ≥18 years, BCLC stage B or C, Child-Pugh A, ECOG PS 0 or 1, and measurable disease per RECIST 1.1. Patients are randomized 6:3:1 to an experimental arm of cabozantinib (40 mg qd) + atezolizumab (1200 mg infusion q3w), a control arm of sorafenib (400 mg bid), and an exploratory arm of cabozantinib monotherapy (60 mg qd). 640 patients are planned to be enrolled at ~200 sites globally. Randomization is stratified by disease etiology (HBV [with or without HCV], HCV [without HBV], or other), region (Asia, other), and the presence of extrahepatic disease and/or macrovascular invasion (yes, no). Overall survival and progression-free survival are coprimary endpoints, and objective response rate is a secondary endpoint. Additional endpoints include safety, pharmacokinetics, and correlation of biomarker analyses with clinical outcomes. The first patient was enrolled in December 2018, and enrollment is ongoing.

Results: N/A, as this is a Trial in Progress

Conclusions: N/A, as this is a Trial in Progress

Posters Posters


P-085 ALBUMIN-BILIRUBIN GRADE CAN SUBCLASSIFY PATIENTS WITH A CHILD-PUGH SCORE OF 5 TREATED WITH SORAFENIB FOR HEPATOCELLULAR CARCINOMA

Hee Yeon Kim* 1, Chang Wook Kim1, Do Seon Song1, U Im Chang1, Jin Mo Yang1, Sung Won Lee1, Hae Lim Lee1, Nam Ik Han1, Sun Hong Yoo1, Jung Hyun Kwon1, Soon Woo Nam1, Pil Soo Sung1, Jeong Won Jang1, Si Hyun Bae1, Jong Young Choi1, Seung Kew Yoon1

1Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic Of

Introduction: The Albumin-Bilirubin (ALBI) grade is a recently developed index to assess hepatic reserve and prognosis in patients with hepatocellular carcinoma (HCC). We aimed to investigate the prognostic value of ALBI grade in advanced HCC patients who received sorafenib.

Methods: From September 2008 to October 2017, a total of 786 consecutive patients with advanced HCC who received sorafenib monotherapy were retrospectively included from six University hospitals in Korea. Serum albumin and bilirubin values were used to determine ALBI grade. Overall survival was stratified by ALBI grade using the Kaplan-Meier method. A Cox proportional hazard model was used to identify independent factors for influencing overall survival

Results: Hepatitis B virus-related HCCs comprised 75.4% (593/786) of enrolled patients. Among 786 enrolled patients, 161 (20.5%), 555 (70.6%), and 70 (8.9%) were classified as ALBI grade 1, 2, and 3, respectively, in baseline. Majority of the patients with ALBI grade 1 (150/161, 93.1%) had a Child-Pugh score of 5. Among patients with ALBI grade 2, 30.9% (172 patients) had a Child-Pugh score of 5 and 52.3% (290 patients) had a Child-Pugh score of 6. The median OS was 16.5, 10.1, and 7.4 months for ALBI grade 1, 2, and 3, respectively (P<0.001). Cox regression analysis showed that baseline ALBI grade strongly influenced the mortality of HCC patients receiving sorafenib. Among patients with a Child-Pugh score of 5, overall survival was significantly different between patients with ALBI grades 1 and 2. However, there were no significant differences in overall survival between patients with ALBI grades 1 and 2 among patients with a Child-Pugh score of 6.

Conclusions: The ALBI grade is of significant prognostic importance in subclassifying patients with a Child-Pugh score of 5 who received sorafenib for HCC.


P-086 THE TORONTO POST LIVER TRANSPLANT HCC RECURRENCE CALCULATOR: A MACHINE-LEARNING APPROACH

Lawrence Lau1, Phillipe Abreu* 1, Walter Nelson2, Andre Gorgen1, Lauren Erdman2, Anna Goldenberg2, Gonzalo Sapisochin1 and Liver Cancer Research Group

1Department of Surgery, 2University of Toronto, Toronto, Canada

Introduction: The liver transplant listing criteria for hepatocellular carcinoma (HCC) is controversial. Policies aim to prevent recurrence but it is difficult to incorporate the numerous contributive factors. This study takes advantage of machine-learning to include all available features in a post-transplant recurrence prediction calculator.

Methods: The calculator was developed using the Toronto General Hospital HCC database which includes all patients with HCC listed for liver transplantation between 2000-2016, and comprehensively includes serial imaging morphology, AFP, bridging therapy, treatment response, and post-transplant outcome. A Cox proportional hazards model was used to model recurrence following transplant. Over-fitting was limited by encouraging coefficient sparsity using a least absolute shrinkage and selection operator (LASSO). The coefficients were calibrated on 90% of the data. Performance was evaluated over 1000 iterations by assessing the AUC and concordance on the held-out data. Variables selected by LASSO in over 50% of iterations were selected to run the analysis of the 5-year recurrence risk in the model. Alternative recurrence risk algorithms (AFP score and MORAL) were compared.

Results: The dataset included 694 patients who underwent liver transplant for HCC. The overall concordance of score with disease-free survival was satisfactory (concordance 0.706, sd: 0.075). The AUC for prediction of recurrence show the predictive power of the model(Figure). Including all variables meeting the selection criteria, the AUC at 5 years post transplantation was 0.742 (95% CI 0.736-0.748). By comparison, the AUC for AFP score at 5 years post transplantation was 0.605 (95% CI 0.598-0.611) and that of MORAL was 0.589 (95% CI 0.583-0.595).

Conclusions: A comprehensive HCC recurrence risk calculator using machine learning is possible with higher accuracy than other available scores.

References: 1. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018.2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation

for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-9.

3. Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol. 2017;14(4):203-17.

provided by Roche Diagnostics, Germany, B. Köhler Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, M.-R. Lisy: None Declared, C. Belz: None Declared, V. Rolny: None Declared, D. Morgenstern: None Declared

P-084 EFFECT OF FRAGMENTATION OF CANCER CARE ON TREATMENT USE AND SURVIVAL IN HEPATOCELLULAR CARCINOMA

Caitlin Hester* 1, Nishika Karbhari1, Michelle Ju1, Nicole Rich2, Mathew Augustine1, John Mansour1, Patricio Polanco1, Matthew Porembka1, Sam Wang1, Herbert Zeh III1, Amit Singal2, Adam Yopp1

1Department of Surgery, 2Internal Medicine, University of Texas Southwestern, Dallas, United States

Introduction: Fragmented cancer care (FC), or care received from multiple institutions, increases systemic health care costs and potentiates cancer care disparities. There is a paucity of data on mechanisms contributing to FC and the resulting effect on patient outcomes. We characterized patient-and hospital-level factors associated with FC and time-to-treatment (TTT) and overall survival (OS) in HCC patients.

Methods: Patients newly diagnosed with HCC from 2004-2015 and receiving treatment were identified in the Texas Cancer Registry. We compared patient- and hospital-level factors across two cohorts: FC and non-fragmented care (NFC) treatment groups. Covariate-adjusted treatment use and OS were compared among the two treatment groups.

Image:

Results: Among 4,329 HCC patients, 1,185 (27.4%) received FC and 3,144 (72.6%) received NFC. Compared to NFC, FC had larger tumors (52.6% vs 35.2% median size ≥ 4 cm, p<0.001) and a higher proportion had regional/metastatic stage (35.9% vs 26.7%, p<0.001). Among patients with localized disease, FC was associated with decreased odds of curative therapy (OR 0.83, 95%XI 0.7-0.9). FC was associated with worse OS (HR 1.14, 95%CI 1.05 – 1.24) and increased TTT (HR 0.76; 95%CI 0.7-0.8). Among the subset of patients with localized stage HCC who received curative therapy, FC was associated with worse OS (median survival 67 vs. 43 months; HR 1.2, 95%CI 1.0-1.4) and increased TTT (HR 0.74; 95%CI 0.7-0.8).

Conclusions: FC patients were less like likely to undergo curative therapy when diagnosed at an early stage. Following covariate adjustment newly diagnosed HCC patients receiving FC had worse OS and increased TTT.

References: 1. In: Levit L, Balogh E, Nass S, Ganz PA, eds. Delivering High-Quality Cancer Care: Charting a New

Course for a System in Crisis. Washington (DC)2013.2. Skolarus TA, Zhang Y, Hollenbeck BK. Understanding fragmentation of prostate cancer

survivorship care: implications for cost and quality. Cancer 2012;118:2837-45.3. Hussain T, Chang HY, Veenstra CM, Pollack CE. Fragmentation in specialist care and stage III

colon cancer. Cancer 2015;121:3316-24.4. Dreiher J, Comaneshter DS, Rosenbluth Y, Battat E, Bitterman H, Cohen AD. The association

between continuity of care in the community and health outcomes: a population-based study. Isr J Health Policy Res 2012;1:21.

5. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington (DC)2001.


Conclusions: Liquid biopsy with CTCs, cfDNA, and EVs shows promise in early diagnosis and prognosis in HCC. Existing studies are limited by heterogeneity in which liquid biopsy components are studied, inconsistent outcome reporting, and ad-hoc cutoffs. Standardized studies are required to clarify potential clinical use of liquid biopsy in HCC.

Disclosure of Interest: V. Chen: None Declared, D. Xu: None Declared, R. Harouaka: None Declared, M. Wicha Conflict with: Honoraria - OncoMed (founder), A. Lok Conflict with: Advisory Board - Epigenomics, N. Parikh Conflict with: Research/Education grant - Bayer, Target Pharmasolutions, Conflict with: Advisory Board - Eisai, Bayer, Exelixis, Wako Diagnostics, Conflict with: Consulting - Bristol-Myers Squibb, Exelixis

P-083 IDENTIFICATION OF MULTIMARKER PANELS FOR EARLY DETECTION OF HEPATOCELLULAR CARCINOMA THROUGH EXHAUSTIVE SEARCH

Magdalena A. Swiatek-De Lange* 1, Henry L.-Y. Chan2, Teerha Piratvisuth3, Tawesak Tanwandee4, Satawat Thongsawat5, Wattana Sukeepaisarnjaroen6, Juan I. E. Mur7, Marta Bes Maijo8, Bruno Köhler9, Marcus-Rene Lisy1, Christine Belz1, Vinzent Rolny1, Dave Morgenstern10

1Roche Diagnostics GmbH , Penzberg, Germany, 2Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, China, 3NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Hat Yai, 4Division of Gastroenterology, Siriraj Hospital, Mahidol University, Bangkok, 5Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, 6Department of Medicine, Srinagarind Hospital, Khon Kaen, Thailand, 7Hospital Vall d'Hebrón, Universitat Autónoma de Barcelona, 8Facultativa Laboratori de Seguretat Transfusional, Banc de Sang i Teixits , Barcelona, Spain, 9University Hospital Heidelberg, National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg, Germany, [email protected], Roche Diagnostic Operations, Inc., Indianapolis, United States

Introduction: Hepatocellular carcinoma (HCC) has limited treatment options when diagnosed at advanced stages so its early detection is crucial to reduce mortality. Regular surveillance with ultrasound is recommended in patients with chronic liver disease. However, ultrasound performance is operator-dependent and can be challenging in the setting of NASH and severe liver disease. Adjunctive use of alpha-fetoprotein (AFP) may improve HCC detection rates but has limited sensitivity for small tumors. To address the unmet medical need for early diagnosis of HCC in at-risk population, we applied a comprehensive approach for evaluation of biomarkers with high sensitivity and specificity for early stages of HCC.

Methods: Biomarker selection was based on the published data and international guideline recommendations and included, amongst others, AFP, PIVKA-II (DCP), AFP-L3, GP73, Glypican-3, DKK1 and Midkine. Altogether, over 60 candidates were evaluated head-to-head in a panel composed of 308 HCC cases, including 125 early stages (BCLC 0 and A) and demographically matched 734 chronic liver disease controls (including HCV, HBV, cirrhosis, ASH and NASH), from a prospective multi-center sample collection in patients under surveillance from APAC (n=877) and EU (n=165) regions. Univariate and multivariate performance was assessed. Multivariate models including all possible 2 to 4 marker combinations were individually trained to separate: (1) early stage HCC from benign controls and (2) all stage HCC from benign controls. Estimations of diagnostic accuracy were done by a nested cross validation. Known risk factors for HCC, e.g. age and gender, were also included as clinical covariates in multivariate model. Finally, performance of the biomarker panels was compared to the diagnostic performance of the GALAD score (Gender, Age, AFP-L3, AFP and DCP).

Results: Over 100.000 biomarker combinations have been analyzed. Multivariate feature selection identified combinations of three biomarkers outperforming AFP. For all combinations, AFP and PIVKA-II with AUC of 83% and 79% respectively, were the strongest features, but their sensitivity toward early stages was limited. Addition of a third biomarker, either AFP-L3 or IGFBP3 or COMP or MMP3 in combination with gender and age further increased accuracy. In comparison to other scores, GALAD showed the highest robustness and superior clinical performance with AUC of over 95% for all HCC and 90% for early stage HCC.

Conclusions: Comprehensive diagnostic evaluation of over 60 biomarker candidates and over 100.000 multi-parameter combinations were performed to identify suitable biomarker/panels for early diagnosis of HCC. In this multi-center study none of the previously reported marker candidates showed sufficient clinical performance as single marker. None of the scores identified by multivariate analyses showed superiority over the GALAD score. Therefore, we propose GALAD as an optimal model for early detection of hepatocellular carcinoma in at-risk patients.

Disclosure of Interest: M. Swiatek-De Lange: None Declared, H. Chan Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, T. Piratvisuth Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, T. Tanwandee Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, S. Thongsawat Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, W. Sukeepaisarnjaroen Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, J. Mur Conflict with: Advisory Board - Study funding was provided by Roche Diagnostics, Germany, M. Bes Maijo Conflict with: Advisory Board - Study funding was

Methods: Total 288 patients with HCC at 13 hospitals in Korea were randomly assigned from May 2016 to May 2018. Patients were treated with placebo cream and urea cream at the same time as starting the treatment of sorafenib. Patients were followed up for up to 12 weeks. HFSR, score for Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire, and adverse event were assessed at 2, 4, 8, and 12 weeks.

Results: After exclusion of 41 patients, 247 patients with 117 patients in placebo control group and 130 patients in urea cream group were analyzed. Urea cream group showed lower cumulative incidence of any grade of HFRS (Log-rank, p = 0.247) and severe HFRS of 2 or more grade Log-rank, p = 0.394) without statistical significance. In the incidence by time point, development of severe HFRS of 2 or more grade were significant lower in urea cream group compared to placebo control group (13.8% vs. 23.9%, p = 0.042). Urea cream group showed significant improved score of HF-QoL questionnaire comparing with placebo control group (11.8 vs. 19.7, p = 0.014) at 12 weeks. There was no significant difference for overall survival (Log-rank, p = 0.748) between two groups. Tumor response were also not significantly different between two groups, which objective response rate was 6.2% in placebo control group and 6.0% in urea cream group (p = 0.957), and disease control rate was 44.3 % in placebo control group and 42.0% in urea cream group (p = 0.741).

Conclusions: Treatment of urea cream showed decreased incidence of severe sorafenib-induced HFRS at 2 weeks and decreased tendency of development of HFRS in patients with HCC. Therefore, treatment of urea cream might be considered in patient that treated with sorafenib for HCC.


P-081 LIQUID BIOPSY FOR DIAGNOSIS AND PROGNOSIS IN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW AND METAANALYSIS

Vincent L. Chen* 1, Dabo Xu1, Ramdane Harouaka2, Max S. Wicha2, Anna S. Lok1, Neehar D. Parikh1

1Division of Gastroenterology and Hepatology, 2Division of Hematology and Oncology, University of Michigan, Ann Arbor, United States

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. HCC early detection strategies are inadequate and tools to predict prognosis are lacking. Liquid biopsy with circulating tumor cells (CTCs), cell-free DNA (cfDNA), and extracellular vesicles (EVs) has attracted interest recently. We investigated potential clinical applications of liquid biopsy for diagnosis and prognosis of HCC.

Methods: We performed a systematic review of the Medline, Embase, and Cochrane databases. Metaanalysis was performed for prognosis by pooling univariate hazard ratios (HR) and confidence intervals, and for diagnosis using the bivariate model.

Results: Systematic review identified 156 studies (124 on diagnosis and 75 on prognosis), of which 78 were included in metaanalysis (72 on diagnosis and 10 on prognosis). CTCs showed moderate sensitivity (62%) and high specificity (93%) for distinguishing HCC from chronic liver disease (CLD). While cfDNA amount and individual gene mutations/methylation showed only modest ability to distinguish HCC from CLD (diagnostic odds ratio < 15 on metaanalysis), polygenic methylation scores showed promise with area under receiver operating characteristic curve >0.90. However, sensitivity for early stage HCC was variable. Presence of CTCs had pooled HR for recurrence after curative therapy of 2.68 (95% CI 2.12-3.40) without significant heterogeneity (I2 = 33.9, p = 0.16; see Figure). CTCs, cfDNA, and EVs had prognostic significance beyond tumor stage alone. Quality assessment showed risk of bias for studies on prognosis.

Image:

Posters Posters


P-090 HUMAN SMALL HEPATOCYTE PROGENITOR CELLS: A NOVEL TOOL TO STUDY HEPATOCELLULAR CARCINOMA

Srikumar Sengupta* 1, Bret Duffin1, Hamisha Ardalani1, James Thomson1

1Regenerative Biology, Morgridge Institute for Research, Madison, United States

Introduction: Primary human hepatocytes do not divide in culture and thus are not amenable to genetic manipulation, making them challenging to use in the study of molecular mechanisms involved in development of hepatocellular carcinoma (HCC). Small hepatocyte progenitor cells (SHPCs) are a population of hepatocytes that regenerates injured livers (1), and rodent SHPCs have been shown to proliferate in culture (2, 3, 4). Here we explore the derivation of SHPCs from primary human hepatocytes (PHHs).

Methods: We cultured PHHs obtained from a 19-year-old male donor in E6 basal medium (5) and explored multiple combinations of small molecules and growth factors known to initiate proliferation of rodent SHPCs. Transcriptome of prospective SHPCs derived from this donor were sequenced using RNA-Seq. We transplanted these cells in a mouse strain that is receptive to donor hepatocytes (Tk-NOG) (6) and performed ELISA to measure human albumin in murine blood.

Results: We derived human SHPCs from a male donor in a culture media containing EGF, Y-27632, A-83-01, and CHIR99021. The proliferative SHPC population retained differentiated morphology, exhibiting bile canalicular structures upon multiple passages. RNA-Seq of this SHPC line indicated expression of hepatocyte specific genes albumin, HNF4A, AAT, APOA1 and other phase I and II metabolic enzymes at levels comparable to the original donor PHHs. These SHPCs also expressed CD44, a marker of SHPCs previously reported in rodents (4, 7). Further, the human SHPCs were able to successfully engraft in Tk-NOG mice, evidenced by the detection of human albumin in mouse peripheral blood that was within 10-fold of that of control PHHs.

Conclusion: Derivation of SHPCs from normal, untransformed PHHs and their engraftment in mouse liver presents a novel in vivo tool that will allow in vitro genetic alterations and exploration of genes and pathways that contribute to the development of HCC.

Image:

References: [1] Best DH, Coleman WB. Liver regeneration by small hepatocyte-like progenitor cells after necrotic

injury by carbon tetrachloride in retrorsine-exposed rats.Exp Mol Pathol. 2010;89(2):92-8. [2] Mitaka T, Sato F, Mizuguchi T, Yokono T, Mochizuki Y. Reconstruction of hepatic organoid by rat

small hepatocytes and hepatic nonparenchymal cells. Hepatology. 1999;29(1):111-25.[3] Gordon GJ, Butz GM, Grisham JW, Coleman WB. Isolation, short-term culture, and transplantation

of small hepatocyte-like progenitor cells from retrorsine-exposed rats. Transplantation. 2002;73 (8):1236-43.

[4] Katsuda T, Kawamata M, Hagiwara K, Takahashi RU, Yamamoto Y, Camargo FD, Ochiya T. Conversion of Terminally Committed Hepatocytes to Culturable Bipotent Progenitor Cells with Regenerative Capacity. Cell Stem Cell. 2017;20(1):41-55.

[5] Chen G, Gulbranson DR, Hou Z, Bolin JM, Ruotti V, Probasco MD, Smuga-Otto K, Howden SE, Diol NR, Propson NE, Wagner R, Lee GO, Antosiewicz-Bourget J, Teng JM, Thomson JA. Chemically defined conditions for human iPSC derivation and culture. Nat Methods. 2011;8(5):424-9.

[6] Hasegawa M, Kawai K, Mitsui T, Taniguchi K, Monnai M, Wakui M, Ito M, Suematsu M, Peltz G, Nakamura M, Suemizu H.The reconstituted 'humanized liver' in TK-NOG mice is mature and functional. Biochem Biophys Res Commun. 2011;405(3):405-10.

[7] Kon J, Ooe H, Oshima H, Kikkawa Y, Mitaka T. Expression of CD44 in rat hepatic progenitor cells. J Hepatol. 2006;45(1):90-8.


P-089 LISTING, DROPOUT AND TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA IN LATIN AMERICA: UNEXPECTED AND PREVIOUSLY NOT REPORTED RESULTS

Federico Piñero* 1, 2, Ilka Boin3, Aline Chagas4, Emilio Quiñonez5, Sebastián Marciano6, 7, Mario Vilatoba8, Adriana Varón9, Lucas McCormack10, Sergio Hoyos Duque11, 12, Agnaldo Soares Lima13, Josemaría Menéndez14, Martín Padilla-Machaca15, Jaime Poniachik16, Rodrigo Zapata17, Martín Maraschio18, Ricardo Chong Menéndez19, Linda Muñoz Espinosa20, Diego Arufe21, Rodrigo Figueroa22, Ariel Gonzalez Campaña1, Simone Perales Reges23, Claudia Maccali4, Rodrigo Vergara Sandoval5, Carla Bermúdez6, Luisa Santos9, Matias Balmer10, Isabel Arenas11, Adrian Gadano6, Juan Mattera5, Elaine C. de Ataide23, Flair Carrilho4, Marcelo Silva1, 2

1Liver Unit, Hospital Universitario Austral, Pilar, 2Latin American Liver Research and Awareness Network, Buenos Aires, Argentina, 3Liver Transplantation, Hospital das Clínicas UNICAMP Campiñas, Campiñas, 4Hepatology and Gastroenterology, Hospital das Clínicas University of São Paulo School of Medicine, São Paulo, Brazil, 5Liver Transplantation and Hepatobiliary Surgery, Hospital El Cruce, Florencia Varela, 6Hepatology Section., 7Department of Clinical Research, Hospital Italiano, Buenos Aires, Argentina, 8Liver Transplantation and Hepatobiliary Surgery, Instituto de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico DF, Mexico, 9Hepatology and Gastroenterology, Fundación Cardioinfantil, Bogotá, Colombia, 10Liver Transplantation and Hepatobiliary Surgery, Hospital Alemán, Buenos Aires, Argentina, 11HPB and Liver Transplant Program, Hospital Pablo Tobón Uribe, 12Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia, 13Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas da UFMG, Minas Gerais, Brazil, 14Liver Transplantation and Hepatology, Hospital de Clínicas, Montevideo, Uruguay, 15Departamento de Trasplantes, Hospital Nacional Guillermo Almenara, Lima, Peru, 16Hepatology and Gastroenterology, Hospital de la Universidad de Chile, 17Hepatology and Gastroenterology, Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile, 18Hepatology and Gastroenterology, Hospital Privado, Córdoba, Argentina, 19Hepatology, Hospital Metropolitano, Quito, Ecuador, 20Hepatology, Hospital Universitario “Dr. José E. González”, Monterrey, Mexico, 21Liver Unit, Sanatorio Sagrado Corazón, Buenos Aires, 22Liver Transplantation and Hepatobiliary Surgery, Sanatorio Allende, Córdoba, Argentina, 23Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas UNICAMP Campiñas, Brazil

Introduction: The dropout cumulative incidence of potential candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC) has been reported to be close to 10% at six months in different observational studies. Given greater liver transplant accessibility and lower dropout rates, a greater benefit has been postulated for patients with HCC compared to other patients on the waiting list. We aimed to describe dropout rates in a Latin American cohort study.

Methods: This multicenter and multinational cohort study conducted in Latin America included adult patients listed for LT with HCC between years 2011-2018. Delisting or dropout for any reason (death, tumor progression, other causes) was evaluated as the primary event. As secondary objective, we evaluated exposure variables associated with dropout due to tumor progression by a multivariable competing risk analysis (competitive event = death or withdrawal from other causes), with Sub-Hazard Ratios (SHR) and respective 95% (95% CI) confidence intervals calculated.

Results: A total of 1117 patients with HCC were evaluated for liver transplantation, 994 (89%) were listed, 799 (80.4%) granted with supplementary MELD points. Of listed patients, 65% (n=650) were transplanted, 10% (n=91) still remained on the waiting list at the end of the study and 25% (n=253) were delisted. Overall cumulative incidence of dropout in a median time on the waiting list of 6.1 months (IQR 2.4-10.4 months) was 25.3% (CI 22.7%>28.2%). Of these, the dropout rate due to death or other causes was 14.3% (CI 12.2%>16.6%), while the dropout rate due to tumor progression was 11.2% (CI 9.7%>13.8%). The type of dropout due to tumor progression was: extrahepatic (n=14), vascular invasion (n=19), intrahepatic diffuse compromise (n=33), multinodular intrahepatic (n=60) and uninodular intrahepatic (n=7). Overall dropout rate due to tumor progression was significantly higher among patients without than with supplementary MELD points [21.0% (CI 15-27.8%) vs 8.8% (CI 6.8-10.9%); P<.0001]. In the competing risk multivariable analysis, independent variables at listing associated with dropout due to tumor progression were Milan criteria SHR 0.60 (CI 0.36-0.98; P = 0.04) and the AFP model SHR 0.56 (CI 0.33-0.96; P=0.03).

Conclusions: In this Latin American cohort, the risk of delisting and dropout was unexpectedly high compared to other reported series. However, the dropout rate due to tumor progression, although high, was as accordingly expected.

Disclosure of Interest: F. Piñero Conflict with: Research/Education grant - National Institute of Cancer, Argentina, Conflict with: Honoraria - Bayer, Conflict with: Advisory Board - Bayer, Conflict with: Consulting - Bayer, I. Boin: None Declared, A. Chagas: None Declared, E. Quiñonez: None Declared, S. Marciano: None Declared, M. Vilatoba: None Declared, A. Varón: None Declared, L. McCormack: None Declared, S. Hoyos Duque: None Declared, A. Soares Lima: None Declared, J. Menéndez: None Declared, M. Padilla-Machaca: None Declared, J. Poniachik: None Declared, R. Zapata: None Declared, M. Maraschio: None Declared, R. Chong Menéndez: None Declared, L. Muñoz Espinosa: None Declared, D. Arufe: None Declared, R. Figueroa: None Declared, A. Gonzalez Campaña: None Declared, S. Perales Reges: None Declared, C. Maccali: None Declared, R. Vergara Sandoval: None Declared, C. Bermúdez: None Declared, L. Santos: None Declared, M. Balmer: None Declared, I. Arenas: None Declared, A. Gadano: None Declared, J. Mattera: None Declared, E. de Ataide: None Declared, F. Carrilho: None Declared, M. Silva: None Declared

P-088 FACTORS ASSOCIATED WITH DETECTION OF THE SINGLE LESS THAN 2CM HEPATOCELLULAR CARCINOMA IN THE UNITED STATES

Ju Dong Yang* 1, 2, 3, Michael Luu4, Mazen Noureddin1, 3, Alexander Kuo1, 3, Walid Ayoub1, 3, Vinay Sundaram1, 3, Honore Kotler3, Irene Kim3, Tsuyoshi Todo3, Kambiz Kosari3, Shelly Lu1, Andrew Hendifar2, Jun Gong2, Nicholas Nissen3

1Division of Digestive and Liver Diseases, 2Samuel Oschin Comprehensive Cancer Institute, 3Comprehensive Transplant Center, 4Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Westhollywood, United States

Introduction: The single < 2 cm hepatocellular carcinoma (HCC) has distinct tumor biology and patients who present at this stage has an excellent prognosis. With the improvement in diagnostic image technology and implementation of the HCC surveillance program in high risk patients, detection of the single < 2 cm HCC is expected to increase. Currently, it remains unknown as to what extent HCCs are detected at this stage in the United States (US). Further, factors associated with their detection are unknown. The aim of the study is to investigate the temporal trend and factors associated with detection of the single < 2 cm HCC.

Methods: The National cancer database (NCDB) represents more than 70 % of newly diagnosed cancer cases nationwide. The NCDB was used to identify all HCC patients who were diagnosed between 2004 and 2014 based on the International Classification of Disease-Oncology-3rd Edition code C22.0 and the histology codes 8170-8175. Factors associated with the single < 2 cm HCC were identified using logistic regression analyses.

Results: A total of 110,182 patients were identified, of whom 6,261 (5.7%) had a single < 2 cm HCC. The proportion of the single < 2 cm HCC has increased 2.7-fold over time from 2.7% in 2004 to 7.3% in 2014. (P<0.01) (Figure). Among demographic features, female sex (adjusted odds ratio [AOR]: 1.73, 95% confidence interval [CI]: 1.61- 1.87, P<0.01) was independently associated with detection of the single < 2cm HCC while age (AOR per 10 years: 0.74, 95% CI: 0.71- 0.77, P<0.01) and Hispanic ethnicity (AOR: 0.86, 95% CI: 0.77- 0.96, P<0.01) vs. White race (reference group) were inversely associated with it. Among socioeconomic factors, insurance status was independently associated with detection of the single < 2cm HCC: private insurance (AOR: 1.63, 95% CI: 1.37- 1.97, P<0.01) or Medicaid/Medicare (AOR: 1.58, 95% CI: 1.32- 1.89, P<0.01) vs. uninsured status (reference group). Among clinical factors, higher Charlson Comorbidity index (AOR: 1.18, 95% CI: 1.07- 1.30, P<0.01) and normal alpha-fetoprotein (AOR: 1.92, 95% CI: 1.78- 2.06, P<0.01) were independently associated with detection of the single < 2 cm HCC while higher MELD score (AOR per 10 unit: 0.81, 95% CI: 0.74- 0.90, P<0.01) was inversely associated with its detection. Facility related factors had the strongest impact on detection of the single < 2cm HCC. Academic cancer center (AOR: 3.78, 95% CI: 2.75- 5.19, P<0.01) and Integrated cancer centers (AOR: 3.06, 95% CI: 2.19- 4.27, P<0.01) vs. community cancer program (reference group) were independently associated with detection of the single < 2cm HCC. Facilities located in Northeast (AOR: 1.23, 95% CI: 1.12- 1.36, P<0.01), Midwest (AOR: 1.15, 95% CI: 1.04- 1.27, P<0.01), and West (AOR: 1.26, 95% CI: 1.14- 1.40, P<0.01) vs. South (reference group) were independently associated with the single < 2cm HCC detection.

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Conclusion: There was an increasing trend of the single < 2cm HCC detection in the US. There were significant racial, socioeconomic, regional, and facility related disparities in detection of the single < 2cm HCC in the US.


4. Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, Ghanekar A, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study. Hepatology. 2016;64(6):2077-88.

5. R. B. An Introduction to Artificial Intelligence: Can Computers Think? San Francisco, CA: Boyd & Fraser Pub Co; 1978.

6. Hashimoto DA, Rosman G, Rus D, Meireles OR. Artificial Intelligence in Surgery: Promises and Perils. Ann Surg. 2018.


8. Mazzaferro V, Sposito C, Zhou J, Pinna AD, De Carlis L, Fan J, et al. Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma. Gastroenterology. 2018;154(1):128-39.

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P-087 COMPARISON OF LONG-TERM OUTCOMES OF MICROWAVE ABLATION VERSUS SURGICAL RESECTION FOR HCC

Jianping Dou* 1, Jie Yu1, Ping Liang1

1Interventional Ultrasound Department, Chinese PLA General Hospital, Beijing, China

Introduction: Thermal ablation challenges the status of surgical resection on small hepatocellular carcinoma (HCC) treatment, while its therapeutic outcomes for larger lesions are still in debate. To compare long-term outcomes of surgical resection (SR) and microwave ablation (MWA) and give clues to treatment decision for HCC ≤ 5 cm

Methods: This retrospective study evaluated 639 patients with solitary HCC who underwent curative SR or MWA from January 2008 to December 2015. Overall survival (OS), free intrahepatic recurrence (FIR) and disease-free survival (DFS) were compared using propensity score matching to control for potential confounders. Co-variables associated with OS and DFS were identified. The risk of death and tumor progression in HCC patients received SR versus MWA was compared

Results: 178 Patients were well matched according to baseline characteristics. The OS rate of 1-, 3-, 5-year were estimated to be 98.9%, 81.2%, 66.4% in MWA group and 98.3%, 85.6%, 75.9% in SR group (p=0.11). No significant differences were found in terms of OS, DFS and FIR rate in subgroup analysis of MWA, anatomic and non-anatomic SR group. Albumin-bilirubin grade (HR, 1.44; 95% CI: 1.11,1.87) was the independent factor associated with DFS and tumor size (HR, 1.25; 95% CI: 1.07, 1.45) was for OS. Patients presented with higher neutrophil to lymphocyte ratio (NLR) grade was associated with higher OS (HR: 0.5 vs. 1.1; Pint = 0.04) after MWA, while patients with lower NLR grade was associated with longer DFS (HR: 0.7 vs. 1.5; Pint=0.02) after SR. Major complication rate was similar while post-treatment stay was significantly longer in SR group

Conclusions: MWA provided non-inferior survival outcomes to SR in solitary HCC≤5cm. MWA provided longer OS in patients with severe inflammation, while SR provided longer DFS in patients with mild inflammation

Posters Posters


P-095 SOMATIC TERT PROMOTOR VARIANTS IN EARLY HEPATOCARCINOGENESIS

Dina M. Sweed* 1, Dina S. El-Azab1, Brandon J. Massengill James2, Mohamed H. Abdel-Rahman1,2,3

1Pathology, National Liver Institute, Menoufia, Egypt, 2Ophthalmology, 3Division of Human Genetics, The Ohio State University, Columbus, OH, United States

Introduction: The present study assessed the role of somatic TERT promotor variants in early steps of hepatitis C viral (HCV) related hepatocarcinogenesis. We also studied the potential diagnostic role of TERT variants in differential diagnosis of small hepatocellular carcinoma (HCC) from dysplastic liver nodules.

Methods: The study included 21 HCC cases less than 3 cm in size and the adjacent non-tumor liver (available on 19), 5 dysplastic nodules, 7 regenerative nodules and 7 normal liver tissues. Direct (Sanger) sequencing was performed on DNA extracted from microdissected material from formalin fixed paraffin embedded tissues. 163 base pairs of TERT promotor region covering the two reported somatic variants -124C>T (g.1295228C>T) and -146C>T (g.1295250C>T) were sequenced.

Results: The TERT promotor variant -124C>T was detected in 16/21 (76%) of the HCC and 3/19 (15.8%) of the non-tumor cirrhotic liver adjacent to the tumors. None of the donor or regenerative nodules showed the two variants. 3/5 of the dysplastic nodules showed TERT promotor variants other than the two commonly reported ones. None of the samples showed the -146C>T variant.

Conclusions: Our results suggest that somatic TERT promotor variants are important in early hepatocarcinogenesis. It also suggests that somatic variation in TERT cannot be used as diagnostic marker to differentiate dysplastic liver nodules from small HCC.


P-096 MOLECULAR CHARACTERISTICS ASSOCIATED WITH 18F-FDG UPTAKE IN INTRAHEPATIC CHOLANGIOCARCINOMA

Keun Soo Ahn* 1, Koo Jeong Kang1, Yong Hoon Kim1, Tae-Seok Kim1, Kyoung Sook Won2

1Surgery, 2Nuclear Medicine, Keimyung University Dongsan Medical Center, Daegu, Korea, Republic Of

Introduction: In intrahepatic cholangiocarcinoma (iCCA), genetic characteristics on 18F-FDG-PET scans are not yet clarified. If they are evaluated, we can predict molecular features based on the FDG uptake. We analyzed RNA sequencing in iCCA patients to evaluate gene expression signatures associated with FDG uptake patterns.

Methods: We performed RNA sequencing of 22 cases iCCA who underwent preoperative 18F-FDG- PET, and analyzed the clinical and molecular features according to the maximum standard uptake value(SUVmax). Genes and biological pathway which are associated with SUVmax were analyzed.

Results: Patients with SUVmax higher than 9.0(n=9) had poorer disease-free survival than those with lower SUVmax(n=13, P=0.035). Genes related to glycolysis and gluconeogenesis, phosphorylation and cell cycle were significantly correlated with SUVmax (| r | ≥0.5). RRM2, which is related to the toxicity of Gemcitabin was positively correlated with SUVmax, and SLC27A2 which is associated with Cisplastin response was negatively correlated with SUVmax. Cell cycle, hypoxia and metabolism-related pathways were enriched in high SUVmax patients.

Conclusions: The genomic features of gene expression and pathways can be predicted by FDG uptake features in iCCA. Patients with high FDG uptake have enriched cell cycle, metabolism and hypoxic pathways, which may lead to a more rational targeted treatment approach.


P-097 PRECLINICAL TESTING OF IMMUNE CHECKPOINT INHIBITION AS LIVER CANCER CHEMOPREVENTION

Andrew Chung* 1, Hao Zhu1

1Children's Research Institute, UT Southwestern Medical Center, Dallas, TX, United States

Introduction: HCC most often arises in the context of longstanding, progressive liver disease. Major risk factors for development of HCC include chronic HBV infection, chronic HCV infection, non-alcoholic fatty liver disease, and alcoholic liver disease. These can cause progression to cirrhosis in a subset of patients, and HCC then develops in 5-30% of cirrhosis patients.1 Thus, cirrhosis represents a pre-malignant state, and the long latency of progression through chronic disease, cirrhosis, on to HCC offers a potential window of intervention prior to the onset of cancer.Work in our lab has shown that cirrhotic livers carry many somatic mutations, and mutational burden correlates with fibrosis stage. These mutations are predicted to produce neoantigens, yet these mutations show a reduced variant allele frequency as compared to non-neoantigen producing mutations. This suggests that immune surveillance selects against certain mutant clones while other mutant clones expand. We sought to use the DEN + CCl4 mouse model of mutagenesis and chronic

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References: 1, Okusaka, T. and M. Ikeda, Immunotherapy for hepatocellular carcinoma: current status and future

perspectives. ESMO Open, 2018. 3(Suppl 1): p. e000455.2. Yadav, R.K., et al., FoxO transcription factors in cancer metabolism. Semin Cancer Biol, 2018.

50: p. 65-76.


P-094 LIM PROTEIN AJUBA PROMOTES CANCER CELL PROLIFERATION AND SURVIVAL IN HEPATOCELLULAR CARCINOMA

Noëlle Dommann* 1, Jacopo Gavini1, Daniel Sánchez-Taltavull1, Tess Brodie2, Michaela Medova3, Magali Humbert4, Mario Tschan4, Daniel Candinas1, Deborah Stroka1

1Department of BioMedical research, Visceral Surgery, University of Bern, Bern, 2Mass Cytometry Facility, University of Zurich, Zurich, 3Department of BioMedical research, Radiation Oncology, 4Institute of Pathology, University of Bern, Bern, Switzerland

Introduction: The LIM-domain protein Ajuba is a structural protein involved in the Hippo pathway and has a role in the maintenance of cell junctions, migration, differentiation, and proliferation. Ajuba can be found in different cellular compartments such as cell-cell junctions or cytoplasma and can be shuttled into the nucleus where it is thought to regulate transcription. There are discrepancies in the literature as to whether it is a driver or suppressor of proliferation and little is known about it in the context of hepatocellular carcinoma (HCC). The aim of this study is to characterize Ajuba expression and function in HCC.

Methods: We screened 10 human liver cancer cell lines and primary tumors comparing them to control liver tissue or cultured primary human hepatocytes for protein and mRNA expression of Ajuba. The function of Ajuba was investigated by modulating its protein level with lentiviruses expressing shRNA targeted sequences or an overexpressing (OE) construct. The biological impact of Ajuba knockdown and OE transduced cells was tested in-vitro with various biological assays including RT2 Profiler PCR Arrays looking at Hippo pathway and cell cycle, Mass spectrometry of exogenous Ajuba and a 42-parameter panel for mass cytometry, and in an in-vivo syngeneic mouse tumor model. We are now generating Ajuba knockout mice by pronuclear CRISPR/Cas9 injection.

Results: Steady state levels of Ajuba mRNA in human liver cancer cell lines and primary tumors were significantly higher than in primary human hepatocytes or control liver tissue. HCC Patients with higher amounts of Ajuba protein expression showed a significantly reduced life expectancy. Lentiviral transduction of HCC cell lines effectively knocked-down Ajuba protein resulting in a decrease of cell proliferation, migration, and colony formation, which coincided with a G2-phase cell cycle arrest and enhanced radiosensitivity. Using mass spectrometr, previously published binding partners of Ajuba could be confirmed and new proteins were identified. Mass cytometry allowed the identification of new pathways in which Ajuba might be involved. Using a syngeneic tumor model in C57BL/6 mice, HCC with knocked-down Ajuba expression had a significantly reduced tumor volume compared to controls.

Conclusions: Ajuba overexpression appears to be central to HCC cell proliferation and knock down reduces tumor growth and cell survival.


P-092 MIR181A LEVELS IN CHOLANGIOCARCINOMA CORRELATE WITH TYROSINE PHOSPHORYLATION OF YAP AND SENSITIVITY TO SRC FAMILY KINASE INHIBITION

Ayano Kabashima1, Nathan Werneburg1, Gregory Gores1, Rory Smoot* 2

1Gastroenterology and Hepatology, 2Surgery, Mayo Clinic, Rochester, United States

Introduction: Treatment options for cholangiocarcioma (CCA) remain limited. In an attempt to identify treatment targets we have previously demonstrated aberrant activity of the Hippo pathway effector protein, YAP, in multiple models of CCA. Furthermore, we demonstrated that tyrosine phosphorylation of YAP, driven by the Src Family Kinase (SFK) LCK, was associated with YAP nuclear localization and activity as a transcriptional co-activator. In further exploring additional regulators of YAP tyrosine phosphorylation we evaluated the role of miR181a.

Methods: In silico analysis of RNA sequencing data from patients with resected intrahepatic cholangiocarcinoma and The Cancer Genome Atlas were undertaken. Levels of mature miR181a-5p were evaluated in both CCA cell lines (HuCCT-1) as well as organoid cell lines developed from CCA patient-derived xenografts by RT-PCR. Total YAP and p-YAPY357 levels were examined by immunoblot analysis. Downregulation of miR181a activity was accomplished with mirVana antagomir. Cell viability in response to the SFK inhibitor dasatinib was determined by the cell titer glow assay.

Results: RNA sequencing data from patients suffering early recurrence following curative-intent resection of intrahepatic cholangiocarcinoma demonstrated altered expression of multiple genes that are targeted by and/or modulate miR181a. Analysis of the TCGA cholangiocarcinoma dataset demonstrated upregulation of all isoforms of miR181 with miR181a having the highest expression levels. RT-PCR analysis of HUCCT-1 cells and multiple CCA organoid cell lines demonstrated differential expression levels of miR181a which directly correlated with p-YAP357 levels. Downregulation of miR181a activity in HuCCT-1 cells utilizing a validated antagomir was associated with a downregulation of p-YAPY357 levels. Finally, sensitivity of the CCA organoids to dasatinib treatment was inversely correlated with miR181a levels.

Conclusions: miR181a levels in CCA predict the tyrosine phosphorylation status of YAP and increased miR181a levels are associated with decreased sensitivity to SFK inhibition by dasatinib. miR181a levels in CCA may serve as a biomarker for YAP directed therapy such as use of SFK inhibitors.


P-093 HEPTOCELLULAR CARCINOMA DERIVED FOXO1 INHIBITED TUMOR PROGRESSION THROUGH SUPPRESSING IL-6 SECRETION FROM MACROPHAGE

Xiao Cui* 1, Qiang Du2, David Geller2

1Department of Surgery, University of Pittsburgh/The Second Hospital of Anhui Medical University, 2Department of Surgery, University of Pittsburgh, Pittsburgh, United States

Introduction: In solid tumors, high density of infiltrated macrophages is generally considered tumor supportive function, but conflict data was noted[1]. Distinct tumor microenvironment may dominate the polarization of macrophages. FOXO1 is a transcription factor that exerted tumor suppressive effects both in tumor cells and immunity cells, respectively[2]. However, the effects of tumor derived FOXO1 exerts in immunity reaction in HCC had not fully clarified. Here we investigated the effects of tumor derived FOXO1 in macrophages in HCC.

Methods: Based on HCC samples from UPMC (n=32) and TCGA dataset (n= 442), clinico-pathological analysis was performed in the relationship between FOXO1 expression in HCC and clinical characteristics. Stably up-regulating Foxo1 HCC cells were constructed in Hepa1-6 and Huh7 cells. The biological effects of FOXO1 in tumor and macrophages were investigated in vivo and vitro. Chromatin immunoprecipitation assay and immunoblotting were employed to explore the possible relationships between FOXO1 and targeting genes. Informed consent was obtained from the patients involved in this research.

Results: FOXO1 expression was suppressed in HCC and negatively correlated with vascular invasion and disease-free survival rate (Fig. 1A, B P < 0.01). Endogenous FOXO1 expression inhibited HCC migration, but promoted infiltration of anti-tumor macrophages (Fig. 2, A, B, C, D P < 0.05). FOXO1 might functions through promoting IRF-1 transcription (Fig. 3, A, B) which inducing CCL2, nitrous oxide expression in HCC, then induced decreasing IL-6 expression in macrophages (Fig. 4). Suppression of IL-6 expression from macrophages inactivated IL6/STAT3 in HCC and inhibited HCC migration.

Conclusions: Here data show a novel role of FOXO1 in HCC tumor biology. FOXO1 exerted anti-tumor effects by suppressing tumor cells growth and mediating macrophage immunity, collaboratively.

P-091 SOMATIC COPY NUMBER PROFILING OF HEPATOCELLULAR CARCINOMA CIRCULATING TUMOR CELLS

Pin Jung Chen1, Colin Court2, Shuang Hou2, Saeed Sadeghi3, Richard Finn3, Fady Kaldas2, Ronald Busuttil2, Thomas Graeber1, James Tomlinson2, Hsian-Rong Tseng1, Vatche G. Agopian* 2

1Molecular and Medical Pharmacology, 2Surgery, 3Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, United States

Introduction: Somatic copy number alterations (SCNAs) are important genetic drivers of many cancers, and are increasingly recognized as playing a vital role in activating oncogenes and inactivating tumor suppressors through changes in gene dosage and structure. SCNAs have shown prognostic and predictive utility in hepatocellular carcinoma (HCC), but their use from percutaneous biopsies is limited due to HCC’s significant tumor heterogeneity. We investigated the feasibility of obtaining SCNA profiles from circulating tumor cells (CTCs) as a molecular liquid biopsy for HCC.

Methods: Using the NanoVelcro HCC-specific CTC assay, CTCs were isolated from 10 HCC patients undergoing surgical resection, and low-resolution whole genome sequencing performed to establish SCNA profiles. Primary tumor, peritumoral normal liver, and germline genomic DNA was sequenced for comparison.

Results: Sequencing of 18 CTC samples (median 4 CTCs/sample) from 10 HCC patients using a low-resolution whole genome sequencing strategy (median 0.88 million reads/sample) revealed frequent copy number changes in previously reported HCC regions such as 8q amplifications and 17p deletions. Analysis of SCNA profiles for primary tumor and CTC samples revealed that CTCs share a median of 80% concordance with the primary tumor and demonstrate the majority of important somatic SCNAs found in the primary tumor (Figure 1). Sequencing of 7 different CTC samples from a single patient established the reproducibility of the assay. Furthermore, CTCs had SCNAs not seen in the primary tumor, some of which have prognostic implications.

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Conclusion: SCNA profiling of HCC-CTCs is feasible and accurately recapitulates SCNAs seen in the primary tumor, providing molecular proof that what is immunocytochemically defined as CTCs are in-fact derived from tumor origin. The use of CTC-derived SCNA profiles as clinically relevant surrogates of the primary HCC tumors demonstrates potential utility and should be further explored.

Posters Posters


Introduction: Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC); however, the drug has moderate response rate and duration, and low disease control rate. Moreover, the survival rate, after administration of sorafenib, is lower in patients with high serum alpha-fetoprotein (AFP) levels. Thus, we hypothesized that AFP inhibition increases the anti-tumor effect of sorafenib on HCC in in vitro and in vivo models.

Methods: AFP-producing Huh-7 cell line was used in this study. The cells were transfected with AFP siRNA for 72 hours followed by treatment with sorafenib (2 μmol/L) for 24 hours. Hoechst 33342 staining was used to analyze cell number using cytation3. Propidium iodide staining was used to assess cell cycle state using flow cytometry. Immunoblotting assay was used to determine apoptosis. Patient-derived xenograft (PDX) models were used to evaluate augmentation effects of AFP inhibition on sorafenib. PDX models were divided into 5 groups for treatment with the following: control; non-target siRNA; AFP siRNA; sorafenib; AFP siRNA + sorafenib. siRNA was intratumorally injected every 3 days and sorafenib (10 mg/kg) was administered orally by gavage once daily. At the end of study, the body weights of the mice were recorded, and the mice were sacrificed their tumors were harvested for analysis.

Results: AFP siRNA inhibited AFP production in HCC cells and also inhibited their proliferation. Inhibition of HCC cell proliferation was greater when treated with both AFP siRNA and sorafenib than when treated with sorafenib or AFP siRNA alone. Sorafenib increased the percentages of Huh-7 cells in the sub-G0/G1 phase; the sub-Go/G1 population was enhanced in AFP-siRNA transfected Huh-7 cells. Cells treated with both AFP siRNA and sorafenib showed increased apoptosis via upregulation of caspase3 and PARP cleavage compared with cells treated with sorafenib alone. In the PDX model, treatment with AFP siRNA and sorafenib significantly inhibited subcutaneous HCC tumor growth in comparison with treatment with sorafenib alone.

Conclusions: AFP suppression augments the anti-proliferative effect of sorafenib in human HCC cells. These results suggest that AFP inhibition may play a synergistic role in the anti-tumor effect of sorafenib in patients with advanced HCC.


P-102 CELLULAR AND MOLECULAR CHARACTERIZATION OF HEPATOCELLULAR CARCINOMA UNDER DIFFERENT STEATOGENIC DIETS

Arturo Simoni-Nieves* 1, Soraya Salas-Silva1, Alejandro Escobedo-Calvario1, Yunuen Ortiz-Pedraza1, Maria C. Gutierrez-Ruiz1, Jens Marquardt2, Luis E. Gomez-Quiroz1

1Ciencias de la Salud, Universidad Autonoma Metropolitana, Mexico City, Mexico, 2Department of Medicine I, Johannes Gutenberg University, Mainz, Germany

Introduction: While the hepatitis B and C viruses remain the most important risk factors, virus-related HCC is expected to decrease in the near future due the new treatments. However, the prevalence of non-alcoholic fatty liver disease (NAFLD), is increasing. Strong evidence has emerged that obesity and NASH are major risk factors for HCC. Dietary cholesterol has been shown to play a role in the development of steatohepatitis (Dominguez-Perez et al., 2018). However, the mechanisms by which cholesterol promotes HCC development is unclear.

Methods: The RNA-seq counts files of 16 patients with HCC with no history of primary risk factor, and 12 samples of NHCC (NAFLD-HCC) and 16 samples of normal liver, were retrieved from The Cancer Genome Atlas (TCGA) database. The parameters for the differential expression analysis were False Discovery Rate (FDR) equal to 0.5, p-value <0.001 and log fold change from -1.5 to 1.5. 64 14-days old male mice (C57/BL6) were randomly separated: i.) Fed with a high cholesterol diet (HC); ii.) HC diet and single intraperitoneal (ip) injection of 10 μg/kg body weight of N-Nitrosodimethylamide (DEN) (HCD); iii.) Fed with Western (W) diet; iv.) W diet and DEN (WD); Chow diet (CW) with v.) Or without vi.) DEN. After 8 months mice were euthanized. Histology was performed by Hematoxylin-Eosin staining (H-E). For total cholesterol was determined by O-Phthalaldehyde. Real-time PCR quantification of mRNA levels was performed. Each experiment was performed at least by triplicate of at least ± 3 different animals. Data are reported as the average ± standard error (SEM). For the comparison of means of different groups, an analysis of variance (ANOVA) was used, followed by multiple comparisons by the Tukey test. The level of significance will be p ≤0.05.

Results: In order to identify the gene expression profile related to NAFLD/NASH-related HCC, we proceeded to the analysis HCC with NAFLD (NHCC) samples, and HCC samples with no history of primary risk factors. Interestingly, the analysis of HCC samples versus NAFLD/NASH-related HCC, exhibited 325 differentially expressed, 242 genes downregulated and 83 upregulated (Figure 1A). In order to validate the findings in human samples, we established a mice model. Histological studies (Figure 2B) revealed high lipid accumulation under experimental diets, particularly the HC diet showed microvesicular steatosis, and the Western diet exhibited both micro and macrovescular lipid accumulation. Tumor areas show the classical loss of normal tissue, with many cells with aberrant mitotic figures. Finally, in order to figure out some parameters of aggressiveness, we addressed qRT-PCR to figure out the levels of different genes related to cancer aggressiveness exhibited an increased expression in all most genes in Western tumor, this preliminary data suggest a differential expression profile between different diets .

Conclusions: Our findings show a differential expression of tumor-related and tumor-suppressor transcripts in single hepatocytes infected with HCV compared to those uninfected, within each patient. Since all four individuals in the study had F0-F1 fibrosis, our findings suggest that the mechanisms related to HCC development during HCV infection arise earlier than the development of cirrhosis or advanced fibrosis.


P-100 DIET-VARIANTS AND IMMUNE CHARACTERIZATION OF A STAGE-DEFINED, TRANSGENIC IMMUNOCOMPETENT MOUSE MODEL OF HCC (ASV-B)

Annemilaï Tijeras-Raballand* 1, Christian Hobeika2, 3, Benoit Rousseau4, 5, Patricia Hainaud6,

7, Philippe Bonnin6, 8, Aurélie Rodrigues5, Fouad Ladfil5, Marc Pocard2, 3, Armand de Gramont9, Eric Raymond9, 10, Evelyne Dupuy6, 7, Valérie Paradis11, Sandrine Faivre12, Clarisse Eveno13, 14

1Preclinical and Translational Research, AFR Oncology, 2Digestive and Cancer Surgery, Lariboisière University Hospital, 3Inserm U1275, Paris, 4Medical and Pharmacology , Mondor University Hospital, 5Innovation and Drug Development Unit, Inserm U955, Créteil, 6Inserm U965, 7Institut des Vaisseaux et du Sang, 8Clinical Physiology-Functionnal Investigations, Lariboisière University Hospital, 9AFR Oncology, 10Medical Oncology, Paris Saint-Joseph Hospital, Paris, 11Pathology, Beaujon University Hospital, Clichy, 12Medical Oncology, Saint-Louis University Hospital, Paris, 13Mucins, Epithelial Differentiation and Carcinogenesis, Inserm 1172-JPARC, 14Digestive and Oncological Surgery, University Hospital C. Huriez, Lille, France

Introduction: Non-alcoholic fatty liver disease (NAFLD), especially non-alcoholic steatohepatitis (NASH) is a chronic liver disease commonly associated with hepatic fibrosis. NASH patients have an increased risk for hepatocellular carcinoma (HCC). Due to western way of life, NASH incidence is rising and predicted to become the leading cause of liver transplant in 2020 and of HCC in the next decades. There is an urgent need for robust animal models fully recapitulating the NASH-related HCC carcinogenesis due to this changing in HCC etiology. In this study, we develop and characterize specific diet-induced variants from our transgenic HCC mouse model, focusing on immune landscape.

Methods: We used in the all study ASV-B mice: a transgenic mouse model (C57BL/6J) spontaneously developing a reproducible stage-defined HCC (hyperplasia at week(W)8, nodular stage at W12, and diffuse carcinoma at W16-20). To mimic NASH, ASV-B mice were exposed to 5 different diets. Ten ASV-B and 5 control mice were fed as follows: classic diet as control (yellow), or a high-fat diet (blue), a diet enriched with saturated fatty acids + 1.25% cholesterol (green), a diet containing 22% of vegetal oil + 0.2% cholesterol (orange), and a 1.25% cholesterol diet containing 21% of milkfat (red). All mice fed with special diets also received 30% fructose in the drink water.RNA was extracted from frozen livers at W20 for the analysis of 40 immune markers using qRT-PCR (LightCycler, Roche). Immune populations were assessed using automated immunohistochemistry (IHC) (Bond Max, Leica).

Results: ASV-B model showed an increase in liver volume and angiogenesis, HCC livers harboring marked arterialization and capillarization as compared to control. Assessing immune markers on 7 evaluable tumor specimens, we observed an increase in CD8, Foxp3, INOS, CD11b, PD-1, PD-L1, IL1ß, IFN-Y, TNF-alpha, IL17A and IL17F mRNA expressions, as frequently observed in human inflammatory HCC. In addition, IHC staining showed intratumoral infiltration of lymphocytes (CD8+) and macrophages (F4/80+, a well-characterized and extensively referenced mouse macrophage marker). By the time of the meeting, we will have the first results showing the effects of an anti-PD1 inhibitor on tumor volume, tumor weight, and macronodules number in this model.ASV-B mice receiving yellow, blue, and green regimens showed similar liver volumes and weights. By macroscopic analysis, we observed increased liver steatosis, and fibrosis in the red and orange regimen compared to others. Moreover, we observed a 40% mortality rate in the orange regimen, and a 20% mortality rate in the blue and green regimens. At the conference, we will show in the diet-variants, the morphologic changes and the immune landscape of the livers using HPS staining and IHC, respectively.

Conclusions: ASV-B transgenic mouse model mimics several characteristics of human HCC developing on healthy liver including inflammatory reaction and immune cell infiltration. In the ASV-B model, we have been able to develop specific-diets variants mimicking NASH characteristics that could be used for drug testing.


P-101 ALPHA-FETOPROTEIN INHIBITION ENHANCES THE IN VITRO AND IN VIVO ANTI-TUMOR EFFECTS OF SORAFENIB ON HEPATOCELLULAR CARCINOMA

Jin Sook Kim* 1, Kyung-Tae Kim2, Joong-Won Park1,3

1Division of Clinical Reserch, 2Division of Cancer Branch, 3Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea, Republic Of

Methods: Clinical, CNV, somatic nucleotide variation (SNV) and mRNA data of TCGA LIHC cohort were retrieved from the cBioPortal website. Tumor immune microenvironment was evaluated by profiling of tumor-infiltrating immune cells using CIBERSORT, and immune-related gene signatures.

Results: We analyzed 338 primary HCC samples in TCGA LIHC cohort. 4.4% harbored focal amplification of 11q13.3. Compared to HCC without focal amplification of 11q13.3, HCC with focal amplification of 11q13.3 had less CTTNB1 mutation (0% vs. 28%, P=0.008) and more CDK4 amplification (13% vs. 0%, P=0.002) in addition to those genes [CCND1 (100% vs 3%, P

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Conclusions: HCC with 11q13.3 amplification is a distinct molecular subtype of HCC with an active immune microenvironment, and a therapeutic potential of combining targeted therapy for CCND1/FGF19 and immunotherapy.


P-099 ALTERED TRANSCRIPTIONAL PROFILES OF TUMOR-RELATED AND TUMOR-SUPPRESSOR GENES IN HCV-INFECTED INDIVIDUALS WITH EARLY FIBROSIS EVIDENCED BY SINGLE HEPATOCYTE RNA SEQUENCING

Jose Debes* 1, 2, Thomas Vanwolleghem2, A. Zwier Groothuismink2, Andre Boonstra2

1University of Minnesota, Minneapolis, United States, 2Erasmus MC, Rotterdam, Netherlands

Introduction: Hepatocellular carcinoma (HCC) related to hepatitis C infection (HCV) occurs almost exclusively in the setting of cirrhosis. The mechanisms leading to this process of viral-carcinogenesis are poorly understood and thought to occur once cirrhosis has become evident.

Methods: We performed single cell RNA sequencing of hepatocytes in four treatment naïve HCV-infected patients with F0-F1 fibrosis as evidenced by liver elastography and biopsy. Isolation of hepatocytes was performed following liver biopsy via cell sorting. Single cell RNA sequencing was achieved by Drop-Seq using DNA library barcodes. Following sequencing, elements in each cell were aligned to that of the HCV genome and stratified by HCV gene expression quantification to differentiate hepatocytes infected or not with HCV within each patient, allowing for characterization of hepatocytes with low, medium or high probability of HCV infection. Characterization of cells as hepatocytes was performed by quantification of albumin expression in each cell. Transcript-path identification was performed via ingenuity pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG).

Results: A total of 320 hepatocytes from four different HCV-infected patients underwent single-cell sequencing. Transcript variation comparison analysis was performed on the top 10 percent highest expressing HCV hepatocytes of each sample to HCV-uninfected hepatocytes. Canonical pathway analysis exposed alterations in transcripts related to cardiac inflammation, renal damage, liver cholestasis and HCC among the most affected genes in HCV-infected hepatocytes. We observed an increased expression of HCC-related genes including TP-53, EGFR, AKT-2, PTEN and HRAS, among others, in HCV-infected hepatocytes, as well as a decreased expression of the tumor suppressor genes MAP2K4, RB1 and BCL11B. Transcripts related to the TP-53 pathway, such as BBC3, CCND1 E2F1 and PPMD1, were particularly up-regulated in cells with highest expression of HCV.

liver damage to test whether immune checkpoint inhibition prior to the onset of tumorigenesis could increase immune surveillance of highly mutated clones, preventing the development of HCC.

Methods: Wild-type male C3H mice were injected with 25 mg/kg of DEN at 2 weeks of age. At 4 weeks of age, the mice were randomized into IgG Control and anti-PD-1 groups. Starting at 6 weeks of age, mice in both groups were given weekly IP injections of 4% CCl4. From 10 weeks of age until 20 weeks, mice were injected with 175 μg isotype control IgG or anti-PD-1 antibody every other week for a total of 6 doses. Blood was collected every 4 weeks for LFT measurements. At 23 weeks of age, all animals were sacrificed for tissue collection and analysis.

Results: Animal weights were not different between groups throughout the duration of the experiment, suggesting limited treatment associated toxicity. AST and ALT were not appreciably different between groups. When treatment was initiated, mice in both groups did not have any tumors, as expected. After 6 treatments, tumor burden was significantly reduced in the anti-PD-1 treated group, with 15% of livers from these animals having < 5 surface tumors, while livers from control animals had an average of 46 surface tumors.

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Conclusion: Our study shows that anti-PD-1 treatment has activity in the DEN + CCl4 mouse model of mutagenesis and chronic liver damage, likely through immune surveillance of pre-malignant clones. Our results bear a striking resemblance to clinical trials of anti-PD-1 therapy in HCC in that the therapeutic efficacy varies from minimal to highly effective.2 This suggests that mutated clones and tumors vary in immunogenicity, depending on the particular neoantigens expressed. Therefore, our results suggest that the value of anti-PD-1 prophylaxis in high-risk cirrhotic patients or in the adjuvant setting must be weighed against the significant toxicities and risks for autoimmunity associated with immune checkpoint inhibition.

References: 1. El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365, 1118–1127 (2011).2. El-Khoueiry, A. B. et al. Nivolumab in patients with advanced hepatocellular carcinoma

(CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 389, 2492–2502 (2017).


P-098 IMMUNOGENOMIC LANDSCAPE OF HEPATOCELLULAR CARCINOMA WITH 11Q13.3 AMPLIFICATION

Anthony W.H. Chan* 1, Zhe Zhang1, Joanna H. Tong1, Stephen L. Chan2, Charing C. Chong3, Nathalie Wong1

1Department of Anatomical and Cellular Pathology, 2Department of Clinical Oncology, 3Department of Surgery, The Chinese University of Hong Kong, Hong Kong, Hong Kong

Introduction: Focal amplification of 11q13.3 is one of recurrent somatic copy number variations (CNVs) in hepatocellular carcinoma (HCC). It harbors clinically actionable oncogenes, CCND1 and FGF19, targeted by CDK4/6 inhibitor and FGFR4 inhibitor, respectively. We recently reported that 11q13.3 amplification is significantly more frequent in lymphoepithelioma-like HCC (LEL-HCC) than conventional HCC (25% vs. 0%) in our local cohort. We aim to further characterize the genomic and immunogenomic landscape of HCC with 11q13.3 amplification by using The Cancer Genome Atlas (TCGA) data.

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11. Wang XS, Wang Y, Guo H, Mendoza TR, Hao XS, Cleeland CS. Chinese version of the M. D. Anderson Symptom Inventory: validation and application of symptom measurement in cancer patients. Cancer. Oct 15 2004;101(8):1890-1901. 

12. Grochowiecki T, Madej K, Galazka Z, et al. Usefulness of Modified Dindo-Clavien Scale to Evaluate the Correlation Between the Severity of Surgical Complications and Complications Related to the Renal and Pancreatic Grafts After Simultaneous Kidney and Pancreas Transplantation. Transplantation proceedings. Jun 2016;48(5):1677-1680. 

13. Coolsen MM, Wong-Lun-Hing EM, van Dam RM, et al. A systematic review of outcomes in patients undergoing liver surgery in an enhanced recovery after surgery pathways. HPB : the official journal of the International Hepato Pancreato Biliary Association. Apr 2013;15(4):245-251. 

14. Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. American journal of surgery. Jun 2002;183(6):630-641. 

15. Luckett T, King MT. Choosing patient-reported outcome measures for cancer clinical research--practical principles and an algorithm to assist non-specialist researchers. European journal of cancer (Oxford, England : 1990). Dec 2010;46(18):3149-3157. 

16. Mercieca-Bebber R, Calvert M, Kyte D, Stockler M, King MT. The administration of patient-reported outcome questionnaires in cancer trials: Interviews with trial coordinators regarding their roles, experiences, challenges and training. Contemporary clinical trials communications. Mar 2018;9:23-32. 

17. Ryu E, Kim K, Cho MS, Kwon IG, Kim HS, Fu MR. Symptom clusters and quality of life in Korean patients with hepatocellular carcinoma. Cancer nursing. Jan-Feb 2010;33(1):3-10. 

18. Shi Q, Wang XS, Vaporciyan AA, Rice DC, Popat KU, Cleeland CS. Patient-Reported Symptom Interference as a Measure of Postsurgery Functional Recovery in Lung Cancer. Journal of pain and symptom management. Dec 2016;52(6):822-831. 

19. Barsevick AM. The concept of symptom cluster. Seminars in oncology nursing. May 2007;23(2):89-98. 

20. Nguyen LT, Alexander K, Yates P. Psychoeducational Intervention for Symptom Management of Fatigue, Pain, and Sleep Disturbance Cluster Among Cancer Patients: A Pilot Quasi-Experimental Study. Journal of pain and symptom management. Jun 2018;55(6):1459-1472 


P-106 PROGNOSTIC IMPACT OF POSTOPERATIVE COMPLICATION AFTER HEPATIC RESECTION IN PATIENTS WITH HEPATOCELLULAR CARCINOMA

Junichi Arita* 1, Takashi Kokudo1, Akihiko Ichida1, Takeaki Ishizawa1, Nobuhisa Akamatsu1, Junichi Kanoko1, Kiyoshi Hasegawa1

1Hepatobiliary-Pancreatic Surgery Division, University of Tokyo, Tokyo, Japan

Introduction: Postoperative complication after resection of various cancers reportedly well correlates with long-term results. This study analyses the prognostic impact of postoperative complication after resection of hepatocellular carcinoma.

Methods: A retrospective cohort study of the patients who underwent initial hepatic resection except liver transplantation between 2002 and 2014 for histological diagnosis of hepatocellular carcinoma was performed.

Results: A total of 716 patients were identified. The mean age was 65.3 years, 566 patients (79.0%) were male, and 168 (23.4%) and 348 (48.6%) patients were positive in HBs-Ag and HCV-Ab, respectively. ICG-R15 was 0-10%, 10-20%, 20-30%, and 30-40% in 253, 294, 108, and 48 patients, respectively. Number of tumors was 1, 2, 3, and 4- in 475, 138, 43, and 60 patients, respectively. The median overall survival time in all 716 patients was 88.1 months and 5-year overall survival rate was 62.7%. The median recurrence-free survival time in all 716 patients was 20.2 months and 5-year recurrence-free survival rate was 27.8%. Postoperative complication rates classified by Clavien-Dindo grade 2, 3, 4, and 5 were 26.1% (187 patients), 9.4% (67 patients, 0.7% (5 patiens), and 0%, respectively. Bile leakage defined by ISGLS was experienced in 12.8% (92 patients), and 119 patients (16.6%) developed collection of ascites of Clavien-Dindo grade 2-4. In Kaplan-Meier methods for overall survival, occurrence of postoperative complication of Clavien-Dindo grade 2 or more was statistically significant (P < 0.001, HR = 1.97 with 95%CI of 1.53 -2.53). Occurrence of postoperative complication of Clavien-Dindo grade 3 or more was also statistically significant on overall survival (P < 0.001, HR =1.91 with 95%CI of 1.35 -2.70). Whereas, occurrence of ascites collection was marginally correlated with overall survival (P = 0.45) and occurrence of bile leakage classified by any ISGLS grade was not correlated with overall survival. Cox proportional hazard model for overall survival demonstrated occurrence of postoperative complication of Clavien-Dindo grade 2 or more (HR 1.95, 95 CI 1.45 - 2.62), as well as portal hypertention, ALICE grade 3, BMI < 23.6, major hepatectomy, 1500 mL or more of estimated blood loss, tumor number 4 or more, maximal tumor size > 2 cm, vascular invasion, and non-well differentiated histology.

Conclusions: Occurrence of postoperative complication after hepatic resection in patients with hepatocellular carcinoma worsens patient long-term results.


P-105 EFFECT OF ENHANCED RECOVERY AFTER SURGERY PROGRAM ON PATIENT-REPORTED OUTCOMES AND FUNCTION RECOVERY IN PATIENTS UNDERGOING LIVER RESECTION FOR HCC

Qiu Ping Ren* 1, Feng Ming Xiao1

1West china hospital of Sichuan University, Chengdu, China

Introduction: Hepatocellular carcinoma (HCC) is a worldwide health problem leading to more than 250,000 deaths annually.Surgical resection is the optimal option for cure . However , HCC patients for receiving liver resection often suffer from various symptoms resulting from both the disease itself and treatments. ERAS is characterized by a series of optimization measures grounded in evidence-based medicine during the perioperative period to attenuate the physical and psychological stress responses and complications, and to potentiate postoperative rehabilitation for patients following a variety of surgical procedures. And the protocol have been shown to reduce morbidity and LOS following liver surgery. However, many of the published studies main focused on outcomes about of using concrete primary end points, including early return of bowel function, lower complication rates, and/or shorter length of inpatient stay. They have not captured crucial outcomes such as symptom burden and functional recovery from a patient’s perspective. (PRO) is “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else”. As patient-reported outcome measures (PROMs) increasingly become key outcome indicators in health care, there is growing interest in patient-reported outcomes (PROs) into Surgical practice for comparative effectiveness research and influence clinical decision making in perioperative period management. Therefore, Our objective was to compare perioperative outcomes with a focus on patient-reported symptom burden and functional recovery before and after implementation of an ERAS program.

Methods: We compared clinical outcomes among a cohort of 275 patient undergoing liver resection before or after implementation of ERAS. The patient-reported outcomes were compared using the MD Anderson Symptom Inventory preoperatively and postoperatively until 14 days after surgery.

Results: The ERAS (enhanced recovery after surgery) patients experienced fewer symptom burden and decreased function recovery time. Patients on ERAS reported less pain (P=.006), fatigue (P=.008), abdominal distension (P=.04), interference with walking (P=.000), and more sleep (P=.03). Those on the ERAS pathway had a significantly shorter median time to return to mild fatigue (5.41 vs 6.87 days, P= .003), mild pain (4.45 vs 6.09 days, P= .001), mild interference with walking (3.85 vs 5.54 days, P=.000), and mild interference with sleeping (5.49 vs 7.43 days, P=.000). There were no significant differences in abdominal distension between the two groups. ERAS patients were more likely to return to functional recovery (5.70 vs 6.79days, P=0.000) status in a shorter time interval. The ERAS pathway, complications and minimally invasive approach were independent predictors of return to functional recovery time.

Conclusions: In HCC liver resection,the primary mechanism of ERAS is to reduce the symptom burden on postoperative interference, and then promote patients return sooner to normal functional .

References: 1. Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma.

Seminars in diagnostic pathology. Mar 2017;34(2):153-159. 2. Jiang JF, Lao YC, Yuan BH, et al. Treatment of hepatocellular carcinoma with portal vein tumor

thrombus: advances and challenges. Oncotarget. May 16 2017;8(20):33911-33921. 3. Ljungqvist O. ERAS--enhanced recovery after surgery: moving evidence-based perioperative care

to practice. JPEN. Journal of parenteral and enteral nutrition. Jul 2014;38(5):559-566. 4. Zhao Y, Qin H, Wu Y, Xiang B. Enhanced recovery after surgery program reduces length of

hospital stay and complications in liver resection: A PRISMA-compliant systematic review and meta-analysis of randomized controlled trials. Medicine. Aug 2017;96(31):e7628. 

5. Melloul E, Hubner M, Scott M, et al. Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations. World journal of surgery. Oct 2016;40(10):2425-2440. 

6. Hughes MJ, McNally S, Wigmore SJ. Enhanced recovery following liver surgery: a systematic review and meta-analysis. HPB : the official journal of the International Hepato Pancreato Biliary Association. Aug 2014;16(8):699-706. 

7. Rouxel P, Beloeil H. Enhanced recovery after hepatectomy: A systematic review. Anaesthesia, critical care & pain medicine. Feb 2019;38(1):29-34. 

8. Powell J, Powell S, Robson A. A systematic review of patient-reported outcome measures in paediatric otolaryngology. The Journal of laryngology and otology. Jan 2018;132(1):2-7. 

9. Bouazza YB, Chiairi I, El Kharbouchi O, et al. Patient-reported outcome measures (PROMs) in the management of lung cancer: A systematic review. Lung cancer (Amsterdam, Netherlands). Nov 2017;113:140-151. 

10. Cottone F, Deliu N, Collins GS, et al. Modeling strategies to improve parameter estimates in prognostic factors analyses with patient-reported outcomes in oncology. Quality of life research: an international journal of quality of life aspects of treatment, care and rehabilitation. Jan 18 2019. 

P-103 SATB2-DEPENDENT CD24 ACTIVATION MAINTAINS SELF-RENEWAL OF HUMAN LIVER CANCER STEM CELLS

Yang Wenjing* 1

1Zhongshan Hospital, affiliated Fudan University, Shanghai, China

Introduction: Liver cancer stem cells (CSCs) have been reported to self-renew and differentiate into heterogeneous tumor cells. However, how these hepatic CSCs were produced and play functions in hepatocellular carcinoma HCC is still unknown.

Methods: SATB2 expression levels in HCC cells and tissues were detected by qPCR and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the oncogenic function of SATB2 in the tumor-initiating cell (TIC)-like phenotype and the tumorigenic capability of liver cancer cells. Chromatin immunoprecipitation (Chip) sequencing and mass spectrometry were performed to determine the potential mechanism of SATB2-mediated HCC stemness.

Results: SATB2 was significantly upregulated in HCC tissues and may be served as an independent biomarker for poor prognosis in HCC patients. SATB2 was required for the self-renewal maintenance of liver CSCs, as SATB2 depletion reduced sphere formation and xenograft tumor growth in mice. Chip-sequencing revealed that SATB2 upregulated several stem cell markers, including CD24, CD44, CD133, OCT4, NANOG, c-MYC and KLF4, among which, CD24 was the most significantly upregulated. We determined that SATB2 acts upstream of the CD24 and that SATB2 recruits the nuclear remodeling factor (NURF) complex to the CD24 promoter, thereby initiating CD24 activation.

Conclusions: Levels of SATB2, CD24 and NURF complex can be detected and served as a predictor for diagnosis and prognosis of HCC patients. These factors may be potential therapeutic targets for eliminating liver CSCs.


P-104 DELETION OF MCC PROMOTES THE PROGRESSION OF PRIMARY LIVER CANCER IN MICE

Jinbiao Chen1, Fan Zhang2, Yang Zhao3, Jade Boland1, Jia Li3, Ngan C. Cheng1, Ken Liu1, Mathew A. Vadas3, Emad EI-Omar2, Jennifer R. Gamble3, Neil Watkins4, Maija Kohonen-Corish2, Geoffrey W. McCaughan* 1

1Liver Injury and Cancer Program, Centenary Institute, Camperdown, 2Microbiome Research Centre (MRC), St George Hospital, UNSW, Sydney, 3Vascular Biology Program, Centenary Institute, Camperdown, 4Garvan Institute of Medical Research, Sydney, Australia

Introduction: The mutated in colorectal cancer (MCC) is a multifunctional gene and its loss of expression is often observed in colorectal and liver cancers. MCC has been reported to play important roles in NF-kB and beta-catenin pathways. Its roles in the development of primary liver cancer is unknown. To this end, the diethylnitrosamine (DEN)-induced liver cancer mouse model, which represents HCC with poor prognosis, was employed to examine effects of hepatocyte-specific MCC deletion in the development of primary liver cancer in mice.

Methods: Hepatocyte-specific MCC knockout (KO) mice were made by crossing Albumin-Cre mice with MCC floxed mice. DEN was given (25mg/kg body weight, i.p.) to wild type and homozygous littermates at postnatal day 14. Samples were harvested at week 19 and 34 post-DEN injection. Histopathology and genome-wide RNA-seq analysis were performed. Student t-test, ANOVA or Mann-Whitney test was used to test the significance of the difference.

Results: Hepatocyte-specific MCC deletion resulted in an increased size of DEN-induced liver cancers compared to wild type in mice, but the number of tumours was not altered, implying a role in liver tumour progression rather than initiation. RNA-seq and immunohistochemical staining results show NF-kB and beta-catenin signalling pathways were only slightly activated. Consistent with results previously reported on colorectal cancers, RNA-seq data showed up-regulation of inflammatory genes such as CCL2 and IL-1b, mainly in DEN-treated non-tumour liver tissues. Interestingly, MCC deletion increased hepatic steatosis in the non-tumour and tumour area compared with wild type. MCC KO tumors, but not non-tumors, had dramatically increased expression of pnpla3 and pnpla5 genes.

Conclusions: MCC deficiency seems to promote liver cancer progression in the mouse. Loss of MCC function might promote tumor progression through several important pathways, e.g. effects on pro-inflammatory tumor microenvironment and on tumor lipid metabolisms, e.g. via pnpla3. It will be very interesting to further check whether pnpla3 mediates effects of MCC on liver cancer progression as PNPLA3 rs738409 C > G polymorphism has been widely confirmed to be associated with an increased risk of human HCC.


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Conclusions: Increasing evidence supports that, in cancer, lipogenesis is overacting to support the tumor growth (Unger et al., 2010), because lipids are required as fuel, building blocks for new cellular membranes, and some lipid intermediaries are essential for post-translational modifications in key proteins such as Ras or heterotrimeric G proteins (Calvisi, Ladu, et al., 2011). Among the proteins correlated with a poorer outcome are c-MET and Nrf1, suggesting that cholesterol could be positioned as a key element in HCC progression. Dietary lipids play a significant role, because they provide the ultimate resources for growth and survival.

References: 1. Dominguez-Perez, M., Simoni-Nieves, A., Rosales, P., Nuno-Lambarri, N., Rosas-Lemus,

M., Souza, V., Gutierrez-Ruiz, M. C. (2018). Cholesterol burden in the liver induces mitochondrial dynamic changes and resistance to apoptosis. J Cell Physiol. doi:10.1002/jcp.27474

2. Unger, R. H., Clark, G. O., Scherer, P. E., & Orci, L. (2010). Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochim Biophys Acta, 1801(3), 209-214. doi:10.1016/j.bbalip.2009.10.006

3. Calvisi, D. F., Ladu, S., Conner, E. A., Seo, D., Hsieh, J. T., Factor, V. M., & Thorgeirsson, S. S. (2011). Inactivation of Ras GTPase-activating proteins promotes unrestrained activity of wild-type Ras in human liver cancer. J Hepatol, 54(2), 311-319. doi:10.1016/j.jhep.2010.06.036

Disclosure of Interest: A. Simoni-Nieves Conflict with: Research/Education grant - Fronteras de la Ciencia-1320, S. Salas-Silva Conflict with: Research/Education grant - Fronteras de la Ciencia-1320, A. Escobedo-Calvario Conflict with: Research/Education grant - Fronteras de la Ciencia-1320, Y. Ortiz-Pedraza Conflict with: Research/Education grant - Fronteras de la Ciencia-1320, M. Gutierrez-Ruiz Conflict with: Research/Education grant - Fronteras de la Ciencia-1320, J. Marquardt Conflict with: Research/Education grant - Fronteras de la Ciencia-1320, L. Gomez-Quiroz Conflict with: Research/Education grant - Fronteras de la Ciencia-1320

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(IQR 16.9-27.1) and median OS was not calculated owing to insufficient follow-up and number of events. Eighteen (42.9%) patients presented 27 AEs, of which 19 were grade I-II; 7 were grade III-IV AEs and 1 a grade V AE. Six out of 7 grade III-IV AEs were considered to be immune-related. Corticosteroids were required for the management of 4 AEs and treatment delays were required in the management of 4 AEs.

Conclusions: The safety profile in this real-life cohort is similar to that reported in clinical trials despite the inclusion of patients in 2L and 3L. The heterogeneity in the patterns of progression before nivolumab and the fact that some patients started nivolumab due to intolerance to sorafenib/regorafenib without presenting radiologic progression highlights the need to consider these confounding factors when evaluating the OS data. The occurrence of grade III-IV immune-AEs leading to treatment delay stresses the importance of early recognition and appropriate management.

References: 1. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet.2017;389:2492–2502.

Disclosure of Interest: L. Da Fonseca Conflict with: Honoraria - Bayer, Ipsen, B. Mínguez Conflict with: Research/Education grant - Proyecto de investigación en Salud AES 2018 (PI18/00961) Instituto de Salud Carlos III. Ministerio de Ciencia Innovación y Universidades, Conflict with: Honoraria - Bayer, Gilead, V. Sapena Conflict with: Research/Education grant - Bayer, C. Perelló: None Declared, M. De La Torre Conflict with: Honoraria - Bayer, L. Márquez Conflict with: Honoraria - Bayer, Gilead, Abbvie, A. Guerrero-Garcia: None Declared, M. Torner Simó: None Declared, M. Pons: None Declared, J. L. Calleja Conflict with: Honoraria - Gilead science, Abbvie, MSD, B. Sangro Conflict with: Honoraria - Terumo, Conflict with: Advisory Board - Adapt immune, Astra-Zeneca, Bayer, BMS, BTG, Eisai, Eli Lilly, Ipsen, Onxeo, Roche, Sirtex, Conflict with: Consulting - Novartis, Sirtex, Astra-Zeneca, Bayer, BMS , A. Matilla Conflict with: Honoraria - Bayer, J. L. Lledó Conflict with: Honoraria - Bayer, M. Varela Conflict with: Honoraria - Bayer, IPSEN, Sirtex, BMS, BTG, J. Rimola Conflict with: Honoraria - Bayer, J. Bruix Conflict with: Research/Education grant - Bayer and BTG, Conflict with: Honoraria - Bayer, BTG- Biocompatibles, Eisai, Terumo, Sirtex, Ipsen, Conflict with: Consulting - Arqule, Bayer, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, Merck, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, M. Reig Conflict with: Research/Education grant - Bayer, Conflict with: Honoraria - Bayer, BMS, Gilead, and Lilly, Conflict with: Consulting - Bayer, BMS, Roche, Ipsen, AstraZeneca and Lilly

P-109 COMPARISON OF THE EFFICACY AND SAFETY OF CONVENTIONAL TRANSARTERIAL CHEMOEMBOLIZATION COMBINED WITH AND WITHOUT CALLISPHERES DRUG-ELUTING BEADS EMBOLIZATION FOR THE TREATMENT OF UNRESECTABLE LARGE HEPATOCELLULAR CARCINOMA

Shiguang Chen* 1

1Interventional Oncology, Fujian Cancer Hospital, Fuzhou, China

Introduction: Hepatocellular carcinoma (HCC) is among the 5 most common cancers worldwide with poor prognosis.[1] Most HCC tumors, especially in China, are large (>5 cm) due to the lack of early detection of screening and awareness programs [2]. Tumor size is a predictor of tumor staging and needs to be considered in patient management and understanding of the patient’s prognosis [3]. Transarterial chemoembolization (TACE) remains the treatment of choice in the management of patients with surgically unresectable large HCC [4, 5]. Drug-eluting beads transarterial chemoembolization (DEB-TACE) is a new drug delivery and embolization system developed in recent years, which can not only load chemotherapeutics and release them slowly in local lesions but can also embolize the tumor-feeding arteries permanently [6-8]. However, for the comparison of DEB-TACE and conventional TACE (cTACE), only limited studies were conducted in a randomized, prospective manner [9-12], and none of them indicated a significant improvement in the hard endpoint.The present study aimed to evaluate the efficacy and safety of DEB-TACE combined with cTACE in the treatment of Chinese patients with unresectable large (main tumor ≥5 cm in diameter) HCC compared to cTACE.

Methods: We reviewed 190 consecutive patients with unresectable large HCC who underwent TACE as the initial treatment in our institution, with either cTACE or DEB-TACE combined cTACE, between May 2017 and September 2018. Of these, 132 patients underwent cTACE treatments by embolization with an emulsion of lipiodol and epirubicin, and following with gelatin sponge particles (GSP), 58 patients underwent DEB-TACE combined with cTACE treatments by embolization with CalliSpheres Beads loaded with epirubicin, and following with lipiodol and GSP. Both groups were compared considering the clinical and laboratory outcomes and imaging findings before and 1 month after TACE. Tumor response time to progression (TTP) and adverse events were also evaluated.

Results: The overall response rate was higher in the DEB-TACE combined with cTACE group than in the cTACE group at 1 month after treatment (70.7% vs 50.8%, P=0.008). The median TTP in the DEB-TACE combined with cTACE group were longer than those of the cTACE group (TTP: 6.9 months vs 4.8months, P = 0.030). The most-common AEs were hematologic toxicity, liver dysfunction, and post-embolization syndrome (including abdominal pain, fever, nausea, and vomiting), in the two groups, however, there was no significant difference between the two groups.

[32] Zhang N, Ma D, Wang L, Zhu X, Pan Q, Zhao Y, et al. Insufficient Radiofrequency Ablation Treated Hepatocellular Carcinoma Cells Promote Metastasis by Up-Regulation ITGB3. J Cancer. 2017;8: 3742-3754.

[33] Yu J, Ren X, Chen Y, Liu P, Wei X, Li H, et al. Dysfunctional activation of neurotensin/IL-8 pathway in hepatocellular carcinoma is associated with increased inflammatory response in microenvironment, more epithelial mesenchymal transition in cancer and worse prognosis in patients. PLoS One. 2013,8(2): e56069. https://doi.org/10.1371/journal.pone.0056069.

[34] Yang K, Guan SH, Zhang H, Pan Y, Wu YY, Wang AH, et al. Enhanced levels of interleukin-8 are associated with hepatitis B virus infection and resistance to interferon-alpha therapy. Int J Mol Sci. 2014;15: 21286-21298. https://doi.org/10.3390/ijms151121286.

[35] Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013,57:1448-1457. https://doi.org/10.1002/hep.26153.

[36] Schueller G, Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Benkoe T, et al. Hyperthermia improves cellular immune response to human hepatocellular carcinoma subsequent to co-culture with tumor lysate pulsed dendritic cells. Int J Oncol. 2003,22:1397-1402. https://doi.org/10.3892/ijo.22.6.1397.

[37] Shen S, Peng H, Wang Y, Xu M, Lin M, Xie X, et al. Screening for immune-potentiating antigens from hepatocellular carcinoma patients after radiofrequency ablation by serum proteomic analysis. BMC Cancer. 2018,18(1):117. https://doi.org/10.1186/s12885-018-4011-8.

[38] Chen L, He Z, Qin L, Li Q, Shi X, Zhao S, et al. Antitumor effect of malaria parasite infection in a murine Lewis lung cancer model through induction of innate and adaptive immunity. PLoS One. 2011,6: e24407. https://doi.org/10.1371/journal.pone.0024407.

[39] Liu Q, Yang YJ, Tan XF, Tao Z, Adah D, Yu SL, et al. Plasmodium parasite as an effective hepatocellular carcinoma antigen glypican-3 delivery vector. Oncotarget. 2017,8: 24785–24796. https://doi.org/10.18632/oncotarget.15806.


P-108 SAFETY AND OUTCOME OF HEPATOCELULLUAR CARCINOMA PATIENTS TREATED WITH NIVOLUMAB IN REAL LIFE OF HEPATO-ONCOLOGY UNITS

Leonardo G. Da Fonseca* 1, Beatriz Mínguez2, Victor Sapena1, Christie Perelló3, Manuel De La Torre4, Laura Márquez5, Antonio Guerrero-Garcia6, Maria Torner Simó7, Monica Pons2, José Luis Calleja3, Bruno Sangro8, Ana Matilla9, José Luis Lledó6, Maria Varela7, Jordi Rimola10, Jordi Bruix1, Maria Reig1

1Barcelona Clínic Liver Cancer (BCLC) Group. Liver Unit, Hospital Clínic of Barcelona. IDIBAPS. CIBERehd, 2Servicio de MI-Hepatología, Hospital Universitario Vall d'Hebron. Vall d'Hebron Institut of Research (VHIR). CIBERehd. Universidad Autónoma de Barcelona, Barcelona, 3Servicio de Digestivo. Unidad de Hepatología, Hospital Universitario Puerta de Hierro. IDIPHISA. CIBERehd, 4Liver Unit, Clinica Universidad de Navarra, 5Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, 6Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal. CIBERehd, Madrid, 7Sección de Hepatología. Servicio de Digestivo., Hospital Universitario Central de Asturias. IUOPA. FINBA, Oviedo, 8Liver Unit, Clinica Universidad de Navarra-IDISNA, CIBERehd, Pamplona, 9Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón. CIBERehd, Madrid, 10Barcelona Clinic Liver Cancer (BCLC) Group, Servicio de Radiodiagnostico, Hospital Clınic of Barcelona, Barcelona, Spain

Introduction: Nivolumab was granted accelerated approval by FDA for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib based on the results of the phase I/II trial Checkmate 040 (1). Yet, phase III data are awaited. We aim to describe the safety and outcome profile of nivolumab in HCC patients outside clinical trials.

Methods: This is a retrospective, observational, multicenter cohort involving 10 institutions with multidisciplinary teams focused on HCC management. Clinical and laboratorial data, previous treatments, adverse events (AE) and overall survival (OS) were recorded.

Results: A total of 118 patients received nivolumab: 76 in clinical trials and 42 outside clinical trials. The median age was 62 years (interquartile interval: 57-71) and 75.8% were male. The most common etiologies were hepatitis C in 57.1% and hepatitis B in 11.9%. 54.6% patients had received locoregional treatment previously. The bi-weekly dose of 240mg was used in 72.7% of the patients. At the last follow-up assessment 25 patients were alive, 24 patients were still on nivolumab, 1 had discontinued it, and 17 had died. The reasons for nivolumab discontinuation were AE in 1, and disease progression in 17 patients. Nivolumab was the first (1L), second (2L) and third-line (3L) treatment in 7 (16.7%), 20 (47.6%) and 15 (35.7%) patients, respectively. Sorafenib was the 1L in 100% of the patients who received nivolumab as 2L or 3L and regorafenib was the 2L in 86.7% of the patients who received nivolumab as 3L. Regarding the 20 patients treated with nivolumab as 2L (50% Child-Pugh A; 40% Child-Pugh B and 100% PS0-1), 10 discontinued the 1L due to AE without radiologic progression and the remaining presented BCLCp-B 20%, BCLCp-C1 50% and BCLCp-C2 30%. In this nivolumab-2L cohort, median follow-up and median OS since the start of 1L was 13.5 months (IQR 8.5-26.2) and 28.8 months (95%CI 9.4-not estimable) respectively. All, except 1 of the 15 patients treated with nivolumab in the 3L (71.4% Child-Pugh A, 71.4% PS0 and 28.6% PS1) received nivolumab due to radiologic progression (BCLCp-B, C1 and C2: 7.1; 35.7 and 57.2%). In this nivolumab-3L cohort, median follow-up since 1L start was 21.8 months

[5] Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology. 2013;57: 1448-1457. https://doi.org/10.1002/hep.26153.

[6] Qiao G, Chen M, Bucsek MJ, Repasky EA, Hylander BL. Adrenergic Signaling: A Targetable Checkpoint Limiting Development of the Antitumor Immune Response. Front Immunol. 2018;9: 164. https://doi.org/10.3389/fimmu.2018.00164.

[7] Pacák K, Baffi JS, Kvetnanský R, Goldstein DS, Palkovits M. Stressor-Specific Activation of Catecholaminergic Systems: Implications for Stress-Related Hypothalamic-Pituitary-Adrenocortical Responses. Advances in Pharmacology. 1998;42: 561-564. https://doi.org/10.1016/S1054-3589(08)60812-1.

[8] Dhabhar FS MB. Acute stress enhances while chronic stress suppresses cell-mediated immunity in vivo_ a potential role for leukocyte trafficking. Brain Behav Immun. 1997;11: 286-306. https://doi.org/10.1006/brbi.1997.0508.

[9] Dhabhar FS MB. Stress-induced enhancement of antigen-specific cell-mediated immunity. J Immunol. 1996;156: 2608-2615.

[10] Dhabhar FS MB. Enhancing versus suppressive effects of stress hormones on skin immune function. Proc Natl Acad Sci U S A. 1999;96: 1059-1064. https://doi.org/10.1073/pnas.96.3.1059.

[11] Dhabhar FS. Effects of stress on immune function: the good, the bad, and the beautiful. Immunol Res. 2014;58: 193-210. https://doi.org/10.1007/s12026-014-8517-0.

[12] Ader R, Felten D, Cohen N. Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol. 1990;30: 561-602. https://doi.org/10.1146/annurev.pa.30.040190.003021.

[13] Pruett SB. Stress and the immune system. Pathophysiology. 2003;9: 133-153. https://doi.org/10.1016/S0928-4680(03)00003-8.

[14] Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011;31: 986-1000. https://doi.org/10.1161/ATVBAHA.110.207449.

[15] Morris TJ, Butcher LM, Feber A, Teschendorff AE, Chakravarthy AR, Wojdacz TK, et al. ChAMP: 450k Chip Analysis Methylation Pipeline. Bioinformatics. 2014;30: 428-430. https://doi.org/10.1093/bioinformatics/btt684.

[16] Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Research. 2015;43: e47. https://doi.org/10.1093/nar/gkv007.

[17] Aryee MJ, Jaffe AE, Corrada-Bravo H, Ladd-Acosta C, Feinberg AP, Hansen KD, et al. Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. Bioinformatics. 2014;30: 1363-1369. https://doi.org/10.1093/bioinformatics/btu049.

[18] Maksimovic J, Phipson B, Oshlack A. A cross-package Bioconductor workflow for analysing methylation array data. F1000Res. 2016;5: 1281. https://doi.org/10.12688/f1000research.8839.1.

[19] Leek JT, Johnson WE, Parker HS, Fertig EJ, Jaffe AE, Storey JD, et al. sva_ Surrogate Variable Analysis2019. R package version 3.30.31.

[20] R. K. pheatmap: Pretty Heatmaps.2015.[21] JC. O. Venny. An interactive tool for comparing lists with Venn's diagrams. 2007-2015: http://

bioinfogp.cnb.csic.es/tools/venny/index.html.[22] Jensen KJ, Alpini G, Glaser S. Hepatic nervous system and neurobiology of the liver. Compr

Physiol. 2013;3: 655-665. https://doi.org/10.1002/cphy.c120018.[23] McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med. 1998;338:

171-179.[24] Zhang Y, Petropoulos S, Liu J, Cheishvili D, Zhou R, Dymov S, et al. The signature of liver cancer

in immune cells DNA methylation. Clin Epigenetics. 2018;10: 8. https://doi.org/10.1186/s13148-017-0436-1.

[25] Dong S, Kong J, Kong F, Kong J, Gao J, Ke S, et al. Insufficient radiofrequency ablation promotes epithelial-mesenchymal transition of hepatocellular carcinoma cells through Akt and ERK signaling pathways. J Transl Med. 2013;11: 273. https://doi.org/10.1186/1479-5876-11-273.

[26] Ader R. Chapter 8 Conditioned immune responses: adrenocortical influences. Progress in Brain Research, 1987, 72(1):79-90. https://doi.org/10.1016/S0079-6123(08)60198-3.

[27] Qiu ZX, Sun RF, Mo XM, Li WM. The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth. PLoS One. 2016;11: e0147185. https://doi.org/10.1371/journal.pone.0147185.

[28] Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res. 2004;10: 8421-8425. https://doi.org/10.1158/1078-0432.CCR-04-0941.

[29] Khajah MA, Mathew PM, Luqmani YA. Inhibitors of PI3K/ERK1/2/p38 MAPK Show Preferential Activity Against Endocrine-Resistant Breast Cancer Cells. Oncol Res. 2017;25: 1283-1295. https://doi.org/10.3727/096504017X14883245308282.

[30] Koul HK, Pal M, Koul S. Role of p38 MAP Kinase Signal Transduction in Solid Tumors. Genes Cancer. 2013;4: 342-359. https://doi.org/10.1177/1947601913507951.

[31] Yuan CW, Wang ZC, Liu K, Liu DJ. Incomplete radiofrequency ablation promotes the development of CD133(+) cancer stem cells in hepatocellular carcinoma cell line HepG2 via inducing SOX9 expression. Hepatobiliary Pancreat Dis Int. 2018;17: 416-422. https://doi.org/10.1016/j.hbpd.2018.09.012.

P-107 THE INTERACTION OF STRESS AND IMMUNITY AFTER THERMAL ABLATION FOR HEPATOCELLULAR CARCINOMA

Yanan Zhao* 1, Kang Li1, Jianping Sun1, Peng Zhao1, Ning He1, Chaoran Zang1, Xiaozhen Yang1, Caixia Hu1, Jiang Long1, Honghai Zhang1, Qi Wang1, Yan Zhao1, Yonghong Zhang1

1Beijing Youan Hospital, Capital Medical University, Beijing, China

Introduction: The effect of stress to neuroendocrine system and immunity system response in hepatocellular carcinoma (HCC) patients under thermal ablation treatment are unclear. We used DNA methylation to investigate the effect of stress to neuroendocrine system and immune system for HCC patients after thermal ablation.

Methods: Five patients were recruited in the study, and their peripheral blood mononuclear cells (PBMCs) were collected at three time points, including before thermal ablation (PR), 1 to 3 days of post-ablation (P1), 6 to 8 days of post-ablation (P7). Illumina 850K methylation microarray was employed to figure out the DNA methylation profile of the three time points. Data were analyzed for different methylation probes with paired t test and Pearson correction test, and the differentially expressed genes related pathway analysis was performed using Ingenuity Pathway Analysis (IPA).

Results: Differential methylation analysis indicated 25722 CGs sites displayed significant difference among PR, P1 and P7 groups(Fig1a,1b). The scope of analysis was then narrowed to the CGs on promoter and proceeded to signaling pathway analysis. The related signaling pathways including adrenomedullin signaling pathway, Th1 and Th2 activation pathway, antigen presentation pathway, CTLA4 signaling in cytotoxic T lymphocytes, iCOS-iCOS L signaling in T helper cells, CD28 signaling in T helper cells, T cell receptor signaling(Fig1c,1d,1e).

Image:

Conclusion: Current analysis reveals that: (1) The adrenomedullin signaling pathway is the major neuroendocrine pathway after ablation; (2) Thermal ablation in HCC patients can activate multiple immune signaling pathways;(3) Antigen-specific T cells immune response were activated after thermal ablation;(4) Incomplete ablation patients may have a different DNA methylation profile in contrast to complete ablation patients.

References: [1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:

GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68: 394-424. https://doi.org/10.3322/caac.21492.

[2] Hocquelet A, Balageas P, Laurent C, Blanc JF, Frulio N, Salut C, et al. Radiofrequency ablation versus surgical resection for hepatocellular carcinoma within the Milan criteria: A study of 281 Western patients. Int J Hyperthermia. 2015;31: 749-757. https://doi.org/10.3109/02656736.2015.1068382.

[3] Napoletano C, Taurino F, Biffoni M, De Majo A, Coscarella G, Bellati F, et al. RFA strongly modulates the immune system and anti-tumor immune responses in metastatic liver patients. Int J Oncol. 2008;32: 481-490. https://doi.org/10.3892/ijo.32.2.481.

[4] Jondal DE, Thompson SM, Butters KA, Knudsen BE, Anderson JL, Carter RE, et al. Heat Stress and Hepatic Laser Thermal Ablation Induce Hepatocellular Carcinoma Growth: Role of PI3K/mTOR/AKT Signaling. Radiology. 2018;288: 730-738. https://doi.org/10.1148/radiol.2018172944.

Posters Posters


Image:

Conclusion: CLCVP safety and efficacy were demonstrated in complex LH for the first time by our randomized clinical trial, and this technique could potentially be applied routinely in LH.

References: 1. Zhu, P. et al. Randomized clinical trial comparing infrahepatic inferior vena cava clamping

with low central venous pressure in complex liver resections involving the Pringle manoeuvre. Br. J. Surg. 99, 781–788 (2012).

2. Jarnagin, W. R. et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Ann. Surg. 236, 397 (2002).

3. Smyrniotis, V., Farantos, C., Kostopanagiotou, G. & Arkadopoulos, N. Vascular control during hepatectomy: review of methods and results. World J. Surg. 29, 1384–1396 (2005).

4. Man, K. et al. Prospective evaluation of Pringle maneuver in hepatectomy for liver tumors by a randomized study. Ann. Surg. 226, 703–704 (1997).

5. Lin, C.-X. et al. Optimal central venous pressure during partial hepatectomy for hepatocellular carcinoma. Hepatobiliary Pancreat. Dis. Int 12, 520–524 (2013).

6. Yin, Z., Fan, X., Ye, H., Yin, D. & Wang, J. Short- and long-term outcomes after laparoscopic and open hepatectomy for hepatocellular carcinoma: a global systematic review and meta-analysis. Ann. Surg. Oncol. 20, 1203–1215 (2013).

7. Aldrighetti, L. et al. Italian experience in minimally invasive liver surgery: a national survey. Updates Surg. 67, 129–140 (2015).

8. Kim, S. H. et al. Peripheral venous pressure as an alternative to central venous pressure in patients undergoing laparoscopic colorectal surgery. Br. J. Anaesth. 106, 305–311 (2011).

9. Pulitano, C. et al. Laparoscopic liver resection without portal clamping: a prospective evaluation. Surg. Endosc. 22, 2196–2200 (2008).

10. Pulitano, C. & Aldrighetti, L. The current role of laparoscopic liver resection for the treatment of liver tumors. Nat. Clin. Pract. Gastroenterol. Hepatol. 5, 648–654 (2008).

11. Smyrniotis, V., Kostopanagiotou, G., Theodoraki, K., Tsantoulas, D. & Contis, J. C. The role of central venous pressure and type of vascular control in blood loss during major liver resections. Am. J. Surg. 187, 398–402 (2004).

12. Ratti, F. et al. Intraoperative monitoring of stroke volume variation versus central venous pressure in laparoscopic liver surgery: a randomized prospective comparative trial. HPB (Oxford). 18, 136–144 (2016).

13. Strasberg, S. M. Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system. J. Hepatobiliary. Pancreat. Surg. 12, 351–355 (2005).

14. Rahbari, N. N. et al. IVC CLAMP: infrahepatic inferior vena cava clamping during hepatectomy-- a randomised controlled trial in an interdisciplinary setting. Trials 10, 94 (2009).

15. Van Dam, R. M. et al. Initial experience with a multimodal enhanced recovery programme in patients undergoing liver resection. Br. J. Surg. 95, 969–975 (2008).

16. Dindo, D., Demartines, N. & Clavien, P.-A. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann. Surg. 240, 205–213 (2004).

17. Malik, N. et al. Air embolism : diagnosis and management. 13, 365–378 (2017).18. Park, E. Y., Kwon, J.-Y. & Kim, K. J. Carbon dioxide embolism during laparoscopic surgery.

Yonsei Med. J. 53, 459–466 (2012).19. Furrer, K., Deoliveira, M. L., Graf, R. & Clavien, P.-A. Improving outcome in patients undergoing

liver surgery. Liver Int. 27, 26–39 (2007).20. Ryckx, A. et al. Central Venous Pressure Drop After Hypovolemic Phlebotomy is a Strong

Independent Predictor of Intraoperative Blood Loss During Liver Resection. Ann. Surg. Oncol. 24, 1367–1375 (2017).

Eastern Cooperative Oncology Group performance status of 0; Child-Pugh class A liver score. Patients with past or ongoing hepatitis C virus infection or with controlled hepatitis B virus infection are eligible if they meet certain criteria. Approximately 950 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks. Treatment will continue for 1 year (approximately 17 cycles) or until documented disease recurrence, unacceptable toxicity, or investigator/patient decision to withdraw, whichever occurs first. Patients will be stratified by geographic region, prior local therapy (resection vs ablation), risk for recurrence, and alpha fetoprotein at initial diagnosis before resection/ablation (<200 ng/mL vs ≥200 ng/mL). Dual primary end points are recurrence-free survival (RFS) and overall survival. Secondary end points are safety and tolerability and patient-reported outcomes (time to deterioration and change from baseline in global quality-of-life score [EORTC QLQ-C30 and EORTC QLQ-HCC18] and characterization of health utilities [EQ-5D-5L]). Exploratory end points include distant metastases-free survival (DMFS), time to recurrence (TTR), and biomarkers of clinical response/resistance. RFS, DMFS, and TTR will be assessed radiographically by the investigator and/or by subsequent biopsy and verified by blinded independent central review. Imaging will be performed every 12 weeks on study and at treatment discontinuation. Adverse events (AEs) will be monitored throughout the study and for up to 30 days after last dose (90 days for serious AEs) and graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

References: [1] Chan ACY et al. Liver Transpl. 2013;19:411-419.[2] Crissien AM, Frenette C. Gastroenterol Hepatol. 2014;10:153-161.

Disclosure of Interest: L. Da Fonseca Conflict with: Honoraria - Bayer, Ipsen, B. Mínguez Conflict with: Research/Education grant - Proyecto de investigación en Salud AES 2018 (PI18/00961) Instituto de Salud Carlos III. Ministerio de Ciencia Innovación y Universidades, Conflict with: Honoraria - Bayer, Gilead, V. Sapena Conflict with: Research/Education grant - Bayer, C. Perelló: None Declared, M. De La Torre Conflict with: Honoraria - Bayer, L. Márquez Conflict with: Honoraria - Bayer, Gilead, Abbvie, A. Guerrero-Garcia: None Declared, M. Torner Simó: None Declared, M. Pons: None Declared, J. L. Calleja Conflict with: Honoraria - Gilead science, Abbvie, MSD, B. Sangro Conflict with: Honoraria - Terumo, Conflict with: Advisory Board - Adapt immune, Astra-Zeneca, Bayer, BMS, BTG, Eisai, Eli Lilly, Ipsen, Onxeo, Roche, Sirtex, Conflict with: Consulting - Novartis, Sirtex, Astra-Zeneca, Bayer, BMS , A. Matilla Conflict with: Honoraria - Bayer, J. L. Lledó Conflict with: Honoraria - Bayer, M. Varela Conflict with: Honoraria - Bayer, IPSEN, Sirtex, BMS, BTG, J. Rimola Conflict with: Honoraria - Bayer, J. Bruix Conflict with: Research/Education grant - Bayer and BTG, Conflict with: Honoraria - Bayer, BTG- Biocompatibles, Eisai, Terumo, Sirtex, Ipsen, Conflict with: Consulting - Arqule, Bayer, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, Merck, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, M. Reig Conflict with: Research/Education grant - Bayer, Conflict with: Honoraria - Bayer, BMS, Gilead, and Lilly, Conflict with: Consulting - Bayer, BMS, Roche, Ipsen, AstraZeneca and Lilly

P-112 ADVANTAGES OF CONTROLLED LOW CENTRAL VENOUS PRESSURE IN LAPAROSCOPIC HEPATECTOMY FOR HEPATOCELLULAR CARCINOMA - A RANDOMIZED CLINICAL TRIAL

Yangxun Pan* 1, Juncheng Wang2, Xiaoyun Lu3, Jinbin Chen1, Wei He2, Jiancong Chen1, Xiaohui Wang1, Yizhen Fu1, Li Xu1, Yaojun Zhang1, Minshan Chen2, Renchun Lai4, Zhonggo Zhou1

1Hepatobiliary pancreatic surgery, Sun Yan-sen University Cancer Center, 2Hepatobiliary pancreatic surgery, Sun Yat-sen University Cancer Center, 3 Anesthesiology, 4Anesthesiology, Sun Yan-sen University Cancer Center, Guangdong, China

Introduction: Excessive intraoperative hemorrhage is a critical factor of poor prognoses after liver resection, especially for laparoscopic hepatectomy (LH) in hepatocellular carcinoma, because of the high technical requirements. Moreover, low central venous pressure (CVP) during parenchymal transection is accepted to reduce intraoperative hemorrhage in open procedures. However, the role of controlled low central venous pressure (CLCVP) in LH is unclear. We hypothesized that CLCVP with vasoactive drugs may effectively reduce intraoperative blood loss during laparoscopy.

Methods: Patients scheduled for elective LH were enrolled and allocated randomly to groups undergoing CVP reduction by anesthesiological interventions, including nitro compounds and opioids, or a control group. The primary efficacy endpoint was total intraoperative blood loss. Analyses were performed following the intention-to-treat principle. The protocol was submitted to the clinicaltrials.gov registry (NCT03422913).

Results: Between January 2017 and October 2018, 146 patients were randomized and eligible for inclusion in the final analyses. Baseline data were similar between the study groups. Compared with patients in the control group, those in the CLCVP group had a significantly lower CVP during resection (4.83±3.41 cm H2O vs. 9.26±3.38 cm H2O; P<0.001) and significantly reduced total intraoperative blood loss (188.00±162.00 mL vs. 346.00±336.00 mL; P<0.001). Notably, pneumoperitoneum and body position were identified as factors impacting CVP under laparoscopy (P<0.001 and P<0.05, respectively). Perioperative adverse events were comparable in both study groups (P=0.313).

Methods: Eligible studies were searched by PubMed, MedLine, Embase, the Cochrane Library, Web of Knowledge, from Jan.1st 2000 to Dec. 31st 2018, comparing the overall survival (OS) rates and disease-free survival (DFS) rates between postoperative adjuvant TACE and operation only for HCC patient with MVI. Hazard ratio (HR) with 95% confidence interval (CI) was used to determine the effect size.

Results: Eight studies were enrolled in this meta-analysis, including 774 patients in the postoperative adjuvant TACE group and 856 patients in the operation only group. The pooled HR for the OS/DFS rates of the postoperative adjuvant TACE group were better than the operation only group (HR 0.57, 95%CI 0.48~0.68, P<0.00001; HR 0.66, 95%CI 0.58~0.74, P<0.00001; respectively). However, in the subgroup analysis stratified by proportion of multiple nodules, no significant differences were observed in the pooled HR for the OS/DFS rates between the postoperative adjuvant TACE group and the operation only group (HR 0.83, 95%CI 0.60~1.13, P=0.23; HR 0.76, 95%CI 0.41~1.40, P=0.37; respectively).

Conclusions: Postoperative adjuvant TACE will benefit patients with HCC and MVI, but not for multiple HCC with MVI.

References: [1] Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates

of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.

[2] Forner A, Reig M, Bruix J. Hepatocellular carcinoma. LANCET 2018;391:1301-1314.[3] EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J HEPATOL

2018;69:182-236.[4] Rd BA, D'Angelica MI, Abbott DE, et al. NCCN Guidelines Insights: Hepatobiliary Cancers,

Version 1.2017. Journal of the National Comprehensive Cancer Network Jnccn 2017;15:563.[5] Forner A, Reig M, Bruix J. Hepatocellular carcinoma. LANCET 2018;391:1301-1314. [6] Rodriguez-Peralvarez M, Luong TV, Andreana L, et al. A systematic review of microvascular

invasion in hepatocellular carcinoma: Diagnostic and prognostic variability. ANN SURG ONCOL 2013;20:325-339.

[7] Han W, Meng-Chao W, Wen-Ming C. Microvascular invasion predicts a poor prognosis of solitary hepatocellular carcinoma up to 2 cm based on propensity score matching analysis. HEPATOL RES

[8] Shen J, Wen J, Li C, et al. The prognostic value of microvascular invasion in early-intermediate stage hepatocelluar carcinoma: A propensity score matching analysis. BMC CANCER 2018;18:278.

[9] Li KW, Wen TF, Li X, et al. The effect of postoperative TACE on prognosis of HCC with microscopic venous invasion. Hepato-gastroenterology 2012;59:1944.

[10] Qi YP, Zhong JH, Liang ZY, et al. Adjuvant transarterial chemoembolization for patients with hepatocellular carcinoma involving microvascular invasion. AM J SURG 2018

[11] Liu S, Li H, Guo L, et al. Tumor size affects efficacy of adjuvant transarterial chemoembolization in patients with hepatocellular carcinoma and microvascular invasion. ONCOLOGIST 2018


P-111 PEMBROLIZUMAB VS PLACEBO AS ADJUVANT THERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AND COMPLETE RADIOLOGIC RESPONSE AFTER SURGICAL RESECTION OR LOCAL ABLATION: PHASE 3 KEYNOTE-937 TRIAL

Andrew X. Zhu* 1, Ann-Lii Cheng2, Arndt Vogel3, Thomas Yau4, Jian Zhou5, Erluo Chen6, Usha Malhotra6, Abby B. Siegel6, Masatoshi Kudo7

1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States, 2National Taiwan University Hospital Cancer Center, Taipei, Taiwan, Province of China, 3Medizinische Hochschule, Hannover, Germany, 4University of Hong Kong, Queen Mary Hospital, Hong Kong, 5Zhongshan Hospital, Fudan University, Shanghai, China, 6Merck & Co., Inc., Kenilworth, United States, 7Kindai University School of Medicine, Higashiosaka, Japan

Introduction: Although surgical resection and local ablation are potentially curative options for patients with HCC, tumor recurrence is not uncommon, with 5-year recurrence rates of 50–80%.1,2 With no current standard of care in the HCC adjuvant setting, a therapy that could prevent disease recurrence and increase survival in postresection/postablation patients is urgently needed. The immune checkpoint inhibitor pembrolizumab, a potent humanized IgG4 monoclonal antibody that blocks the interaction between the programmed death 1 (PD-1) receptor and its ligands PD-L1 and PD-L2, is approved for the treatment of patients with HCC previously treated with sorafenib. Although there is no direct evidence of benefit with pembrolizumab in the HCC adjuvant setting, a favorable benefit to risk profile is anticipated in this patient population based on data from other indications. The KEYNOTE-937 study (NCT03867084) is a randomized, placebo-controlled, double-blind, multicenter phase 3 trial being conducted to determine the safety and efficacy of adjuvant pembrolizumab versus placebo in patients with HCC and radiologic complete response after surgical resection or local ablation.

Methods: Eligible patients are ≥18 years and have radiologically and/or pathologically confirmed HCC after complete resection or local ablation; no radiologic evidence of disease before enrollment;

Table 1: In the two groups were followed up for 1 month objective response

Treatment group CR PR SD PD ORR(%) X2 P

DEB-TACE combined with cTACE

0 41 13 4 41/58(70.7) 6.526 0.008

cTACE 1 66 46 19 67/132(50.8)

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DEB-TACE, drug-eluting beads transarterial chemoembolization; cTACE, conventional transarterial chemoembolization.

Conclusions: Compared to cTACE treatment, DEB-TACE combined with cTACE treatment significantly increased tumor-response rate at 1 month after treatment of unresectable larger HCC, and have a longer time in TTP, without any significant increase in severe adverse events. However, long-term clinical efficacy and survival benefits need to be further analyzed in future studies.

References: [1] Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN

2008. Int J Cancer 2010;127:2893–917.[2] Ke S, Ding X, Gao J, et al. Solitary huge hepatocellular carcinomas 10 cm or larger may be

completely ablated by repeated radiofrequency ablation combined with chemoembolization: Initial experience with 9 experience with 9 patients. Mol Med Rep. 2012;5:832–836.

[3] Xue T, Le F, Chen R, et al. Transarterial chemoembolization for huge hepatocellular carcinoma with diameter over ten centimeters: a large cohort study. Med Oncol. 2015;32:64.

[4] Llovet JM, Real MI, Montana X, et al; Barcelona Liver Cancer Group: Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359(9319): 1734–1739.

[5] Lo CM, Ngan H, Tso WK et al.:Randomized controlled trial of transarterial lipiodol chemo-embolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–1171.

[6] Lewis AL, Gonzalez MV, Lloyd AW, Hall B, Tang Y, Willis SL, et al. DC bead: in vitro characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006;17:335–342.

[7] Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999;19:329–338.

[8] Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.

[9] Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41–52.

[10] Reyes DK, Vossen JA, Kamel IR, Azad NS, Wahlin TA, Torbenson MS, et al. Single-center phase II trial of transarterial chemoembolization with drug-eluting beads for

patients with unresectable hepatocellular carcinoma: initial experience in the United States. Cancer J. 2009;15(6):526–32.

[11] Sacco R, Bargellini I, Bertini M, Bozzi E, Romano A, Petruzzi P, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol. 2011;22(11):1545–52.

[12] Van Malenstein H, Komuta M, Verslype C, Vandecaveye V, Van Calster B, Topal B, et al. Histology obtained by needle biopsy gives additional information on the prognosis of hepatocellular carcinoma. Hepatology research : the official journal of the Japan Society of Hepatology. 2012;42(10):990–8.


P-110 DOES POSTOPERATIVE ADJUVANT TRANSARTERIAL CHEMOEMBOLIZATION BENEFIT FOR ALL PATIENTS WITH HEPATOCELLULAR CARCINOMA COMBINED WITH MICROVASCULAR INVASION: A META-ANALYSIS

Qiao Ke* 1

1Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, China

Introduction: The incidence of hepatocellular carcinoma is increasing worldwide[1], and surgical resection is still one of the potential curative treatment[2-4]. However, the overall prognosis of HCC remains poor, mainly due to the high recurrence[5]. Hence, strategies designed to reduce the recurrence have been tried in clinical. Postoperative adjuvant transarterial chemoembolization (TACE) has been carried out prevalently, although it remains controversial whether postoperative adjuvant TACE is beneficial for all patients with HCC[3,4].Typically, 15%~57% of patients with HCC are accompanied with microvascular invasion (MVI)[6], which is confirmed to be an independent risk factor for recurrence[7,8]. Patients with HCC and MVI are considered to be benefited more from postoperative adjuvant TACE, but the clinical results are different from each other[9-11]. Hence, a meta-analysis based on the most updated and published data is needed to evaluate the long-term outcomes of postoperative adjuvant TACE for patients with HCC and MVI.

Posters Posters


Results: The study included 150 patients with cirrhosis (60% males, mean age 60+/-12.4 years), and 150 patients without cirrhosis (56% males, mean age 52.4+/-20.3 years). Biliary cannulation was successful in 98% and 98.3% of patients with and without cirrhosis. Clinical pancreatitis, perforation, bleeding and cardiopulmonary complications were not different in patients with and without cirrhosis (8% vs 9.3, 0% vs 2%, 3.3% vs 4%, and 4% vs 2% respectively), while cholangitis occurred more frequently in patients with cirrhosis (13.3% vs 1.3% respectively). Hospital stay was longer and mortality and costs were significantly higher among patients with cirrhosis. Patients with Child C cirrhosis developed more complications and had higher mortality. A MELD score cut off of ≥11.5 separated all mortalities. Similarly, MELD-Na and APRI separated patients with cirrhosis who had more frequent complications and mortalities.

Conclusions: Patients with cirrhosis experienced more complications and costs, and patients with cirrhosis who developed moderate to severe complications were more likely to die.


P-117 PROGNOSTIC VALUES OF TUMOR MARKERS IN PATIENTS WHO ACHIEVED COMPLETE RESPONSE TO TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA

Jae Seung Lee* 1, Beom Kyung Kim1, Jun Yong Park1, Do Young Kim1, Sang Hoon Ahn1, Kwang-Hyub Han1, Wonseok Kang2, Dong-Hyun Sinn2, Moon Seok Choi2, Geum-Youn Gwak2, Yong-Han Paik2, Joon Hyeok Lee2, Kwang Cheol Koh2, Seung Woon Paik2, Hwi Young Kim3, Tae Hun Kim3, Kwon Yoo3, Yeonjung Ha4, Young Eun Chon4, Mi Na Kim4, Joo Ho Lee4, Seong Gyu Hwang4, Soon Sun Kim5, Hyo Jung Cho5, Jae Youn Cheong5, Sung Won Cho5, Seung Ha Park6, Nae-Yun Heo6, Young Mi Hong7, Ki Tae Yoon7, Mong Cho7, Jung Gil Park8, Min Kyu Kang8, Soo Young Park9, Young Oh Kweon9, Won Young Tak9, Se Young Jang9, Seung Up Kim1 and The Korean TACE Study Group

1Department of Internal Medicine, Yonsei University College of Medicine, 2Department of Medicine, Samsung Medical Center, 3Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, 4Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, 5Department of Gastroenterology, Ajou University School of Medicine, Suwon, 6Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, 7Liver Center, Pusan National University Yangsan Hospital, Yangsan, 8Department of Internal Medicine, Yeungnam University Medical Centre, 9Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea, Republic Of

Introduction: The prognostic values of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in patients with hepatocellular carcinoma (HCC) are well-known. We investigated whether these tumor markers is prognostic in patients with HCC who achieved radiological complete response (R-CR) after trans-arterial chemoembolization (TACE).

Methods: Between 2005 and 2018, 873 patients (552 treatment-naïve [TN-HCC] and 321 with recurrent HCC after curative resection [R-HCC]) achieved R-CR (index date), based on the modified RECIST criteria, after TACE were recruited. Tumor marker non-response was defined as less than 50% reduction from the baseline after TACE.

Results: The median age of patients in TN-HCC (394 male) and those in R-HCC group (276 male) was 61.9 and 59.8 years, respectively. During the follow-up period, 366 (68.8%) in TN-HCC and 252 (78.5%) in R-HCC group experienced recurrent HCC. In addition, 296 (55.6%) in TN-HCC and 125 (38.9%) in R-HCC group experienced mortality. The median progression-free survival (PFS) in TN-HCC and R-HCC groups was 16.1 and 15.4 months, respectively, whereas the overall survival (OS) was 56.8 vs. 90.4 months, respectively. In TN-HCC group, higher baseline alpha-fetoprotein (AFP) >20 ng/mL (hazard ratio [HR=1.241]), AFP non-response (HR=1.642), and BCLC stage C (HR=1.618) independently predicted the shorter PFS (all P<0.05), whereas only multiple tumors independently predicted the shorter PFS in R-HCC group (HR=1.856, P<0.001). In TN-HCC group, higher DCP independently predicted shorter OS (HR=1.003), together with multiple tumor (HR=1.907) and longer prothrombin time (HR=21.140) (all P<0.05). In R-HCC group, higher DCP independently predicted shorter OS (HR=1.001), together with higher total bilirubin level (HR=1.450) (all P<0.05).

Conclusion: At the time of R-CR, AFP non-response was independently predictive of recurrence in treatment-naïve patients after TACE and higher DCP level was independently predictive of mortality. Thus, AFP and DCP level should be used for a more detailed risk stratification in spite of R-CR after TACE.

References: Kim et al. Complete response at first chemoembolization is still the most robust predictor for favorable outcome in hepatocellular carcinoma. J Hepatol. 2015 Jun;62(6):1304-10.


Image:

Conclusion: We concluded sPD-L1 was a prognostic indicator for poor outcomes after TACE. High sPD-L1 indicated an increased activation of immunity with an immunosuppressive environment which hindered activity of anti-tumor response. Eradicating sPD-L1 might pave a novel avenue towards preventing progression after TACE.


P-115 PROGNOSTIC ROLE OF SERUM WISTERIA FLOIRBUNDA AGGLUTININ-POSITIVE MAC-2 BINDING PROTEIN LEVEL AFTER HEPATOCELLULAR CARCINOMA RESECTION

Joseph Lin* 1

1General Surgery, Changhua Christian Hospital, Changhua, Taiwan, Province of China

Introduction: The aim of the current analysis was to evaluate the prognostic value of Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) in predicting overall survival for patients with early-stage hepatocellular carcinoma (ESHCC) after liver resection.

Methods: Following institutional review board approval, data were extracted from our prospective maintained database to identify ESHCC patients treated at Changhua christian hospital between 2009 and 2016. Exclusion criteria were stage III/IV HCC, lost to follow up, and non-cancer related death. Post-operative survival rates were compared according to WFA+-M2BP and tumor stage.

Results: Six hundred and ten patients were identified and 128 were removed after application of the exclusion criteria, this left a final cohort of 482 patients. The number of cases of HBV HCC, HCV HCC, cryptogenic HCC, alcoholic HCC, and HBV/HCV coinfection HCC were 240 (49.8%), 172 (35.7%), 37 (7.7%), 21 (4.4%) and 12 (2.5%) respectively. The median follow up time was 4.27 years, and cancer related death occurred in 141 (29.3%) patients. Age (p = 0.06), cancer stage (p = 0.02) and WFA+-M2BP level (p < 0.001) were identified as independent risk factors for poor overall survival in patient with ESHCC. The optimal cutoff point to predict overall survival was 1.12 COI. The overall survival rates for ESHCC at 3 and 5 years for patients with WFA+-M2BP <1.12 were 0.92 and 0.90 respectively, and for WFA+-M2BP >1.12 were 0.75 and 0.64 (p < 0.001). During the analysis of the best model for survival prediction, serum WFA+-M2BP level exhibited the highest log-likelihood and the lowest AIC value (log likelihood -792; AIC 1586).

Conclusions: It was demonstrated that serum WFA+-M2BP level provided important prognostic information after curative hepatic resection in our study. However, the choice of an ideal system is a controversial subject and future studies with larger numbers of patients are necessary for the validation of serum WFA+-M2BP level as the method of choice for other population.


P-116 SAFETY, RISK STRATIFICATION AND COST OF ERCP IN PATIENTS WITH CIRRHOSIS

Esam Elshimi* 1 and Mai Magdi, Ahmed Attia, Gamal Badra and Imam Waked

1Menoufia University, National Liver Institute, Shebeen Elkom, Egypt

Introduction: Procedure related complications and cost of therapeutic ERCP in patients with cirrhosis were compared to patients without cirrhosis. Disease severity scores were used to stratify procedure risks.

Methods: Outcome and complications of therapeutic ERCP were prospectively studied in patients with cirrhosis and compared to patients without cirrhosis undergoing ERCP. Patients with cirrhosis were evaluated using Child Pugh classification, Model of End stage Liver Disease (MELD) and MELD Na scores and aspartate aminotransferase to platelet ratio index (APRI). Safety was assessed up to 30 days following the procedure

Image:

Conclusion: The woodchuck model of spontaneous HCC is insofar the only animal model with imaging detectable endogenous woodchuck PSMA expression in HCC. Furthermore, peptide and antibody that are designed to bind/stain human PSMA both worked well with the native vascular PSMA associated with spontaneous HCC in the woodchuck models. Specifically, the 68Ga-labeled peptides developed against human PSMA seemed to bind with the woodchuck native PSMA in its liver tumor-associated neovasculature.

References: Chang SS, Reuter VE, Heston WD, Bander NH, Grauer LS, Gaudin PB. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res 1999; 59(13): 3192-8. Aggarwal S, Ricklis RM, Williams SA, Denmeade SR. Comparative study of PSMA expression in the prostate of mouse, dog, monkey, and human. The Prostate 2006; 66(9): 903-10. Denmeade SR, Mhaka AM, Rosen DM, et al. Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy. Science translational medicine 2012; 4(140): 140ra86. Sasikumar A, Joy A, Nanabala R, Pillai MR, Thomas B, Vikraman KR. (68)Ga-PSMA PET/CT imaging in primary 1hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2016; 43(4): 795-6. Kesler M, Levine C, Hershkovitz D, Mishani E, Menachem Y, Lerman H, Zohar Y, Shibolet O, Even-Sapir E. 68Ga-PSMA is a novel PET-CT tracer for imaging of hepatocellular carcinoma: A prospective pilot study. J Nucl Med. 2018 Jul 12. doi: 10.2967/jnumed.118.214833.


P-114 ELEVATED LEVEL OF SOLUBLE PROGRAMMED DEATH-LIGAND 1 INDICATED IMMUNOSUPPRESSION AND POOR PROGNOSIS IN HEPATOCELLULAR CARCINOMA PATIENTS UNDERGOING TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION

Xiaolu Ma* 1

1Laboratory of Medicine, Shanghai Cancer Center, Fudan University, Shanghai, China

Introduction: Soluble Programmed Death-ligand 1 (sPD-L1) is associated with prognosis in hepatocellular carcinoma (HCC) after resection, however, it has not been evaluated in patients with unresectable HCC. Present study aimed to explore the prognostic significance of sPD-L1 in HCC patients undergoing Transcatheter Arterial Chemoembolization (TACE).

Methods: 114 HCC patients receiving TACE from 2012 to 2013 were recruited and sPD-L1 levels were determined by ELISA. Prognosis evaluation was conducted according to mRESIST criteria. Prognostic value was evaluated by Cox regression and Kaplan-Meier analysis. Correlations between sPD-L1 with systemic inflammation index (SII), soluble interleukin-2 receptor (sIL-2R), IL-10, HBV-DNA loads, and C-reactive protein were further evaluated.

Results: sPD-L1 level was significantly elevated in patients who encountered progression (P=0.002) and death (P<0.001). Patients with higher pre-treatment sPD-L1 had significantly shorter time to progression (10.50 vs. 18.25 months, P=0.001) and overall survival (16.50 vs. 28.50 months, P=0.003). sPD-L1 retained its prognostic value in low-recurrence-risk subgroups (all P<0.050). Importantly, multivariate regression confirmed that pre-treatment sPD-L1 was an independent predictor for both progression (hazard ratio 1.82; P=0.032) and survival (HR 1.84; P=0.009). Moreover, sPD-L1 showed positive correlation with SII (r=0.284, P=0.002), sIL-2R (r=0.239, P=0.010), IL-10 (r=0.283, P=0.002), HBV-DNA loads (r=0.229, P=0.014), and CRP (r=0.237, P=0.011).

21. Ueno, M. et al. Partial clamping of the infrahepatic inferior vena cava for blood loss reduction during anatomic liver resection: A prospective, randomized, controlled trial. Surg. (United States) 161, 1502–1513 (2017).

22. Lee, J. J. et al. Laparoscopic versus open liver resection for hepatocellular carcinoma at a North-American Centre: a 2-to-1 matched pair analysis. HPB (Oxford). 17, 304–310 (2015).

23. Chan, A. C. Y. et al. Laparoscopic versus open liver resection for elderly patients with malignant liver tumors: a single-center experience. J. Gastroenterol. Hepatol. 29, 1279–1283 (2014).

24. Dunki-Jacobs, E. M., Philips, P., Scoggins, C. R., McMasters, K. M. & Martin, R. C. G. 2nd. Stroke volume variation in hepatic resection: a replacement for standard central venous pressure monitoring. Ann. Surg. Oncol. 21, 473–478 (2014).

25. Egger, M. E. et al. Anesthetic and operative considerations for laparoscopic liver resection. Surg. (United States) 161, 1191–1202 (2017).

26. Ishizawa, T., Gumbs, A. A., Kokudo, N. & Gayet, B. Laparoscopic segmentectomy of the liver: From segment i to VIII. Ann. Surg. 256, 959–964 (2012).

27. Hughes, M. J., Ventham, N. T., Harrison, E. M. & Wigmore, S. J. Central venous pressure and liver resection: a systematic review and meta-analysis. HPB (Oxford). 17, 863–871 (2015).

28. Wang, W.-D., Liang, L.-J., Huang, X.-Q. & Yin, X.-Y. Low central venous pressure reduces blood loss in hepatectomy. World J. Gastroenterol. 12, 935–939 (2006).

29. Li, Z. et al. Controlled low central venous pressure reduces blood loss and transfusion requirements in hepatectomy. World J. Gastroenterol. 20, 303–309 (2014).

30. Kobayashi, S. et al. An Experimental Study on the Relationship Among Airway Pressure, Pneumoperitoneum Pressure, and Central Venous Pressure in Pure Laparoscopic Hepatectomy. Ann. Surg. 263, 1159–1163 (2016).

31. Eyraud, D. et al. Hemodynamic and hormonal responses to the sudden interruption of caval flow: insights from a prospective study of hepatic vascular exclusion during major liver resections. Anesth. Analg. 95, 1173–8, table of contents (2002).


P-113 TUMOR-ASSOCIATED VASCULAR MARKER IN LIVER CANCER

Zhenghong Lee* 1, Olga Sergeeva1, Yifan R. Zhang1, maxim Sergeev2, Wei Xin1, Norbert Avril1, Sandra Sexton3, Renuka Iyer3, Jonathan Kenyon1

1Case Western Reserve university, 2University Hospitals Cleveland Medical Center, Cleveland, 3Roswell Park Cancer Institute, Buffalo, United States

Introduction: Small molecule peptide ligands targeting prostate specific membrane antigen (PSMA) have been developed for PET imaging of prostate cancer, but have shown uptake in primary liver cancer such as hepatocellular carcinoma (HCC). It was believed that the target PSMA is expressed on liver tumor associated vascular endothelial cells since HCC cells usually do not express PSMA. However, investigation into this liver tumor-associated vascular endothelial PSMA expression has been slow due to the lack of a clinically relevant animal model. PSMA, human or murine, was not detected on the vessels of any tumors grown in mice, regardless the type of tumor, site of implantation, or tissue of origin. We discovered the naturally occurring woodchuck model of HCC for its detectable and targetable native PSMA on tumor-associated vascular endothelium. This study is to further characterize tumor-associated vascular PSMA expression in HCC.

Methods: 37 MBq (1.0 mCi) of Gallium-68 labeled clinical grade peptide ligand 68Ga-PSMA-11 was given IV to the woodchucks bearing naturally occurring HCC after two-four years of chronic viral hepatitis infection. PET acquisition started upon 68Ga-PSMA-11 injection in list-mode and lasted for 60 min. The PET acquisitions were binned into 10 X 0.5, 5 X 1 and 10 X 5 min frames for reconstruction using CT-based attenuation correction. Patlak and Logan graphical analyses were performed, using weighted heart and portal vein activity curves as a composite input function. For some animals, multi-phase contrast-enhanced CT scan was also performed. Some other animals were selected for additional scanning with lipid-based small molecule radiotracers, either 11C-choline and/or 11C-acetate for PET or MRI for comparison with the PSMA scan. At the end of the study, animals were euthanized and liver tissues harvested, some for PCR and Western Blot, and others fixed for H&E staining as well as PSMA staining. PSMA gene sequences were compared between human and woodchuck; their protein sequences were also compared.

Results: HCCs showed 68Ga-PSMA-11 uptake inside and around the tumor independent of choline and acetate uptake status, but similar to MR contrast scan indicating a vascular pattern. These observations were in accordance with multi-phase contrast-enhanced CT scans. PSMA staining on harvested tissue samples post-imaging confirmed positive for PSMA. The human and woodchuck PSMA genes were 100% homologous between exon 1 to exon 4; the protein sequences of the two were 89% identity. The amino acids in the binding pocket of alpha-NAAGA were preserved, and confirmed through modeling by crystal structure showed the docking for PSMA-11 to the target. Analysis of PET image revealed poor fit for Patlak analysis in tumor and liver regions while excellent fit was obtained from Logan analysis. PCR and Western Blot results confirmed the existence of a higher level woodchuck PSMA in its HCC, while on-going single cell RNA-seq will further validate this tumor-associated vascular endothelial expression of PSMA in HCC.

Posters Posters


P-122 LHPP INHIBIT THE CELL PROLIFERATION EPITHELIAL-TO-MESENCHYMAL TRANSITION VIA THE TGFß/SMAD3 SIGNALING PATHWAY IN INTRAHEPATIC CHOLANGIOCARCINOMA

Dan Wang* 1

1Department of Integrative Oncology, Fudan University Shanghai Cancer center, Shanghai, China

Introduction: Intrahepatic cholangiocarcinoma(iCCA) is the second most common primary hepatic malignancy with an increasing incidence and a high mortality. Though next-generation sequencing techniques have provided a chance to understand the molecular pathogenesis of iCCA, it is still necessary to identify novel therapeutic targets. Recently, histidine phosphatase LHPP (phospholysine phosphohistidine inorganic pyrophosphate phosphatase) was reported as a tumor suppressor for HCC. Here, we hypothesized that LHPP might be also related to the tumorigenesis of iCCA.

Methods: We analyzed the expression level of LHPP in The Cancer Genome Atlas Cholangio-carcinoma (TCGA-CHOL) cohort, and we conformed LHPP expression and the clinical significance of LHPP. We transfected the iCCA cell lines (RBE and HCCC-9810) with LHPP over-expression lentivirus and small interfering RNA against LHPP. Cell proliferation were evaluated with the CCK-8 cell proliferation assays and colony formation assays. Cell apoptosis was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess cell migration. Gene Set Enrichment Analysis (GSEA) was performed to identify genes and signaling pathways associated with LHPP in TCGA-CHOL cohort. Markers of EMT and TGFß/SMAD3 signaling were evaluated by quantitative PCR and western blotting.

Results: In this study, LHPP was downregulated in tumor tissues both in TCGA-CHOL cohort and patient tissues, and low level LHPP predicted a poor survival in patient samples. We also found that LHPP suppressed RBE and HCCC-9810 cells growth and colony formation, while moderately promote cell apoptosis. Moreover, LHPP suppressed the cell invasion and EMT. Importantly, we found that TGFß signaling pathway was significantly activated in LHPP-high group (p<0.0001, FDR=10%) by GSEA analysis. The expression of TGFß1 was negatively correlated with LHPP (p=0.0001, R2=0.488). Finally, TGFß/SMAD3 was inhibited in LHPP over-expression cells, and was activated in LHPP down-expression cells.

Conclusions: Our results demonstrated that LHPP also serve as a suppressor gene to inhibit cell proliferation and cell invasion. Mechanically, LHPP inhibit TGFß/SMAD signaling.


P-123 INTERFERON-INDUCED TRANSMEMBRANE PROTEIN 3 EXPRESSION UPREGULATION IS INVOLVED IN PROGRESSION OF HEPATOCELLULAR CARCINOMA

Yuli Hou1, Ling Qin1, Meng Dan Gao1, Jian Ping Sun 1, Yonghong Zhang1, Yan Zhao* 1

1Bei Jing You'An hospital, Capital Medical University, Beijing, China

Introduction: Hepatocellular carcinoma (HCC) gives rise to approximately 745,500 deaths worldwide and is the second leading cause of cancer-related death according to the data from world health organization (WHO). Interferon-induced transmembrane protein 3 (IFITM3) has been reported to be a key signaling molecule regulating cell growth in some tumors, and according to our previous studies, IFITM3 plays an important role in the progression of HCC and its polymorphisms might play different effects, while its function and mechanism in hepatocellular carcinoma (HCC) remains unknown. In order to address this issue, this study investigated the relationship between the expression of IFITM3 and HCC development to identify the effect of IFITM3 rs12252-CC genotype on the expression of IFITM3.

Methods: IFITM3 expression was first investigated with immunohistochemistry and western blotting by using HCC tissue samples. Then PLC/PRF/5 cells were transfected with lentivirus to knockdown the expression of IFITM3 (LV-IFITM3), empty lentivirus was employed as negative control (LV-NC). IFITM3 expression, cell proliferation and migration were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR), QuantiGene Plex 2.0 assay, western blotting, immunohistochemistry, cell counting kit (CCK)-8 and wound healing tests.RNA-seq technology identified the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway as an IFITM3-related signaling pathway for investigation.

Results: First, the expression of IFITM3 protein in 14 pairs of hepatic tissues was compared with adjacent normal hepatic tissues to determine the difference of expression level of IFITM3 protein in HCC samples and non-tumor samples. IFITM3 was positively stained in the HCC tissues, while weakly stained in the adjacent normal tissues (Fig. 1A-D). The expression of IFITM3 was higher in HCC tissues than adjacent normal tissues, and moreover the level of IFITM3 was higher in HCC tissues with low differentiation and metastatic potential than those with high/medium differentiation and without metastatic potential. Secondly, knockdown of IFITM3 in PLC/PRF/5 cells inhibited cell proliferation and migration. Thirdly, screening for DEGs between the LV-NC and the LV-IFITM3 cells using NOISeq found that the PI3K-AKT signaling pathway played an essential role in regulating

Methods: Transcriptomic-sequencing was performed to interrogate the expression of 21 known histone chaperones in 16 pairs of primary HCC and their corresponding non-tumorous livers. CRISPR-based gene activation and knockout systems were employed to establish FACT complex gain-of-function and loss-of-function models. The functions of FACT complex in HCC growth and metastasis were tested in HCC cell lines and orthotopic tumor implantation model in nude mice. Mechanisms and functions of FACT complex in oxidative stress response was investigated by ChIP assay, flow cytometry, gene expression assays, and 4su-DRB transcription elongation assay. Therapeutic effect of FACT complex inhibitor, Curaxin, was tested in both in vitro and in vivo models.

Results: We showed that FACT complex was remarkably up-regulated in HCC and associated with poor prognosis. Overexpression of FACT complex promoted HCC proliferation and migration, while knockout of FACT complex abolished HCC growth and metastasis both in vitro and in vivo. Importantly, we unprecedentedly revealed an indispensable role of FACT complex in NRF2-driven oxidative stress response. Oxidative stress prevented NRF2 and FACT complex from KEAP1-mediated protein ubiquitination and degradation. Stabilized NRF2 and FACT complex form a positive feed-back loop; on one hand NRF2 transcriptionally activates the FACT complex expression, on the other hand, FACT complex promotes the transcription elongation of NRF2 and its down-stream antioxidant genes through facilitating rapid nucleosome disassembly for the passage of RNA polymerase. Knockout of FACT complex abolished the NRF2-mediated antioxidant genes induction and remarkable increased HCC cell apoptosis upon oxidative stress insult. Therapeutically, FACT complex inhibitor, Curaxin, effectively suppressed HCC growth and sensitized HCC cell to Sorafenib treatment.

Conclusions: In conclusion, our findings demonstrated that FACT complex is essential for the expeditious HCC oxidative stress response and is a potential therapeutic target for HCC treatment.


P-121 ONCOGENIC ARGONAUTE 2 PROMOTES HEPATOCELLULAR CARCINOGENEIS THROUGH DEREGULATION OF THE MRNA TRANSCRIPTOME

Hien Dang*1, Yotsawat Pomyen2, Kai Zhang3, Subreen Khatib4, Sean P. Martin2, Dana A. Dominguez2, Marshonna Forgues2, Lucy Knight2, Xin W. Wang2, Anna Barry1

1Surgical Research, Thomas Jefferson University, Philadelphia, 2Laboratory of Human Carcinogenesis, National Institutes of Health/National Cancer Institute, Bethesda, 3Dept. of Surgery, 1025 Walnut Street, 603, Thomas Jefferson University, Philadelphia, 4National Institutes of Health/National Cancer Institute, Bethesda, United States

Introduction: Global transcriptomic alterations are evolutionary selected during carcinogenesis. The steady-state transcriptome is regulated not only by the rate of transcription but also RNA degradation. However, the underlying mechanism of how RNAs are stabilized is largely unexplored. The RNA binding protein (RBP) Argonaute 2 (AGO2) is essential for miRNA and siRNA mediated post-transcriptional gene-silencing as a catalytic center for the RNA-induced silencing complex (RISC). Although much is known about AGO2’s role in silencing RNAs through a RISC, AGO2’s role as an RNA binding protein has not been explored.

Methods: In this study, we analyzed genomic alterations amongst a family of more than 800 mRNA binding proteins in more than 1,200 clinical specimens from four independent cohorts. Pearson correlation, Kaplan-Meier analyses, and Gene Set Enrichment Analysis (GSEA) was performed to identify the importance of AGO2 in HCC clinical samples. We employed CRISPR/Cas9, siRNA assays, and RNP in vitro assays to demonstrate AGO2’s importance in regulating the mRNA transcriptome. In addition, in vivo assays were used to demonstrate AGO2’s importance in tumor initiation.

Results: In HCC, AGO2 is highly expressed and associated with poor outcome. While the activation of AGO2 induced an oncogenic phenotype, the abrogation of AGO2 in HCC cells significantly decreased cancer associated phenotypes such as cell proliferation, migration/invasion and tumorigenicity in vivo. Further analyses demonstrate that patients with high levels of AGO2 are more likely to acquire mRNA alterations through a RISC-independent manner and have elevated copies of MYC, an oncogene that regulates more than 15% of the genome. Since MYC overexpression is highly toxic to cells, its half-life is approximately 30 mins. However, in cancer cells MYC is often amplified, altering the transcriptome to promoter tumorigenesis. Our current work in HCC cell models reveal that AGO2 regulates the stability of the MYC mRNA transcript by binding to its 3’UTR, subsequently doubling its half-life. We employed CRISPR/Cas9 to genomically knockout DICER, an important protein involved in the maturation of miRNAs to test whether AGO2 regulates the MYC transcript independent of RISC. In genomically engineered cells without the presence of mature microRNAs, we show that AGO2 remains bound to MYC to regulate its stability.

Conclusions: Our current work provide evidence that oncogenic AGO2 promotes HCC through the stabilization of oncogenes, including MYC.


Introduction: Treatment of glypican-3 (GPC3) expressing hepatocellular carcinomas (HCC) with HN3-based immunotoxins has been shown to cause potent tumor regression by blocking protein synthesis and by down-regulating the Wnt signaling pathway. However, the immunogenicity and short serum half-life may limit their transition to the clinic.

Methods: To address these concerns, we constructed HN3-based immunotoxins with various deimmunized Pseudomonas exotoxin domains. These included HN3-T20 which contains a domain II truncation and mutations in domain III to remove T-cell epitopes. We compared them to the previously reported B cell deimmunized HN3 immunotoxin and the original HN3-PE38 with wild-type Pseudomonas exotoxin.

Results: All of our HN3-based immunotoxins had high affinity, with HN3-T20 having a KD value of 7.4 nM. HN3-T20 retained 73% enzymatic activity when compared to the wild-type immunotoxin in ADP-ribosylation assay. Interestingly, a real-time cell growth inhibition assay demonstrated that a single dose of HN3-T20 at 62.5 ng/ml (1.6 nM) was capable of inhibiting nearly all cell proliferation during the 10-day experiment. To enhance HN3-T20’s serum retention, we tested the effect of adding a streptococcal domain (ABD) and a llama heavy chain antibody domain (ALB1). We developed a highly sensitive ELISA for the detection of Pseudomonas exotoxin in mouse serum and found that HN3-ABD-T20 had a 45-fold higher serum half-life than HN3-T20 (326 min vs 7.3 minutes); consequently, addition of an ABD resulted in HN3-ABD-T20 mediated tumor regression at 1 mg/kg.

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Conclusion: These data suggest that the deimmunized HN3-ABD-T20 immunotoxin is a high potency therapeutic that can be beneficial to HCC patients.


P-120 HISTONE CHAPERONE FACT COMPLEX MEDIATES OXIDATIVE STRESS RESPONSE TO PROMOTE LIVER CANCER PROGRESSION

Jialing Shen1,2, Chui Nog-Qin*1,2, Derek Lee1,2, Ng Irene1,2, Carmen Wong1,2, Chun Ming Wong* 1,2

1Pathology, 2State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, Hong Kong

Introduction: The high-order chromatin structure determines the genome architecture and gene expression of eukaryotic cells. Histone chaperones are key proteins that function at multiple steps of nucleosome package and disassembly. However, their roles in cancer development remain poorly understood. Facilitates Chromatin Transcription (FACT) complex is a histone chaperone participating in DNA repair- and transcription-related chromatin dynamics. In this study, we investigated its oncogenic functions, underlying mechanisms, and therapeutic implications in human hepatocellular carcinoma (HCC).

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P-118 RAS PATHWAY ACTIVATION OF LIN28B, WHICH IN TURN SUPPRESSES METTL7A, TO DRIVE HEPATOCELLULAR CARCINOMA DEVELOPMENT

Yonglong Wei* 1, Lin Li1, Katelyn Doxtader2, Jung Yoon1, Yunsun Nam2, Hao Zhu1

1Children’s Medical Center Research Institute, 2Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, United States

Introduction: Mounting evidence has shown that RNA-binding proteins (RBPs) are important for cancer development. However, the underlying mechanisms by which RBPs promote tumorigenesis remain obscure. Previous reports demonstrated that the LIN28A and LIN28B oncogenic RBPs label the diethylnitrosamine (DEN) induced cancer cell of origin, but the functional significance of this observation was unknown. Here, we show that the Lin28 RBPs are essential for DEN-mediated liver cancer development.

Methods: Because DEN tumors are Ras driven, we used a hydrodynamic transfection mediated Nras/P53 hepatocellular carcinoma (HCC) model to explore the mechanistic underpinnings of Lin28 activities. Lin28b was expressed in the early premalignant lesions of the Nras/P53 model. To determine if Lin28a/b was required for the development of HCC, we generated liver-specific Lin28a; Lin28b; Trp53 triple KO mice.

Results: Nras activation in these mice failed to generate any HCCs, indicating a requirement for Lin28s. Intriguingly, Lin28b but not Lin28a could rescue Nras/P53 HCC development in these triple KO mice. As both Lin28a and Lin28b can repress Let-7s’ maturation, we hypothesized that Lin28b may promote HCC initiation by regulating targets in a Let-7-independent fashion. Intriguingly, enhanced RBP crosslinking and immunoprecipitation (eCLIP) showed that many m6A RNA modifying enzymes are bound by LIN28B. Among these enzymes, METTL7A is negatively regulated by LIN28B, and METTL7A is also decreased in Nras/P53-driven HCCs. Previous work has shown that METTL7a has tumor suppressor activities in HCC and in vitro, we have shown that METTL7a has RNA methyltransferase activity. We are currently elucidating the molecular function and targets of METTL7A in liver cancer development.

Conclusions: Taken together, we found that LIN28B-METLL7A may be a critical signal pathway to drive liver tumor initiation/maintenance and represent a potentially targetable pathway in HCC.


P-119 THE ENGINEERED ANTI-GPC3 IMMUNOTOXIN, HN3-ABD-T20, HAS PROLONGED SERUM RETENTION AND CAUSES REGRESSION IN MOUSE LIVER CANCER XENOGRAFTS

Bryan D. Fleming* 1, Daniel J. Urban2, Matthew Hall2, Thomas Longerich3, Tim Greten2, Ira Pastan1, Mitchell Ho1

1Laboratory Of Molecular Biology, National Cancer Institute, 2National Institutes Of Health, Bethesda, United States, 3Institute Of Pathology, Heidelberg, Germany

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P<0.001) decreased significantly in the EBD group, and such an advantage was demonstrated in perihilar cholangiocarcinoma, distal cholangiocarcinoma and pancreatic cancer(OR=0.27, 95%CI 0.13~0.56, P<0.001; OR=0.32, 95%CI 0.17~0.60, P<0.001; OR=0.27, 95%CI 0.19~0.40, P<0.001; respectively).

Conclusions: Although more evidence is needed to get to a final conclusion, EBD seems to be better than PTBD in the prevention of seeding metastasis for the resectable MBO.

References: 1. Masato N,Tomoki E,Yukihiro Y, et al. Evolution of Surgical Treatment for Perihilar

Cholangiocarcinoma: A Single-Center 34-Year Review of 574 Consecutive Resections. Annals of Surgery 2013;258:129-140.

2. Calogero I,Andrea R,Tommaso C, et al. Role of Preoperative Biliary Drainage in Jaundiced Patients Who Are Candidates for Pancreatoduodenectomy or Hepatic Resection: Highlights and Drawbacks. Annals of Surgery 2013;257:191-204.

3. Y F, K S G, Q W, et al. Meta-Analysis of Randomized Clinical Trials on Safety and Efficacy of Biliary Drainage before Surgery for Obstructive Jaundice. British Journal of Surgery 2013;100:1589-1596.

4. Umeda J, Itoi T. Current Status of Preoperative Biliary Drainage. Journal of Gastroenterology 2015;50:940.

5. Kato A,Shimizu H,Ohtsuka M, et al. Downsizing Chemotherapy for Initially Unresectable Locally Advanced Biliary Tract Cancer Patients Treated with Gemcitabine Plus Cisplatin Combination Therapy Followed by Radical Surgery. Annals of Surgical Oncology 2015;22:1-7.

6. Lee JL, Song CK, Kim JH, et al. Prospective Efficacy and Safety Study of Neoadjuvant Gemcitabine with Capecitabine Combination Chemotherapy for Borderline-Resectable or Unresectable Locally Advanced Pancreatic Adenocarcinoma. Surgery 2012;152:851-862.

7. Nagino M, Hayakawa N, Nimura Y, et al. Percutaneous Transhepatic Biliary Drainage in Patients with Malignant Biliary Obstruction of the Hepatic Confluence. Hepato-gastroenterology 1992;39:296.

8. Takada T, Hanyu F, Kobayashi S, et al. Percutaneous Transhepatic Cholangial Drainage: Direct Approach under Fluoroscopic Control. Journal of Surgical Oncology 2010;8:83-97.

9. Uemura K, Murakami Y, Satoi S, et al. Impact of Preoperative Biliary Drainage on Long-Term Survival in Resected Pancreatic Ductal Adenocarcinoma: A Multicenter Observational Study. Annals of Surgical Oncology 2015;22:1-9.

10. Higuchi R, Yazawa T, Uemura S, et al. Enbd Is Associated with Decreased Tumor Dissemination Compared to Ptbd in Perihilar Cholangiocarcinoma. J Gastrointest Surg 2017;21:1506-1514.

11. Miura F, Sano K, Wada K, et al. Prognostic Impact of Type of Preoperative Biliary Drainage in Patients with Distal Cholangiocarcinoma. Am J Surg 2017;214:256-261.

12. Komaya K, Ebata T, Yokoyama Y, et al. Verification of the Oncologic Inferiority of Percutaneous Biliary Drainage to Endoscopic Drainage: A Propensity Score Matching Analysis of Resectable Perihilar Cholangiocarcinoma. Surgery 2016;161.

13. Wiggers JK, Groot Koerkamp B, Coelen RJ, et al. Percutaneous Preoperative Biliary Drainage for Resectable Perihilar Cholangiocarcinoma: No Association with Survival and No Increase in Seeding Metastases. Ann Surg Oncol 2015;22 Suppl 3:S1156-1163.

14. Kawakami H, Kuwatani M, Onodera M, et al. Endoscopic Nasobiliary Drainage Is the Most Suitable Preoperative Biliary Drainage Method in the Management of Patients with Hilar Cholangiocarcinoma. J Gastroenterol 2011;46:242-248.

15. Hirano S, Tanaka E, Tsuchikawa T, et al. Oncological Benefit of Preoperative Endoscopic Biliary Drainage in Patients with Hilar Cholangiocarcinoma. J Hepatobiliary Pancreat Sci 2014;21:533-540.

16. Komaya K, Ebata T, Fukami Y, et al. Percutaneous Biliary Drainage Is Oncologically Inferior to Endoscopic Drainage: A Propensity Score Matching Analysis in Resectable Distal Cholangiocarcinoma. J Gastroenterol 2016;51:608-619.

17. Hwang S, Song GW, Ha TY, et al. Reappraisal of Percutaneous Transhepatic Biliary Drainage Tract Recurrence after Resection of Perihilar Bile Duct Cancer. World J Surg 2012;36:379-385.

18. Murakami Y, Uemura K, Hashimoto Y, et al. Does Preoperative Biliary Drainage Compromise the Long-Term Survival of Patients with Pancreatic Head Carcinoma? J Surg Oncol 2015;111:270-276.

19. Wang L, Liu Z, Liu X, et al. The Hepatectomy Efficacy of Huge Hepatocellular Carcinoma and Its Risk Factors: A Meta Analysis. Medicine 2017;96:e9226.

20. Higgins JP, Thompson SG. Quantifying Heterogeneity in a Meta-Analysis. Statistics in Medicine 2002;21:1539-1558.

21. Strom TJ, Klapman JB, Springett GM, et al. Comparative Long-Term Outcomes of Upfront Resected Pancreatic Cancer after Preoperative Biliary Drainage. Surg Endosc 2015;29:3273-3281.

22. Mansour JC, Aloia TA, Crane CH, et al. Hilar Cholangiocarcinoma: Expert Consensus Statement. Hpb 2015;17:691-699.

23. Banales JM, Cardinale V, Carpino G, et al. Expert Consensus Document: Cholangiocarcinoma: Current Knowledge and Future Perspectives Consensus Statement from the European Network for the Study of Cholangiocarcinoma (Ens-Cca). Nature Reviews Gastroenterology & Hepatology 2016;13:261.

24. Tempero MA, Malafa MP, Alhawary M, et al. Pancreatic Adenocarcinoma, Version 2.2017, Nccn Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network Jnccn 2017;15:1028.

Introduction: To evaluate the effects of dose escalation by intensity-modulated radiotherapy (IMRT) in liver-directed concurrent chemoradiotherapy for locally advanced Barcelona Clinic Liver Cancer stage C hepatocellular carcinoma (BCLC-C HCC).

Methods: During 2005-2016, 637 patients with BCLC-C HCC received RT with concurrent hepatic arterial 5-fluorouracil. Patients were divided into two groups according to the biologically effective doses for a tumor (alpha//ß=10 Gy): <72 Gy (536 patients) and ≥72 Gy (101 patients). In each group, 128/536 (24%) and 94/101 patients (93%) used IMRT, respectively.

Results: The median follow-up for patients alive at the time of analysis was 36 months (range, 6–159 months). For ≥72 Gy and <72 Gy groups, the median overall survival (OS) was 21 and 13 months, respectively (P =.002). The 1-year local failure-free survival (LFFS) were significantly higher in high-dose group (95% vs. 79%; P <.001). After propensity score matching, high-dose group still had significantly better 1-year OS (62% vs. 51%; P =.03) and 1-year LFFS (95% vs. 78%; P =.008). In the multivariate model, RT dose was an independent predictor of LFFS and OS. The surgical conversion rate was significantly higher in high-dose group (20% vs. 12%, P =.03), with substantially increased median OS among patients who underwent surgery (104 months vs. 11 months; P <.001). There were no significant differences in gastrointestinal bleeding or radiation-induced liver disease.

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Conclusion: In liver-directed concurrent chemoradiotherapy, radiation dose escalation by IMRT increased LFFS and OS for locally advanced BCLC-C HCC. It also increased the conversion rate to curative resection, which was attributable to increased OS.


P-128 ENDOSCOPIC BILIARY DRAINAGE IS SUPERIOR TO PERCUTANEOUS TRANSHEPATIC BILIARY DRAINAGE FOR RESECTABLE MALIGNANT BILIARY OBSTRUCTION IN THE PREVENTION OF SEEDING METASTASIS: A META-ANALYSIS

Nanping Lin* 1, Lei Wang1, Yongyi Zeng1, Jingfeng Liu1


Introduction: Resection is still the only potentially curative treatment for resectable malignant biliary obstruction (MBO), but it remained controversy which of the preoperative biliary drainage (PBD) was the best strategy. Seeding metastasis was one of the common complications related to PBD procedure, and was associated with prognosis of MBO. However, there were no systematic review and meta-analysis focused on it. Hence, we conducted a meta-analysis to compare the incidence of seeding metastasis between different PBD strategies for MBO.

Methods: Eligible studies were identified by PubMed, MedLine, Web of Knowledge, and other databases up to March 2018, which were designed for the comparison of the seeding metastasis rate between endoscopic biliary drainage (EBD) and percutaneous biliary drainage (PTBD) for malignant biliary obstruction (MBO). Studies which met the inclusion criteria were included, and analyses were then assessed using a fixed or random effects model.

Results: A total of 10 studies were enrolled in this meta-analysis, which included 1085 cases in the PTBD group and 1379 cases in the EBD group. Meta-analysis revealed that there were significant differences between PTBD and EBD in the seeding metastasis rates (OR=0.35, 95%CI 0.23~0.53, P<0.00001). Subgroup results showed that both the rate of peritoneal metastasis(OR=0.42, 95%CI 0.31~0.57, P<0.001) and tube-related seeding metastasis(OR=0.17, 95%CI 0.10~0.29,

Methods: To generate MCTS, HCC cells and stromal cells (LX2, WI38, and HUVECs) were mixed with 1:1 ratio at a density of 6 × 103 cells/well in 96-well round-bottom ultra-low attachment microplates. To generate cell lines stably expressing YAP/ TEAD2DN, SNU449 and Hep3B HCC cell lines were maintained in media containing G418 disulfate salt following transfection with plasmids expressing individual DNA. For drug penetration study, fluorescent chemicals (e.g., verteporfin) were used and the distribution of drug within MCTS was determined by a LSM780 confocal microscope and LSR fortessa Flow Cytometry with a 425 to 440nm excitation and a 700 to 730nm emission filter set.

Results: Well differentiated SNU449 MCTS with low level of YAP/TAZ showed the least compactness of tumor spheroids, while Hep3B MCTS had the highest compactness with highest level of YAP/TAZ expression. Using stable cell lines, we confirmed the amount of verteporfin intercellular in SNU449-YAP MCTS were dramatically lower than SNU449-MCTS, while the amounts in Hep3B-TEAD2DN MCTS were dramatically higher than Hep3B-MCTS. HCC MCTS with higher YAP/TAZ levels increased the compactness and facilitated making a barrier to drug treatment.

Conclusions: In this study, diverse MCTS models have been developed using established HCC cell lines with different cell differentiation and stromal cells such as HSCs, fibroblasts, and endothelial cells. MCTS with poorly differentiated HCC showed an increased compactness of spheroids, an elevated level of YAP/TAZ and a limited drug penetration.


P-125 STUDY OF THE LIPOGENESIS REGULATORY PROTEINS IN HEPATOCELLULAR CARCINOMA

Dina M. Sweed* 1, Rehab M. Samaka2, Mohammad I. Shaban 2, Mervat M. Sultan1, Shereen F. El-Goday2, Mahmoud M. Macshut3, Mohamed H. Abdel-Rahman1, 4, 5

1Pathology, National Liver Institute, 2Pathology, Faculty of Medicine, 3Hepato-pancreatobiliary Surgery, National Liver Institute, Menoufia, Egypt, 4Ophthalmology, 5Division of Human Genetics, The Ohio State University, Columbus, Ohio, United States

Introduction: Multiple lines of evidence suggest that statins can prevent the development of hepatocellular carcinoma (HCC). The goal of the study was to assess the role of alteration in the lipogenic pathway regulating proteins in viral related liver diseases and non-alcoholic fatty liver disease (NAFLD). We also assessed the in-vitro impact of statins on tumorigenesis of HCC cell lines.

Methods: We included liver tissues from 100 HCC tumors, 95 adjacent non-tumor tissues, 50 cirrhotic livers from subjects with no HCC, 50 chronic viral hepatitis and 20 NAFLD. We also studied 8 different HCC cell lines. We assessed the expression SREBP1a, SREBP2, FASN and c-MYC by immunohistochemistry in tumor tissues and by Western blot in cell lines. We also assessed the in-vitro anti-tumor effect of fluvastatin and simvastatin on two liver cell lines with differential expression of SREBP1a, SREBP2 and FASN.

Results: We observed a stepwise decreased expression of SREBP1a with the progression of the disease with highest expression in viral related chronic hepatitis followed by cirrhosis with the lowest expression in HCC (P<0.001). On the contrary there was a stepwise increased expression of SREBP2 with the highest expression in HCC (P<0.001). FASN and c-MYC showed no significant differential expression between chronic hepatitis, cirrhosis and HCC (P=0.21 and 0.29, respectively). SREBP1a and c-MYC overexpression were significantly associated with large tumors and high-grade, (P=0.002 and 0.01, respectively) and lymph node metastasis (P=0.002 and 0.03, respectively). SREBP2 expression was associated low grade and better patients’ overall survival (P=0.04 and 0.03, respectively). For the cell lines, 6/8, 5/8, 4/8 and 8/8 showed expression of SREBP1a, SREBP2, FASN and c-MYC respectively. Significant variation in the anti-proliferative and anti-migration was observed between simvastatin and fluvastatin in the two cell lines with differential expression of SREBP1a, SREBP2 and FASN.

Conclusions: Our results suggest different roles of various members of lipogenesis pathway in hepatocarcinogenesis with SREBP1a being essential in early hepatocarcinogenesis while SREBP2 having a more important role in progression of the disease. Statins don’t have uniform effect on lipogenesis pathway. Further studies of the timing of different statin administration for prevention of HCC are warranted.


P-126 DOSE ESCALATION BY INTENSITY MODULATED RADIOTHERAPY IN LIVER-DIRECTED CONCURRENT CHEMORADIOTHERAPY FOR LOCALLY ADVANCED BCLC STAGE C HEPATOCELLULAR CARCINOMA

Hwa Kyung Byun* 1, Hyun Ju Kim2, Do Young Kim3, Kwang-Hyub Han3, Jinsil Seong1

1Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 2Radiation Oncology, Gachon University Gil Medical Center, 3Internal medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, Republic Of

the EMT of HCC progression with a large number of DEGs (9 genes). Real time PCR verification was undertaken of genes related with the PI3K/AKT signaling pathway including PI3K, AKT and mTOR,blocked the expression of the PI3K/AKT/mTOR signaling pathway, and decreased the expression of vimentin. Furthermore, a higher RNA level of IFITM3 was found in samples with IFITM3 rs12252-CC genotype rather than the TT genotype.

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Conclusion: The upregulation of IFITM3 plays an important role in the development of HCC, which possibly affects the regulation of HCC cell proliferation and migration. And moreover, these effects are found associated with PI3K/AKT/mTOR signaling pathway. In addition, the upregulation of IFITM3 is strongly associated with the genotype of IFITM3 rs12252-CC.

References: 1. Torre L A, Bray F, Siegel R L, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015,65

(2):87-108.2. Xu Q, Liu X, Liu Z, et al. MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal

transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway[J]. Mol Cancer, 2017,16(1):103.

3. Chen W, Zheng R, Baade P D, et al. Cancer statistics in China, 2015. CA Cancer J Clin, 2016,66(2):115-132.

4. Cui S, Zhang K, Li C, et al. Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A. Oncotarget, 2016,7(47):78009-78028.

5. Palmer D H, Johnson P J. Evaluating the role of treatment-related toxicities in the challenges facing targeted therapies for advanced hepatocellular carcinoma. Cancer Metastasis Rev, 2015,34(3):497-509.

6. Hou Y, Zhang Y, Qin L, Zhang C, Wang S, Chen D, Li A, Lou J, Yu Y, Dong T, Li N, Zhao Y. Interferon-induced transmembrane protein-3 rs12252-CC is associated with low differentiation and progression of hepatocellular carcinoma. Medicine (Baltimore). 2019;98(2):e13996.

7. Zhang Y H, Zhao Y, Li N, et al. Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. Nat Commun, 2013,4:1418.


P-124 THE DEGREE OF HCC DIFFERENTIATION DETERMINES THE DRUG DIFFUSION IN MCTS

Kyungjoo Cho* 1, Hyuk Moon1, Sunyeong Shin1, Woensang S. Ro1, Jun Yong Park 1, 2, Do Young Kim1, 2, Kwang-Hyub Han1, 2

1Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea, 2Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea, Republic Of

Introduction: Hepatocellular carcinoma (HCC) treatment with multikinase inhibitor such as sorafenib is the most option for advanced HCC. Due to tumor heterogeneity, its efficacy greatly varies among patients and is limited due to adverse effects and drug resistance. Previous studies have shown that response to chemotherapy is highly affected by drug permeability through tumor tissue, highlighting the role of tumor microenvironment in cancer chemotherapy. As multi-cellular tumor spheroid (MCTS) is superior to tumor cell monolayer culture in terms of mimicking tumor microenvironment, MCTS seems to be a suitable model for studying drug penetration into tumor.

Posters Posters


Results: A total of 179 patients with HCC were listed for transplant between 2012-2018. Of those, 138 (77.1%) were male. 100 (55.9%) had hepatitis C cirrhosis, 21 (11.7%) had alcoholic cirrhosis, and 14 (7.8%) had non-alcoholic steatohepatitis. For those who underwent transplantation, the mean AFP at diagnosis, evaluation start, listing, and peak AFP prior to transplant listing was significantly lower compared to those not transplanted. For those who dropped off the waitlist, the mean AFP at diagnosis, evaluation start, listing, and peak AFP prior to listing was significantly higher than for those who did not dropout. Finally, mortality was also affected with significantly highermean AFP at diagnosis, evaluation start, listing, and peak AFP prior to transplant listing. (Table)

Conclusions: Our results demonstrate that AFP values at diagnosis of HCC followed by peak AFP prior to transplant listing correlated most significantly with rates of transplant, dropout and mortality. Significantly higher AFP values were noted in patients who dropped out of the list or passed away. This suggests that an early elevated AFP portends a poorer prognosis regardless of subsequent AFP values, and can be a useful tool for predicting outcomes of patients on the transplant list. Future studies should continue to identify the role of biomarkers in determining transplant eligibility and outcomes.


P-131 A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF TRANSARTERIAL CHEMOEMBOLIZATION COMBINED WITH DURVALUMAB OR DURVALUMAB PLUS BEVACIZUMAB THERAPY IN PATIENTS WITH LOCOREGIONAL HEPATOCELLULAR CARCINOMA (HCC): EMERALD-1

Bruno Sangro* 1, Masatoshi Kudo2, Shukui Qin3, Zhenggang Ren 4, Stephen Chan 5, Joseph Erinjeri6, Yasuaki Arai7, Helen Mann8, Shethah Morgan9, Gordon Cohen10, Gordana Vlahovic10, Riccardo Lencioni11

1Liver Unit, Clínica, Clinica Universidad de Navarra, Pamplona, Spain, 2Kinki University School of Medicine, Kindai University, Osaka, Japan, 3Department of Medical Oncology, PLA Cancer Center & Bayi Clinical Trial Institute, Nanjing, 4Zhongshan Hospital, Fudan University, Shanghai, China, 5Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, Hong Kong, 6Memorial Sloan Kettering Cancer Center, New York, United States, 7National Cancer Center, Tokyo, Japan, [email protected], 9AstraZeneca, Cambridge, United Kingdom, 10AstraZeneca, Gaithersburg, United States, 11University of Pisa School of Medicine, Pisa, Italy

Introduction: Since curative therapy is not always feasible and there is no standard systemic therapy, patients with intermediate-stage HCC are treated with locoregional therapy such as transarterial chemoembolization (TACE). TACE therapy achieves tumor responses, but progression and recurrence are common and often occur within 1 year.Early evidence shows encouraging activity and durable clinical response for checkpoint inhibitors (CIs), such as durvalumab, as treatment for advanced HCC (Kelley, et al. ASCO 2017) and combined with TACE (Duffy, et al. J Hepatology, 2017). CIs combined with VEGF inhibitors (Pishvaian, et al. ESMO 2018) also show promise in advanced HCC. Taken together, combining D, VEGF inhibitors, and TACE therapies warrants evaluation in patients with locoregional HCC.EMERALD-1 (NCT03778957) is a randomized, double-blind, placebo-controlled, multicenter Phase 3 study assessing efficacy and safety for durvalumab monotherapy when given with either drug-eluting bead (DEB)-TACE or conventional TACE (cTACE) followed by durvalumab with or without bevacizumab therapy in patients with HCC not amenable to curative therapy.

Methods: 600 patients will be randomized 1:1:1 to Arm A (DEB-TACE or cTACE + durvalumab and following last TACE procedure, durvalumab + placebo), Arm B (DEB-TACE or cTACE + durvalumab followed by durvalumab + bevacizumab), or Arm C (DEB-TACE or cTACE). Durvalumab therapy will begin at least 7 days following the initial TACE procedure. Durvalumab ± bevacizumab will begin at least 14 days following the last TACE procedure. Eligible patients must have confirmed HCC not amenable to curative therapy, have Child-Pugh score class A to B7, and an ECOG PS of 0 or 1. Patients with a history of nephrotic or nephritic syndrome, clinically significant cardiovascular disease, extrahepatic disease, or main portal vein thrombosis (Vp3/Vp4) are excluded. Patients with active (controlled) or past hepatitis virus B or C infection may be enrolled.The primary endpoint is progression-free survival (PFS) for Arm A vs Arm C by blinded independent radiology review using RECIST v1.1. Secondary endpoints include PFS for Arm B vs Arm C, overall survival, health-related quality of life measures, and safety.

Results: N/A

Conclusions: N/A

Disclosure of Interest: B. Sangro Conflict with: Advisory Board - Bayer; Bristol-Myers Squibb; Sirtex Medical, Conflict with: Consulting - AstraZeneca; Bayer; Bristol-Myers Squibb; BTG; Merck; Onxeo; Sirtex Medical, M. Kudo Conflict with: Research/Education grant - - Abbvie (Inst); Astellas Pharma (Inst); Bristol-Myers Squibb Japan (Inst); Chugai Pharma (Inst); Daiichi Sankyo (Inst); Otsuka (Inst); Taiho Pharmaceutical (Inst), Conflict with: Honoraria - Abbvie; Bayer; Bristol-Myers Squibb Japan; EA Pharma; Eisai; Gilead Sciences; Merck Serono; Merck Serono; MSD; Novartis; Pfizer;

22. Bang, J.Y.; Navaneethan, U.; Hasan, M.; Hawes, R.; Varadarajulu, S. (2018) Stent placement by EUS or ERCP for primary biliary decompression in pancreatic cancer: a randomized trial (with videos). GASTROINTEST ENDOSC 88 (1). DOI:10.1016/j.gie.2018.03.012

23. Okuno, N.; Hara, K.; Mizuno, N.; Kuwahara, T.; Iwaya, H.; Ito, A.; Kuraoka, N.; Matsumoto, S.; Polmanee, P.; Niwa, Y. (2018) Efficacy of the 6-mm FCSEMS during EUS-guided hepaticogastrostomy as a primary biliary drainage for the cases estimated difficult ERCP: a prospective clinical study. Journal of Gastroenterology & Hepatology. DOI: 10.1111/jgh.14112.

24. Pang, L.; Zhang, Y.; Wang, Y.; Kong, J. (2018) Transcystic versus traditional laparoscopic common bile duct exploration: its advantages and a meta-analysis. SURG ENDOSC 32 (11), 4363-4376.

25. Lyu, Y.; Cheng, Y.; Wang, B.; Zhao, S.; Chen, L. (2018) Early versus delayed laparoscopic cholecystectomy for acute cholecystitis: an up-to-date meta-analysis of randomized controlled trials. SURG ENDOSC 32 (12), 4728-4741.

26. Higgins, J.P.; Thompson, S.G.; Deeks, J.J.; Altman, D.G. (2003) Measuring inconsistency in meta-analyses. BMJ 327 (7414), 557-560.

27. Higgins, J.P.; Thompson, S.G. (2002) Quantifying heterogeneity in a meta-analysis. STAT MED 21 (11), 1539. DOI:10.1002/sim.1186

28. Paik, W.H.; Lee, T.H.; Park, D.H.; Choi, J.H.; Kim, S.O.; Jang, S.; Kim, D.U.; Shim, J.H.; Song, T.J.; Lee, S.S.; Seo, D.W.; Lee, S.K.; Kim, M.H. (2018) Correction: EUS-Guided Biliary Drainage Versus ERCP for the Primary Palliation of Malignant Biliary Obstruction: A Multicenter Randomized Clinical Trial. AM J GASTROENTEROL. DOI: 10.1038/s41395-018-0238-x.

29. Giovannini, M.; Moutardier, V.; Pesenti, C.; Bories, E.; Lelong, B.; Delpero, J.R. (2001) Endoscopic ultrasound-guided bilioduodenal anastomosis: a new technique for biliary drainage. ENDOSCOPY 33 (10), 898-900.

30. Castano, R.; Lopes, T.L.; Alvarez, O.; Calvo, V.; Luz, L.P.; Artifon, E.L. (2010) Nitinol biliary stent versus surgery for palliation of distal malignant biliary obstruction. SURG ENDOSC 24 (9), 2092-2098.

31. Ban, T.; Kawakami, H.; Kubota, Y. (2018) Transgastric reintervention for self-expandable metallic stent dysfunction following endoscopic ultrasonography-guided hepaticogastrostomy. Dig Endosc 30 (5), 682-683.

32. Vila, J.J.; Perez-Miranda, M.; Vazquez-Sequeiros, E.; Abadia, M.A.; Perez-Millan, A.; Gonzalez-Huix, F.; Gornals, J.; Iglesias-Garcia, J.; De la Serna, C.; Aparicio, J.R.; Subtil, J.C.; Alvarez, A.; de la Morena, F.; Garcia-Cano, J.; Casi, M.A.; Lancho, A.; Barturen, A.; Rodriguez-Gomez, S.J.; Repiso, A.; Juzgado, D.; Igea, F.; Fernandez-Urien, I.; Gonzalez-Martin, J.A.; Armengol-Miro, J.R. (2012) Initial experience with EUS-guided cholangiopancreatography for biliary and pancreatic duct drainage: a Spanish national survey. GASTROINTEST ENDOSC 76 (6), 1133-1141.

33. Martins, F.P.; Rossini, L.G.; Ferrari, A.P. (2010) Migration of a covered metallic stent following endoscopic ultrasound-guided hepaticogastrostomy: fatal complication. ENDOSCOPY 42 (S 02), E126-E127.

34. Kawakubo, K.; Isayama, H.; Kato, H.; Itoi, T.; Kawakami, H.; Hanada, K.; Ishiwatari, H.; Yasuda, I.; Kawamoto, H.; Itokawa, F. (2013) Multicenter retrospective study of endoscopic ultrasound-guided biliary drainage for malignant biliary obstruction in Japan. GASTROINTEST ENDOSC 77 (5), AB417-AB417.

35. Lu, L.; Tang, X.; Jin, H.; Yang, J.; Zhang, X. (2017) Endoscopic Ultrasound-Guided Biliary Drainage Using Self-Expandable Metal Stent for Malignant Biliary Obstruction. Gastroenterology Research and Practice, (2017-4-4) 2017, 1-10.

36. Ogura, T.; Sano, T.; Onda, S.; Imoto, A.; Masuda, D.; Yamamoto, K.; Kitano, M.; Takeuchi, T.; Inoue, T.; Higuchi, K. (2015) Endoscopic ultrasound-guided biliary drainage for right hepatic bile duct obstruction: novel technical tips. ENDOSCOPY 47 (1), 72-75.

37. Park, S.J.; Choi, J.H.; Park, D.H.; Choi, J.H.; Lee, S.S.; Seo, D.W.; Lee, S.K.; Kim, M.H. (2013) Expanding indication: EUS-guided hepaticoduodenostomy for isolated right intrahepatic duct obstruction (with video). GASTROINTEST ENDOSC 78 (2), 374-380.


P-130 ALPHA FETOPROTEIN LEVELS: WHEN DO THEY CORRELATE STRONGEST WITH OUTCOMES?



Introduction: For patients with hepatocellular carcinoma (HCC) on the transplant list, alpha-fetoprotein (AFP) levels are obtained in conjunction with imaging at regular intervals for disease surveillance. Routine surveillance provides information regarding progression of disease as well as response to therapy. In this study, we investigated whether AFP levels correlated with rates of transplant, list dropout, and mortality, and if so, at which point in the transplant process they correlated strongest.

Methods: Patients with HCC listed for transplant between 2012-2018 at a tertiary care high volume transplant center were included in this study. Patients were excluded if HCC was incidentally noted in the explant only. Data collected included patient demographics, mortality, date of listing, date of evaluation, and date of transplant or dropout. AFP levels were recorded at each of these time points. The Wilcoxon Rank Sum Test was then used to determine which AFP values correlated strongest with outcomes including rates of transplant, risk of dropout from the waitlist and mortality.

3. Tempero, M.A.; Malafa, M.P.; Al-Hawary, M.; Asbun, H.; Bain, A.; Behrman, S.W.; Benson, A.R.; Binder, E.; Cardin, D.B.; Cha, C.; Chiorean, E.G.; Chung, V.; Czito, B.; Dillhoff, M.; Dotan, E.; Ferrone, C.R.; Hardacre, J.; Hawkins, W.G.; Herman, J.; Ko, A.H.; Komanduri, S.; Koong, A.; LoConte, N.; Lowy, A.M.; Moravek, C.; Nakakura, E.K.; O'Reilly, E.M.; Obando, J.; Reddy, S.; Scaife, C.; Thayer, S.; Weekes, C.D.; Wolff, R.A.; Wolpin, B.M.; Burns, J.; Darlow, S. (2017) Pancreatic Adenocarcinoma, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 15 (8), 1028-1061.

4. Peng, C.; Nietert, P.J.; Cotton, P.B.; Lackland, D.T.; Romagnuolo, J. (2013) Predicting native papilla biliary cannulation success using a multinational Endoscopic Retrograde Cholangiopancreatography (ERCP) Quality Network. BMC GASTROENTEROL, 13, 147. DOI:10.1186/1471-230X-13-147

5. Enochsson, L.; Swahn, F.; Arnelo, U.; Nilsson, M.; Lohr, M.; Persson, G. (2010) Nationwide, population-based data from 11,074 ERCP procedures from the Swedish Registry for Gallstone Surgery and ERCP. GASTROINTEST ENDOSC 72 (6), 1175-84, 1184.e1-e3.

6. Williams, E.J.; Ogollah, R.; Thomas, P.; Logan, R.F.; Martin, D.; Wilkinson, M.L.; Lombard, M. (2012) What predicts failed cannulation and therapy at ERCP? Results of a large-scale multicenter analysis. ENDOSCOPY, 44 (7) 674-683.

7. Tol, J.A.; van Hooft, J.E.; Timmer, R.; Kubben, F.J.; van der Harst, E.; de Hingh, I.H.; Vleggaar, F.P.; Molenaar, I.Q.; Keulemans, Y.C.; Boerma, D.; Bruno, M.J.; Schoon, E.J.; van der Gaag, N.A.; Besselink, M.G.; Fockens, P.; van Gulik, T.M.; Rauws, E.A.; Busch, O.R.; Gouma, D.J. (2016) Metal or plastic stents for preoperative biliary drainage in resectable pancreatic cancer. GUT 65 (12), 1981-1987.

8. Angsuwatcharakon, P.; Rerknimitr, R.; Ridtitid, W.; Ponauthai, Y.; Kullavanijaya, P. (2012) Success rate and cannulation time between precut sphincterotomy and double-guidewire technique in truly difficult biliary cannulation. J Gastroenterol Hepatol 27 (2), 356-361.

9. Lee, J.H.; Krishna, S.G.; Singh, A.; Ladha, H.S.; Slack, R.S.; Ramireddy, S.; Raju, G.S.; Davila, M.; Ross, W.A. (2013) Comparison of the utility of covered metal stents versus uncovered metal stents in the management of malignant biliary strictures in 749 patients. GASTROINTEST ENDOSC 78 (2), 312-24.

10. Kawakubo, K.; Kawakami, H.; Kuwatani, M.; Kubota, Y.; Kawahata, S.; Kubo, K.; Sakamoto, N. (2016) Endoscopic ultrasound-guided choledochoduodenostomy vs. transpapillary stenting for distal biliary obstruction. ENDOSCOPY 48 (2), 164-169.

11. Dhir, V.; Itoi, T.; Khashab, M.A.; Park, D.H.; Yuen, B.T.A.; Attam, R.; Messallam, A.; Varadarajulu, S.; Maydeo, A. (2015) Multicenter comparative evaluation of endoscopic placement of expandable metal stents for malignant distal common bile duct obstruction by ERCP or EUS-guided approach. GASTROINTEST ENDOSC 81 (4), 913-923.

12. Sharaiha, R.Z.; Kumta, N.A.; Desai, A.P.; Defilippis, E.M.; Gabr, M.; Sarkisian, A.M.; Salgado, S.; Millman, J.; Benvenuto, A.; Cohen, M. (2016) Endoscopic ultrasound-guided biliary drainage versus percutaneous transhepatic biliary drainage: predictors of successful outcome in patients who fail endoscopic retrograde cholangiopancreatography. Surgical Endoscopy 30 (12), 1-6.

13. Sharaiha, R.Z.; Khan, M.A.; Kamal, F.; Tyberg, A.; Tombazzi, C.R.; Ali, B.; Tombazzi, C.; Kahaleh, M. (2017) Efficacy and safety of EUS-guided biliary drainage in comparison with percutaneous biliary drainage when ERCP fails: a systematic review and meta-analysis. GASTROINTEST ENDOSC 85 (5), 904-914.

14. Baniya, R.; Upadhaya, S.; Madala, S.; Subedi, S.C.; Mohammed, T.S.; Bachuwa, G. (2017) Endoscopic ultrasound-guided biliary drainage versus percutaneous transhepatic biliary drainage after failed endoscopic retrograde cholangiopancreatography: a meta-analysis. Clinical & Experimental Gastroenterology 10, 67-74.

15. Park, D.H.; Song, T.J.; Eum, J.; Moon, S.H.; Lee, S.S.; Seo, D.W.; Lee, S.K.; Kim, M.H. (2010) EUS-guided hepaticogastrostomy with a fully covered metal stent as the biliary diversion technique for an occluded biliary metal stent after a failed ERCP (with videos). GASTROINTEST ENDOSC 71 (2), 413-419.

16. Dhir, V.; Bhandari, S.; Bapat, M.; Maydeo, A. (2012) Comparison of EUS-guided rendezvous and precut papillotomy techniques for biliary access (with videos). GASTROINTEST ENDOSC 75 (2), 354-359.

17. Hara, K.; Yamao, K.; Hijioka, S.; Mizuno, N.; Imaoka, H.; Tajika, M.; Kondo, S.; Tanaka, T.; Haba, S.; Takeshi, O. (2013) Prospective clinical study of endoscopic ultrasound-guided choledochoduodenostomy with direct metallic stent placement using a forward-viewing echoendoscope. ENDOSCOPY 45 (05), 392-396.

18. Artifon, E.L.A.; Okawa, L.; Takada, J.; Gupta, K.; Moura, E.G.H.; Sakai, P. (2011) EUS-guided choledochoantrostomy: an alternative for biliary drainage in unresectable pancreatic cancer with duodenal invasion. GASTROINTEST ENDOSC 73 (6), 1317-1320.

19. Brewer, G.O.; Nieto, J.; Irani, S.; James, T.; Pieratti, B.R.; Chen, Y.I.; Bukhari, M.; Sanaei, O.; Kumbhari, V.; Singh, V.K.; Ngamruengphong, S.; Baron TH; Khashab, M.A. (2017) Double endoscopic bypass for gastric outlet obstruction and biliary obstruction. Endosc Int Open 5 (9), E893-E899.

20. Park, J.K.; Woo, Y.S.; Noh, D.; Yang, J.I.; Bae, S.Y.; Yun, H.S.; Lee, J.K.; Lee, K.T.; Lee, K.H. (2018) Efficacy of EUS- and ERCP-guided biliary drainage for malignant biliary obstruction: prospective randomized controlled study. GASTROINTEST ENDOSC. DOI: 10.1016/j.gie.2018.03.015.

21. Paik, W.H.; Lee, T.H.; Park, D.H.; Choi, J.H.; Kim, S.O.; Jang, S.; Kim, D.U.; Shim, J.H.; Song, T.J.; Lee, S.S.; Seo, D.W.; Lee, S.K.; Kim, M.H. (2018) EUS-Guided Biliary Drainage Versus ERCP for the Primary Palliation of Malignant Biliary Obstruction: A Multicenter Randomized Clinical Trial. AM J GASTROENTEROL 113 (7), 987-997.

25. Rerknimitr R, Angsuwatcharakon P, Ratanachu-Ek T, et al. Asia-Pacific Consensus Recommendations for Endoscopic and Interventional Management of Hilar Cholangiocarcinoma. Journal of Gastroenterology & Hepatology 2013;28:593-607.

26. Yamaguchi K, Okusaka T, Shimizu K, et al. Clinical Practice Guidelines for Pancreatic Cancer 2016 from the Japan Pancreas Society: A Synopsis. Pancreas 2017;46:595.

27. Masaru M, Hideyuki Y, Shuichi M, et al. Clinical Practice Guidelines for the Management of Biliary Tract Cancers 2015: The 2(Nd) English Edition. Journal of Hepato-Biliary-Pancreatic Sciences 2015;22:249-273.

28. China Anti-Cancer Association Guideline for the diagnosis and therapy of hilar cholangiocarcinoma (2015) Chinese Journal of Hepatobiliary Surgery. DOI: 10.3760/cma.j.issn.1007-8118.2015.08.001.

29. CACA Guideline for the diagnosis and treatment on inferior bile duct and ampullary carcinomas. National conference on biliary cancer of China Anti-cancer Association Biliary cancer professional committee.2011, 2011..

30. J Gu, KL Tian, ZL Chen, et, al. Efficacy of preoperative biliary drainage in the pancreatico-duodenectomy for malignant obstruction jaundice: a Meta-analysis. Chinese Journal of Digestive Surgery 2015; 14(4):298-304.

31. Celotti A, Solaini L, Montori G, et al. Preoperative Biliary Drainage in Hilar Cholangiocarcinoma: Systematic Review and Meta-Analysis. European Journal of Surgical Oncology the Journal of the European Society of Surgical Oncology & the British Association of Surgical Oncology 2017.

32. Mahjoub AA, Menahem B, Fohlen A, et al. Preoperative Biliary Drainage in Patients with Resectable Perihilar Cholangiocarcinoma: Is Percutaneous Transhepatic Biliary Drainage Safer and More Effective Than Endoscopic Biliary Drainage? A Meta-Analysis. Journal of Vascular & Interventional Radiology 2017;28:576-582.

33. Takahashi Y, Nagino M, Nishio H, et al. Percutaneous Transhepatic Biliary Drainage Catheter Tract Recurrence in Cholangiocarcinoma. Br J Surg 2010;97:1860-1866.


P-129 ENDOSCOPIC ULTRASOUND-GUIDED BILIARY DRAINAGE VERSUS ENDOSCOPIC RETROGRADE CHOLANGIOPANCREATOGRAPHY FOR THE PRIMARY PALLIATION OF MALIGNANT BILIARY OBSTRUCTION: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS.

Nanping Lin* 1, Lei Wang1, Yongyi Zeng1, Jingfeng Liu1


Introduction: Endoscopic ultrasound biliary drainage (EUS-BD) has been an alternative treatment for percutaneous transhepatic biliary drainage (PTBD) after endoscopic retrograde cholangiopancreatography (ERCP) failed, but it remained a controversial that EUS-BD be taken as first-line procedure for the primary palliation of malignant biliary obstruction (MBO). To address this, we conducted a meta-analysis of randomized controlled trials (RCTs).

Methods: Eligible studies were searched by PubMed, MedLine, and so on, from Jan 1st 1990 to Aug 30st 2018. Comparing the efficacy and safety between EUS-BD and ERCP for the primary palliation of MBO, primary endpoint was the procedure–related adverse events, including pancreatitis, cholangitis, bile peritonitis, and pneumoperitoneum. Secondary endpoints included technical success, clinical success, and re-intervention. Effect size on outcomes was calculated using a fixed- or random-effect model, accompanied with risk ratio (RR) and 95% confidence interval (CI).

Results: Three RCTs were enrolled in this meta-analysis, including 111 cases in the EUS-BD group and 109 cases in the ERCP group, respectively. And, all the MBO occurred at the distal duct. Results showed that EUS-BD was superior to ERCP in pancreatitis (RR=0.09, 95%CI 0.01~0.67, P=0.02) and re-intervention rate (RR=0.40, 95%CI 0.23~0.72, P=0.002). While, it was equivalent between EUS-BD and ERCP in the rate of technical success, and clinical success. And, there were no differences between EUS-BD and ERCP in the rate of cholecystitis, bile peritonitis and pneumoperitoneum.

Conclusions: EUS-BD was associated with fewer re-intervention and pancreatitis rates, and comparable technical and clinical success rates, compared with ERCP for the primary palliation of MBO. Hence, EUS-BD could be preferentially in selected patients, such as distant MBO.

References: 1. Nakai, Y.; Isayama, H.; Yamamoto, N.; Matsubara, S.; Kogure, H.; Mizuno, S.; Hamada, T.;

Takahara, N.; Uchino, R.; Akiyama, D. (2017) Indications for endoscopic ultrasonography (EUS)-guided biliary intervention: Does EUS always come after failed endoscopic retrograde cholangiopancreatography? DIGEST ENDOSC 29 (5), AB332-AB332.

2. O'Reilly, D.; Fou, L.; Hasler, E.; Hawkins, J.; O'Connell, S.; Pelone, F.; Callaway, M.; Campbell, F.; Capel, M.; Charnley, R.; Corrie, P.; Elliot, D.; Goodburn, L.; Jewell, A.; Joharchi, S.; McGeeney, L.; Mukherjee, S.; Oppong, K.; Whelan, P.; Primrose, J.; Neoptolemos, J. (2018) Diagnosis and management of pancreatic cancer in adults: A summary of guidelines from the UK National Institute for Health and Care Excellence. PANCREATOLOGY18 (8), 962-970.

Posters Posters


Image:

Conclusions: In this Latin American cohort, the only prognostic factor associated with post progression survival was early recurrence presentation. Sytemic treatment after recurrence was associated with better post progression survival regardless of time to recurrence.

Disclosure of Interest: F. Piñero Conflict with: Research/Education grant - National Institute of Cancer, Argentina, Conflict with: Honoraria - Bayer, Conflict with: Advisory Board - Bayer, I. Boin: None Declared, A. Chagas: None Declared, E. Quiñonez: None Declared, S. Marciano: None Declared, M. Vilatoba: None Declared, A. Varón: None Declared, M. Anders: None Declared, S. Hoyos Duque: None Declared, A. Soares Lima: None Declared, J. Menéndez: None Declared, M. Padilla-Machaca: None Declared, J. Poniachik: None Declared, R. Zapata: None Declared, M. Maraschio: None Declared, R. Chong Menéndez: None Declared, L. Muñoz Espinosa: None Declared, D. Arufe: None Declared, R. Figueroa: None Declared, A. Soza: None Declared, M. Fauda: None Declared, S. Perales Reges: None Declared, C. Maccali: None Declared, R. Vergara Sandoval: None Declared, C. Bermúdez: None Declared, L. Santos: None Declared, I. Arenas: None Declared, O. Gil: None Declared, S. Gerona: None Declared, L. McCormack: None Declared, J. Mattera: None Declared, A. Gadano: None Declared, J. Parente García: None Declared, F. Carrilho: None Declared, M. Silva: None Declared

P-135 DEVELOPMENT AND EXTERNAL VALIDATION OF PROGNOSTIC NOMOGRAMS IN HEPATOCELLULAR CARCINOMA PATIENTS: A POPULATION BASED STUDY

Yongcong Yan* 1, Kai Mao1, Haohan Liu1, Changliang Lai1, Jianlong Zhang1, Jie Wang1, Zhiyu Xiao1

1Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

Introduction: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second most deadly cause of cancer mortality worldwide. Improvements in treatment strategies have markedly improved the overall survival (OS) and cancer-specific survival (CSS) of HCC patients, although the long-term survival rate remains low. We attempted to construct and validate novel nomograms to predict OS and CSS in HCC patients.

Methods: A total of 15394 HCC patients were included in the study and randomly divided into a discovery set (n=10262) and an internal testing set (n=5132) obtained from the Surveillance, Epidemiology, and End Results (SEER) database. We used a univariate Cox regression analysis to screen for clinicopathological risk factors for OS and CSS in the SEER discovery set. We further performed multivariate Cox regression analysis to screen for independent important factors for HCC patients without violating the PH assumption. Based on univariate and multivariate Cox regression analyses, we identified independent risk factors for OS and CSS. Concordance indexes (c-indexes) were used to evaluate model discrimination. Calibration plots were constructed to validate the accuracy and reliability of the nomograms. The predictive accuracy and clinical values were measured by decision curve analysis (DCA).

Results: The 1-, 3- and 5-year OS rates were 63.99%, 40.91%, 30.78% and 80.10%, 58.36%, 45.19%, respectively, while the 1-, 3- and 5-year CSS rates were 73.12%, 54.25%, 45.42% and 88.68%, 69.70%, 50.23% in the SEER and the Sun Yat-sen Memorial Hospital (SYMH) cohorts. The c-index for the OS prediction nomogram was 0.753 (95% CI, 0.745-0.761) based on age, sex, race, marital status, histological grade, TNM stage, tumor size, and surgery performed in the discovery set, while the c-indexes for TNM stage, histologic grade and tumor size for OS prediction were 0.555 (95% CI, 0.547-0.563), 0.654 (95% CI, 0.646-0.662), and 0.618 (95% CI, 0.612-0.624), respectively. Similarly, Our CSS nomogram with a c-index of 0.748 (95% CI, 0.740-0.756) was higher than the c-indexes for TNM stage, grade and tumor size. The calibration curves fit well. DCA showed that the two nomograms provided substantial clinical value. Based on risk stratification

Conclusions: HCC patients with EGV who underwent SR had a significantly higher OS and RFS rates than those who received RFA. Hence, SR could be recommended as the first-line treatment modality for patients with HCC and with EGV.

Disclosure of Interest: C.-Y. Wei: None Declared, C.-W. Su Conflict with: Advisory Board - Gilead Sciences, W.-Y. Kao: None Declared, P.-H. Chen: None Declared, Y.-H. Huang: None Declared, M.-C. Hou: None Declared, J.-C. Wu: None Declared

P-134 ANALYSIS OF PROGNOSTIC AND PREDICTIVE FACTORS OF POST RECURRENCE SURVIVAL AFTER LIVER TRANSPLANTATION FOR HEPATOCELLULAR CARCINOMA: A MULTICENTER COHORT STUDY FROM LATIN AMERICA

Federico Piñero* 1, 2, Ilka Boin3, Aline Chagas4, Emilio Quiñonez5, Sebastián Marciano6, 7, Mario Vilatoba8, Adriana Varón9, Margarita Anders10, Sergio Hoyos Duque11, 12, Agnaldo Soares Lima13, Josemaría Menéndez14, Martín Padilla-Machaca15, Jaime Poniachik16, Rodrigo Zapata17, Martín Maraschio18, Ricardo Chong Menéndez19, Linda Muñoz Espinosa20, Diego Arufe21, Rodrigo Figueroa22, Alejandro Soza23, Martín Fauda1, Simone Perales Reges24, Claudia Maccali4, Rodrigo Vergara Sandoval5, Carla Bermúdez6, Luisa Santos9, Isabel Arenas11, Octavio Gil22, Solange Gerona14, Lucas McCormack10, Juan Mattera5, Adrian Gadano6, Jose H. Parente García25, Flair Carrilho4, Marcelo Silva1, 26

1Liver Unit, Hospital Universitario Austral, Pilar, 2Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires, Argentina, 3Liver Transplantation, Hospital das Clínicas UNICAMP Campiñas, Campiñas, 4Hepatology and Gastroenterology, Hospital das Clínicas University of São Paulo School of Medicine, São Paulo, Brazil, 5Liver Transplantation and Hepatobiliary Surgery, Hospital El Cruce, Florencia Varela, 6Hepatology Section., 7Department of Clinical Research, Hospital Italiano, Buenos Aires, Argentina, 8Liver Transplantation and Hepatobiliary Surgery, Instituto de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico DF, Mexico, 9Hepatology and Gastroenterology, Fundación Cardioinfantil, Bogotá, Colombia, 10Liver Transplantation and Hepatobiliary Surgery, Hospital Alemán, Buenos Aires, Argentina, 11HPB and Liver Transplant Program, Hospital Pablo Tobón Uribe, 12Grupo de Gastrohepatología, Universidad de Antioquia, Medellín, Colombia, 13Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas da UFMG, Minas Gerais, Brazil, 14Liver Transplantation and Hepatology, Hospital de Clínicas, Montevideo, Uruguay, 15Departamento de Trasplantes, Hospital Nacional Guillermo Almenara, Lima, Peru, 16Hepatology and Gastroenterology, Hospital Clínico de la Universidad de Chile, 17Hepatology and Gastroenterology, Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile, 18Hepatology and Gastroenterology, Hospital Privado, Córdoba, Argentina, 19Hepatology, Hospital Metropolitano, Quito, Ecuador, 20Hepatology, Hospital Universitario “Dr. José E. González”, Monterrey, Mexico, 21Liver Unit, Sanatorio Sagrado Corazón, Buenos Aires, 22Liver Transplantation and Hepatobiliary Surgery, Sanatorio Allende, Córdoba, Argentina, 23Hospital de la Universidad Catól¡ca, Santiago, Chile, 24Liver Transplantation and Hepatobiliary Surgery, Hospital das Clínicas UNICAMP Campiñas, Campiñas, 25Liver Transplantation and Hepatobiliary Surgery, Hospital University of Ceará, Ceará, Brazil, 26Latin American Liver Research and Awareness Network, Buenos Aires, Argentina

Introduction: Patients with recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) have been excluded from first and second line trials of systemic treatments of HCC. However, in the daily practice, many of these patients are treated with antiangiogenics or other therapies. With the advent of new systemic treatment options, knowing prognostic factors of post-recurrence survival would be useful to select better candidates for such treatments. We aimed to assess prognostic and predictive variables of post recurrence survival in a Latin American cohort study.

Methods: This multicenter and multinational cohort study conducted in Latin America included adult patients who received a first LT for HCC between years 2005-2018. Surveillance for HCC recurrence was done with triphasic imaging scans with/without alpha-fetoprotein levels every 3-6 months after transplantation. Post progression survival (or post recurrence survival) was considered as the main end-point and was analyzed from the date of recurrence diagnosis until death or last follow-up. Type of HCC recurrence at diagnosis was registered: liver, extrahepatic (lungs, bones, other metastasis). Time to recurrence was calculated since date of transplantation to recurrence diagnosis and “early recurrence” was considered when presented during the first 12 months after transplant. Associated exposure variables with post progression survival were evaluated by a multivariable Cox regression analysis, with Hazard Ratios (HR) and 95% confidence intervals calculated (95% CI).

Results: From a total of 1085 transplanted patients with HCC, 105 presented recurrence, with a cumulative incidence of 9.7% (CI 7.9-11.6%) during a median post transplant follow-up of 26.5 months (range 7.8-48.9 months). Median time to recurrence was 13.0 months (range 6.0-26.0 months), 47.6% (n=50) presented with early recurrence. Regarding the type of tumor recurrence at diagnosis, 44.7% presented with liver involvement and 76.2% with extrahepatic metastasis (lungs n=36, bones n=33, other n=29). Overall, treatment after recurrence was performed in 55.2% of the patients (n=58/105). Independent prognostic variables at HCC recurrence diagnosis were evaluated and the only tumor factor associated with worst post progression survival was early recurrence with an adjusted HR of 1.92 (CI 1.22; 3.03). After adjusting this prognostic factor with predictive variables after treatment of HCC recurrence, any locorregional therapy (surgery/TACE) HR 0.29 (CI 0.14;0.61; P=0.001) and treatment with sorafenib HR 0.36 (CI 0.22;0.59; P<0.0001) were independently associated with better post recurrence survival. The effect of sorafenib was independent from HCC recurrence presentation, either early or late recurrence (Figure).

with: Honoraria - no, Conflict with: Stocks - no, Conflict with: Advisory Board - no, Conflict with: Consulting - no, A. Prieto: None Declared, A. Mesa Conflict with: Research/Education grant - no, Conflict with: Honoraria - no, Conflict with: Stocks - no, Conflict with: Advisory Board - no, Conflict with: Consulting - no, C. Álvarez-Navascués Conflict with: Advisory Board - Gilead, Abbvie, Intercept, Conflict with: Consulting - Gilead, M. L. González-Diéguez Conflict with: Research/Education grant - NO, Conflict with: Honoraria - NO, Conflict with: Stocks - NO, Conflict with: Advisory Board - Gilead, Abbvie, Novartis, Conflict with: Consulting - Gilead, V. Cadahía Conflict with: Research/Education grant - none, Conflict with: Honoraria - none, Conflict with: Stocks - none, Conflict with: Advisory Board - none, Conflict with: Consulting - none, M. Rodríguez Conflict with: Advisory Board - Intercept, Abbvie, Gilead, MSD, Conflict with: Consulting - Intercept, Abbvie, Gilead, MSD, M. Varela Conflict with: Advisory Board - Bayer, BMS, BTG, Sirtex

P-133 A COMPARISON OF PROGNOSIS BETWEEN SURGICAL RESECTION AND RADIOFREQUENCY ABLATION THERAPY FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA AND WITH ESOPHAGOGASTRIC VARICES

Cheng-Yi Wei* 1, Chien-Wei Su1, Wei-Yu Kao2, Ping-Hsien Chen3, Yi-Hsiang Huang1, Ming-Chih Hou1, Jaw-Ching Wu4

1Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, 3Endoscopy Center for Diagnosis and Treatment, 4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Province of China

Introduction: Surgical resection (SR) is not recommended for patients with hepatocellular carcinoma (HCC) and with esophagogastric varices (EGV) due to the potential risk of post-hepatectomy liver failure by the current HCC practice guidelines. Instead, radiofrequency ablation (RFA) therapy is suggested in this clinical setting. However, the treatment efficacy and long-term outcomes between SR and RFA for such patients has not been well investigated till now. We aimed to compare the long-term prognosis between SR and RFA for patients with HCC and with EGV

Methods: This retrospective study enrolled 251 patients with treatment-naïve HCC and with EGV who underwent SR or RFA as the first-line treatment from 2003 to 2017. EGV was diagnosed by an esophagogastroduodenoscopy at the time of HCC diagnosis. Prognostic factors were analyzed by the Cox proportional hazards model.

Results: A total of 68 patients underwent SR and the remaining 183 patients received RFA, respectively. Compared to their counterparts, patients who underwent SR were younger in age, more male gender, more presence of hepatitis B surface antigen in sera, larger tumor size, lower alpha-fetoprotein (AFP) level and better liver functional reserve presenting by higher serum albumin level, lower total bilirubin and shorter prothrombin time, and higher platelet counts. After a median follow-up duration of 45.1 months, 151 patients died. The cumulative 5-year overall survival (OS) rate was significantly higher in patients who underwent SR than those treated by RFA (66.7% vs. 36.8%, P <0.001). Multivariate analysis showed that patient with age > 65 years (hazard ratio HR 1.778, 95% confidence interval CI 1.261- 2.507, p =0.01), RFA (HR 2.093, 95% CI 1.315- 3.332, p =0.002), multiple tumors (HR 1.478, 95% CI 1.026- 2.129, p =0.036), and serum albumin level less than 3.5g/dL (HR 1.539, 95% CI 1.059- 2.163, p =0.013) were the independent risk factors predictive of poor OS for HCC patients with EGV. Regarding tumor recurrence, multivariate analysis disclosed that serum albumin < 3.5 g/dL (HR: 1.562, 95% CI 1.179-2.068, p=0.002), AFP > 20 ng/mL (HR 1.367, 95% CI 1.041-1.794, p=0.025), multiple tumors (HR 1.447, 95% CI 1.048-1.999, p=0.025) and RFA (HR 1.400, 95% CI 1.015-1.930, p=0.040) were associated with poorer recurrence-free survival (RFS). Subgroup analysis also demonstrated that patients who underwent RFA had poorer OS and RFS compared to those underwent SR in most of the subgroups.

Image:

Taiho , Conflict with: Consulting - Bayer; Bristol-Myers Squibb; Eisai; MSD, S. Qin : None Declared, Z. Ren : None Declared, S. Chan Conflict with: Research/Education grant - Novartis; Sirtex Medical, Conflict with: Honoraria - Bayer, Conflict with: Advisory Board - Amgen; Bayer; Eisai, Conflict with: Consulting - AstraZeneca/ MedImmune; MSD Oncology; Novartis, J. Erinjeri Conflict with: Consulting - Galil Medical, AstraZeneca, BTG, Canon, Y. Arai Conflict with: Honoraria - Guerbet Japan; Kyorin Pharma; Canon Medical, Fuji Pharma, Sumitomo Bakelite, Conflict with: Advisory Board - Japan Lifeline, Kyorin Pharma, H. Mann Conflict with: Stocks - AstraZeneca, Conflict with: Consulting - AstraZeneca, S. Morgan Conflict with: Stocks - AstraZeneca, Conflict with: Consulting - AstraZeneca, G. C. Gordon Cohen Conflict with: Stocks - AstraZeneca, Conflict with: Consulting - AstraZeneca, G. V. Gordana Vlahovic Conflict with: Stocks - AstraZeneca, Conflict with: Consulting - AstraZeneca, R. Lencioni Conflict with: Research/Education grant - BTG, Conflict with: Consulting - Bayer; BTG; Eisai; Guerbet

P-132 IMPORTANCE OF COMORBIDITY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) TREATED WITH PERCUTANEOUS TERMOABLATION

Pablo Florez1, Maria Torner-Simó1, Andrés Castaño-García1, Amador Prieto2, Alicia Mesa2, Carmen Álvarez-Navascués1, Maria Luisa González-Diéguez1, Valle Cadahía1, Manuel Rodríguez1, Maria Varela* 1, and Multidisciplinary team of HCC of Hospital Universitario Central de Asturias

1Liver Unit, 2Radiology, Hospital Universitario Central de Asturias, Oviedo, Spain

Introduction: Thermal ablation is the standard of care for patients with HCC stage BCLC 0-A not suitable for surgery. At least 40% of patients with cirrhosis have comorbidities that increase mortality. Different models such as Charlson comorbidity index (CCI) and CirCom score have been proposed to measure the impact of comorbidities in survival, although they have not been evaluated in patients with initial HCC subjected to termoablation.

Aim: Analysis of comorbidities as predictors of mortality in patients treated with percutaneous termoablation (radiofrequency (RF) or microwave (MW)).

Methods: Retrospective observational unicentric study on patients with HCC who received RF / MW as initial treatment decided on a multidisciplinary committee (MC). Visits were made at baseline, one month post-RF/MW and every 4 months if evidence of a complete response (mRECIST criteria), deciding subsequent therapies in MC in case of partial response, stable disease or progression. Presence of comorbidities diagnosed in each patient, both individually and as part of the CCI and CirCom, as well as the pharmacological treatments at the time of the first thermoablation were assessed.

Results: from Apr-2014 to Mar-2019 95 patients were included, follow-up until Mar 25th 2019. Majority were male (n=78), median age 69 years (IQR 61-76), cirrhotic (n=81); alcohol (n=44), hepatitis C (n=35); Child A-5 (n=56), BCLC-A (n=72), treated with RF (n=48) MW (n=47). There were no differences in mortality regarding type of ablation (RF vs MW), size of the tumor (less or greater than 2 cm) or number of tumors (uninodular vs 2-3 nodules).Nine comorbidities have been included in the CirCom score based on Cox regression to assign severity weights to comorbilities with an adjusted mortality hazard ratio ≥ 1.20. The frequency of these comorbidities in our cohort is: chronic obstructive pulmonary disease (COPD) n=14 (14.7%), acute myocardial infarction (AMI) n=9 (9.5%), peripheral arterial disease n=12 (12.6%), epilepsy n=6 (6.3%), substance abuse (excluding alcohol) n=6 (6.3%), heart failure n=11 (11.6%), nonmetastatic cancer n=18 (18.9%), metastatic cancer n=0, and chronic kidney disease n=4 (4.2%). Two important diseases not included in CirCom were present in 66.3% of patients, diabetes (n=35, 36.8%) and arterial hypertension (n=39, 41.1%).Median survival censored at the end of the follow up was 40 months (95% CI 36.262-43.738; IQR 28-56). At multivariate analysis, 2 comorbidities were independent predictors of survival, AMI (22 vs 40 months; p=0.042, HR 3.332, 95% CI 1.044-10.637) and diabetes (38 vs 56 months; p=0.041, HR 2.551, 95% CI 1.037-6.274). The median CCI was 8 (IQR 7-10) and it is an independent predictor of survival (p=0.012, HR 1.423, 95% CI 1.082-1.870). CirCom score classifies our patients into 2 groups: 3+0 (n=91, 95.8%) and 3+1 (n=4, 4.2%), since the presence of HCC supposes a high score in the final result (at least 3+0), and it is not an independent predictor of survival (p=0.558).89 patients (93.7%) received at least 1 drug at the moment of the first termoablation: proton pump inhibitors (43, 45.3%), beta blockers (43, 45.3%), diuretics (35, 36.8%), psychiatric drugs (34, 35.8%), antiplatelets (24, 25.3%), oral antidiabetics (24, 25.3%) and angiotensin-converting enzyme inhibitors (19, 20%).

Conclusion: Comorbidity, measured as CCI, in patients with HCC treated with termoablation is frequent and impacts on survival. CirCom score doesn’t predict mortality. The diseases independently associated with mortality were AMI and diabetes.

Disclosure of Interest: P. Florez Conflict with: Research/Education grant - no, Conflict with: Honoraria - no, Conflict with: Stocks - no, Conflict with: Advisory Board - no, Conflict with: Consulting - no, M. Torner-Simó Conflict with: Research/Education grant - none, Conflict with: Honoraria - none, Conflict with: Stocks - none, Conflict with: Advisory Board - none, Conflict with: Consulting - none, A. Castaño-García Conflict with: Research/Education grant - no, Conflict

Posters Posters



4. Xiao GQ, Song JL, Shen S, Yang JY, Yan LN. Living donor liver transplantation does not increase tumor recurrence of hepatocellular carcinoma compared to deceased donor transplantation. World J Gastroenterol. 2014;20(31):10953-9.

5. Wan P, Zhang JJ, Li QG, Xu N, Zhang M, Chen XS, et al. Living-donor or deceased-donor liver transplantation for hepatic carcinoma: a case-matched comparison. World J Gastroenterol. 2014;20(15):4393-400.

6. Sugawara Y, Tamura S, Makuuchi M. Living Donor Liver Transplantation for Hepatocellular Carcinoma: Tokyo University Series. Digestive Diseases. 2007;25(4):310-2.


P-139 LYMPHOCYTES AND NEUTROPHILS TO LYMPHOCYTES RATIO (NLR) CHANGES AFTER SELECTIVE INTERNAL RADIATION TREATMENT (SIRT) FOR HCC

Maud Pedrono1, Florian Estrade1, Céline Lescure1, Marc Pracht1, Samuel Le Sourd1, Yan Rolland2, Etienne Garin3, Julien Edeline* 1

1Medical Oncology, 2Radiology, 3Nuclear Medicine, Centre Eugene Marquis-Rennes, Rennes, France

Introduction: Lymphocytes play an important role in antitumor immunity. Variations of lymphocytes have been described in several tumors after radiotherapy. We studied the prognostic role of the variations of lymphocyte count and the neutrophils to lymphocytes ratio (NLR) after Selective Internal Radiation Treatment (SIRT) for hepatocellular carcinoma (HCC).

Methods: Retrospective analysis of 232 patients with HCC and treated with SIRT at one center. Clinical, biological and radiological follow-up was regular until progression or death. A blood test was taken the week before the gesture and then at 3 months. The main objective of the study was to study changes in blood count after SIRT and to evaluate their prognostic values in terms of overall survival (OS). A ROC curve analysis was done to determine the most discriminating threshold for continuous variables. Survival was analyzed by the Kaplan-Meier method and a univariate and then multivariate Cox model.

Results: The median follow-up was 63 months, and median OS was 17.6 months. An objective response rate of 71% was observed. The main toxicities described were asthenia, abdominal pain and hepatic decompensation. Grade 3 or more toxicity was reported in 17% of patients.The decrease in lymphocytes was a mean of 44% at 3 months. At 3 months, 31.5% of patients had a lymphocyte count of 500 to 750 / mm3 and 23% a rate of less than 500 / mm3. The higher the dose of radiation received by the healthy liver, the lower the lymphocyte count and the higher the NLR. At 3 months, lymphopenia less than 1000 / mm3 was observed in 78.9% of patients with a median survival of 17.3 months (95% CI: 13.4-21.3) versus 19.9 months (95% CI: 7.8-32) in the 21.1% of patients with a lymphocyte count greater than 1000 / mm3, HR 1.502 (95% CI 0.984-2.293), p = 0.06. At 3 months, the NLR was an independent prognostic factor (in continuous variable: HR 1.06 (95% CI 1.03-1.09), p <0.01) and the threshold of 7.2 for NLR was also found as a prognostic factor independent of tumor characteristics and therapeutic response (HR 1.67 (95% CI 1.16-2.38) p = 0.005). The median OS in patients below this threshold was 9.8 months (95% CI 6.2-13-5) and in patients above 19.8 months (95% CI 16. 3-23.3), p = 0.003.

Conclusions: A NLR ≥ 7.2 3 months after hepatic intra-arterial SIRT treatment of a CHC is a poor prognostic factor, independent of tumor characteristics and therapeutic response. The frequent decrease of lymphocytes is to be considered when combination studies of SIRT with immunotherapy are underway.

Disclosure of Interest: M. Pedrono: None Declared, F. Estrade: None Declared, C. Lescure: None Declared, M. Pracht: None Declared, S. Le Sourd: None Declared, Y. Rolland Conflict with: Honoraria - BTG, Conflict with: Consulting - BTG, E. Garin Conflict with: Research/Education grant - BTG, Conflict with: Honoraria - BTG, Conflict with: Advisory Board - BTG, Conflict with: Consulting - BTG, J. Edeline Conflict with: Research/Education grant - BTG, Conflict with: Honoraria - BTG

P-140 SAFETY AND EFFECTIVENESS OF ENHANCED RECOVERY AFTER SURGERY (ERAS) IN PATIENTS WITH HEPATOCELLULAR CARCINOMA UNDERGOING PARTIAL HEPATECTOMY: A MULTICENTRE, RANDOMISED, CONTROLLED CLINICAL STUDY

Pei-Yao Fu* 1, Bo Hu1, Wei-Dong Jia2, Qiang Xia3, Kui Wang4, Dou-Sheng Bai5, Jia Fan1, Yang Xu1, Jian Zhou1

1Department of Liver Surgery, Zhongshan Hospital, Fudan University, Shanghai, 2Department of General Surgery, Anhui Provincial Hospital, Hefei, 3Department of Liver Surgery, Renji Hospital, 4Department of Liver Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, 5Department of General Surgery, Subei People's Hospital, Yangzhou, China

Conclusions: LT is an effective treatment modality for patients with HCC on top of chronic liver disease. Extending the selection criteria beyond Milan and within SF criteria did not adversely affect the transplant outcome particularly with regard to HCC recurrence.


P-138 IMPROVED OUTCOMES OF LIVE DONOR LIVER TRANSPLANTATION COMPARED TO RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA LESS THAN 3CM: AN INTENTION-TO-TREAT AND PROPENSITY SCORE MATCHING ANALYSIS

Phillipe Abreu* 1, Andre Gorgen1, Hala Muaddi1, Walter Nelson2, Adam Doyle2, Robert Beecroft2, John Kachura2, Bettina E. Hansen2, Anand Ghanekar1, Les Lilly1, Mark Cattral1, Zita Galvin2, Markus Selzner1, Mamatha Bhat2, Nazia Selzner3, Ian McGilvray1, Paul D. Greig1, David R. Grant1, Gonzalo Sapisochin1 and Liver Cancer Research Group

1Department of Surgery, 2University of Toronto, 3Univeristy of Toronto, Toronto, Canada

Introduction: Radiofrequency ablation (RFA) and liver transplantation (LT) are considered curative therapies for small single hepatocellular carcinoma (HCC). We aimed to compare the long-term outcomes of patients with single HCC ≤3cm treated with RFA with those that received a live donor liver transplant (LDLT) as their first treatment.

Methods: Patients with single HCC ≤3cm treated between 2000-2017 were included in an intention-to-treat analysis (ITT). Patients were divided according to the initial treatment intended: RFA or LDLT. Study outcomes were overall survival (OS) and disease-free survival (DFS). Outcomes were assessed by the Kaplan-Meier method and compared using the log-rank test. Multivariable Cox regression was applied to account for a priori selected clinical confounders. A propensity score matching was performed to reduce potential selection bias by equating groups based on initial MELD score and Child-Pugh-Turcotte (CPT) classification.

Results: We included 340 patients: 296 (87.10%) patients underwent RFA with curative intent and 44 (12.90%) patients were listed for LDLT. Median follow up time was 3.68 (IQR 2.21-5.96) years. At baseline, differences were observed in MELD [8.18 (IQR 6.86-10.10) vs. 12.00 (IQR 9.00-13.75), p<0.001], CPT (p<0.001) and etiology of liver disease (p<0.001) at time of diagnosis. After a multivariable regression, the hazard ratio for HCC recurrence was 0.11 (95% CI 0.04-0.33) for LDLT over RFA. The propensity matched cohort was composed of 18 RFA and 18 LDLT patients (Table 1). The median follow up time was 3.98 (IQR 1.95-8.81) years. The actuarial 1-, 3- and 5-year OS was 88.9%, 77.4%, 54.3% for RFA and 94.3%, 82.5%, 82.5% for LDLT (p=0.04)[Figure 1], while the 1-, 3- and 5-year DFS was 50%, 17%, 17% for RFA and 88.6%, 88.7%, 82.7% for LDLT, p<0.001.

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Conclusions: This study suggests that LDLT may be a better treatment option for patients with single HCC ≤3cm. LDLT should be considered and offered as a treatment modality to patients if available.

References: 1. Mittler J, Heinrich S, Lang H. [Indications for transplantation and bridging procedures for primary

hepatobiliary malignancies]. Der Chirurg; Zeitschrift fur alle Gebiete der operativen Medizen. 2018.

2. Irtan S, Barbier L, Francoz C, Dondero F, Durand F, Belghiti J. Liver transplantation for hepato-cellular carcinoma: is zero recurrence theoretically possible? Hepatobiliary & pancreatic diseases international : HBPD INT. 2016;15(2):147-51.

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Conclusions: Our new risk prediction model can be used to stratify different prognoses in patients with HCC treated with TARE. Validation studies are required.

References: McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015;19: 223-238.Kim HC. Radioembolization for the treatment of hepatocellular carcinoma. Clin Mol Hepatol. 2017;23: 109-114.Lewandowski RJ, Sato KT, Atassi B, et al. Radioembolization with 90Y microspheres: angiographic and technical considerations. Cardiovasc Intervent Radiol. 2007;30: 571-592.Lee YK, Kim SU, Kim DY, et al. Prognostic value of alpha-fetoprotein and des-gamma-carboxy prothrombin responses in patients with hepatocellular carcinoma treated with transarterial chemoembolization. BMC Cancer. 2013;13: 5.Kim MN, Kim BK, Han KH, Kim SU. Evolution from WHO to EASL and mRECIST for hepatocellular carcinoma: considerations for tumor response assessment. Expert Rev Gastroenterol Hepatol. 2015;9: 335-348.


P-137 GOING OUTSIDE MILAN AND WITHIN SAN FRANCISCO CRITERIA DOES NOT INCREASE RECURRENCE RATE OF HCC POST LIVER TRANSPLANT

Elwy Soliman* 1, Sarra Yousif1, Mohamed Shawkat1, Isam Salih1, Ali Albenmousa1, Waleed Alhamoudi1, Khalid Bzeizi1

1Organ Transplant Centre, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

Introduction: Liver transplantation (LT) for hepatocellular carcinoma (HCC) is guided by several recognized criteria that aim for reducing recurrence risk. The most widely followed is the Milan Criteria even though it is often seen as restrictive that may result in excluding proportion of patients who may benefit from transplantation. The aim of this study is to report the outcome of LT from both deceased and living donors in a center that extends the criteria of transplantation beyond Milan Criteria and within San Francisco (SF) criteria.

Methods: A retrospective chart review was carried out on patients underwent LT (from deceased or Living donors) for HCC at King Faisal Specialist Hospital and Research Center (KFSHRC), Saudi Arabia, during the period between June 2001 and March 2018. Patient were included if their tumor was within SF criteria and were divided into within Milan (WM) and outside Milan (OM) groups. Patients who had transplant outside KFSHRC were excluded. Demographic data as well as type of transplant, cause of liver disease, disease recurrence and survival were collected and analyzed using SPSS version 19.

Results: One hundred eighty-two patients were included in the study. The mean age of this cohort was 57.8±8.6 years, 5.5% transplanted above age of 70 and 67.8% were males. Organs from deceased donors were used in 42.6% while living donor transplantation was more frequently done (57.4%). All patients had cirrhosis and the commonest etiologies were HCV (47.5%) & HBV (31.7%). Those WM criteria were 134 (73.6%) and patients OM were 48(26.4). After a median follow up of 45.4 months (0-210 months), the overall mortality of this cohort was 21.3% however 14 patients (7.7%) had early death (within 3 months after transplantation) and the cause of death was related to sepsis and multi-organ failure (9), hemorrhagic shock (2) and graft vascular thrombosis (3). Recurrence of HCC was diagnosed in 11 patients (6%) of the whole cohort and 6.5% of patients who survived > 3months). The recurrence rate did not differ between WM (7/134) and OM (4/48) groups (5.2 vs 8.3% p= 0.484). The median time to recurrence was 8.3 months (4-29 months). Recurrent HCC was the cause of death in 9 patients while 2 patients lost follow up. There was no difference between patients who had recurrence and those who did not in regard to age (p= 0.787), gender distribution (p= 0.179) and type of donation (0.761).

by the nomograms, in the low-, intermediate- and high-risk subgroups, the 1-year OS rates were 85.59%, 52.78%, and 20.57%, the 3-year OS rates were 63.72%, 22.64%, and 4.38%, the 1-year CSS rates were 90.69%, 59.95%, and 23.39%, and the 3-year CSS rates were 75.23%, 31.18%, and 6.88%, respectively. Internal validation produced c-indexes of 0.758 and 0.752 for OS and CSS, respectively, while external validation in the SYMH cohort produced a c-indexes of 0.702 and 0.686 for OS and CSS, respectively.

Image:

Conclusions: Based on the clinical risk factors identified in a large population-based cohort, we established practical prognostic nomograms that can objectively and accurately predict long-term OS and CSS in HCC. Moreover, the internal and external cohort validation results demonstrate that these nomograms perform very well and have high accuracy and reliability. Our nomograms may enable more accurate individualized predictions of OS and CSS to help doctors better formulate individual treatment and follow-up management strategies.


P-136 ESTABLISHMENT OF A RISK PREDICTION MODEL IN PATIENTS WITH HEPATOCELLULAR CARCINOMA TREATED WITH TRANS-ARTERIAL RADIOEMBOLIZATION

Jae Seung Lee* 1, Han Ah Lee2, Mi Young Jeon1, 3, Tae Seop Lim1, 3, Beom Kyung Kim1, 3, 4, Jun Yong Park1, 3, 4, Do Young Kim1, 3, 4, Sang Hoon Ahn1, 3, 4, Soon Ho Um2, Kwang-Hyub Han1, 3, 4, Yeon Seok Seo2, Seung Up Kim1, 3, 4

1Department of Internal Medicine, Yonsei University College of Medicine, 2Department of Internal Medicine, Korea University College of Medicine, 3Yonsei Liver Center, Severance Hospital, 4Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea, Republic Of

Introduction: Few studies have reported the treatment outcomes of trans-arterial radioembolization (TARE) using yttrium-90 (90Y) for hepatocellular carcinoma (HCC). We established and validated a new risk prediction model for patients with HCC treated with TARE.

Methods: Between 2010 and 2017, 113 and 35 patients with intrahepatic HCC treated with TARE were selected for the training and validation cohorts, respectively. The modified response evaluation criteria in solid tumors (mRECIST) were used for response evaluation.

Results: In the training cohort, the median age was 64.1 years (92 male and 19 female) and the mean survival after TARE was 50.3 months. The cumulative survival rates at six and 12 months were 92.0 and 84.0%, respectively. A new risk prediction model for patients with HCC treated with TARE (Y-scoring system) was established from the training cohort using five independent baseline variables (serum albumin <3.5 g/dL, hazard ratio [HR]=5.446; alpha-fetoprotein >200 ng/mL [HR=5.071]; tumor number ≥3 [HR=2.933]; portal vein thrombosis [HR=4.915]; and hepatic vein invasion [HR=8.500]) and two on-treatment variables (no des-gamma-carboxy prothrombin response [HR=15.346] and progressive disease at three months [HR=4.154]) for mortality (all P<0.05). The predictive accuracy of the Y-scoring system was acceptable to predict six- (area under the curve [AUC]=0.845), nine- (AUC=0.868), and 12-month mortality (AUC=0.886) (all P<0.05). The predictive accuracy of the system was similarly maintained in the validation cohort (AUC 0.737-0.901 at six to 12 months).

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Methods: Between 2005 and 2016, 124 patients underwent preoperative TACE before liver resection (LR), and 166 underwent preoperative TACE before liver transplantation (LT). Pathologic response (PR) was defined as the mean percentage of necrotic tumor area, and pCR was defined as the absence of viable tumor. Preoperative TACE was usually performed for bridging treatment or downsizing of the intrahepatic tumor. After preoperative TACE, Milan criteria were usually used to select patients for LT, although patients with tumors exceeding Milan criteria occasionally got LT.

Results: A total of 34 (27%) and 38 (23%) patients had pCR before LR and LT, respectively. Alpha fetoprotein (AFP) < 100 ng/mL in the LR group and single tumor in the LT group were significant preoperative predictors of pCR. Subgroup analyses for patients with complete radiological response (no viable tumor in preoperative dynamic imaging studies) also identified same factors as significant predictors of pCR. Five-year overall survival (OS) was significantly higher in patients with pCR than in those without pCR after LR and LT. On multivariate analyses, PR ≥ 90% remained an independent predictor of better OS and recurrence-free survival in LR and LT groups.

Conclusion: Overall, our data clearly demonstrate that pCR predicts favorable prognosis after curative surgery for HCC, and predictors of pCR are AFP < 100 ng/mL with LR and single tumor with LT.

References: Ann Surg 262:536-545; discussion 543-535.J Hepatol 63:83-92.


P-145 THE MECHANISMS RESPONSIBLE FOR TUMOR INVASIVENESS IN CK19-POSITIVE HEPATOCELLULAR CARCINOMA

Chao-Wei Lee* 1, Chi-Neu Tsai2, Ming-Chin Yu1

1Surgery, Chang Gung Memorial Hospital, 2Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan, Province of China

Introduction: Previous study showed that CK19 expression in hepatocellular carcinoma (HCC) is an indicator of HCC invasiveness including lymph node metastasis (LNM), tumor infiltration/non-encapsulation, and poor prognosis. The exact mechanism by which CK19 expression results in poor prognosis remains unclear. The present study investigated the possible mechanism responsible for the invasiveness and poor prognosis of CK19(+) HCC.

Methods: By using Western blot analysis, various HCC cell lines were examined for their respective CK19 expressions. RNA interference and plasmid transfection were employed to silence or over-express CK19 in CK19(+) or CK19(-) HCC cell lines, respectively. Affymetrix Human trasncriptome Array 2.0 and Human Phospho-Kinase Antibody Array were adopted to examine downstream effects of manipulating CK19 expressions. Fresh tumor specimens obtained from patients receiving hepatectomy were subjected to appropriate analysis in order to confirm the in vitro findings.

Results: Western blot analysis identified Hep3B, Huh7, and PLC5 to be CK19(+) HCC cell lines, while HepG2 was CK19(-) HCC cell line. After transfecting HepG2 cells with FLAG®-CK19, the resultant stable CK19 transfectant was subjected to Human Phospho-Kinase Antibody Array study. The result showed that CK19 over-expression led to increased phosphorylation of mTOR and p70S6 kinase. Western blot analysis of silenced or over-expressed HCC cell lines confirmed these findings. In addition, the expressions of these proteins were also elevated in tumor specimens of CK19(+) HCC. Furthermore, we also discovered that autophagy was induced upon activation of p70S6 kinase in CK19(+) HCC. Like our previous reports, these CK19(+) HCC had significantly poorer disease-free and overall survival.

Conclusions: Our study demonstrated that the invasive behavior and poor prognosis of CK19(+) HCC may be due to its effect on mTOR and p70S6 kinase, two interacting proteins known to be associated with aggressive tumor behavior and decreased overall survival of HCC. This novel CK19-mTOR-p70S6 kinase-autophagy axis not only provides new insight into the pathogenesis of CK19(+) HCC, but also offers new treatment strategy towards this aggressive subset of HCC.


P-146 MESSENGER RNA HYPERMETHYLATION FUELS CANCER-PROMOTING INFLAMMATION IN HEPATOCELLULAR CARCINOMA

Jiajie Hou* 1, He Zhang2

1QIMR Berghofer Medical Research Institute, Herston, Australia, 2The University of Hong Kong, Shenzhen Hospital, Shenzhen, China

Introduction: Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the post-transcriptional outcomes of m6A-methylation in hepatocellular carcinoma (HCC).

Methods: Using liquid chromatography-tandem mass spectrometry and m6A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6A-mRNA levels in

This work aims to analyse the prognosis of patients in BCLC stage 0 and A with TMS and to compare the prognosis of this group with the BCLC stage B patients.

Methods: A prospective observational study has been conducted. One-hundred and twenty-five patients with newly diagnosed hepatocellular carcinoma (HCC) were included from January 2011 to September 2018. Tumour stage was assigned following BCLC classification, and treatment decision were made in a multidisciplinary team. Epidemiological, clinical and prognostic variables were recorded. Non-parametric tests were used to identify demographical or clinical differences between groups. Survival analysis in each BCLC stage was performed (BCLC stage 0 and BCLC stage A formed a unique group). Significance was fixed at 0.05.

Results: Eighty-eight patients (14 women; mean age 64.9 years [SD=9.19]) were classified in BCLC stage 0-A and 30 patients (5 women; mean age 68.9 years [9.16]) were classified in BCLC stage B. Thirty-seven percent patients (32) from BCLC stage 0-A presented a TSM. The main causes of TSM were the advanced age and the presence of comorbidities. In this regard TSM patients were older (p=.009) and had a larger lesion (p=.006) than non-TSM patients. Most of the TMS patients were treated with Transcatheter Arterial Chemoembolization (81.3%, 26 patients). The rest of the patients received best supportive care. The Progression Free Survival (PFS) of BCLC stage 0-A TSM patients was significantly shorter than in non-migrated patients (31.05 months vs. 80.91 months; Log-Rank, p=.002) (figure 1B). The overall survival (OS) of BCLC stage 0-A TSM patients was significantly shorter than the OS of non-migrated patients (23.6 months vs. 71.37 months; Log-Rank, p<.00001) (figure 1A). Patients classified in BCLC stage B presented a higher number of lesions (p<.00001) and a larger mean size of the tumour (p<.00001) than the TSM patients from BCLC stage 0-A. There was no difference in the PFS (17.17 months vs. 11.77 months; Log-Rank, p=.473) and OS (23.6 months vs. 26.67 months; Log-Rank, p=.318) between both groups (figure 1C and 1D).A univariate COX regression analysis in TSM patients was performed. It showed that MELD score (HR=1.10), lesion size (HR=1.04) and TSM secondary to impairment of liver function (HR=2.93) were associated with a bad prognosis concerning OS. All these variables remained statistically significant in the multivariate analysis.

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Conclusions: Treatment stage migration in BCLC stage 0-A patients significantly decreases OS and PFS. The prognosis of these patients seems to be as in the BLCB stage B group.

References: 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management

of hepatocellular carcinoma. J Hepatol [Internet]. 2018 Apr 5.2. D’Avola D, Iñarrairaegui M, Pardo F, Rotellar F, Marti P, Bilbao JI, et al. Prognosis of hepatocellular

carcinoma in relation to treatment across BCLC stages. Ann Surg Oncol. 2011 Jul;18(7):1964–71.


P-144 PATHOLOGIC COMPLETE RESPONSE TO CHEMOEMBOLIZATION IMPROVES SURVIVAL OUTCOMES AFTER CURATIVE SURGERY FOR HEPATOCELLULAR CARCINOMA: PREDICTIVE FACTORS OF RESPONSE

Pil Soo Sung1, Si Hyun Bae*1, Hyun Yang1, Seung Kew Yoon1

1The Catholic University of Korea, Seoul, Korea, Republic Of

Introduction: Until recently, there have been many studies on the efficacy of locoregional treatments before curative surgery in hepatocellular carcinoma (HCC). . However, the impact of preoperative locoregional treatment on survival outcomes is still controversial. In this study, we aimed to confirm the predictive factors and prognostic significance of a preoperative transarterial chemoembolization (TACE)-induced pathologic complete response (pCR) in HCC.

Introduction: AFP is elevated in 70% of HCC and is associated with poor prognosis. The role of AFP as a biomarker of response to systemic treatments has not been established, though small, retrospective studies show association between AFP decline and survival on sorafenib. The relationship between AFP changes and response to immune checkpoint inhibitors (CPI) has not been reported. This study examines AFP changes on treatment for association with outcomes on first-line (1L) SOR and any subsequent CPI in a contemporary, multicenter U.S. population.

Methods: Design: Multicenter retrospective case series. Key eligibility: Received 1L SOR or SOR-based combination for advanced HCC; ≥1 post-treatment AFP value available; enrolled on IRB-approved registry. Objectives: associate absolute AFP changes within 3 months of start of treatment with overall survival (OS) and time on treatment (TOT) on 1L SOR and any subsequent CPI; associate baseline AFP with OS and TOT for SOR and CPI; relate baseline AFP and changes on treatment to clinical covariates.

Results: 176 patients were identified from 3 centers. Baseline characteristics: M/F 154/22; HBV/HCV/nonviral 44/82/48; Child Pugh A/B 153/22; BCLC A/B/C: 4/16/156. Baseline AFP <400/≥400 ug/L:104/72. 46 received CPI after SOR. See Table. Baseline AFP was not related to TOT or OS for SOR or CPI.

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Conclusions: This series is the largest reported multicenter analyses of AFP response to systemic therapy with SOR and CPI. AFP decrease and increase within the first 3 months of treatment with SOR and CPI were inversely and significantly associated with median OS. AFP warrants further study in randomized cohorts as a biomarker of response to systemic therapy in HCC, now with multiple treatment options available at progression.

References: 1. Kelley et al ESMO 2018; abstract 702P2. Lee et al J Hepatocell Carcinoma 2015; 2:39-473. Yamashita et al Cancer Res 2008; 68:1451-614. Zhu et al Lancet 2015; 16:859-705. Sánchez et al Oncol Lett 2018; 15:8863-706. Personeni et al J Hepatol 2012; 57:101-77. Yau et al Oncologist 2011; 16:1270-798. Shao et al Cancer 2010; 116:4590-69. Chan et al J Clin Oncol 2009; 27:446-5210. Xu et al World J Gastroenterol 2012; 18:7242–5011. Raoul et al Liver Cancer 2014; 3:439-5012. Vora et al Oncologist 2009; 14:717-2513. Chau et al Br J Cancer 2018; 119:19-26


P-143 NON-CURATIVE TREATMENT IN VERY EARLY AND EARLY HEPATOCELLULAR CARCINOMA: A PROGNOSTIC MIGRATION TO BCLC STAGE B

Silvia Acosta-López* 1, Julio Plata-Bello2, Dácil Díaz Bethencourt1, Luis Cejas Dorta1, Ángel Febles González1, Javier García Solo de Zaldívar1, Francisco Andrés Pérez Hernández1

1Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, 2Hospital Universitario de Canarias, San Cristóbal de La Laguna, Spain

Introduction: The Barcelona Clinic Liver Cancer (BCLC) classification is a stage system that relates each stage to an estimated prognosis and recommended treatment [1]. Treatment stage migration (TSM) is a concept use when a treatment recommended for another stage is chosen like first-line treatment[1]. It is generally accepted that curative treatment has better overall survival than non-curative therapies in very early (BCLC stage 0) and early stages (BCLC stage A) [2]. However, it is still unknown if the prognosis of TMS patients in BCLC stage 0-A differs from the prognosis of intermediate stage (BCLC stage B).

Introduction: Enhanced recovery after surgery (ERAS) is a multimodal perioperative management approach that is used to accelerate recovery, reduce morbidity, and shorten hospital stay after a major surgery. However, solid evidence that proves its safety and effectiveness in liver surgery for patients with hepatocellular carcinoma, which is always combined with liver cirrhosis and hepatitis infection in China, remains lacking. In this multicentre randomised controlled clinical trial, we compared ERAS and traditional treatment approach for hepatocellular carcinoma (HCC) patients who underwent partial hepatectomy.

Methods: A total of 222 HCC patients recruited from five medical centres in China were randomly assigned into ERAS and control groups (1:1) to compare the short-term effects of ERAS and those of conventional perioperative managements, including preoperative education about ERAS, early oral intake and out-of-bed activity and multimodal analgesia.

Results: The overall complication rate in the ERAS group was significantly lower than that in the control group (25.2 vs. 45.9%, p<0.01**). The mean length of postoperative hospital stays decreased from 8 to 7 days (p<0.01). The rates of vomiting (10.8 vs. 22.5%, p=0.02*) and ascites (5.4 vs. 13.5%, p=0.03*) in the ERAS group were significantly less than those in the control group. Pain and insulin resistance after surgery were significant in the ERAS group based on the visual analogue scale and homeostatic model assessment for insulin resistance (HOMA-IR) score (all p<0.05).

Conclusions: ERAS accelerated recovery in HCC patients who underwent partial hepatectomy, even those with severe cirrhosis.


P-141 SAFETY OF TRANSARTERIAL CHEMOEMBOLIZATION IN PATIENTS WITH RECURRENT HEPATOCELLULAR CARCINOMA AFTER LIVER TRANSPLANTATION

Jieun Lee* 1

1Internal medicine, National Cancer Center, Republic of Korea, Gyeonggi-Do, Korea, Republic Of

Introduction: Transarterial chemoembolization (TACE) is a widely accepted therapeutic modality for multinodular hepatocellular carcinoma (HCC). TACE is generally considered as a safe procedure even after surgical resection, but the safety data of TACE after transplantation is still lacking. The aim of this study is to investigate the safety of TACE for recurrent HCC after liver transplantation.

Methods: Medical records of 38 patients who had received living donor liver transplantation and then underwent TACE for recurrent HCC January 2001 to December 2018 were retrospectively reviewed.

Results: A total of 112 TACE procedures were performed for 38 patients, and complications were occurred in 25 patients (65%) with the incidence of 42% (48/113) per TACE procedures. Out of 112 TACE procedures performed, most frequently encountered complications were as follows: postembolization syndrome (n=19, 17%), biloma (n=10, 8.9%), liver abscess (n=7, 6.2%), intrahepatic duct dilatation (n=6, 5.4%), bacteremia (n=2, 1.8%), hepatic artery stenosis (n=1, 0.9%), biliary stricture (n=1, 0.9%), and hematoma (n=1, 0.9%). The median interval between TACE and the diagnosis of complications was 3 days (interquartile range 0-81). Most cases were managed conservatively. However, endoscopic stenting was required for intrahepatic duct obstruction (n=2),biloma (n=1) and liver abscess(n=2) required endoscopic stenting or percutaneous drainage. No one died of complications. Of 24 patients who had postoperative biliary complications after transplantation, 18 patients (75%) had TACE-related complications with incidence of 42.6% (29/68) per TACE procedure, while out of the remaining 14 patients who had no postoperative complications, 7 (50%) had TACE-related complications with incidence of 28.8% (13/45) per procedure.

Conclusions: TACE is still regarded a safe procedure; however, biliary or infectious complications seem more frequently occurred in recurrent HCC following living donor liver transplantation.


P-142 CHANGES IN ALPHA-FETOPROTEIN (AFP) AND SYSTEMIC THERAPY OUTCOMES IN ADVANCED HEPATOCELLULAR CARCINOMA (HCC): A MULTICENTER RETROSPECTIVE ANALYSIS

Robin K. Kelley* 1, Andrea G. Bocobo2, Lipika Goyal3, Anna Parks4, Lindsay M. Hannan5, Kelly Bauer2, Islam Baiev3, Caroline Dinicola3, John D. Gordan1, Alan P. Venook1, William P. Harris6, Paige M. Bracci7

1Department of Medicine (Hematology/Oncology), 2Gastrointestinal Oncology, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, 3Hematology/Oncology, Massachusetts General Hospital, Boston, 4School of Medicine, University of California, San Francisco, San Francisco, 5School of Medicine, University of Washington, 6Department of Medicine, University of Washington/Fred Hutchinson Cancer Center, Seattle, 7Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, United States

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Conclusions: These data suggest that primary and metastatic hepatobiliary cancers have unique immune activation status and MDSC signatures. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, they may comprise a potential target for immunotherapies.


P-150 SUPPRESSING DRP1-MEDIATED MITOPHAGY INCREASES THE APOPTOSIS OF HEPATOCELLULAR CARCINOMA IN THE SETTING OF CHEMOTHERAPY

Rongxin Chen* 1, Min Ma1

1Zhongshan Hospital of Fudan University, Shanghai, China

Introduction: Most systemic chemotherapies demonstrate limited efficacy in the treatment of advanced HCC. We aimed to evaluate the effects of targeting mitophagy on HCC and investigate underlying mechanisms that can potentiate chemotherapy.

Methods: HCC cells were subject to cisplatin treatment and cisplatin-induced mitophagy was quantified by immunofluorescence. The dynamin-related protein 1 (DRP1) inhibitor (Mdivi-1) was used to study the role of DRP1in HCC mitophagy induced by cisplatin.

Results: Cisplatin induced mitophagy in surviving HCC cells by activating DRP1. DRP1 inhibitor (Mdivi-1) increased the apoptosis of cisplatin-treated HCC cells by targeting mitophagy in vitro and in vivo. Mechanistically, Mdivi-1upregulated Bax and downregulated Bcl-xL, leading to the increase of mitochondrial membrane permeability and the subsequent release of cytochrome C from mitochondria into cytosol. Moreover, Mdivi-1 acted synergistically with cisplatin to suppress HCC xenograft growth in vivo.

Conclusions: Our results demonstrate that targeting cisplatin-mediated mitophagy increases the apoptosis in HCC via DRP1 inhibition.


P-151 TMEM88 INHIBITED PROLIFERATION AND METASTASIS VIA GSK-3ß/ß-CATENIN SIGNALING IN HCC

Wenxin Li1, Xicheng Wang1, Xining Wang1, Tao Chen1, Jie Chen* 1

1Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

Introduction: Tumor proliferation and metastasis is an essential process for cancer progressin. Transmembrane protein 88(TMEM88) is lowly expressed in hepatocellular carcinoma (HCC). Thus, we investigated the role of TMEM88 in tumor proliferation and metastasis during HCC development.

Methods: In this study, the protein and mRNA levels of TMEM88 in matched HCC and adjacent noncancerous liver tissues from 65 patients were determined using immunohistochemistry and real-time quantitative PCR, respectively. Two HCC cell lines (Huh7 and sk-hep-1) were used to investigate the anti-proliferation and anti-metastasis effect of TMEM88 by using colony formation, EDU and transwell migration assays. The expression levels of GSK-3ß and ß-catenin of HCC cells were detected by western blot.

Results: In 65 HCC patients, the expression of TMEM88 mRNA was positively correlated with adverse HCC characteristics and shorter recurrence-free survival and overall survival rates. In vitro, cell proliferation and cell migration were decreased with enhancing expression of TMEM88 in HCC cells. In vivo, TMEM88 inhibited the tumor growth of HCC xenografts in nude mice. Increasing the expression of TMEM88 inhibited HCC progression by enhancing GSK-3ß and downregulation of the ß-catenin transferring to nuclear in HCC cells.

Conclusions: Increasing TMEM88 level inhibited proliferation and migration in HCC cells by enhancing the GSK-3ß and decreases ß-catenin transferring to nuclear.

References: 1. Cai, S.P., et al., Transmembrane protein 88 attenuates liver fibrosis by promoting apoptosis and

reversion of activated hepatic stellate cells. Mol Immunol, 2016. 80: p. 58-67.2. Zhang, X., et al., Cytosolic TMEM88 promotes invasion and metastasis in lung cancer cells by

binding DVLS. Cancer Res, 2015. 75(21): p. 4527-37.3. Yu, X., et al., Cytosolic TMEM88 promotes triple-negative breast cancer by interacting with Dvl.

Oncotarget, 2015. 6(28): p. 25034-45.


References: 1. Radin DP, Patel P. BDNF: An Oncogene or Tumor Suppressor? Anticancer Res. 2017;37(8):3983–90. 2. Chen B, Liang Y, He Z, An Y, Zhao W, Wu J. Autocrine activity of BDNF induced by the STAT3

signaling pathway causes prolonged TrkB activation and promotes human non-small-cell lung cancer proliferation. Sci Rep [Internet]. 2016;6:30404.

3. Okugawa Y, Tanaka K, Inoue Y, Kawamura M, Kawamoto A, Hiro J, et al. Brain-derived neurotrophic factor/tropomyosin-related kinase B pathway in gastric cancer. Br J Cancer. 2013 Jan 15;108 (1):121–30.


P-149 MYELOID-DERIVED SUPPRESSOR CELLS EXPAND IN PATIENTS WITH HEPATOBILIARY MALIGNANCIES AND PREDICT POOR PROGNOSIS

Adam Lauko* 1, Defne Bayik2, Emily Serbinowski2, Gustavo A. Roversi2, Lou-Anne Acevedo-Moreno3, Christopher Lanigan4, Mushfig Orujov4, 5, Daniel J. Silver2, Tyler J. Alban2, J. M. Brown2, 6, Daniela Allende4, 6, Justin D. Lathia2, 6, Federico N. Aucejo3, 6

1Cleveland Clinic Lerner College of Medicine, 2Lerner Research Institute, 3Department of General Surgery, 4Department of Pathology, Cleveland Clinic, Cleveland, United States, 5Department of Pathological Anatomy, Azerbaijan Medical University, Baku, Azerbaijan, 6Liver Center of Excellence, Cleveland Clinic, Cleveland, United States

Introduction: Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immunosuppressive cells that are augmented in patients with malignancies and limit anti-tumor immune response. It has been reported that circulating MDSC frequencies are increased in patients with viral-derived hepatocellular carcinoma (HCC) but the relevance of these findings in the context of other liver tumors remain poorly defined. The objective of this study was to investigate distinct associations between MDSCs with different types of hepatobiliary tumors with varying disease pathobiology.

Methods: We analyzed the frequency of total MDSCs, monocytic MDSC (mMDSCs), granulocytic MDSCs (gMDSCs), regulatory T cells (Tregs) and activated CD8+ T cells from the peripheral mononuclear cells of 100 patients with primary hepatobiliary malignancies or metastatic liver lesions with multi-color flow cytometry. We further studied the infiltration of MDSCs, antigen-presenting cells and macrophages into malignant liver cancers versus benign lesions via immunohistochemistry staining of CD33, HLA-DR and CD68. Finally, we analyzed the Cancer Genome Atlas (TCGA) database to establish a correlation between MDSC prevalence and overall survival in HCC patients.

Results: Our results demonstrated that non-viral HCC patients and patients with neuroendocrine tumors (NET) had the highest level of MDSCs (CD33+CD11b+HLA-DRlow/-) in peripheral blood, followed by colorectal carcinoma patients with liver metastases (CRLM). In contrast, MDSC levels were not significantly elevated in cholangiocarcinoma (CCA) cases compared to patients with benign lesions. mMDSC subset (CD33+CD11b+HLA-DRlow/-CD14+) accounted for >90% of the total MDSCs in blood in all tumor types. Another immunosuppressive cell population, Tregs were not augmented in the circulation of patients with primary or secondary liver tumors with respect to those with benign lesions, suggesting that elevated MDSC levels are linked with malignancy. [AL1] Investigation of intralesional myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors showed that the frequency of CD33+ and HLA-DR+ cells marking antigen-presenting cells were limited with average peak counts 31 and 12, while these cells were present significantly at higher rates in benign lesions. Bioinformatic analysis of the TCGA database demonstrated that a high MDSC score in HCC patients predicted poor disease outcome with a 2-fold reduction in survival duration.

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Results: Mice fed the CD-HFSC diet developed HCC as early as 46 weeks of age with high penetrance (60.7%) at 55-56 weeks in the absence of obesity. 92.9% of these mice developed hyperplastic nodules and 89.3% had dysplastic nodules. Seven fatty acids exhibited significantly lower plasma levels (as assessed using a one-way ANOVA test with a P<0.05) in CD-HFSC diet fed mice with pre-malignant lesions and mice with HCC compared to mice with NAFLD fed the control diet at both 32 weeks and 55 weeks. Low levels of these fatty acids were also seen in HCC tissue at 55 weeks. Of these fatty acids, 5 were polyunsaturated fatty acids (PUFAs) (ω3 and ω6 linolenic α and γ acids, ω3 eicosapentanoic acid, ω3 docosahexanoic acid, and ω6 linoleic acid), 1 was a saturated fatty acid (arachidic acid), and another was monounsaturated fatty acid (palmitoleic acid). The same 5 PUFAs showed increased levels at 55 weeks compared to 32 weeks in mice with pre-malignant lesions.

Conclusions: Certain PUFAs (ω3 and ω6 linolenic α and γ acids, ω3 eicosapentanoic acid, ω3 docosahexanoic acid, and ω6 linoleic acid) decrease with disease progression in lean NASH-HCC and the same fatty acids increase over time in mice that develop only pre-malignant lesions. These results suggest that these PUFAs may have anti-carcinogenic properties in the development of lean NASH-HCC. Their cancer preventive properties should be investigated further in future studies.

References: 1. Younossi Z. The epidemiology of nonalcoholic steatohepatitis. Clinical Liver Disease.

2018;11(4):92-94;2. Kumar R, Mohan S. Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and

Implications. J Clin Transl Hepatol. 2017;5(3):216-223;PMC5606968.;3. Bedossa P, Poitou C, Veyrie N, et al. Histopathological algorithm and scoring system for

evaluation of liver lesions in morbidly obese patients. Hepatology. 2012;56(5):1751-1759; 4. Muir K, Hazim A, He Y, et al. Proteomic and lipidomic signatures of lipid metabolism in NASH-

associated hepatocellular carcinoma. Cancer Res. 2013;73(15):4722-4731;PMC3855016.


P-148 EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) AND ITS RECEPTORS IN HEPATOCELLULAR CARCINOMA

Silvia Acosta-López* 1, Julio Plata-Bello2, Dacil Díaz Bethencourt1, Francisco Andrés Pérez Hernández1

1Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, 2Hospital Universitario de Canarias, San Cristóbal de La Laguna, Spain

Introduction: Brain-derived Neurotrophic Factor (BDNF) belongs to the neurotrophins family and it is essential for the growth and survival of neural cells. BDNF interacts with two transmembrane receptors: the nerve growth factor receptor (NGFR) and the neurotrophic receptor tyrosine kinase 2 (NTRK2) [1].BDNF and its receptors have been associated with the carcinogenesis process in some tumors, but their role in hepatocellular carcinoma (HCC) is still uncertain [2,3]. This work aims to analyze the mutational and mRNA expression profile of BDNF, NGFR and NTRK2 in HCC patients included in the “The Cancer Genome Atlas” (TCGA) database; and to evaluate the transcriptome profile of BDNF, NGFR and NTRK2 as prognostic biomarkers.

Methods: Three-hundred and sixty patients were included in the study (117 women; mean age 59.43 years [SD=13.12]). Their clinical and molecular data (mutations, copy number variations [CNV], RNA sequencing, miRNA sequencing and protein expression) were available at the TCGA database. Statistical analysis was performed using the software SPSS v.20.0. Non-parametric tests were used to perform comparisons between groups and COX regression was used to identify prognostic factors by performing a uni- and a multivariate analysis. Survival analysis demanded the transformation in normal distribution of those variables without this distribution (Kolmogorov-Smirnov test). Significance was fixed at 0.05.

Results: Mutational profile analysis of BDNF, NGFR and NTRK2 showed a low prevalence of mutations and CNVs in HCC patients (3.6%). Bearing in mind the transcriptomic profile, all the studied genes presented an overexpression (compared to normal liver tissue) in most of the patients (92.5% overexpression of BDNF; 92.8% of NTK2; and 97.2 of NGFR). Only NTRK2, with other clinical variables, showed a significant association with overall survival in the univariate analysis (HR=.776, CI 95% = .613 - .982; p=.035). This association was also supported by the multivariate analysis (HR=.665, CI 95% = .515 - .858; p=.002). A comparison between patients with high expression and low expression of NTRK2 was performed using the median of NTRK2 expression as cutoff. Patients with low NTRK2 expression presented higher percentage of necrosis, tumoral cells and vascular invasion. Furthermore, patients with high NTRK2 expression showed higher levels of BDNF and NGFR, as well as Akt expression at protein level. Finally, NTRK2 expression seemed to be regulated by HAS-miR-429.

Conclusions: BDNF, NTRK2 and NGFR are overexpressed in most HCC patients. The NTRK2 expression increase is associated with a better overall survival. This finding may be associated with a higher expression of miRNA with tumor-suppressor function and with the activation of alternative pathways of PI3K-Akt with antitumoral activity.

human HCC. Then we evaluated the expression of m6A enzymes. The m6A ‘reader’ YTH domain family 2 (YTHDF2) and associated genes were knocked down or overexpressed in SMMC7721 or MHCC97H cell lines; we analyzed their proliferation and pro-angiogenic function, and tumor growth and vasculature in a xenograft mouse model. We also generated a chemical-induced HCC model using the liver-specific Ythdf2 knockout mouse strain. RNA lifetime, m6A- and YTHDF2-immunoprecipitation, fluorescent in situ hybridization, and luciferase reporter assay were performed to validate the targets of YTHDF2.

Results: Hypoxic HCC exhibited a characteristic gain of m6A modification in tandem with an increase of mRNA expression. Loss of YTHDF2, which predicted poor classification and prognosis of HCC patients, highly correlated with HCC m6A landscape. YTHDF2 silenced in human HCC cells or depleted in mouse hepatocytes evoked pro-inflammatory responses and accelerated tumor growth and metastatic progression. Under hypoxia, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2alpha (HIF-2alpha).

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Conclusions: Our findings provide a new insight into the mechanism by which hypoxia adapts epitranscriptome to promote inflammation and HCC.


P-147 REDUCTION OF SPECIFIC POLYUNSATURATED FATTY ACIDS WITH TUMOR PROGRESSION IN A LEAN NONALCOHOLIC STEATOHEPATITIS-ASSOCIATED HEPATOCELLULAR CARCINOMA MOUSE MODEL

Paraskevi Farazi* 1, 2, Elizabeth Vlock1, 2, Geoffrey Talmon3

1Epidemiology, University of Nebraska Medical Center, Omaha, 2Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, University of Nebraska Lincoln, Lincoln, 3Pathology and Microbiology, University of Nebraska Medical Center, Omaha, United States

Introduction: The global prevalence of non-alcoholic fatty liver disease (NAFLD) is 24% and is predicted to be the leading cause for liver transplantation in the United States by 2030. The disease starts out as fatty liver and can progress to non-alcoholic steatohepatitis (NASH) and eventually hepatocellular carcinoma (HCC). NAFLD develops in lean individuals with a prevalence of 7% in the US and 25-30% in some Asian countries as a result of a diet high in fructose/fat/cholesterol and genetic predisposition that impacts on lipid export from the liver. Currently, there is limited molecular understanding of lean NASH-HCC pathogenesis, necessitating molecular investigations in this area. Certain polyunsaturated fatty acids have been shown to exhibit lower levels in HCC and have liver tumor suppressive properties both in vivo and in vitro. The relevance of these polyunsaturated fatty acids has not been investigated in lean NASH-HCC, warranting further studies in this area.

Methods: Thirty-five mice were fed a choline deficient, high trans-fat, sucrose, cholesterol (CD-HFSC) diet and fifteen mice were fed an isocaloric control low fat diet starting at 4 weeks of age. Liver tissue was analyzed post mortem to assess nodule development and liver histology in order to determine the development of NAFL, NASH, and HCC. Plasma was obtained from 5 mice with NAFL fed a low fat diet, 5 mice with pre-malignant lesions (regenerative nodules and dysplastic nodules) fed the CD-HFSC diet, and 5 mice with NASH-HCC fed the CD-HFSC diet at 32 weeks and 55 weeks of age (endpoint of the study). In addition, HCC tissue was taken from the same mice at 55 weeks. Metabolomics for 30 fatty acids (saturated, monounsaturated and polyunsaturated) was performed on these plasma and HCC tissue samples.

Posters Posters


Introduction: Transcription factor activating enhancer-binding protein-4 (TFAP4) is known to serve an essential role in tumorigenesis and tumor progression. It is involved in the regulation of cellular proliferation, stemness, and epithelial-mesenchymal transition (EMT).1 Moreover, high expression level of TFAP4 was identified as a biomarker for poor prognosis for hepatocellular carcinoma (HCC).2 Binding of transcription factors to the telomerase reverse transcriptase (TERT) promoter is expected to increase the activity of TERT promoter and transcription of TERT.3 Sequence analysis identified several putative binding sites of TFAP4 on the TERT promoter.4 However, no further studies were conducted to identify the exact binding site of TFAP4, and the transcriptional regulation of TFAP4 on TERT promoter remains unclear. In this study, we investigated if TFAP4 might play an important role in the reactivation of the TERT gene.

Methods: TERT mRNA expression levels were assessed upon stable knockdown of TFAP4, which was established using short-hairpin RNA expressing vectors in HCC cell lines. The open reading frame of TFAP4, wild-type TERT promoter, and various forms of putative TFAP4 binding site mutants with point mutation at -111, -234, or -286 upstream of the transcription start site of the TERT promoter were constructed. Dual Luciferase® Reporter Assay was performed to assess the promoter activities of both wild-type TERT promoter and mutated TERT promoters upon the overexpression of TFAP4 in HepG2 cells.

Results: Gene expression analysis with The Cancer Genome Atlas (TCGA) database shows that TFAP4 is upregulated in HCC tumors, as compared with the corresponding non-tumor liver samples. Additionally, the gene expression analysis between TERT and TFAP4 using TCGA database shows a positive correlation (R2= 0.03871, p = 0.0001) between the two in mRNA level in 371 cases of HCC tumor samples. As measured by quantitative RT-PCR, we found that TERT mRNA expression levels were decreased by approximately 2 folds upon knockdown of TFAP4 in Hep3B, MHCC97L, and PLC/PRF/5 cells. In addition, ectopic expression of TFAP4 in HepG2 cells led to a significant increase in the wild-type TERT promoter activity as measured by Dual Luciferase® Reporter Assay. Furthermore, the activity of the TERT promoter was abolished when a mutation at nucleotide 111 upstream of the transcription start site was created by mutagenesis, as compared to the promoter activities of wild-type TERT promoter and other mutated promoters.

Conclusions: Our findings suggest that TFAP4 might play a role in the reactivation of the TERT gene. TFAP4 is expected to bind 111 bp upstream of the transcription start site of the TERT promoter and regulate its transcriptional activity in HCC.

References: 1. Jackstadt R, Röh S, Neumann J, Jung P, Hoffmann R, Horst D, Berens C, Bornkamm GW,

Kirchner T, Menssen A, Hermeking H. AP4 is a mediator of epithelial-mesenchymal transition and metastasis in colorectal cancer. The Journal of Experimental Medicine. 2013; 210: 1331-1350.

2. Hu BS, Zhao G, Yu HF, Chen K, Dong JH, Tan JW. High expression of AP-4 predicts poor prognosis for hepatocellular carcinoma after curative hepatectomy. Tumor Biology. 2013; 34: 271-276.

3. Quaas A, Oldopp T, Tharun L, Klingenfeld C, Krech T, Sauter G, Grob TJ. Frequency of TERT promoter mutations in primary tumors of the liver. Virchows Arch. 2014; 465: 673-677.

4. Cong YS, Wen J, Bacchetti S. The human telomerase catalytic subunit hTERT: organization of the gene and characterization of the promoter. Human Molecular Genetics. 1999; 8: 137-142.


P-154 DOSE ESCALATION IN RADIOTHERAPY FOR INCOMPLETE TRANSARTERIAL CHEMOEMBOLIZATION OF HEPATOCELLULAR CARCINOMA

Hwa Kyung Byun* 1, Hyun Ju Kim2, Do Young Kim1, Kwang-Hyub Han1, Jinsil Seong1

1Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 2Radiation Oncology, Gachon University Gil Medical Center, Seoul, Korea, Republic Of

Introduction: To investigate efficacy of radiation dose escalation in patients with hepatocellular carcinoma (HCC) after incomplete transarterial chemoembolization (TACE).

Methods: This study evaluated retrospective data of 323 HCC patients who received radiotherapy after incomplete TACE during 2001–2016. Radiation dose in biologically effective dose (BED) (α/β=10) was categorized as <72 Gy (261 patients) and ≥72 Gy (62 patients). Simultaneous integrated boost-intensity modulated radiation therapy (SIB-IMRT) was significantly more used in high-dose group (64.5% vs. 12.9%; P <.001). Local failure-free rate (LFFR), progression-free rate (PFR), and toxicities were compared between two groups. Additionally, propensity score matching was performed.

Results: Median follow-up time for patients who were alive at time of analysis was 47 months (range, 18–189 months). Median overall survival after radiotherapy was 14 months. In multivariate analysis, BED ≥72 Gy was an independent predictor of favorable LFFR (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14–0.72; P=.006) and PFR (HR, 0.67; 95% CI, 0.45–0.98; P=.04). In propensity score-matched cohort (62 pairs), 1-year LFFR (94% vs. 81%; P=.002) and 1-year PFR (49% vs. 42%; P=.01) were significantly higher in high-dose group. Treatment-related toxicity in high-dose group, which involved radiation-induced liver disease (5 patients) and gastrointestinal bleeding (2 patients), was comparable to that of low-dose group.

30. Kavoosi F, Dastjerdi MN, Valiani A, Esfandiari E, Sanaei M, Hakemi MG. Genistein potentiates the effect of 17-beta estradiol on human hepatocellular carcinoma cell line. Adv Biomed Res 2016;5:133.

31. Wu H, Yao S, Zhang S, Wang JR, Guo PD, Li XM, Gan WJ, et al. Elevated expression of Erbin destabilizes ERalpha protein and promotes tumorigenesis in hepatocellular carcinoma. J Hepatol 2017;66:1193-1204.

32. Chen JJ, Tang YS, Huang SF, Ai JG, Wang HX, Zhang LP. HBx protein-induced upregulation of microRNA-221 promotes aberrant proliferation in HBVrelated hepatocellular carcinoma by targeting estrogen receptor-alpha. Oncol Rep 2015;33:792-798.

33. Liu WH, Yeh SH, Lu CC, Yu SL, Chen HY, Lin CY, Chen DS, et al. MicroRNA-18a prevents estrogen receptor-alpha expression, promoting proliferation of hepatocellular carcinoma cells. Gastroenterology 2009;136:683-693.

34. Deng L, Yang H, Tang J, Lin Z, Yin A, Gao Y, Wang X, et al. Inhibition of MTA1 by ERalpha contributes to protection hepatocellular carcinoma from tumor proliferation and metastasis. J Exp Clin Cancer Res 2015;34:128.

35. Liu C, Fu H, Liu X, Lei Q, Zhang Y, She X, Liu Q, et al. LINC00470 Coordinates the Epigenetic Regulation of ELFN2 to Distract GBM Cell Autophagy. Mol Ther 2018.

36. Gu J, Wang Y, Wang X, Zhou D, Wang X, Zhou M, He Z. Effect of the LncRNA GAS5-MiR-23a-ATG3 Axis in Regulating Autophagy in Patients with Breast Cancer. Cell Physiol Biochem 2018;48:194-207.

37. Gu J, Wang Y, Wang X, Zhou D, Shao C, Zhou M, He Z. Downregulation of lncRNA GAS5 confers tamoxifen resistance by activating miR-222 in breast cancer. Cancer Lett 2018;434:1-10.

38. Liu C, Zhang Y, She X, Fan L, Li P, Feng J, Fu H, et al. A cytoplasmic long noncoding RNA LINC00470 as a new AKT activator to mediate glioblastoma cell autophagy. J Hematol Oncol 2018;11:77.

39. Tang Y, He Y, Zhang P, Wang J, Fan C, Yang L, Xiong F, et al. LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis. Mol Cancer 2018;17:77.

40. Zlotorynski E. Non-coding RNA: Circular RNAs promote transcription. Nat Rev Mol Cell Biol 2015;16:206.

41. Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucleic Acids Res 2016;44:2846-2858.

42. Fu L, Yao T, Chen Q, Mo X, Hu Y, Guo J. Screening differential circular RNA expression profiles reveals hsa_circ_0004018 is associated with hepatocellular carcinoma. Oncotarget 2017;8:58405-58416.

43. Tian M, Chen R, Li T, Xiao B. Reduced expression of circRNA hsa_circ_0003159 in gastric cancer and its clinical significance. J Clin Lab Anal 2018;32.

44. Yin WB, Yan MG, Fang X, Guo JJ, Xiong W, Zhang RP. Circulating circular RNA hsa_circ_0001785 acts as a diagnostic biomarker for breast cancer detection. Clin Chim Acta 2017.

45. Zuo QF, Zhang R, Li BS, Zhao YL, Zhuang Y, Yu T, Gong L, et al. MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ. Cell Death Dis 2015;6:e1623.

46. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 2008;10:593-601.

47. Sun HQ, Yamamoto M, Mejillano M, Yin HL. Gelsolin, a multifunctional actin regulatory protein. J Biol Chem 1999;274:33179-33182.

48. Liao CJ, Wu TI, Huang YH, Chang TC, Wang CS, Tsai MM, Hsu CY, et al. Overexpression of gelsolin in human cervical carcinoma and its clinicopathological significance. Gynecol Oncol 2011;120:135-144.

49. Deng B, Fang J, Zhang X, Qu L, Cao Z, Wang B. Role of gelsolin in cell proliferation and invasion of human hepatocellular carcinoma cells. Gene 2015;571:292-297.

50. Chen CF, Hsu EC, Lin KT, Tu PH, Chang HW, Lin CH, Chen YJ, et al. Overlapping high-resolution copy number alterations in cancer genomes identified putative cancer genes in hepatocellular carcinoma. Hepatology 2010;52:1690-1701.

51. Kramer MC, Liang D, Tatomer DC, Gold B, March ZM, Cherry S, Wilusz JE. Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins. Genes Dev 2015;29:2168-2182.

52. Bai R, Yang F, Zhang Y, Zhao Z, Liao Q, Chen P, Zhao P, et al. Preparation of elastic diglycolamic-acid modified chitosan sponges and their application to recycling of rare-earth from waste phosphor powder. Carbohydr Polym 2018;190:255-261.


P-153 TRANSCRIPTION FACTOR ACTIVATING ENHANCER-BINDING PROTEIN-4 (TFAP4) IS INVOLVED IN REACTIVATION OF TELOMERASE REVERSE TRANSCRIPTASE (TERT) IN HEPATOCELLULAR CARCINOMA

Huiju Lim* 1, Karen M.-F. Sze1, Irene O.-L. Ng1

1Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong

References: 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer

J Clin 2011;61:69-90.2. Njei B, McCarty TR, Sharma P, Lange A, Najafian N, Ngu JN, Ngomba VE, et al. Bariatric Surgery

and Hepatocellular Carcinoma: a Propensity Score-Matched Analysis. Obes Surg 2018.3. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7-30.4. El-Serag HB, Mason AC, Key C. Trends in survival of patients with hepatocellular carcinoma

between 1977 and 1996 in the United States. Hepatology 2001;33:62-65.5. Li Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in

liver cancer. Cell 2012;148:72-83.6. Wang SH, Chen PJ, Yeh SH. Gender disparity in chronic hepatitis B: Mechanisms of sex

hormones. J Gastroenterol Hepatol 2015;30:1237-1245.7. Ahlbory-Dieker DL, Stride BD, Leder G, Schkoldow J, Trolenberg S, Seidel H, Otto C, et al. DNA

binding by estrogen receptor-alpha is essential for the transcriptional response to estrogen in the liver and the uterus. Mol Endocrinol 2009;23:1544-1555.

8. Yu MW, Chang HC, Chang SC, Liaw YF, Lin SM, Liu CJ, Lee SD, et al. Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk. Hepatology 2003;38:1393-1400.

9. Wang SH, Yeh SH, Lin WH, Yeh KH, Yuan Q, Xia NS, Chen DS, et al. Estrogen receptor alpha represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4alpha. Gastroenterology 2012;142:989-998 e984.

10. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007;317:121-124.

11. Villa E, Colantoni A, Grottola A, Ferretti I, Buttafoco P, Bertani H, De Maria N, et al. Variant estrogen receptors and their role in liver disease. Mol Cell Endocrinol 2002;193:65-69.

12. Jiang SY, Shyu RY, Yeh MY, Jordan VC. Tamoxifen inhibits hepatoma cell growth through an estrogen receptor independent mechanism. J Hepatol 1995;23:712-719.

13. Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ, Soo KC, et al. High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial. Hepatology 2002;36:1221-1226.

14. Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci U S A 1976;73:3852-3856.

15. Jeck WR, Sorrentino JA, Wang K, Slevin MK, Burd CE, Liu J, Marzluff WF, et al. Circular RNAs are abundant, conserved, and associated with ALU repeats. RNA 2013;19:141-157.

16. Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 2013;495:333-338.

17. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature 2013;495:384-388.

18. Yang W, Du WW, Li X, Yee AJ, Yang BB. Foxo3 activity promoted by non-coding effects of circular RNA and Foxo3 pseudogene in the inhibition of tumor growth and angiogenesis. Oncogene 2016;35:3919-3931.

19. Treiber T, Treiber N, Meister G. Regulation of microRNA biogenesis and function. Thromb Haemost 2012;107:605-610.

20. Chen Q, Yin D, Zhang Y, Yu L, Li XD, Zhou ZJ, Zhou SL, et al. MicroRNA-29a induces loss of 5-hydroxymethylcytosine and promotes metastasis of hepatocellular carcinoma through a TET-SOCS1-MMP9 signaling axis. Cell Death Dis 2017;8:e2906.

21. Li GH, Arora PD, Chen Y, McCulloch CA, Liu P. Multifunctional roles of gelsolin in health and diseases. Med Res Rev 2012;32:999-1025.

22. Chen P, Murphy-Ullrich JE, Wells A. A role for gelsolin in actuating epidermal growth factor receptor-mediated cell motility. J Cell Biol 1996;134:689-698.

23. Lader AS, Lee JJ, Cicchetti G, Kwiatkowski DJ. Mechanisms of gelsolin-dependent and -independent EGF-stimulated cell motility in a human lung epithelial cell line. Exp Cell Res 2005;307:153-163.

24. Deng R, Hao J, Han W, Ni Y, Huang X, Hu Q. Gelsolin regulates proliferation, apoptosis, migration and invasion in human oral carcinoma cells. Oncol Lett 2015;9:2129-2134.

25. Megger DA, Bracht T, Kohl M, Ahrens M, Naboulsi W, Weber F, Hoffmann AC, et al. Proteomic differences between hepatocellular carcinoma and nontumorous liver tissue investigated by a combined gel-based and label-free quantitative proteomics study. Mol Cell Proteomics 2013;12:2006-2020.

26. Han D, Li J, Wang H, Su X, Hou J, Gu Y, Qian C, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression. Hepatology 2017;66:1151-1164.

27. Sayeed A, Konduri SD, Liu W, Bansal S, Li F, Das GM. Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis. Cancer Res 2007;67:7746-7755.

28. Maynadier M, Ramirez JM, Cathiard AM, Platet N, Gras D, Gleizes M, Sheikh MS, et al. Unliganded estrogen receptor alpha inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21(WAF1)). FASEB J 2008;22:671-681.

29. Zhou J, Teng R, Xu C, Wang Q, Guo J, Xu C, Li Z, et al. Overexpression of ERalpha inhibits proliferation and invasion of MKN28 gastric cancer cells by suppressing beta-catenin. Oncol Rep 2013;30:1622-1630.

P-152 TARGETING THE ESTROGEN RECEPTOR ALPHA-MEDIATED CIRC-SMG1.72/MIR-141-3P/GELSOLIN SIGNALING TO BETTER SUPPRESS THE HCC CELL INVASION

Yao Xiao* 1, Liansheng Gong1

1Xiangya Hospital of Central South University, Changsha, China

Introduction: Early studies indicated that estrogen receptor α (ERα) might impact the progression of hepatocellular carcinoma (HCC). However, the detail mechanisms, especially its linkage to the gelsolin (GSN)-mediated cell invasion, remain unclear.

Methods: Cell cultureHuman HCC specimensReagents and MaterialsLentiviral expression plasmids and virus productionRNA extraction and qRT-PCR analysisCell Invasion AssayWestern Blot AnalysisRNA Immunoprecipitation (RIP)Chromatin Immunoprecipitation Assay (ChIP)Luciferase Reporter AssayThe circRNA-miRNA pull-down assayIn vivo studiesImmunohistochemical (IHC) staining:Statistics

Results: Here we found that ERα could decrease HCC cell invasion via suppressing the circular RNA (circRNA), SMG1.72 (circ-SMG1.72), expression via direct binding to the 5' promoter region of its host gene SMG1. ERα-suppressed circ-SMG1.72 could then sponge and inhibit the micro RNA (miRNA, miR), miR-141-3p, expression, which can then result in increasing the GSN messenger RNA translation via a reduced miR binding to its 3' untranslated region (3'UTR). The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the human HCC dastabase analysis and tissue staining also confirmed the linkage of ERα/miR-141-3p/GSN signaling to the HCC progression.

Image:

Conclusions: Our findings suggest that ERα can suppress HCC cell invasion via altering the ERα/circ-SMG1.72/miR-141-3p/GSN signaling, and regulating this newly identified signaling with small molecules may help in the development of novel therapies to better suppress the HCC progression.

Posters Posters


Results: Out of 733 patients, 480 (65.5%) were White, 175 (23.9%) were Black, and 78 (10.6%) were Other race. Survival was found to be significantly different across races (p = 0.041), but these differences were diminished when cases were stratified by local and distant stages (p = 0.069 and p = 0.87 respectively). In the multivariate analysis, the proportional hazards were stratified by stage and treatment. Other race patients were found to have significantly better survival relative to White patients (HR: 0.66, 95% CI: 0.45-0.97). Patients who lived in neighborhoods with higher concentrations of Blacks/African-Americans were found to have significantly higher risk of mortality (HR: 1.19 per one-point change in Black isolation, 95% CI: 1.02-1.38). Neighborhood socioeconomic status and rurality were not found to be significantly associated with liver cancer survival.

Image:

Conclusions: Racial differences in liver cancer survival were identified and persisted even after controlling for other clinical variables. Patients who were neither Black nor White tended to have the best liver cancer survival. Racial residential segregation of Blacks/African Americans was shown to be associated with poorer survival.

References: 1. (2013) Fast Stats: An interactive tool for access to SEER cancer statistics. In: Surveill. Res.

Program, Natl. Cancer Inst. http://seer.cancer.gov/faststats. Accessed 1 Jan 20162. Siegel RL, Miller KD, Jemal A (2016) Cancer statistics. CA Cancer J Clin 66:7–30 . doi:

10.3322/caac.21332.


P-159 THE EFFECT OF METABOLIC FACTORS ON PROGNOSIS OF HBV-ASSOCIATED HEPATOCELLULAR CARCINOMA

Lei Xiao1, Yi Xiong1, Xin Yang1, Yongxing Bao* 1

1Cancer Center, 1st affiliated hospital of XinJiang Medical University, Urumqi, China

Introduction: To study the effect of metabolic risk factors on the survival and prognosis of HBV-associated hepatocellular carcinoma.

Methods: 404 patients of hepatocellular carcinoma with HBV admitted to the first affiliated hospital of Xinjiang Medical University from May 2000 to November 2016. Obesity, hyperglycemi, hypertriglyceridemia, hypercholesterolemia and hypertension as baseline data were assigned to different metabolic risk categories. According to the level of hepatitis B DNA load, the cases were grouped and Kaplan-Meier curves were plotted. Interlayer stratification differences are determined by using Wilcoxon test to understand the effects of metabolic risk factors on the prognosis of hepatocellulthe carcinoma.

Results: Different metabolic risk factors have significant differences in the survival and prognosis of hepatocellular carcinoma. In the low hepatitis B DNA load group (<10000 copies/ml), there was no statistical difference in the effect of metabolic risk factors on the prognosis of hepatocellular carcinoma (P=0.234); In the high hepatitis B DNA load group( ≥ 10000 copy/ml), the mortality risk of HBV-associated hepatocellular carcinoma with obesity and/or hyperglycemia were significantly increased (P=0.019). In addition, the risk of death raised with the increase of metabolic factors (P=0.007).

Conclusions: Metabolic factors increase the risk of death in HBV-associated hepatocellular carcinoma patients in the group of high HBV DNA load.


Methods: Multicenter, observational, retrospective study. Adult pt with uHCC who had RCDP on SFLT since January 2017 and a minimum follow-up after disease progression of at least 7 weeks were included.

Results: A total 87 pt from 9 tertiary hospitals in Spain were included in the analysis. At uHCC diagnosis, median age was 66 years, 92.0% of pt were male. The most common etiological factors of HCC were alcohol abuse (57.5%), hepatitis C (43.7%), hepatitis B (9.2%) and nonalcoholic steatohepatitis (8.0%). Median BMI was 27.6 kg/m2 (range 19.9-36.0), 43.7% of pt had hypertension, 18.4% dyslipidemia and 32.2% diabetes mellitus. Most pt (90.8%) had ECOG PS 0-1, 78.1% Child-Pugh A and 6.9% B7 and 12.6% mild to moderate ascites. More than 2/3 of pt (67.8%) were BCLC stage B or C, 20.7% extrahepatic spread and 17.2% vascular invasion. Regarding locoregional treatments, 39% of pt received TACE (81.3% had 1 or 2 TACE) and 9.2% radioembolization; 24.1% local ablation, 17.2% surgical resection and 9.2% liver transplant.At end of SFLT, 67.1% of pt had ECOG PS 0-1, 52.8% Child-Pugh A, 32.9% ascites (8.6% severe) and 3 pt had encephalopathy; 42.9% had extrahepatic spread, 38.6% vascular invasion (14.3% portal principal vein) and 84.3% were BCLC stage B or C.Radiological evaluation was performed every 8 or 12 weeks during first-line treatment and after radiological progression on SFLT (56.3%/40.0%) and blood tests every 2 or 4 weeks (75.5%/88.3%) respectively.Sorafenib was the SFLT for 97.7% of pt. Median sorafenib treatment duration was 6.7 months (range 2.0-39.4) and median initial dose 800 mg/day (range 200-800). The radiologic progression pattern to SFLT was intrahepatic growth (IG) (45.3%), new intrahepatic lesions (NIL) (28.5%), extrahepatic growth (EG) (14.5%) and new extrahepatic lesions (NEL) (11.6%).After first-line disease progression, 44.8% of pt did not receive treatment, 18.4% continued treatment with sorafenib and 36.8% received second-line treatment. 81.3% of pt that received second-line systemic treatment received regorafenib.. Median duration of regorafenib treatment was 1.6 months (range 0.2-6.0) and median initial dose 160 mg/day (range 80-160). Among the pt who continued with sorafenib after first line disease progression, progression pattern was: 48.7% IG, 40.8% NIL, 28.0% EG and 40.0% NEL.

Conclusions: Pt receiving sorafenib in real-life practice in Spain are BCLC stages B/C. In referral hospitals, pt receive no more than 2 previous TACE, which may contribute to preserving liver function prior to the initiation of SFLT. Although liver function and PS are maintained in the vast majority of pt who progress after SFLT, approximately 1/3 of them receive treatment with regorafenib. The progression pattern does not seem to influence the decision to switch to regorafenib treatment. A significant number of pt who progress after SFLT continue sorafenib and almost half of them do not receive any treatment.

Disclosure of Interest: A. Matilla Conflict with: Research/Education grant - Bayer, Conflict with: Advisory Board - Bayer, J. Lledo Conflict with: Research/Education grant - Bayer, Conflict with: Advisory Board - Bayer, T. Ferrer Conflict with: Consulting - Bayer, J. Montero Conflict with: Advisory Board - Bayer, S. Pascual Conflict with: Advisory Board - Bayer, B. García Paredes Conflict with: Advisory Board - Sanofi, T. Serrano Conflict with: Honoraria - Abbvie, Astellas, Novartis and Gilead, Conflict with: Consulting - Bayer, R. Díaz Beveridge: None Declared, S. Coll Conflict with: Advisory Board - Bayer (2017)

P-158 SURVIVAL DIFFERENCES IN LIVER CANCER DUE TO PATIENT RACE AND RACIAL RESIDENTIAL SEGREGATION

Amin Bemanian* 1, Kia Saeian2, Laura D. Cassidy1, Raphael Fraser1, Purushottam W. Laud1, Kirsten M. Beyer1

1Institute for Health and Equity, 2Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, United States

Introduction: Liver cancer incidence and mortality has significant racial disparities in the United States. Black/African-Americans have 1.4 times the liver cancer incidence relative to non-Hispanic Whites, while Hispanics, Asians and Pacific Islanders (APIs), and American Indian/Alaskan Natives (AI/ANs) have nearly two times the incidence [1]. Liver cancer survival is poor with a five-year survival rate of 18% [2], but differences in survival across race remains understudied. Additionally, previous studies have not explored how social environmental factors such as racial segregation and neighborhood socioeconomics affect liver cancer survival. This study investigated racial differences in liver cancer survival and how these differences are affected by social and environmental variables.

Methods: A retrospective analysis of 733 liver cancer cases from the Milwaukee and Racine, Wisconsin metropolitan areas was conducted. Patients were classified as either White (i.e. non-Hispanic White), Black/African-American, or Other (APIs, AI/ANs, or Hispanics of any race). These cases were geocoded to their home census tracts and linked to a measure of racial segregation (the Transportation Related Exposure/Isolation index), a socioeconomic index (combination of median household income, four-year college graduation rate, and unemployment rate), and the degree of rurality in the tract. Cases were also linked to their history of chronic liver disease, cancer stage at diagnosis, and treatment history. Survival was estimated using the Kaplan-Meier method and differences across race were tested using the log-rank test. Multivariate survival analysis was conducted using a Cox proportional hazards regression.

Results: Eight researches were enrolled in this meta-analysis, including 371 patients in the postoperative adjuvant chemo (embolization) therapy group and 473 patients in the operation only group. The pooled HR for the overall RFS of the postoperative adjuvant chemo (embolization) therapy group was 0.54 (95% CI 0.41~0.71, P<0.0001), compared with the operation only group. But, in the subgroup analysis, compared with operation only, the pooled ORs for the 1-, 2, 3-year RFS rates were in favor of both postoperative adjuvant chemo (embolization) therapy group (OR=3.00, 95% CI =1.81~4.95, P<0.0001; OR=2.22, 95% CI =1.50~3.30, P<0.0001; OR=2.27, 95% CI =1.52~3.40, P<0.0001; respectively) and postoperative chemotherapy group(OR=3.45, 95% CI =1.49~7.97, P=0.004; OR=2.72, 95% CI =1.51~4.91, P=0.0009; OR=2.14, 95% CI =1.34~3.43, P=0.001; respectively), but only the pooled ORs for the 1-year RFS rates was in favor of postoperative TACE (OR=2.61, 95% CI =1.35~5.02, P=0.004).

Conclusions: Postoperative adjuvant chemotherapy was more effective in the prevention of recurrence for HCC patients with PVTT than postoperative TACE, but it deserved additional relevant trials to confirm.

References: 1. Zanetto A, Campello E, Spiezia L, Burra P, Simioni P and Russo FP. Cancer-Associated

Thrombosis in Cirrhotic Patients with Hepatocellular Carcinoma. Cancers (Basel). 2018; 10(11).2. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial chemoembolization (TACE) in

hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol. 2008; 103(4):914-921.

3. Zhang ZM, Lai EC, Zhang C, et al. The strategies for treating primary hepatocellular carcinoma with portal vein tumor thrombus. Int J Surg. 2015; 20:8-16.

4. Zhang B, Zhang B, Zhang Z, et al. 42,573 cases of hepatectomy in China: a multicenter retrospective investigation. Sci China Life Sci. 2018; 61(6):660-670.

5. Minagawa M and Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol. 2006; 12(47):7561-7567.

6. Forner A, Reig M and Bruix J. Hepatocellular carcinoma. Lancet. 2018; 391(10127):1301-1314.

7. Kokudo T, Hasegawa K, Matsuyama Y, et al. Survival benefit of liver resection for hepatocellular carcinoma associated with portal vein invasion. J Hepatol. 2016; 65(5):938-943.

8. Liang L, Chen TH, Li C, et al. A systematic review comparing outcomes of surgical resection and non-surgical treatments for patients with hepatocellular carcinoma and portal vein tumor thrombus. HPB (Oxford). 2018; 20(12):1119-1129.

9. Zhang XP, Wang K, Li N, et al. Survival benefit of hepatic resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis. BMC Cancer. 2017; 17(1):902.

10. Ye JZ, Zhang YQ, Ye HH, et al. Appropriate treatment strategies improve survival of hepatocellular carcinoma patients with portal vein tumor thrombus. World J Gastroenterol. 2014; 20(45):17141-17147.

11. Zhou Q, Wang Y, Zhou X, et al. Prognostic analysis for treatment modalities in hepatocellular carcinomas with portal vein tumor thrombi. Asian Pac J Cancer Prev. 2011; 12(11):2847-2850.

12. Zhang YF, Shang H, Zeng XL, Ji H, Li YM and Lu HW. Postoperative adjuvant chemo (embolization) therapy for hepatocellular carcinoma with portal vein tumor thrombosis. Onco Targets Ther. 2018; 11:5407-5417.


P-157 MANAGEMENT OF PATIENTS WITH UNRESECTED HEPATOCELLULAR CARCINOMA AFTER RADIOLOGICALLY CONFIRMED DISEASE PROGRESSION ON SYSTEMIC FIRST-LINE TREATMENT. RESULTS OF THE RETROSPECTIVE HERACLES STUDY

Ana Matilla* 1, Jose L. Lledo2, Teresa Ferrer3, Jose L. Montero4, Sonia Pascual5, Beatriz García Paredes6, Trinidad Serrano7, Roberto Díaz Beveridge8, Susana Coll9

1Gastroenterology Department, Hospital Universitario Gregorio Marañon, 2Gastroenterology Department, Hospital Universitario Ramon y Cajal, Madrid, 3Digestive System Unit, Hospital Virgen del Rocío, Sevilla, 4Hepatology Unit, Hospital Universitario Reina Sofía de Córdoba, Córdoba, 5Hepatic Unit. Digestive System Department, CIBERehd. Hospital General Universitario de Alicante, Alicante, 6Medical Oncology Department, Hospital Clinico San Carlos, Madrid, 7Digestive System Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, 8Medical Oncology Service, Hospital Universitari i Politecnic La Fe, Valencia, 9Liver Section, Gastroenterology Department, Hospital del Mar. IMIM Hospital del Mar Medical Research Institute, Barcelona, Spain

Introduction: HCC is the most frequent primary liver cancer and the third leading cause of cancer death. Sorafenib is standard systemic first-line therapy (SFLT) for patients (pt) with unresectable hepatocellular carcinoma (uHCC). In Spain there is no approved systemic therapy after progression on SFLT. This study aims to describe the clinical characteristics and clinical pathways for uHCC pt with radiologically confirmed disease progression (RCDP) on SFLT in Spain according to routine clinical practice. Secondary objectives are to describe progression pattern, clinical procedures and administered treatments.

Conclusions: Radiation dose with BED ≥72 Gy improved LFFR and PFR without increasing toxicity. In radiotherapy for incomplete TACE of HCC, dose escalation using SIB-IMRT needs active consideration to improve oncologic outcome.


P-155 THE INFLUENCE OF ABO BLOOD GROUP ON WAITLIST AND TRANSPLANT OUTCOMES



Introduction: Studies have shown an increase in graft survival in liver transplantation with the utilization of ABO matched or compatible organs. To our knowledge, there is limited data examining the effect of blood group on transplant outcomes for patients with hepatocellular carcinoma (HCC). In this study, we aim to determine the impact of blood group on transplant wait times, list dropout, and mortality for this patient population.

Methods: Patients with HCC listed for transplant between 2012-2018 at a tertiary care high volume transplant center were included in this study. Patients were excluded if HCC was incidentally noted in the explant only. Data collected included patient demographics, blood type, date of listing, date of transplant or dropout and mortality. The four blood groups were then compared in terms of time from listing to transplant, and whether dropout or death occurred.

Results: A total of 179 patients with HCC were listed for transplant between 2012-2018. Of those, 138 (77.1%) were male. 100 (55.9%) had hepatitis C cirrhosis, 21 (11.7%) had alcoholic cirrhosis, and 14 (7.8%) had non-alcoholic steatohepatitis. For blood groups A, B, AB, and O, the rates of transplant were 74.2%, 90.9%, 87.5%, and 74.7% (P=0.328) and the time from listing to transplant for groups A, B, AB, and O were 207.1 ± 134.8, 153.2 ± 194.2, 35.4 ± 27.7, and 178.1 ± 208.1 days (P<0.001), respectively. The rates of list dropout for blood groups A, B, AB, and O were 22.6%, 9.1%, 12.5%, and 25.3% (P=0.423) and the rates of mortality were 19.4%, 13.6%, 37.5%, and 25.3%, respectively (P=0.432).

Conclusions: These results suggest that for patients undergoing liver transplant for HCC, the rates of liver transplant, waitlist dropout, and mortality are similar between the four blood groups. The time from listing to transplant is noted to be significantly longer for those with blood group A as suspected, and shortest for those with blood group AB. Our results likely reflect the distribution of blood groups within our region, and the flexibility of the AB blood group in receiving all other blood group donor organs. This should highlight the need to consider blood group A patients listed for transplant with HCC to consider options of living donor liver transplant or receipt of extended criteria donor organs to reduce their waiting times on the transplant list. This is especially important if we see time to transplant for HCC patients increase in the future.


P-156 COULD POSTOPERATIVE ADJUVANT CHEMO (EMBOLIZATION) THERAPY REDUCE THE RECURRENCE OF HEPATOCELLULAR CARCINOMA WITH PORTAL VEIN TUMOR THROMBOSIS: A META-ANALYSIS

Qiao Ke* 1


Introduction: Portal vein tumor thrombus (PVTT) is the portal vein thrombosis (PVT) related to tumor, which is typically accompanied with cirrhotic patients with hepatocellular carcinoma (HCC)[1]. The incidence is reported to 20-40% worldwide[2], and the incidence in China was reported to be 44%~62.2%[3]. PVTT is also one of the most critical prognostic factors for HCC[4, 5], and the prognosis is very poor with 2.7~4.0 months median survival time. HCC typically with PVTT is beyond of resection according to the Barcelona-Clinic Liver Cancer (BCLC) algorithm[6]. However, selected patients with HCC and PVTT are subjected to resection, especially in experienced eastern Asia liver centers[4, 7], and the surgical efficacy was confirmed in recent systematic reviews[8, 9].

Postoperative adjuvant therapy, such as transarterial chemoembolization(TACE) and portal vein chemotherapy (PVC), is effective in prolonging the overall survival time of HCC with PVTT[10, 11]. But, the latest meta-analysis found that postoperative TACE could only improve the 1-year OS rate[12]. Since recurrence is the most common causes of HCC related death, we hypothesized that postoperative adjuvant TACE couldn’t prevent the late recurrence of HCC. Hence, a meta-analysis based on the most updated and published data is needed to evaluate the efficacy of postoperative adjuvant chemo (embolization) for HCC with PVTT in the prevention of recurrence.

Methods: Eligible studies were searched by PubMed, MedLine, SinoMed, and so on, from Jan.1st 2000 to Dec.31st 2018, comparing the recurrence-free survival (RFS) rates between postoperative adjuvant chemo (embolization) therapy and operation only for HCC patient with PVTT. Hazard ratio (HR) or odds ratio (OR) with 95% confidence interval (CI) was used to determine the effect size.

Posters Posters


Disclosure of Interest: K. Tsuchiya Conflict with: Honoraria - Bayer, Eisai, W. Wan: None Declared, S. Kaneko: None Declared, N. Tamaki: None Declared, Y. Yasui: None Declared, H. Nakanishi: None Declared, J. Itakura: None Declared, M. Kurosaki Conflict with: Honoraria - Bayer, Eisai, Conflict with: Advisory Board - Bayer, Eisai, N. Izumi Conflict with: Honoraria - Bayer, Eisai

P-164 TREATMENT STRATEGY USING BODY COMPOSITION FOR ADVANCED HEPATOCELLULAR CARCINOMA: HEPATIC ARTERIAL INFUSION CHEMOTHERAPY VS. SORAFENIB

Issei Saeki* 1, Takahiro Yamasaki2, Yurika Kotoh1, Taro Takami1, Isao Sakaida1

1Dep. of Gastroenterology & Hepatology, 2Dep. Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan

Introduction: Sorafenib (SORA) is used worldwide as a first line treatment for patients with advanced hepatocellular carcinoma (HCC). However, hepatic arterial infusion chemotherapy (HAIC) is one of the recommended treatments in Japan, but not in other counties. Although randomized controlled trials comparing SORA with HAIC have been conducted, several retrospective analyses have shown no significant differences in survival between the two therapies. Hence, we explored the role of body composition as a factor affecting the survival benefit of HAIC compared to SORA for advanced HCC and proposed a treatment strategy using body composition for advanced HCC.

Methods: We analyzed 133 patients who received SORA or HAIC as a first-line treatment for advanced HCC from 2009 to 2016. The skeletal muscle index (SMI) and visceral fat area (VFA) were measured as body composition using computed tomography before treatment induction. Muscle depletion and high-VFA (H-VFA) were defined using published cut-offs. We analyzed clinical parameters including body composition as prognostic factors.

Results: HAIC and SORA were administered to 55 and 78 patients, respectively. There were significant differences in age, Child-Pugh score, extra-hepatic spread (EHS), tumor number, maximum tumor size, and macrovascular invasion in the two groups. The objective response rate was better in those who received HAIC (HAIC, 29.6 vs. SORA, 5.7%; p < .001), but the disease control rate was equivalent (HAIC, 70.4 vs. SORA, 64.3%; p = .565). Similar prognoses were shown in the two groups (median survival time (MST): HAIC, 12.5 vs. SORA, 12.1 months, p = .828). In the SORA group, multivariate analysis identified tumor number < 7 (hazard ratio [HR], .475; p = 0.008), EHS (HR, 1.959; p = .015), muscle depletion (HR, 1.802; p = .044), and H-VFA (HR, .483; p = .015) as favorable prognostic factors for survival. In contrast, a positive response to HAIC (HR, .438; p = .022) and conversion from HAIC to SORA (HR, 0.374; p = .008) were extracted in the HAIC group.

Conclusions: It was found that body composition significantly affected prognosis in the SORA group, but not in the HAIC group. Furthermore, a positive response to HAIC and conversion from HAIC to SORA were independent prognostic factors in the HAIC group. When a positive response to HAIC is not obtained, longer survival may be expected by switching to SORA immediately. We previously developed the ACTH (Assessment for Continuous Treatment with HAIC) score as a scoring system, which evaluates the response of HAIC during the middle of the treatment cycle based on three parameters: the Child-Pugh score, AFP (alpha-fetoprotein), and DCP (des-gamma-carboxy prothrombin). We finally combined the findings of this study with the ACTH score, and found that it is possible to propose this treatment strategy for advanced HCC.Body composition may be a useful biomarker for the identification of patients likely to experience survival benefits from either HAIC or SORA for the treatment of advanced HCC.


P-165 ACUTE STROKE AFTER TRANSARTERIAL CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA

Peixin Huang* 1, Zhiying Zhao1, Jinglin Xia1, Zhenggang Ren1

1Liver cancer institute, Zhongshan Hospital, Fudan University, Shanghai, China

Introduction: Transarterial chemoembolization (TACE) plays a vital role in the management of unresectable hepatocellular carcinoma (HCC) and other liver malignancies. Acute stroke after TACE including cerebral lipiodol embolism (CLE) and intracerebral hemorrhage (ICH) is a rare and severe complication of TACE. Its risk and prognostic factors are not well studied. The aim of this study is to elucidate the incidence and characteristics of CLE and ICH in HCC patients accepting TACE procedures.

Methods: We presented six cases with acute stroke after TACE since Jan, 2009 to Dec, 2014 in our institution and reviewed the cases reported since 2004. The clinical manifestations and characteristics of CLE and ICH were summarized. The potential risk and prognostic factors of acute stroke after TACE were analyzed.

Results: The frequency of CLE and ICH after TACE was 0.1% (6/4140). Elder age, male, huge tumor size, large dose of lipiodol, right inferior phrenic artery (IPA) feeding and repeated TACE procedures may be the potential risk factor of CLE. Brian metastasis and the history of peripheral vessels injury may result in ICH. Elder age and right hepatic and IPA feeding may impact the prognosis.

Results: By utilizing first order ordinary differential equations (ODE) and MatLab, a hybrid SIR + IPM model was developed with the reference to the schema shown below.The model showed that by 3 years, the number of patients with HCC will be about 10,232.The deterministic model is: = S(α-β) -µІ …………………… (1)This is the rate of change of number of susceptibles (S) over time. - · = µІ-I (r +β) ………………………………… (2)This is the rate of change of infected persons (I) over time. - · =rI+ R (α+ β) .…………………….…………. (3) This is the rate of change of the number recovered (R) over time,Where S, I and R are the numbers of susceptible, infected and recovered patients from liver cancer.

Conclusions: There is an exponential increase in burden of liver cancer from 257 at baseline to 10,382 in year three. The projected rates indicate that liver cancer in Western Kenya will be increasing over time unless it is controlled.

References: 1. Mugisha J.Y.T. (2009). The role of mathematical modeling; lecture notes in biomathematics.

A course conducted at Nelson Mandela Metropolitan University.2. Mukerji S. (1989). Dynamics of population and family welfare. Eds. Srinivasan K. and Pathak

K.B. New Delhi: Himalaya Publishing House.3. Yang H.I., Lu S.N., Liaw Y.F., You S.L., Sun C.A. and Wang U.Y. (2002). Hepatitis B e antigen and

the risk of hepatocellular carcinoma. New. Engl. J. Med. 168– 174.4. Barendregt J.J., Baan C.A. and Bonneux L. (2000). An indirect estimate of the incidence of

non-insulin-dependent diabetes mellitus. Epidemiology. 11:274- 279.5. Bauch, Chris, and David Earn. (2003). "Interepidemic Intervals in Forced and Unforced SEIR

models.". Dynamical Systems and Their Applications in Biology. Ed. Shigui Ruan, Gail S. Wolkowicz and Jianhong Wu. New York: American Mathematical Society, 10: 33-43.

6. Rhodes John A. and Elizabeth S. (2003). Allman. Mathematical Models in Biology: An Introduction. New York: Cambridge UP.

Disclosure of Interest: A. Otedo Conflict with: Research/Education grant - Yes, Conflict with: Honoraria - None, Conflict with: Stocks - None, Conflict with: Advisory Board - None, Conflict with: Consulting - None, O. Ongati: None Declared, V. Were: None Declared, B. Estambale: None Declared, K. Simbiri: None Declared

P-163 CLINICAL OUTCOME AND BIOMARKERS IN JAPANESE PATIENTS TREATED WITH REGORAFENIB IN REAL WORLD PRACTICE

Kaoru Tsuchiya* 1, Wang Wan1, Shun Kaneko1, Nobuharu Tamaki1, Yutaka Yasui1, Hiroyuki Nakanishi1, Jun Itakura1, Masayuki Kurosaki1, Namiki Izumi1

1Department of Gastoroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

Introduction: Regorafenib has been approved in patients with unresectable HCC (u-HCC) since Jun 2017 in Japan and the patients who experienced tyrosine kinase inhibitors (TKIs) have been able to receive lenvatinib therapy as well as TKI naïve patients since Mar 2018. We investigated the clinical outcome and predictors in patients treated with regorafenib.

Methods: A total of 30 u-HCC patients received regorafenib at our institution between July 2017 and Dec 2018 were included. Tumour assessments in accordance with modified RECIST was done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0.

Results: Median age was 74 (31-86) years, and median body weight was 58 (30-81) kg. The baseline liver function was Child-Pugh class A in 28 (93%) patients and 17 (57%) patients were BCLC stage C. Median overall survival (OS) and follow-up duration were 12.8 and 10.8 months. Median OS from beginning of sorafenib therapy was 25.6 months. Median progression free survival (PFS) was 5.2 months. Based on mRECIST, CR was shown in 0 (0%), PR in 5 (17%), SD in 18 (60%), and PD in 7 (23%). Overall response rate (ORR) and disease control rate (DCR) were 17% and 77%. Regorafenib was stopped in 24 patients because of radiological progression (n=17) or adverse events (n=7). Post-regorafenib therapies were performed in 18 of 24 (75%) patients. Nine patients received lenvatinib as a third-line therapy. ORR and DCR in lenvatinib therapy post regorafenib were 44% and 78%. As pretreatment predictors, hand-foot skin reaction (HFSR) during sorafenib (p=0.004) was significantly associated with OS in regorafenib therapy. HFSR during regorafenib (p=0.003) and AFP decrease during regorafenib (p=0.002) were significantly associated with OS. Plasma VEGF decrease during regorafenib was significantly associated with HFSR during regorafenib (p=0.04), however, not associated with AFP decrease. The patients who could receive post-regorafenib anticancer therapies had better survival than the patients without post-regorafenib therapy (p<.0001).

Conclusions: The clinical outcome of regorafenib therapy in real world practice in Japan was better than the phase 3 (RESORCE) trial. Post-regorafenib therapies including lenvatinib would contribute to good prognosis. HFSR during sorafenib and regorafenib, and AFP decrease during regorafenib were significant predictors in regorafenib therapy.

[6] Alexandre S. Bezerra, Giuseppe D’Ippolito, Salomão Faintuch et al. Determination of Splenomegaly by CT: Is There a Place for a Single Measurement?. AJR:184, May 2005

[7] Zhoubing Xu, Adam L. Gertz, Ryan P. Burke et al. Improving Spleen Volume Estimation via Computer Assisted Segmentation on Clinically Acquired CT Scans. Acad Radiol. 2016 October; 23(10): 1214–1220


P-161 FACTORS ASSOCIATED WITH POSTPROGRESSION SURVIVAL IN ADVANCED HEPATOCELLULAR CARCINOMA PATIENTS WITH POST-SORAFENIB PROGRESSION NOT ELIGIBLE FOR REGORAFENIB

Hee Yeon Kim* 1, Chang Wook Kim1, Sang Wook Choi1, Do Seon Song1, U Im Chang1, Jin Mo Yang1, Sung Won Lee1, Hae Lim Lee1, Nam Ik Han1, Sun Hong Yoo1, Jung Hyun Kwon1, Soon Woo Nam1, Pil Soo Sung1, Jeong Won Jang1, Si Hyun Bae1, Jong Young Choi1, Seung Kew Yoon1

1Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic Of

Introduction: We aimed to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients who showed radiological progressive disease (PD) following sorafenib monotherapy, and were not eligible for 2nd-line regorafenib treatment.

Methods: A total of 223 patients who were confirmed with radiological PD following sorafenib monotherapy from September 2008 to December 2017 were enrolled. We define those with Child-Pugh class A, ECOG PS 0 or 1 at progression, and who had tolerated sorafenib as candidates eligible for 2nd line regorafenib therapy.

Results: Among 223 patients with PD after sorafenib treatment, 126 (56.5%) patients met eligibility criteria for regorafenib treatment at first radiological confirmation of PD. The median PPS of the candidates for regorafenib treatment (12.1 months) was statistically longer (P<0.001) than that of the non-candidates (3.2 months). Prognostic factor associated with good PPS in non-candidates for regorafenib therapy was absence of macrovascular invasion [hazard ratio = 0.5 (95% confidence interval 0.33-0.76)] at initial radiological PD.

Conclusions: Absence of macrovascular invasion at initial radiological PD following sorafenib may predict good PPS in advanced HCC patients who had progressed after sorafenib monoterapy and were not eligible for 2nd-line regorafenib treatment.


P-162 MATHEMATICAL MODELLING OF BURDEN OF HEPATOCELLULAR CARCINOMA IN WESTERN KENYA

Amos Otedo* 1, Omolo N. Ongati2, Vincent Were3, Benson Estambale4, Kenneth Simbiri5

1Internal medicine and Gastroenterology, Kisumu County Hospital, Kisumu, 2Mathematics, Jaramogi Oginga Odinag University of science and technology, Bondo, 3Epidemiology and biostatistics, Kenya Medical Research Institute, Kisumu, 4Deputy vice chancellor, Jaramogi Oginga Odinga University of science and technology, Bondo, Kenya, 5Biology, Temple University, Pennsylvania, United States

Introduction: Mathematical modeling is the process of describing a real world problem (biological or physical) in mathematical terms and then using mathematical methods to analyze the problem with the intention of establishing a solution [1]. Mathematical modeling also helps the health care worker to improve on the management and prevention of diseases [1,2]. Hepatocellular carcinoma is a global public health problem and a “silent killer,” because signs and symptoms usually don’t appear until the disease is at an advanced stage. The survival period in untreated cases is between 3-6 months. [3]. Indeed, liver cancer is referred to as a recalcitrant cancer, which is a cancers that have 5-year relative survival rates below 50%. Data on prevalence and incidence is scanty leading to inability to predict the burden of HCC in the developing world leading to poor planning and policy framework for management and control of HCC. We estimated the burden of liver cancer in western Kenya using a hybrid model of incidence, prevalence and mortality (I.P.M) and susceptible, infected and recovered (S.I.R) [4.5].

Methods: We applied an integrated incidence-prevalence-mortality (IPR) model and susceptible-Infectious- Recovery model (SIR) format and the primary outcome was diagnosis of HCC, and the parameters representing IPM and SIR which were obtained both from empirical data and secondary data. Parameters used were obtained from grey, published literature and empirical data from a cross-sectional study among all patients who presented with abdominal swelling and diagnosed to have HCC and who were seeking care at Kisumu County and referral Hospital. A model schema was then developed which describes a population in two states; as being diseased or susceptible. The model then allows for calculation of burden of HCC disease using ODEs and Matlab software. Analysis was done by utilizing first order ordinary differential equations (ODE) and MatLab to model liver cancer in western Kenya.

P-160 IMPACT OF SPLEEN SIZE ON CLINICAL OUTCOME OF PATIENTS WITH HEPATOCELLULAR CARCINOMA TREATED BY TRANSARTERIAL CHEMOEMBOLIZATION

Cheol Bae Ham* 1, Nam Hee Kim2, Won Sohn1, Yong Kyun Cho1, Hong Joo Kim1, Woo Kyu Jeon1, Byung Ik Kim1

1Kangbuk Samsung Hospital, Gastroenterology, 2Kangbuk Samsung Hospital, Preventive Healthcare Center, Seoul, Korea, Republic Of

Introduction: Portal hypertension is an important prognostic factor in the treatment of hepatocellular carcinoma(HCC) [1][2][3]. Spleen size is an surrogate marker of portal hypertension and can be easily measured from computed tomography (CT) or magnetic resonance imaging (MRI)[4][5][6][7]. In a Japanese study of patients who underwent hepatectomy with HCC, spleen volume was a poor prognostic factor. The purpose of this study was to evaluate the effect of spleen size on clinical outcome in patients undergoing transarterial chemoembolization(TACE) for HCC.

Methods: A retrospective data analysis was performed for a total of 386 patients who underwent TACE as first line therapy for HCC from January 2000 to June 2014. The Spleen index(SI) was used as representative value of spleen size or spleen volume (SI(cm3)= W(cm) * T(cm) * L(cm), W : width at the point of maximum width of the spleen, T : thickness at the midpoint of the section where W was determined, L : maximum cranio-caudal length of the spleen) [6][7]. Spleen index of enrolled patients was calculated using CT or MRI performed at the time of HCC diagnosis. We compared the cumulative occurrence rate of complete response (CR), progression-free survival (PFS), overall survival (OS) and 5-year survival according to SI, which was divided into three groups according to the value (Group 1 : SI<356.5 cm3, Group 2 : 356.5 cm3 - 576.4 cm3, Group 3 : SI>576.4 cm3),at the time of diagnosis of HCC.

Results: Multivariate analysis showed a statistically significant poor prognosis for OS in Group 3(aHR 1.86, confidence interval [95% CI], 1.132-3.040, p value 0.014)(Table. 1). As the SI increase, the mortality rate per 1000-person-years also increased significantly(Group 1: 8.07, [95% CI] 5.77-11.3, Group 2: 9.11, [95% CI] 6.57-12.63, Group 3: 14.41, [95% CI] 10.95-18.96)(Table 1). Five-year OS rate was significantly lower in group 3 compared to group 1(42.4% vs 60.4%) and group 2(42.4% vs 62.2%). However, PFS and occurrence rate of CR were statistically insignificant.

person-

timedeaths

Mortality rate per 1,000

person-years (95% CI)

Model 1

aHR (95% CI)

Model 2

aHR (95% CI)

Spleen index tertile

Group1(356.5<)

4211 34 8.07 (5.77-11.3)

1 (reference) 1 (reference)

Group2(356.5 - 576.4)

3953 36 9.11 (6.57-12.63)

1.12 (0.700-1.797)

1.16 (0.704-1.906)

Group3(>576.4)

3539 51 14.41 (10.95-18.96)

1.60 (1.030-2.508)

1.86 (1.132-3.040)

p for trend 0.033 0.014

Table 1 Comparison of overall survivalModel 1: adjusted for age and sex, Model 2 : adjusted for age, sex, tumor size, number of tumor, tumor site, BCLC stage , Cause of HCC, Portal vein thrombus

Conclusions: Spleen index reflecting spleen size or volume can be easily obtained from CT or MRI performed at HCC diagnosis without additional examination. Spleen index could be considered as a useful prognostic factor for patients with HCC undergoing TACE.

References: [1] Nam Hee Kim, Taeheon Lee, Yong Kyun Cho, Byung Ik Kim, Hong Joo Kim. Impact of clinically

evident portal hypertension on clinical outcome of patients with hepatocellular carcinoma treated by transarterial chemoembolization. Journal of Gastroenterology and Hepatology 33 (2018) 1397–1406

[2] Kazuki Takeishi, Hirofumi Kawanaka, Shinji Itoh et al. Impact of Splenic Volume and Splenectomy on Prognosis of Hepatocellular Carcinoma Within Milan Criteria After Curative Hepatectomy. World J Surg (2018) 42:1120–1128

[3] Kuan-Chieh Fang, Chien-Wei Su, Yi-You Chiou et al. The impact of clinically significant portal hypertension on the prognosis of patients with hepatocellular carcinoma after radiofrequency ablation: a propensity score matching analysis. Eur Radiol (2017) 27:2600–2609

[4] Ulrika Asenbaum, MD, Ahmed Ba-Ssalamah, MD, Mattias Mandorfer, MD et al. Effects of Portal Hypertension on Gadoxetic Acid–Enhanced Liver Magnetic Resonance. Investigative Radiology, Volume 52, Number 8, August 2017

[5] P. Prassopoulos, M. Daskalogiannaki, M. Raissaki et al. Determination of normal splenic volume on computed tomography in relation to age, gender and body habitus. Eur. Radiol. 7, 246–248 (1997)

Posters Posters


Methods: The subjects were 21 unresectable advanced ICC patients treated using subcutaneous PEG-IFN α-2b (50-100 μg on day 1 of every week, for 4 weeks) and intra-arterial infusion of 5-FU (250 mg/day for 5 h on days 1-5 of every week, for 4 weeks). One treatment cycle lasted 4 weeks. Therapy was discontinued in patients with progressive disease (PD). For responses other than PD, treatment was repeated for ≥ 1 cycle.

Results: The objective early response rate was 61.9%. Cumulative survival rates were 73.1% at 6 months, 56.0% at 12 months, 31.6 % at 18 months, 18.2 % at 24 months and 18.2 % at 36 months. Median survival time was 17.0 months.All adverse reactions were controllable by temporary suspension of treatment. Serious complications and treatment related deaths were not observed.

Conclusions: The combination therapy of PEG-IFN α-2b and 5-FU for unresectable advanced ICC seems to be better than the results of the previous studies. In addition, most adverse effects are transient and well tolerated. Although a larger prospective study involving a larger population of patients with advanced ICC is needed to evaluate this combination therapy, this combination therapy may be useful for patients with unresectable advanced ICC as one of the therapeutic option.


P-170 RISK FACTORS ASSOCIATED WITH FAILURE OF ENHANCED RECOVERY AFTER HEPATECTOMY: ESTABLISHMENT OF A PREDICTION MODEL

Jia Weidong* 1

1Department of Liver Surgery, Affiliated Provincial Hospital, Anhui Medical University, Hefei, China

Introduction: Although enhanced recovery after surgery (ERAS) protocols have been proven to be beneficial for hepatectomy, they may result in adverse clinical outcomes if failed. The aim of this study was to investigate factors associated with enhanced recovery failure (ERF) and incorporate them into a risk prediction model.

Methods: Data were collected from January 2014 to April 2017 including 460 patients underwent hepatectomy within ERAS protocols. According to their clinical outcomes, cases were divided into enhanced recovery (ER) group and ERF group. Univariate and multivariate analysis were performed to determine independent risk factors for ERF and develop the risk prediction model.

Results: Sixty-three patients failed ERAS protocols (13.7%). Independent risk factors for ERF were ASA score＞II (OR 4.209; 95% CI 1.903-9.310; P＞0.001); serum ALT＞40U/L (OR 3.676; 95% CI 1.961-6.888; P＞0.001); total bilirubin＞21μmol/L (OR 2.245; 95% CI 1.045-4.822; P=0.038); blood loss≥400mL (OR 3.292; 95% CI 1.550-6.995; P=0.002) and major hepatectomy (OR 2.202; 95% CI 1.085-4.469; P=0.029). The model offered good discrimination (area under the receiver operating characteristic curve=0.810, 95% CI 0.696-0.924) and calibration (c2=3.589, P=0.732) for the external validation set.

Conclusions: The prediction model incorporated five preoperative and intraoperative factors and had been successfully externally validated. After prospective researches on the basis of this study, the risk prediction model may be modified, updated and used as a tool to limit ERF rates, reduce morbidity and cost, facilitate planning and allocation of resources.


P-171 OPTIMIZING THE DIAGNOSTIC ROLE OF ALPHA-FETOPROTEIN AND ABDOMINAL ULTRASOUND

BY ADDING OVEREXPRESSED BLOOD MRNA MATRIX METALLOPROTEINASE-12 FOR DIAGNOSIS OF HCV-RELATED HEPATOCELLULAR CARCINOMA

Esam Elshimi* 1 and Mostafa Abdel-Samed Mostafa Sakr Wesam Saber Morad Lobna Mohammad


Introduction: Matrix metalloproteinase-12 (MMP-12) is involved in tumor invasiveness and metastasis and significantly overexpressed in hepatocellular carcinoma (HCC) tissues. We aimed to investigate the diagnostic and prognostic value of blood mRNA MMP-12 overexpression in patients with HCC.

Methods: From January 2017 to June 2017, 100 patients with HCC (HCV-related cirrhosis) and 100 patients with HCV-related cirrhosis (without HCC) were included in this study. All patients were subjected to triphasic CT abdomen when indicated, liver profile, alpha-fetoprotein (AFP), and molecular characterization of metalloproteinase-12 expression.

remaining patient had a 4.2 cm lesion prior to RFA. Two patients developed new lesions on follow up imaging prior to LT. None of the included patients developed post-transplant HCC recurrence during the post-LT follow up period (54 months, range 1-131 months) and the overall survival was 76%.

Conclusions: The HCC histopathologic characteristics in the explanted liver at the time of LT has a dual function in both reflecting the efficacy of preoperative locoregional therapy and as a predictive factor for HCC recurrence. Our data suggests that RFA can afford HCC patients excellent short-term tumor control even when their cancer is multifocal in nature, provided that the largest tumor is < 3 cm. This study also provides further evidence that modern imaging is still fallible in demonstrating active HCC especially in those with multifocal tumors prior to RFA.


P-168 PREDISPOSING FACTORS OF HEPATOCELLULAR CARCINOMA RECURRENCES FOLLOWING COMPLETE REMISSION BY TRANSARTERIAL CHEMOEMBOLIZATION: FOCUSED ON THE RECURRENCE PATTERNS

Wonhyeong Park* 1, Miran Lee1, Seoungmok Shin1, Seungmoon Han1, Seoung whan Kim1

1Internal Medicine, Veterans Health Service Medical Center, Seoul, Korea, Republic Of

Introduction: Although the efficacies of many therapeutic modalities for hepatocellular carcinoma (HCC) are progressively improved, the survival periods of HCC patients are still disappointing, mainly due to frequent tumor recurrences despite excellent response to treatments. In this study, we intended to determine the predisposing factors of recurrences in patients with HCC who had achieved complete remission (CR) by transarterial chemoembolization (TACE) and also examined the rates and patterns of recurrences.

Methods: A total of 440 consecutive HCC patients who had achieved CR by TACE followed for a median period of 74 months (range, 12-180). CR was defined as complete lipiodol uptake on CT scan evaluated 4 weeks after TACE and no additional tumor staining on follow-up angiography. Serum alpha-fetoprotein (AFP) levels and computerized tomography and/or magnetic resonance imaging were assessed every 3 to 6 months following CR. The recurrence pattern was classified as local recurrence (within 2cm from the primary tumor) and secondary tumor (>2cm apart from the primary tumor) according to the location of recurrence.

Results: During the follow-up period, of the 440 patients, 338 (77%) showed HCC recurrences following CR; 182 local recurrences (53.8%), 122 secondary tumor (36.1%), 34 both (10.1%). HCC recurred within 12 months following CR (early recurrence) in 90 cases out of 338 patients (26.6%); (62.2% local recurrences, 28.9% secondary tumor, 8.9% both); >12 months (late recurrence) in the remaining 248 cases (73.4%) (50.8% local recurrences, 38.7% secondary tumor, 10.5% both). As expected, the cumulative survival rates of HCC patients with recurrence were significantly shorter than those of patients without recurrence (1-, 3- and 5-year rates; 100%, 91% and 56% vs. 100%, 97% and 89%, respectively; P<0.001). Interestingly, the cumulative survival rates of HCC patients with late recurrence were shorter than those of early recurrence (1-, 3- and 5-year rates; 100%, 89% and 50% vs. 100%, 91% and 58%, respectively; P=0.043). However, the cumulative survival rates were not different from each other between patients with local recurrence and those with secondary tumor. In univariate and multivariate analysis, multinodular type of HCC (HR 3.3, P<0.001) and high post-TACE serum AFP level (HR 2.3, P=0.02) were significant predictors of early HCC recurrence; advanced liver cirrhosis (HR 2.1, P<0.001) was independent risk factor for late HCC recurrence following CT by TACE.

Conclusions: Our data suggested that the early recurrence following CR by TACE may be mainly due to undetectable remaining tumor and that, in contrast, the most of late recurrences may be caused by newly appeared tumor at the advanced cirrhotic background liver.


P-169 HEPATIC ARTERIAL INFUSION CHEMOTHERAPY (HAIC) USING 5-FLUOROURACIL WITH SYSTEMIC PEGYLATED INTERFERONα-2B FOR UNRESECTABLE ADVANCED INTRAHEPATIC CHOLANGIOCARCINOMA.

Kei Sawara* 1, 2, Takayoshi Oikawa1, Hidekatu Kuroda1, Yasuhiro Takikawa1, Kazuhiro Kasai3

1Gastroenterology And Hepatology, Iwate Medical University, Morioka, 2Sawara hospital, Kitakata, 3IMS Sapporo Digestive Disease Center General Hospital,, Sapporo, Japan

Introduction: Cholangiocarcinoma is categorized into intrahepatic cholangiocarcinoma (ICC) and extrahepaticcholangiocarcinoma (ECC). The prognosis of ICC is far worse than that of ECC. In this study, the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) combined with subcutaneous administration of pegylated interferon (PEG-IFN) α-2b for patients with unresectable advanced ICC was evaluated.

P-166 MONOCYTE-TO-LYMPHOCYTE RATIO WAS CORRELATED WITH NIVOLUMAB RESPONSE IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA

Zhen Feng Zhu* 1, Li Tao Xu1, Zhi Qiang Meng1

1Fudan University Shanghai Cancer Center, Shanghai, China

Introduction: Immune checkpoint inhibitors have achieved fruitful results in clinical trials for the treatment of advanced hepatocellular carcinoma1,2, and recently nivolumab has been approved by the US FDA for second-line treatment of advanced hepatocellular carcinoma3. However, only a subset of about 20 percent of patients shows an objective response to nivolumab therapy. Furthermore, response to nivolumab is not correlated with programmed cell death 1 ligand 1 (PD-L1) expression in tumor tissue4. Therefore, it is urgent to find out a biomarker to predict nivolumab response.

Methods: A retrospective study was conducted at the Fudan University Shanghai Cancer Center from October 2017 to October 2018. The monocyte-to-lymphocyte ratio (MLR) was analyzed using a receiver operating characteristic curve. Log-rank test were used to analyze the relationship between the MLR value and time to progression (TTP).

Results: A total of 34 advanced HCC patients, including 28 men and 6 women, were enrolled in this retrospective study. The median age was 52.5 years (range 25-71). The optimal cut-off point for MLR was 0.35. With regard to the MLR value at baseline, the median TTP in the low and high MLR groups was 32 weeks and 17 weeks, respectively (HR: 0.2602, 95% CI: 0.1080-0.6266, p=0.0027).

Conclusions: MLR can predict nivolumab response, and a high MLR is correlated with short TTP in patients with advanced HCC

References: 1. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular

carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-2502.

2. Vokes EE, Ready N, Felip E, et al. Nivolumab versus docetaxel in previously treated advanced non-small-cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases. Ann Oncol. 2018;29(4):959-965.

3. Nivolumab Approved for Liver Cancer. Cancer Discov. 2017;7(11):OF3.4. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations Associated with Acquired Resistance to

PD-1 Blockade in Melanoma. N Engl J Med. 2016;375(9):819-829


P-167 EFFICACY OF RADIOFREQUENCY ABLATION IN THE TREATMENT OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND COMPENSATED LIVER DISEASE: A PATHOLOGICAL EVALUATION OF LIVER EXPLANTS

Waleed Al-Hamoudi* 1, 2, Issam Salih1, Sarra Yousif1, Abdullah Al-osaimi1, Khalid Bzeizi1, Saleh Alqahtani1, Ali Albenmousa1, Bandar Safar3, Mark Sturdevant1, Dieter Broering1, Hamad Alsuhaibani3

1Department of Liver Transplantation and Hepatobiliary Surgery, King Faisal Specialist Hospital and Research Center, 2Department of Medicine, King Saud University, 3Department of Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Introduction: Radiofrequency ablation (RFA) is a safe and effective treatment for patients with limited hepatocellular carcinoma (HCC). Promising ablative outcomes have been largely based on radiological response, and confirmatory data based on histological review are limited. The aim of this study is to correlate the radiological tumor response of RFA with the histopathologic examination of explanted livers following liver transplantation (LT).

Methods: All compensated patients treated with RFA prior to LT at our institution from 2007-2018 were included in this study. Clinical, pathological explant evaluation and survival outcomes were collected from our prospectively collected database. Decompensated patients (child B and C) and patients who received other forms of locoregional treatment were excluded.

Results: 29 (19 males and 10 females) patients were treated with RFA prior to LT. Mean age was 58 years (range 21-75). The average time between RFA and LT was 8 months (range 1-24). The etiology of liver disease was as follows: HCV 13 (44.8%), HBV 9 (31%), Non-alcoholic steatohepatitis 5 (17.2%) and progressive familial intrahepatic cholestasis 2 (7%). 12(41%), 12 (41%), and 5 (18%) of patients had a single, two, or three lesions, respectively. 17 (58.6 %), 8 (27.6%), 3 (10.3%), and 1 (3.4%) received 1, 2, 3, and 4 sessions, respectively. Average pretreatment alfa fetoprotein was 139 (range 3.5-2159). When comparing RFA for single or multiple HCC with no lesion more than 3 cm pathological cure was significantly higher, 85% (12/14) of cases vs 46% (7/15) in patients with lesions exceeding 3 cm (p value=0.027). Pathological cure was 100% (4/4) in patients with a single lesion less than 3 cm. Furthermore, 6 patients had lesions on the explant examination that were not demonstrated on the pretransplant imaging, of them 5 patients had multifocal HCC while the

Conclusions: Patient with the potential risk factors of CLE and ICH should be hyper-vigilant about the occurrence of acute stroke after TACE. The characteristics summarized in our study will help providing early detection and management of acute stroke after TACE.

References: 1. Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national

incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789–1858.

2. Omata M, Cheng AL, Kokudo N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11(4):317–370.

3. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 2012;56:908–943.

4. Kim HK, Chung YH, Song BC, et al. Ischemic bile duct injury as a serious complication after transarterial chemoembolization in patients with hepatocellular carcinoma. J CLIN Gastroenterol 2001;32:423-427.

5. Leung TK, Lee CM, Chen HC: Anatomic and technical skill factor of gastroduodenal complication in post-transarterial embolization for hepatocellular carcinoma: A retrospective study of 280 cases. World J Gastroenterol 2005;11:1554-1557.

6. Honda Y, Kimura T, Aikata H,et al. Pilot study of stereotactic body radiation therapy combined with transcatheter arterial chemoembolization for small hepatocellular carcinoma. Hepatogastroenterology 2014;61:31-36.

7. Liapi E, Geschwind JF: Transcatheter arterial chemoembolization for liver cancer: Is it time to distinguish conventional from drug-eluting chemoembolization? Cardiovasc Intervent Radiol 2011;34:37-49.

8. Lu Q, Chen L, Zeng J, et al: Clinical features of liver cancer with cerebral hemorrhage. Med Sci Monit 2016;22:1716-1723.

9. Jang SY, Kim CH, Cheong JH, et al. Concomitant subdural hemorrhage and intracerebral hemorrhage due to brain metastasis of the hepatocellular carcinoma. Brain Tumor Res Treat 2015;3:48-51.

10. Talwalkar JA, Gores GJ: Diagnosis and staging of hepatocellular carcinoma. Gastroenterology 2004;127:S126-S132.

11. Hsiao SY, Chen SF, Chang CC, et al. Central nervous system involvement in hepatocellular carcinoma: Clinical characteristics and comparison of intracranial and spinal metastatic groups. J CLIN NEUROSCI 2011;18:364-368.

12. Chu HJ, Lee CW, Yeh SJ, et al. Cerebral lipiodol embolism in hepatocellular carcinoma patients treated with transarterial Embolization/Chemoembolization. PLOS ONE 2015;10:e129367.

13. Matsumoto K, Nojiri J, Takase Y, et al. Cerebral lipiodol embolism: A complication of transcatheter arterial chemoembolization for hepatocellular carcinoma. Cardiovasc Intervent Radiol 2007;30:512-514.

14. Bansaghi Z, Kaposi PN, Lovas G, et al. Cerebral iodized lipid embolization via a pulmonary arteriovenous shunt: Rare complication of transcatheter arterial embolization for hepatocellular carcinoma. WORLD J SURG ONCOL 2013;11:122.

15. Chu HJ, Lee CW, Yeh SJ, et al. Cerebral lipiodol embolism in hepatocellular carcinoma patients treated with transarterial Embolization/Chemoembolization. PLOS ONE 2015;10:e129367.

16. Hatamaru K, Azuma S, Akamatsu T, Seta T, Urai S, Uenoyama Y, Yamashita Y, Ono K: Pulmonary embolism after arterial chemoembolization for hepatocellular carcinoma: An autopsy case report. World J Gastroenterol 2015;21:1344-1348.

17. Pai YW, Hsieh PF, Tung H, Wu CY, Ching CT, Chang MH: Prognosis of cerebral lipiodol embolism caused by transarterial chemoembolization. NEUROL RES 2016;38:857-863.

18. Wu RH, Tzeng WS, Chang CM: Iodized oil embolization to brain following transcatheter arterial embolization of liver. J Gastroenterol Hepatol 2005;20:1465-1467.

19. Ishikawa T, Kubota T, Abe H, Toduka Y, Horigome R, Watanabe Y, Kimura N, Honda H, Iwanaga A, Seki K, Honma T, Yoshida T, Sato M: Case of cerebral lipiodol embolism after repeated transcatheter arterial chemoembolization of hepatocellular carcinoma. HEPATOL RES 2013;43:1251-1252.

20. Lee CS, Kim SJ, Choi JW, et al. Cerebral lipiodol embolism proven by dual-energy computed tomography: A case report. J Comput Assist Tomogr 2010;34:105-106.

21. Zach V, Rapaport B, Yoo JY, et al. Multiple ischemic strokes after transcatheter arterial chemoembolization for hepatocellular carcinoma with a radiographic and pathological correlate. J Stroke Cerebrovasc Dis 2012;21:217-224.

22. Li Z, Ni RF, Busireddy KK, et al. Cerebral lipiodol embolism following transcatheter arterial chemoembolization for hepatocellular carcinoma: A report of two cases and literature review. Chin Med J (Engl) 2011;124:4355-4358.

23. Jia ZZ, Tian F, Jiang GM: Cerebral lipiodol embolism after transarterial chemoembolization for hepatic carcinoma: A case report. World J Gastroenterol 2012;18:4069-4070.

24. Wan CC, Liu KL: Cerebral Lipiodol embolism. LIVER INT 2015;35:673.25. Bansaghi Z, Kaposi PN, Lovas G, et al. Cerebral iodized lipid embolization via a pulmonary

arteriovenous shunt: Rare complication of transcatheter arterial embolization for hepatocellular carcinoma. WORLD J SURG ONCOL 2013;11:122.

Posters Posters


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P-177 KNOCKDOWN OF ATG7 SUPPRESSES TUMORIGENESIS IN HCC MOUSE MODELS INDUCED BY HRASG12V AND SHP53

Sunyeong Shin* 1, 2, Beom Kyung Kim2, 3, Weonsang S. Ro2, Hyuk Moon2, Kwang-Hyub Han2, 3

1Brain Korea 21 Plus Project For Medical Science, Yonsei University, 2Yonsei Liver Center, 3Internal Medicine, Institute Of Gastroenterology, Yonsei University, Seoul, Korea, Republic Of

Introduction: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the second leading cause of cancer-related deaths worldwide. Many studies showed that autophagy is associated with liver cancer. ATG7 is a critical component for the formation of autophagosome and thus required for autophagy processes. To investigate the effect of autophagy on liver cancer, we utilized ATG7 knock-down transgenic mouse models.

Methods: Transposon vectors encoding short hairpin RNA downregulating ATG7 (ATG7 shRNA) were constructed. Transposons encoding ATG7 shRNA were mixed with those encoding HRASG12V and shp53 and then injected into the lateral tail veins of 5-week-old C57BL/6 mice. The development of liver cancer was observed grossly and histologically at 5-6weeks post hydrodynamic injection. Expression of genes related to autophagy process was assessed using western blotting and immunohistochemistry.

Results: We assessed knockdown efficiency of various ATG7 shRNAs in NIH3T3 cells. ATG7.1536 shRNA was most effective in downregulating ATG7. Mice were hydrodynamically transfected with transposons encoding shATG7 and then analyzed for tumor development in the liver. We found that the size and numbers of tumor nodules significantly decreased in the ATG7 knockdown groups compared to control. Histological examination of tumors from shATG7 mice showed knock-down of ATG7 and suppression of autophagic processes.

Conclusions: Knockdown of ATG7 led to a significant decrease in tumroigenesis induced by HRASG12V and shp53. Inhibiting the autophagosome formation is expected to be a therapeutic option for liver cancer.


P-178 TUMOR-ASSOCIATED ANTIGEN SPECIFIC T-CELL IMMUNE RESPONSE IN HEPATOCELLULAR CARCINOMA

Chaoran Zang* 1, Ling Qin1, Jianping Sun1, Kang Li1, Yanan Zhao1, Yonghong Zhang1

1Beijing Youan Hospital, Captial Medical University, Beijing, China

Introduction: HCC is a worldwide major health problem[1]. And there are studies did prove the existence of TAA-specific immune responses in HCC patients[2-12]. However, the relationship between the progression of HCC and T cell immune response is also deserved to be investigated.

Methods: We obtained 52 samples from AIDS biobank, peripheral blood mononuclear cells (PBMC) were isolated, used enzyme-linked immunospot assay with different TAAs including SALL-4, MAGE-A1, MAGE-A3, NY-ESO-1, SSX-2 and AFP to detect the immune response. SPSS v.22 was used for statistical analysis, Graph Pad Prism 5.0 was used to draw the statistical charts.

Conclusions: The annual incidence of HCC is increasing by more than 20% because of the aging cohort effect of the current HCV and obesity epidemics. This is projected to reach 500 patients per annum by 2030. The proportion of new HCC cases in patients with NASH without cirrhosis is also increasing, raising the issue of which patients with NASH should undergo HCC surveillance.


P-175 CLINICAL CHARACTERISTICS AND OUTCOMES OF CRYPTOGENIC HEPATOCELLULAR CARCINOMA IN TAIWAN

Po-Yao Hsu* 1, Cheng-Ting Hsu1, Chia-Yen Dai1, 2, Ming-Lung Yu1, 2, Jee-Fu Huang1, 2, Wan-Long Chuang1, 2

1Kaoshiung Medical University Hospital, 2Hepatobiliary Division, Department of Internal Medicine, Kaohsiung, Taiwan, Province of China

Introduction: While chronic chronic hepatitis B and chronic hepatitis C are still the leading causes of cirrhosis and hepatocellular carcinoma (HCC), some liver cancers are not caused by hepatitis B virus (HBV) or hepatitis C virus (HCV). The aim of this study was to compare the clinical characteristics and overall survival of non-B non-C, non-alcohol related HCC, also known as cryptogenic HCC (cHCC) and viral-related HCC.

Methods: This retrospective cohort study recruited those HCC patients newly-diagnosed and treated at a referral medical centre in Taiwan from January 2008 to August 2018. Their clinical data and outcomes were analyzed.

Results: A total of 332 patients had cHCC. The mean age of cHCC patients was significantly older (69.9 ± 11.9 years) than HBVHCC group (61.9 ± 11.4 years, p < 0.05), and it was comparable with HCV HCC group (68.9 ± 9.1 years, p > 0.05) and HBV/HCV HCC (66.6 ± 10.7 years, p > 0.05). cHCC (61.7 %) and HBVHCC (76.3%) patients had a higher proportion of males than HBV-HCC group (p < 0.05). cHCC patients carried a higher proportion of obesity (BMI ≥ 27 kg/m2) and hypertension than HBV-HCC group. cHCC patients also had higher incidence of diabetes (43.9%) compared to those with HBV-HCC (27.1%, p < 0.05) or HCV-HCC (30.2%, p < 0.05). The median survival of cHCC patients was 1.75 years, which was the shortest among the four groups. Multivariate analysis demonstrated that HCV infection, gender, body weight, AFP level, cirrhosis, BCLC stage and primary treatment modalities were independent predictors of survival.

Conclusions: cHCC patients had higher incidence of diabetes, more advanced stages of disease and worse overall survival compared to those with HBV-HCC or HCV-HCC. The advanced BCLC stage in cHCC patients highlights the necessity of regular surveillance for NAFLD patients.


P-176 PREOPERATIVE PRACTICAL AND PERSONALIZED PREDICTORS OF EARLY OUTCOMES AFTER MAJOR HEPATECTOMY FOR CHOLANGIOCARCINOMAS LOCATED NEAR TO THE HILUM

Nicolas Golse1, Julio Nunez1, Cyril Cosse1, Marc Antoine Allard1, Oriana Ciacio1, Gabriella Pittau1, Antonio Sa Cunha1, Denis Castaing1, Daniel Cherqui1, René Adam1, Eric Vibert* 1

1Liver Transplantation and HPB surgery, Paul Brousse Hospital, Paris, France

Introduction: Curative treatment of both perihilar cholangiocarcinoma (PHCC) and intrahepatic cholangiocarcinoma (ICC) located near to the hilum require major hepatectomy with high morbi-mortality. Nomograms are available to anticipate outcomes but they are mainly based on pathological analysis, and no preoperative nomogram exists to guide surgeons in patient’s selection and information. We aimed to propose patient specific predictors for severe morbidity and early mortality (6 months) after resection.

Methods: We reviewed all patients resected for PHCC and ICC between March 2012 and March 2018 in our tertiary centre. We first defined predictors of the 2 endpoints in a multivariate regression model using the stepwise method. Then, the ß-coefficients from a final non-linear model were used to construct Kattan-style nomograms.

Results: We included 103 patients (68 PHCC + 35 ICC). By multivariate analysis, the predictors of severe morbidity were: tobacco, Psoas Muscle Area [PMA]/height2, future remnant liver volume, haemoglobin, albumin, retention rate of ICG, bilirubin level, number of biliary drainage procedures, interval between drainage and surgery and the number of embolization procedures. The nomogram presented a C-index of 0.787. The predictors of mortality at 6 months were: age, diabetes, PMA/height2, bilirubin level, albuminemia, number of drainage procedures. The nomogram presented a C-index of 0.834.

Conclusions: We provide accurate and practical nomograms to predict severe morbidity and early mortality after resection of PHCC and central ICC, based on exclusively preoperative data. They focus on well-known risk-factor (sarcopenia, bilirubin level, age, diabetes, smoking) and highlight the negative impact of complications after preoperative preparation leading to delayed surgery. External validation in now required to confirm these preliminary results.

hnRNP L in HCC tissues was significantly associated with age, vascular invasion, Edmondson grade and Barcelona Clinic Liver Cancer stage (all P<0.05). Furthermore, the expression intensity of hnRNP L was positively correlated with the expression of CD68 and CD206 (all P<0.001), but negatively correlated with the expression of CD11c (P<0.001). In addition, lincRNA-EPS was up-regulated in HCC tissues.

Conclusions: The expression of hnRNP L in HCC tissues was significantly up-regulated and correlated with malignant features of HCC. Also, the increase in hnRNP L levels in HCC is correlated with the polarization of macrophages.

References: 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018:

GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424.

2. Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates and Trends--An Update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16-27.

3. Crocetti L, Bargellini I, Cioni R. Loco-regional treatment of HCC: current status. Clinical radiology. 2017;72(8):626-635.

4. Blechacz B, Mishra L. Hepatocellular carcinoma biology. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer. 2013;190:1-20.

5. Yang Q, Zhang J, Xu S, et al. Knockdown of PHF5A Inhibits Migration and Invasion of HCC Cells via Downregulating NF-kappaB Signaling. Biomed Res Int. 2019;2019:1621854.


P-174 CHANGING EPIDEMIOLOGY AND AETIOLOGY OF HEPATOCELLULAR CARCINOMA IN NEW ZEALAND: AUDIT FROM NZ LIVER TRANSPLANT UNIT

Debi Prasad* 1, 2, Edward Gane2, David Orr2, John McCall2, Andrew Holden2, Adam Bartlet2

1Institute Of Liver Studies, Kings College Hospital, London, United Kingdom, 2Liver Transplant Unit, New Zealand Liver Transplant Unit, Auckland, New Zealand

Introduction: Objectives: The objectives were to describe changing trends in epidemiology and aetiology of hepatocellular carcinoma (HCC) in New Zealand since the introduction of a centralised HCC service in 1995.

Methods: HCC incidence data from NZLTU HCC multidisciplinary meeting (MDM) was correlated with clinical notes and liver cancer mortality data accessed from the National registry. Trends in incidence of HCC were analysed in addition to changes in aetiology of HCC and proportion of HCC in patients without cirrhosis. Since 1998, patients with the new diagnosis of HCC are presented to NZLTU MDM, where management recommendations are conveyed to the referring physician. Majority of therapeutic interventions (liver transplant, resection, percutaneous and laparoscopic ablation and Trans arterial chemoembolization) are performed at NZLTU.

Results: HCC incidence rates have increased significantly during the study period – 7 cases were diagnosed in 1992m 68 cases in 2005, 124 cases in 2010 and 263 in 2015, an increase of 22% per annum. The aetiology of HCC has also changed during the study period. The proportion of new HCC cases due to HBV has decreased from 85% in 1992 to 30% in 2015. During the same period, the proportion due to HCV has increased from to 33% in 2015 and the proportion due to NASH has also increased from 3% to 15%. In 1992, almost all cases are due to HBV. As a direct result of increasing NASH-related HCC, the proportion of cases with non-cirrhotic HCC has increased from 22% to 31%.

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Results: There were no statistically significant differences between both groups regarding CBC parameters and liver profile (p value >0.05). There was a statistically significant difference between patients with and without HCC regarding blood mRNA MMP-12 overexpression (p value <0.01), blood mRNA MMP-12, and/or AFP (sensitivity 84.0%, specificity 60.0%, PPV 51.2%, and NPP 88.2%). The accuracy of mRNA MMP-12 and/or AFP in detection of HCC was 68.0%.

Conclusions: Blood mRNA MMP-12 has a good sensitivity and a bad specificity but is accurate in HCC diagnosis. Adding blood mRNA MMP-12 to AFP optimizes the current screening program to improve early diagnosis of HCC and hence better prognosis.


P-172 LOW LEVELS OF TUMOR SUPPRESSOR CANDIDATE 3 PREDICT POOR PROGNOSIS OF PATIENTS WITH HEPATOCELLULAR CARCINOMA

Jia Weidong* 1

1Department of Liver Surgery, Affiliated Provincial Hospital, Anhui Medical University, hefei, China

Introduction: The tumor suppressor candidate 3 (TUSC3) has been considered to be closely associated with the occurrence, development and invasion of various malignant tumors. However, the expression of TUSC3 in hepatocellular carcinoma (HCC) tissues remains ambiguous .The purpose of this research was to investigate the expression of TUSC3 in HCC tissues and analyze the relationship between TUSC3 levels and clinicopathological characteristics and prognosis of HCC patients

Methods: Immunohistochemistry was used to detect the expression of TUSC3 in HCC and the corresponding para-cancerous tissues from 92 samples of HCC patients. mRNA and protein expression levels of TUSC3 were evaluated by quantitative reverse transcription PCR and Western blot assays in 25 paired HCC and corresponding adjacent nontumor tissues. Furthermore, statistical analysis was applied to evaluate the correlation between TUSC3 level and the clinicopathological features and prognosis of HCC patients

Results: Immunohistochemical assay indicated that the expression of TUSC3 was significantly lower in HCC tissues when compared with the corresponding para-cancerous tissues (χ2=11.512, P=0.001). The analysis of clinicopathological characteristics showed that low expression of TUSC3 in HCC tissues was significantly associated with Edmondson grade, Barcelona Clinic Liver Cancer stage and tumor size (P=0.008, 0.009 and 0.020, respectively). Univariate analysis showed that the expression of TUSC3 was strongly correlated with overall survival (OS) and disease-free survival (DFS) after radical surgery in HCC patients (P<0.001, P<0.001, respectively). Multivariate analysis revealed that the TUSC3 level was an independent risk factor for OS and DFS in HCC patients (P=0.001, P<0.001, respectively). Results of qRT-PCR and Western blot assays indicated that the level of TUSC3 in HCC tissues were significantly lower than that in the corresponding adjacent noncancerous tissues (P<0.01, P<0.001)

Conclusions: The expression of TUSC3 in HCC was significantly downregulated and was correlated with tumor progression and prognosis, which could be used as an independent predictor of prognosis in HCC patients


P-173 INCREASED LEVELS OF HNRNP L IN HCC CORRELATE WITH THE POLARIZATION OF MACROPHAGES

Yongsheng Ge* 1

1Department of Hepatic Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China

Introduction: Heterogeneous nuclear ribonucleoprotein L (HnRNP L) has been considered to be closely related to varieties of malignant tumors. Recently, studies have shown that high titers of hnRNP L autoantibodies are associated with increased tumor size and decreased survival in hepatocellular carcinoma (HCC) patients. However, the expression and role of hnRNP L in HCC tissues are not clear. The purpose of this study was to explore the expression of hnRNP L in HCC tissues and analyze its relationship with clinicopathological features of HCC patients and macrophage polarization.

Methods: The expression of hnRNP L and macrophage polarization related marker (CD68, CD206, and CD11c) in HCC tissues and para-cancerous tissues from 90 samples of HCC patients was detected by immunohistochemistry. The expression levels of hnRNP-L in 20 paired HCC and para-cancerous tissues were assessed by qRT-PCR and Western blot assays. Besides, the expression of long noncoding RNA EPS (lincRNA-EPS) was also assessed. Finally, statistical analysis was performed on the above data.

Results: The immunohistochemistry, qRT-PCR and Western blot assays results showed that the expression of hnRNP L was significantly higher in HCC tissues compared with the para-cancerous tissues (all P<0.05). Clinicopathological features analysis showed that high-level expression of

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in phase III clinical trial in diabetes with a good safety profile. Imeglimin stands as an AMPK activator and based on historical data with metformine may be a safe potentially interesting novel therapeutic drugs for patients with HCC. Hence, the current study aims to evaluate the effects of imeglimin alone or in combination with sorafenib compared to metformin in an experimental model of HCC.

Methods: All in vivo experiments were carried out with ethical committee approval and met the standards required by the UKCCCR guidelines. HepG2 HCC cells were injected subcutaneously (2x106cells) into the flank of female athymic nude mice. Two weeks after cell inoculation, 90% mice developed single subcutaneous palpable tumors. Mice were randomized in the groups of treatment. Mice were then treated 5 days a week by oral gavage with 75 mg/kg/day metformin (n=14), 75 mg/kg/day imeglimin (n=14), 40 mg/kg/day sorafenib (n=14), metformin plus sorafenib (n=14) or imeglimin plus sorafenib (n=14). Body weight and tumor volumes were assessed thrice a week. Mice were sacrificed after 63 days of treatment to meet ethical requirements (tumor volume < 2000 mm3). Tumorweight were recorded at mice sacrifice. After mice sacrifice, tumors were excised and OCT-embedded to prevent tissue degradation from frozen conservation.

Results: Our experiments showed a 90% uptake in the engrafted mice. Regardless of the administrated treatment, no toxicity was found as shown by the body weight follow-up. After 63 days of treatment, each treatment arm showed a slight difference with placebo (n=14). Mean tumor volumes were 1096±208 mm3 (P>0.5), 795±222 mm3(P>0.5), and 495±163 mm3(P<0.05) for Metformin alone, imeglimin alone or sorafenib alone, respectively, versus 1132±156 mm3 in the placebo group . Moreover, the combination of imeglimin plus sorafenib (375±121 mm3) displayed an increased antitumor activity compared to Metformin plus sorafenib (515±112 mm3). In addition, at day 57 of treatment, we reached a tumor growth inhibition of 66% in the combination group imeglimin plus sorafenib. At the time of the meeting, we will be displayed IHC analysis in addition to assess tumor angiogenesis.

Conclusions: This study showed the antitumor effects of imeglimin, a novel AMPK activator in human HCC. Furthermore, imeglimin potentiates the antitumor effects of sorafenib. Our experiment showed that imeglimin is more potent than sorafenib in HCC either alone or in combination with sorafenib and may represent an interesting drug for patients with HCC.

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P-183 BASAL NOTCH4 ACTIVATION IS A DRUGGABLE MARKER OF AGGRESSIVENESS IN A PANEL OF HUMAN LIVER CANCER CELL LINES

Lucile Astorgues-Xerri* 1, Matthieu Martinet1, Eric Raymond2, Sandrine Faivre3, Annemilaï Tijeras-Raballand1

1Preclinical and Translational Research, AFR Oncology, 2Medical Oncology, Paris Saint-Joseph Hospital, 3Medical Oncology, Saint-Louis University Hospital, Paris, France

Introduction: Notch pathway has been involved in cell fate determination, cell differentiation, cell proliferation, apoptosis, angiogenesis and drug resistance, as well as epithelial-to-mesenchymal transition (EMT). Our team has demonstrated the involvement of the PlGF/VEGFR1/Notch4 axis in the angiogenesis of hepatocellular carcinoma (HCC). But what about the role of Notch pathway in tumor cells of primary liver cancers including HCC and cholangiocarcinoma (CK)? The aim of this work is to characterize the basal activation and the role of Notch4 in a panel of human liver cancer cell lines.

Conclusions: Vimentin and E-cadherin were the most powerful prognostic EMT markers in HCC especially in prediction of recurrence. So, it is recommended to perform these 2 markers as complementary to the traditional prognostic factors in HCC.


P-181 LINK BETWEEN M1/M2 HUMAN MACROPHAGES AND EPITHELIAL-MESENCHYMAL STATUS IN LIVER CANCER CELL LINES

Lucile Astorgues-Xerri* 1, Matthieu Martinet1, Eric Raymond2, Sandrine Faivre3, Annemilaï Tijeras-Raballand1

1Preclinical and Translational Research, AFR Oncology, 2Medical Oncology, Paris Saint-Joseph Hospital, 3Medical Oncology, Saint-Louis University Hospital, Paris, France

Introduction: Liver cancer is the second most deadly cancer in the world. While in the majority of cases, patients suffer from hepatocellular carcinoma (HCC), 10 to 20% of people develop a second primary form of cancer, cholangiocarcinoma (CK). Both forms are related to poor outcome, and in need of innovative approaches. Epithelial-to-mesenchymal transition (EMT) is considered a critical step for tumor progression by increased motility and invasiveness of tumor cells. Macrophages, a major component of the tumor microenvironment, were recently described as involved in EMT. Our team recently demonstrated a link between macrophages, EMT and migration in H&N cancer. The aim of this study is to understand the interactions between human antitumoral M1/protumoral M2 macrophages and EMT-dependent liver cancer cells with different EMT status, with the aim of developing new therapeutic approaches for liver cancer patients.

Methods: M1 and M2 macrophages were obtained from THP-1 cell line (human monocyte) after 48h exposure to 25nM of PMA followed by 48h of recovery culture medium, and 72h exposure to 1ng/ml LPS + 20ng/ml IFNgto obtain M1 phenotype or 20ng/ml IL4 + 20ng/ml IL13 to obtain M2 phenotype. Differentiation status was validated by immunofluorescence (IF) using CD14 for monocyte, CD68 for macrophages, CD80 for M1, and CD163 for M2. Six cholangiocarcinoma (CK)and ten hepatocellular carcinoma (HCC) cell lines were characterized for their EMT status (E-cadherin/vimentin expression) by western blot. In each tumor type, 1 epithelial and 1 mesenchymalcell lines were selected to study the effect of M1 and M2 conditioned medium (CM) on cell proliferation. In addition, we also analyzed the effects of CM from epithelial and mesenchymal liver cancer cells on macrophages differentiation using IF.

Results: We confirmed the differentiation of monocytes into macrophages by a decrease of CD14 expression and an increase of CD68 expression, and the differentiation of macrophages into M1 and M2 by an increase of CD80 and CD163 expression, respectively. Among the 6 CK cell lines, 3 cell lines showed an epithelial status (high E-cadherin expression), one a mesenchymal status (high vimentin expression), and 2 a mixed status. HCC cell lines panel showed 3 epithelial, 3 mesenchymal, and 4 EMT-mixed cell lines. Based on these results, we chose to expose SNU1196 and C3A (epithelial) and SNU1079 and SKHep1 (mesenchymal) cells to M1 or M2 CM. M1 CM inhibited the proliferation in all exposed cell lines. A higher effect was observed on epithelial cell versus mesenchymal cell in CK, whereas M1 CM displayed higher antiproliferative effects on mesenchymal cell versus epithelial cell in HCC. In contrast, M2 CM had no significant effect on proliferation. Macrophages exposed to CM from epithelial cancer cells displayed a M1 phenotype with an increased expression of CD80, while macrophages exposed to CM from mesenchymal cancer cells exhibited a M2 phenotype with an increased expression of CD163. We will further analyze the effect of M1 and M2 MC on migration in the selected human liver cancer cell lines.

Conclusions: In vitro,using CM, we showed that M1 displayed anti-proliferative effects on liver cancer cells, correlated with the epithelial/mesenchymal status of the cells. In addition, we showed that factors secreted by epithelial vs mesenchymal liver cancer cells induced macrophages differentiation into M1 and M2, respectively. These results open up new perspectives on the role of M1/M2 macrophages in EMT-dependent liver cancers.


P-182 IMEGLIMIN ALONE OR IN COMBINATION WITH SORAFENIB SHOWED POTENT ANTI-TUMOR EFFECT IN HUMAN HEPATOCELLULAR CARCINOMA

Annemilaï Tijeras-Raballand* 1, Matthieu Martinet1, Valérie Paradis2, Jean-Pierre Bizzari3, Eric Janin4, Eric Raymond5

1Preclinical and Translational Research, AFR Oncology, Paris, 2Pathology, Beaujon University Hospital, Clichy, France, 3Consultant at JPB, New-York, United States, 4Consultant at EJ, Toulouse, 5Medical Oncology, Paris Saint-Joseph Hospital, Paris, France

Introduction: Diabetes as a standalone or as part of metabolic syndrome is recognized as a major risk factor in hepatocellular carcinoma (HCC). Metformin one of the most widely used first-line drug for the treatment of type II diabetes showed antitumor activity in preclinical models of HCC, and in some clinical trials. Imeglimin, a first-in-class tetrahydrotriazine oral antidiabetic agents, is currently

P-179 CHARACTERISTICS OF TP53 AND CTNNB1 MUTATION ACCORDING TO THE SERUM TUMOR MARKERS IN HEPATOCELLULAR CARCINOMA

Keun Soo Ahn* 1, Daniel O'Brein2, Hiroyuki Yamada3, Jung Won Park4, Koo Jeong Kang1, Lewis R. Roberts5

1Surgery, Keimyung University Dongsan Medical Center, Daegu, Korea, Republic Of, 2Biomedical statistics and Informatics, Mayo Clinic, Rochester, 3Wako Pure Chemical Corporation, CA, United States, 4Internal Medicine, National Cancer Center, Goyang, Korea, Republic Of, 5Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States

Introduction: Serum alpha-fetoprotein (AFP), Lens culinaris agglutinin-readtive alpha-fetoprotein (AFP-L3) and des-gamma-carboxyprothrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). Association between molecular characteristics and serum biomarkers has not been evaluated yet. We analyzed DNA mutation from The Cancer Genome Atlas (TCGA) data in conjunction with clinical data, especially focused on serum biomarkers.

Methods: DNA mutations of LIHC data were obtained from TCGA data portal (https://tcga-data.nci.nih.gov) Preoperative serum AFP, DCP and AFP-L3 were measured in 91 samples from 3 clinics using preoperatively obtained frozen stored serum. Clinical data, three serum biomarkers and DNA mutation of those 91 patients were analyzed.

Results: The patient population consisted of 64 men and 27women, with a median age of 59 years (range 23–85years). AFP level was highly correlated with AFP-L3 (r=0.70), but less between AFP and DCP (r=0.37), and DCP and AFP-L3 (r=0.26). Since AFP and AFP-L3 were correlated relation and majority patients who elevated AFP or AFP-L3 were overlapped each other, we divided patients into 4 groups ; patients with elevated AFP alone or AFP-L3 alone (AFP & L3 group, N=26), DCP along (DCP group, N=13), elevated all 3 biomarkers (All group, N=21) and normal tumor marker (Normal group, N=26), except 3 patients of elevating AFP and DCP, and 2 patients of elevating DCP and AFP-L3. TP53 mutation was most frequently found in AFP&AFP-L3 group (N=8, 30.8%) and All group (N=8, 38.1%). In DCP group, although CTNNB1 mutation was most common (N=7, 53.8%), TP53 mutation (N=4, 30.8%) was also commonly found mutation. In Normal group, CTNNB1 mutation was most common (N=10, 38.5%). Patients with CTNNB1 mutation in DCP group showed significant poor survival than those in Normal group (Figure 4(B)). On mutation hotspot of TP53, majority TP53 mutations in patients of AFP&AFP-L3 group were located on the C terminal site (6 of 8, 75.0%), region of interaction with E4F1 (256 – 294) or 53BP2SH3 domain (241 – 248), while TP53 mutation in patients of DCP group were located on the N terminal site, region of interaction with FBXO42 (JFK, 113 - 236) The overall survival rate between patients with TP53 mutation in AFP&AFP-L3 group and those in DCP group was not different.

Conclusions: Serum AFP, AFP-L3 and DCP are helpful to predict mutation profile of HCC, especially TP53 and CTNNB1 mutations. CTNNB1 mutation is related to low AFP and AFP-L3 level and it has two different forms depending on the biomarker; good prognosis in CTNNB1 mutation with normal biomarker and poor prognosis in that with elevated DCP level. TP53 mutation is associated with elevated AFP or DCP and TP53 mutation hotspot is different between TP53 mutation with elevated AFP and elevated DCP. These clinical oriented finding may lead to more rational, targeted approach to treatment easily.


P-180 THE PROGNOSTIC VALUE OF EPITHELIAL-MESENCHYMAL TRANSITION MARKERS IN HCV-ASSOCIATED HEPATOCELLULAR CARCINOMA: A MULTIVARIATE FOLLOW UP STUDY

Thanaa Helal1, Asmaa I. Gomaa2, Dina Sweed* 3, Nermine Ehsan3

1Pathology, Faculty of Medicine, Cairo, 2Hepatology, 3Pathology, National Liver Institute, Menoufia Univesity, Shebin ElKom, Egypt

Introduction: Background and objectives: The present study assessed the prognostic value of nine epithelial-mesenchymal transition (EMT) markers in HCV-associated hepatocellular carcinoma (HCC) in order to select the most relevant ones to be used in routine practice as an adjunct to the conventional prognostic factors.

Methods: One hundred and nine cases of HCV-associated HCC were selected to examine their tumor tissue by means of immunohistochemistry for the following markers: vimentin, E-cadherin, N-cadherin, Stat3, Snail1, Slug, Twist1, Zeb1 and integrin α5. In addition, PCR technique was performed on fresh tissue samples which were available in 20 out of 109 cases.

Results: The level of immunoexpression of EMT markers was 71% for vimentin, 25% for E-cadherin, 26% for N-cadherin, 27% for Stat3, 9% for snail1, 4% for slug, 72% for twist1, 47% for Zeb1 and 87% for integrin α5. Multivariate analysis showed that vimentin was independent predictor of large tumor size (P=0.001), vascular invasion (P=0.004), high risk of recurrence (HRR) (P=0.006) and shorter disease free survival (P=0.03). Reduced E-cadherin was a predictor of poor histologic grade and HRR (P=0.002 for each). Spearman rank correlation test revealed that most of the EMT markers were significantly correlated with each other.

Results: 1. Screening immunocompetent T-cell antigen: Observing the response frequency of T cells

corresponding to 6 TAAs, AFP presented the highest response frequency (55.77%), and was as same as SALL-4. Second, MAGE-A3 was higher (32.69%), and MAGE-A1 (21.15%), NY-ESO-1 (15.39%) and SSX-2 (11.54%) decreased in turn (Fig.1).

2. Screening high response magnitude antigen: Regarding response magnitude, AFP was the highest, followed by SALL-4, MAGE-A3, MAGE-A1, NY-ESO-1 and SSX-2 (Fig. 2).

3. Analysing the relationship between HCC stage and TAA response: According to the Barcelona (BCLC) stage, all patients were divided into 0, A, B, C and D phases, where 0 and A phases were classified as early stage, B phase as moderate, C and D phases as late. The positive and negative patients were counted for every TAA at different stages, the relationship with disease stage was analyzed. Results showed that there was a significant difference in the response frequency of total TAAs between different stages (Fig. 3).

4. Analysing the relationship between HCC stage and the number of responsed TAAs: The staging method is described above. Count the number of responsive TAA species in 3 stages of each patient. Results showed that the majority with early stage response to 2 TAAs (31%) (Fig. 4a), the reaction of 1 kind of TAA at mediate stage (56%) (Fig. 4b), most patients appear no response to TAA at late stage (31 %) (Fig. 4c).

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Conclusions: The response frequency and magnitude of PBMCs to AFP were the highest. With the progression of HCC, the number of responsive TAAs also decreased which may imply the importance of TAA specific-T cell response in HCC.

References: [1] Zheng R, Qu C, Zhang S, Zeng H, Sun K, Gu X, et al. Liver cancer incidence and mortality in

China: Temporal trends and projections to 2030. Chin J Cancer Res 2018;30(6):571-579.[2] Gehring AJ, Ho ZZ, Tan AT, Aung MO, Lee KH, Tan KC, et al. Profile of Tumor Antigen-

Specific CD8 T Cells in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma. Gastroenterology 2009;137(2):682-90.

[3] Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, et al. Immunodominance and Functional Alterations of Tumor-Associated Antigen-Specific CD8+ T-Cell Responses in Hepatocellular Carcinoma. Hepatology 2014;59(4):1415-26.

[4] Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP, et al. Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 2004;10(13):4332-4341.

[5] Komori H, Nakatsura T, Senju S, Yoshitake Y, Motomura Y, Ikuta Y, et al. Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma. Clin Cancer Res 2006;12:2689-2697.

[6] Mizukoshi E, Nakamoto Y, Tsuji H, Yamashita T, Kaneko S. Identification of alpha-fetoprotein-derived peptides recognized by cytotoxic T lymphocytes in HLA-A24+ patients with hepatocellular carcinoma. Int J Cancer 2006;118:1194-1204.

[7] Hiroishi K, Eguchi J, Baba T, Shimazaki T, Ishii S, Hiraide A, et al. Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol 2010;45(4):451-8.

[8] Mizukoshi E, Yamashita T, Arai K, Sunagozaka H, Ueda T, Arihara F, et al. Enhancement of Tumor-Associated Antigen-Specific T Cell Responses by Radiofrequency Ablation of Hepatocellular Carcinoma. Hepatology 2013;57(4):1448-57.

[9] Inada Y, Mizukoshi E, Seike T, Tamai T, Iida N, Kitahara M, et al. Characteristics of immune response to tumor-associated antigens and immune cell profile in hepatocellular carcinoma patients. Hepatology 2019;69(2):653-665.

[10] Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Sakai A, Sakai Y, et al. Comparative Analysis of Various Tumor-Associated Antigen-Specific T-Cell Responses in Patients with Hepatocellular Carcinoma. Hepatology 2011;53(4):1206-16.

[11] Forghanifard MM, Gholamin M, Farshchian M, Moaven O, Memar B, Forghani MN, et al. Cancer-testis gene expression profiling in esophageal squamous cell carcinoma: identification of specific tumor marker and potential targets for immunotherapy. Cancer Biol Ther 2011;12(3):191-7.

[12] Park TS, Groh EM, Patel K, Kerkar SP, Lee CC, Rosenberg SA. Expression of MAGE-A and NY-ESO-1 in Primary and Metastatic Cancers. J Immunother 2016;39(1):1-7.

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P-189 SIZE OF INTRAHEPATIC LESIONS PREDICTS EFFICACY OF SORAFENIB IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA

Yoshiyuki Wada* 1, Yuko Takami1, Shin Sasaki1, Tomoki Ryu1, Hideki Saitsu1

1Department of Hepato-Biliary Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

Introduction: It is considered that the control of intrahepatic lesion is important for treatment of hepatocellular carcinoma (HCC) with extrahepatic metastasis or not. Sorafenib was established for systemic chemotherapeutic agent for advanced HCC, however, it remains obscure how condition of intrahepatic lesions influences on efficacy of sorafenib treatment. The aim of this study was to clarify efficacy of sorafenib treatment depends on condition of intrahepatic lesions in advanced HCC patients.

Methods: This retrospective study reviewed 140 advanced HCC patients with Child Pugh scores ≤7 and concomitant with intrahepatic lesions. Predictive factors for Overall survival (OS) and progression-free survival (PFS) were assessed.

Results: Of the 140 patients, the median age was 69.0 years old. 111 were male and 29 were female. Median tumor diameter and number of intrahepatic lesion was 2.3 (1-12) cm and 6 (1-50), respectively. 54 patients (38.8%) had extrahepatic spread and 30 (22.4%) had macrovascular invasion. Median OS was 15.4 months and median PFS was 4.4 months. Multivariate analysis identified the following independent predictors of OS: BCLC [stage B] (Hazard ratio (HR) 0.37), tumor diameter of intrahepatic lesions [≤3.5cm] (HR 0.53), extrahepatic spread (HR 2.16), macrovascular invasion (HR 2.16), and α-fetoprotein [≥200 ng/ml] (HR 2.06). Whearas, the following independent predictors of PFS were identified by multivariate analysis: BCLC [B] (HR 0.59), tumor diameter of intrahepatic lesion [≤3.5m] (HR 0.53), and tumor number of intrahepatic lesion [≥10] (HR 2.08). Extrahepatic spread and macrovascular invasion was not significant predictors of PFS. Moreover, to clarify the characteristics of patients exhibited rapid progression for sorafenib treatment, correlation to time-to progression ≤60 days was investigated. Tumor diameter of intrahepatic lesion [≤3.5 cm] showed significant correlation, however, tumor number did not show.

Conclusions: Intrahepatic tumor size is associated with tumor response to sorafenib treatment in patients with advanced HCC concomitant with intrahepatic lesions.


P-190 PRESENCE OF PORTAL VEIN TUMOR THROMBOSIS IS AN INDEPENDENT FACTOR FOR SURVIVAL IN HCC PATIENTS WHO UNDERWENT TRANS-ARTERIAL RADIOEMBOLIZATION

Pil Soo Sung1, Si Hyun Bae1, Hyun Yang*1, Hee Chul Nam1, Jong Young Choi1, Seung Kew Yoon1

1The Catholic University of Korea, Seoul, Korea, Republic Of

Introduction: Trans-arterial radioembolization (TARE) is a form of radiation therapy performed by selective intra-arterial injection of microspheres loaded with Yttrium-90. TARE has been shown in many clinical trials to be safe and effective in the management of unresectable HCC. The aim of this study is to identify prognostic factors for overall survival (OS) and time to progression (TTP) in patients with HCC undergoing TARE.

Methods: This study included 65 consecutive HCC patients who underwent TARE from Jul 2009 to Jan 2018. The tumor responses to TARE were assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST).

Results: Study cohort comprised nineteen patients (29.2%) in BCLC-A stage, 21 (32.3%) patients in BCLC-B stage and 25 (38.5%) patients in BCLC-C stage. Among 65 patients, 4 (6.2%) obtained complete response (CR) and 27 (41.5%) showed partial response (PR) at 3 months after TARE. Median OS was 16.90 months and TTP was 4.90 months. Fifty-one patients underwent salvage treatment after TARE and 18 achieved objective response (OR); 14 achieved CR and 4 achieved PR.Multivariate analysis showed that the presence of portal vein tumor thrombus (PVTT) (hazard ratio [HR], 5.862; 95% confidence interval [CI], 2.380-14.437, p=0.000) and multiplicity of HCC nodules (HR, 2.205; 95% CI, 1.058-4.594, p=0.04) were independent factors for OS. The presence of PVTT (HR, 3.961; 95% CI, 1.924-8.155, p=0.000) and tumor diameter >10 cm (HR, 2.167; 95% CI 1.152-4.076, p=0.016) were independent prognostic factors for TTP.Subgroup analysis of 40 patients without PVTT showed that the degree of tumor burden (HR, 44.317; 95% CI, 5.042-389.505, p=0.001), the achievement of OR at 3 months after TARE (HR, 8.561; 95% CI, 3.321-103.738, p=0.001) and receiving salvage treatment (HR, 24.307; 95% CI, 4.709-125.481, p=0.000) were shown to affect OS.

Conclusions: TARE is an effective therapy for patients with advanced HCC. PVTT before TARE is an independent predictive factor for both OS and TTP.


Methods: Patients with intrahepatic HCC treated with TARE between 2011 and 2017 were recruited. The rCR was defined according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Cox-regression analysis was used to find independent predictors of rCR.

Results: The median age of the study population (83 males and 19 females) was 64.3 years. The mean survival after TARE was 55.5 months and 21 (20.6%) patients were dead during the study period. The rCR was achieved in 14 (13.7%) patients who had significantly higher serum albumin level (median 4.1 vs. 3.9 g/dL), lower total bilirubin level (median 0.6 vs. 0.7 mg/dL), lower aspartate aminotransferase level (median 30.0 vs. 43.0 IU/L), lower alkaline phosphatase level (median 79.0 vs. 103.0 IU/L), lower alpha-fetoprotein level (median 12.7 vs. 39.9 ng/mL), lower des-gamma-carboxyprothrombin level (median 575.5 vs. 2772.0 mAU/mL), lower MELD score (median 6.0 vs. 7.0), and smaller maximal tumor diameter (median 6.3 vs. 9.0 cm) than those of patients without rCR (all P<0.005). Multivariate Cox-regression analysis showed that lower MELD score (hazard ratio [HR]=0.436, P=0.015) and maximal tumor size < 9 cm (HR=11.180, P=0.020) independently predicted the increased probability of rCR after TARE.

Conclusions: Low MELD score and smaller maximal tumor size were independently associated with the increased probability of rCR after TARE in patients with intrahepatic HCC.


P-188 IMPROVED OUTCOMES OF LAPAROSCOPIC LIVER RESECTION FOR HEPATOCELLULAR CARCINOMA LOCATED IN POSTEROSUPERIOR SEGMENTS OF THE LIVER

Jai Young Cho* 1, Kwon Yujin2, Boram Lee3

1Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, 2Surgery, Seoul Medical Center, Seoul, 3Seoul National University Bundang Hospital, Seongnam, Korea, Republic Of

Introduction: LLR is widely adapted for HCC, while LLR in PS segments is still challenging. However, with recent improvement of techniques and accumulation of experiences, LLR in PS segments is feasible. We compared outcomes of laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) located in posterosuperior (PS) segments before and after the adaptation of technological improvements.

Methods: We retrospectively analyzed 149 patients who underwent LLR for HCC located in PS segments from September 2003 to December 2016. The patients were divided into group 1 (n=43) and group 2 (n=106) who underwent LLR before and after 2012, when advanced techniques including use of intercostal trocars, Pringle maneuver, and semi-lateral position of patient were adapted. We also compared these patients with those who underwent open liver resection (OLR; n=124) for HCC in PS segments at the same period.

Results: Mean operative time (395 minutes vs 331 minutes; P=0.013), intraoperative blood loss (1545 ml vs 1219 ml; P=0.020), and hospital stay (12 days vs 9, P<0.001) were significantly less in group 2. Postoperative complication rate (18.6% vs 18.9%; P=0.970), open conversion rate (23% vs 17%; P=0.374), 5-year overall survival (79% vs 89%; P=0.607) and 5-year disease free survival (52% vs 53%; P=0.657) rates were not significantly different between the groups. The proportion of LLR increased (36% vs 69%, P<0.001). Compared to OLR group, complication rate (40.3% vs 18.8%; P< 0.001) and hospital stay (18 days vs 10 days; P< 0.001) were significantly lower in LLR group.

Conclusions: The complexity of LLR for HCC in PS segments has been gradually overcoming by the adaptation of advanced techniques.


P-185 PROSPECTIVE PHASE 2 STUDY OF STEREOTACTIC BODY RADIATION THERAPY IN HCC PATIENTS AFTER FAILURE OF TACE

Andre T. C. Chen* 1, Fabio Payao2, Aline Chagas3, Regiane Alencar3, Claudia Tani3, Karina Vasconcelos1, Manoel Rocha4, Heloisa A. Carvalho5, Paulo Hoff6, Flair J. Carrilho3

1Radiation Oncology, 2Radiology, 3Gastroenterology, Instituto do Cancer do Estado de Sao Paulo, University of Sao Paulo School of Medicine, 4Radiology, 5Radiation Oncology, Hospital das Clinicas da Faculdade de Medicina da USP, 6Clinical Oncology, Instituto do Cancer do Estado de Sao Paulo, University of Sao Paulo School of Medicine, Sao Paulo, Brazil

Introduction: There is need for effective local therapies for hepatocellular carcinoma (HCC) after failure of transarterial chemoembolization (TACE). Stereotactic Body Radiation Therapy (SBRT) is an emerging treatment option that uses highly focused radiation in few sessions to treat HCC. Phase I and II studies have shown encouraging results(1,2), but incorporation of SBRT by guidelines has been heterogeneous(3-6). Our objective was to test in the setting of a phase II prospective study, the efficacy and safety of SBRT in patients unresponsive or unsuitable for TACE.

Methods: Patients with HCC and up to five liver-only lesions received SBRT with the dose of 30 to 50 Gy in 5 fractions. All patients were Child-Pugh A. Primary endpoint was local progression-free survival (PFS). Secondary endpoints were liver PFS, distant PFS, overall survival (OS) and toxicity. Survival was estimated by the method of Kaplan-Meier and compared using log-rank test. Continuous variables were compared using Wilcoxon rank-sum test. Hazard Ratios (HR) were calculated using Cox regression. This study was conducted at a tertiary hospital and is registered at clinicaltrials.gov NCT02221778.

Results: From Nov 2014 through Jun 2018, 19 patients received SBRT with a median dose of 40Gy. Median age was 67 years. Underlying liver disease was hepatitis C in 42% of patients, hepatitis B in 26% and alcohol in 26%. 84% received previous TACE, with a median of two TACEs (range 0-5). Of these, the status after last TACE was progressive disease in 56% and stable disease (no response) in 44% of patients. Barcelona Clinic Liver Cancer Classification was A in 27%, B in 26% and C in 47% of cases. Patients had a median of two lesions, with median size of 4cm (range 1.5-10cm). 32% had tumor vascular thrombosis; median pretreatment alpha-fetoprotein (AFP) was 142.5ng/ml (range 4.2–5494ng/ml). 1y-local PFS was 80% (95% CI, 50% to 93%). Patients that received >45 Gy had a greater chance of local control (median LPFS was not reached vs 12.1 months)(p=0.0278; HR 0.11, 95% CI, 0.01 to 1.09). 1y-liver PFS, distant PFS and OS were, respectively, 52%, 82% and 84%. No patient had clinical grade 3 or 4 toxicities. Laboratory toxicities up to grade 3 occurred in three patients (16%). Complete radiological response was seen in 53% of patients, 42% had partial response. Median AFP 3 months after treatment was reduced to 13 ng/mL (IQR 6.3 ng/mL to 85.6 ng/mL; p = 0.012).

Conclusions: Stereotactic Body Radiation Therapy is an effective, safe and noninvasive treatment option in HCC patients unresponsive or unsuitable for TACE. In our opinion, these patients should be offered SBRT before referral to systemic therapy.

References: 1. Andolino DL, Johnson CS, Maluccio M, Kwo P, Tector AJ, Zook J, et al. Stereotactic body

radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2011;81(4): 447–53.

2. Bujold A, Massey CA, Kim JJ, Brierley J, Cho C, Wong RKS, et al. Sequential Phase I and II Trials of Stereotactic Body Radiotherapy for Locally Advanced Hepatocellular Carcinoma. J Clin Oncol. 2013 May;31(13):1631–9.

3. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14.4. National Comprehensive Cancer Network. Hepatobiliary Cancers [Internet]. Vol. 4, NCCN Clinical

Practice Guidelines in Oncology, Hepatobiliary Cancers. 2018. p. 1–94.5. Verslype C, Rosmorduc O, Rougier P. Hepatocellular carcinoma: ESMO-ESDO Clinical Practice

Guidelines for diagnosis, treatment and follow-up. Ann Oncol [Internet]. 2012 Oct 1;23(suppl 7):vii41-vii48.

6. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018 Jan;67(1):358–80.


P-187 PREDICTORS OF RADIOLOGICAL COMPLETE RESPONSE IN PATIENTS WITH INTRAHEPATIC HEPATOCELLULAR CARCINOMA TREATED WITH TRANSARTERIAL RADIOEMBOLIZATION

Yoon Ah Kim* 1, Jae Seung Lee1, Beom Kyung Kim1, 2, 3, Jun Yong Park1, 2, 3, Do Young Kim1, 2, 3, Sang Hoon Ahn1, 2, 3, Kwang-Hyub Han1, 2, 3, Seung Up Kim1, 2, 3

1Internal Medicine, 2Institute of Gastroenterology, Yonsei University College of Medicine, 3Yonsei Liver Center, Severance Hostpital, Seoul, Korea, Republic Of

Introduction: Transarterial radioembolization (TARE) has shown promising results for treating hepatocellular carcinoma (HCC). We identified the independent predictors of radiological complete response (rCR) in patients with intrahepatic HCC treated with TARE.

Methods: We characterized a panel of 5 CK and 10 HCC human cancer cell lines for Notch4 intracellular domain (NICD4), HES1 (a target gene of Notch activation), NUMB (a protein involved in NICD proteasomal degradation), E-cadherin, and Vimentin expressions by Western Blot. In each tumor type, cell lines with high, moderate, and low Notch4 activationwere selected to assess the role of Notch4 basal activation in cellular properties such as proliferation and migration, using MTT and wound-healing assays, respectively. Then, we studied Notch inhibition effects on cancer cells proliferation and signaling, using the Notch inhibitor PF-03084014. In addition, we explored the effect of Notch activation on cell signaling, using one of the Notch ligand Delta-like 4 (DLL4).

Results: Notch4 activation assessed by NICD4 expression was observed in 4/5 CK, and 7/10 HCC cell lines.Interestingly, in HCC cell lines, Notch4 activation seemed to be correlated with high Vimentin expression. However, no correlation were found between NUMB and NICD4 expression. Thus, we investigated the role of Notch4 basal activation in proliferation and migration properties of tumor cells on selected cell lines. In CK cell lines, Notch4 activation is associated with an increased proliferation rate, whereas no effect was observed on the HCC cell lines. Interestingly, in both CK and HCC cell lines, Notch4 activation was associated with an increased basal migration. Furthermore, the CK and HCC cell lines with high and moderate NICD4 expression were more sensitive to PF-03084014 than the cells with low NICD4 expression. In CK and HCC cells, PF-03084014 displayed no effect on Notch4 activation. However, we observed a significant decrease in HES1 expression in high Notch4 activated cells. On the contrary,AKT phosphorylation was increased in low Notch4 activated CK cells. In both CK and HCC cell lines, DLL4 (Notch ligand) had no effect on NICD4, pAKT, and pERK expression, whereas an increased expression of HES1 in high Notch4 activated cells was observed. We will further analyze the effect of Notch inhibition with or without Notch activation on cell signaling and migration.

Conclusions: In this study, we showed the high prevalence of Notch4 basal activation in a panel of liver cancer cell lines, suggesting a role in cellular activities of cancer cells. We demonstrated a correlation between high Notch4 basal activation and increased basal proliferation/migration in a panel of CK and HCC human cancer cell lines, as well as an enhanced sensitivity to the Notch inhibitor PF-03084014. In high Notch4 activated CK and HCC cells, PF-03084014 inhibited Notch signaling pathway, whereas we observed an activation of AKT survival pathway in the low Notch4 activated CK cells. Since Notch inhibition is an interesting topic for antitumor therapy, this study could help to select the types of tumors that could be good candidate for Notch inhibition in the clinics.


P-184 EFFICACY AND SAFETY OF LENVATINIB FOR UNRESECTABLE HEPATOCELLULAR CARCINOMA IN CLINICAL PRACTICE

Yoshiyuki Wada* 1, Yuko Takami1, Shin Sasaki1, Tomoki Ryu1, Hideki Saitsu1

1Department of Hepato-Biliary Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

Introduction: Lenvatinib has recently been developed as a first-line tyrosine-kinase inhibitor for unresectable hepatocellular carcinoma (HCC). However, its clinical features remain to be fully elucidated in clinical practice. This retrospective study investigated the efficacy and safety of lenvatinib for treating unresectable HCC.

Methods: In total, 37 patients with unresectable HCC treated with lenvatinib were reviewed. Therapeutic effect was determined at week 8 using modified Response Evaluation Criteria In Solid Tumors. Patients received 12 or 8 mg/day oral lenvatinib (body weight >60 or <60 kg, respectively). Dose interruptions followed by reductions for lenvatinib-related toxicities were permitted. Grades of adverse events complied with the Common Terminology Criteria for Adverse Events version 4.0.

Results: The mean patient age was 71.8 years, with 31 (81.6%) patients being male. Of all patients, 30 and 7 patients exhibited Child–Pugh grades A and B, respectively; 13 and 24 patients had Barcelona Clinic Liver Cancer stages B and C, respectively. Furthermore, 15 patients had a history of sorafenib treatment; 12 (32.4%), 11 (29.7%), and 14 (37.8%) patients exhibited partial response, stable disease, and progressive disease, respectively. Median time to progression (TTP) was 4.5 months; however, median overall survival was not reached within the observation period. For adverse events, 22, 19, 19, 14, and 13 patients showed fatigue, increased transaminase/total bilirubin levels, hypertension, proteinuria, and hand–foot syndrome. Patients with Child–Pugh A grade showed a higher incidence of adverse effects than those with Child–Pugh grade B. Treatment withdrawal was needed in 25 (67.6%) patients. The most common reasons were fatigue (n = 9) and gastrointestinal tract bleeding (n = 5). Dose modification was required in 20 (54.0%) patients, and the most common reason was fatigue (n = 9). Furthermore, predictive factors of TTP were Child–Pugh score of 5 [hazard ratio (HR) 0.34, 95% confidential interval (CI) 0.14–0.77, p = 0.01] and treatment withdrawal (HR 2.73, 95% CI 1.10–8.27, p = 0.03). Additionally, fatigue was associated with albumin–bilirubin grades 1 (8.8%), 2 (88.9%), and 3 (100%) (p = 0.01).

Conclusions: Lenvatinib treatment was safe and showed a good response in clinical practice. The most common adverse event was fatigue, which may cause treatment withdrawal and result in a poor TTP; therefore, careful treatment of fatigue is necessary.

Posters Posters

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 1 0 1I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S 1 0 0

(per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST v1.1] by blinded independent central review [BICR]). History of or current hepatitis C virus infection and presence of controlled hepatitis B virus are allowed. Seven hundred fifty patients will be randomly assigned (1:1) to receive lenvatinib 12 mg (body weight [BW] ≥60 kg) or 8 mg (BW <60 kg) orally once daily plus intravenous (IV) pembrolizumab 200 mg or IV placebo every 3 weeks. Treatment will continue for approximately 2 years (35 cycles of pembrolizumab) or until disease progression or unacceptable toxicity, whichever occurs first. Patients will be stratified per geographic region (Asia vs Japan and Western regions), macroscopic portal vein invasion or extrahepatic spread, or both (yes vs no), alpha fetoprotein (≤400 ng/mL vs >400 ng/mL), and ECOG PS (0 vs 1). Dual primary end points are PFS assessed per RECIST v1.1 by BICR and OS. Secondary end points are ORR, duration of response, disease control rate, and TTP per RECIST v1.1 by BICR, efficacy per modified RECIST, pharmacokinetics, and safety. Tumor imaging will be performed every 9 weeks on study. Adverse events (AEs) will be monitored throughout the treatment period and for 90 days after the last dose of study drug (120 days for serious AEs) and will be graded per National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0.

Disclosure of Interest: J. Llovet Conflict with: Research/Education grant - Bayer Schering Pharma, Blueprint Medicines, BMS, Eisai, Conflict with: Advisory Board - Lilly, Bayer, BMS, Eisai, Celsion, Incyte, Exelxis, Glycotest, Conflict with: Consulting - Lilly, Bayer, BMS, Eisai, Celsion, Incyte, Exelxis, Glycotest, M. Kudo Conflict with: Research/Education grant - Chugai, Otuka, Takeda, Taiho, Sumitomo Dainippon, Daiichi Sankyo, MSD, Eisai, Bayer, Abbvie, Conflict with: Honoraria - Bayer, Eisai, MSD, Conflict with: Advisory Board - Kowa, MSD, BMS, Bayer, Chugai, Taiho, Conflict with: Consulting - Kowa, MSD, BMS, Bayer, Chugai, Taiho, A.-L. Cheng Conflict with: Honoraria - Bayer Yakuhin, AstraZeneca, Genentech/Roche, Eli Lilly, Conflict with: Advisory Board - Bristol-Myers Squibb, Bayer Schering Pharma, Novartis, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, CSR Pharma Group, Inc., MSD, BeiGene, Ltd., Conflict with: Consulting - Bristol-Myers Squibb, Bayer Schering Pharma, Novartis, Eisai, Ono Pharmaceutical, AstraZeneca, Genentech/Roche, CSR Pharma Group, Inc., MSD, BeiGene, Ltd., R. Finn Conflict with: Research/Education grant - Bayer, BMS, Eisai, Merck, Eli Lilly, Novartis, Roche/ Genentech, Conflict with: Honoraria - Bayer, BMS, Eisai, Eli-Lilly, Pfizer, Merck, Conflict with: Advisory Board - Astra Zeneca, Bayer, BMS, Eisai, Eli-Lilly, Pfizer, Merck, Roche/ Genentech, Conflict with: Consulting - Astra Zeneca, Bayer, BMS, Eisai, Eli-Lilly, Pfizer, Merck, Roche/ Genentech, P. Galle Conflict with: Research/Education grant - Bayer, Conflict with: Honoraria - Bayer, Lilly, Sirtex, MSD, BMS, AstraZeneca, Eisai, Ipsen, Conflict with: Advisory Board - Bayer, Lilly, Sirtex, MSD, BMS, AstraZeneca, Eisai, Ipsen, Conflict with: Consulting - Bayer, Lilly, Sirtex, MSD, BMS, AstraZeneca, Eisai, Ipsen, S. Kaneko Conflict with: Research/Education grant - Eisai, Bayer, MSD, Bristol Myers Squibb, Conflict with: Honoraria - Eisai, Bayer, MSD, Bristol Myers Squibb, Lilly, Kowa, Ono, Conflict with: Stocks - Pepatidream Inc, Conflict with: Advisory Board - Eisai, Bayer, MSD, Bristol Myers Squibb, Lilly, Kowa, Conflict with: Consulting - Eisai, Bayer, MSD, Bristol Myers Squibb, Lilly, Kowa, T. Meyer Conflict with: Research/Education grant - Ipsen, Bayer, BTG, Conflict with: Advisory Board - BMS, Eisai, Ipsen, Tarveda Therapeutics, BTG, Beigene, MSD, Conflict with: Consulting - BMS, Eisai, Ipsen, Tarveda Therapeutics, BTG, Beigene, MSD, S. Qin: None Declared, C. Dutcus Conflict with: Research/Education grant - Eisai, E. Chen: None Declared, L. Dubrovsky: None Declared, A. Zhu Conflict with: Research/Education grant - Lilly, Bayer, BMS, Novartis, Merck, Conflict with: Advisory Board - Eisai, BMS, Merck, Novartis, AstraZeneca, Bayer, Exelixis, Lilly, Roche/Genetech, Conflict with: Consulting - Eisai, BMS, Merck, Novartis, AstraZeneca, Bayer, Exelixis, Lilly, Roche/Genetech

P-196 UTILITY OF CONTRAST ENHANCED ULTRASONOGRAPHY IN MONITORING RECURRENCE AFTER A FIRST THERAPEUTIC PROCEDURE FOR HEPATOCELLULAR CARCINOMA

Laura Iliescu* 1, Mugur Grasu2, Radu Dumitru2, Mihai Toma2, Simona Ioanitescu1, Adriana Mercan-Stanciu1, Letitia Toma1

1Internal Medicine, 2Radiology, Fundeni Clinical Institute, Bucharest, Romania

Introduction: Contrast-enhanced ultrasonography (CEUS) is a non-invasive non-irradiant means of evaluating focal liver lesions and portal vein thrombosis. Its efficacy in the diagnosis of hepatocellular carcinoma (HCC) and the differentiation between malignant and benign portal vein thrombosis has been clearly established. We aim to determine the efficacy of CEUS in the early diagnosis of HCC recurrence and the development of HCC associated portal-vein thrombosis (PVT).

Methods: This is a prospective observational study including 215 patients admitted to our clinic from March 2017 to March 2018, diagnosed with hepatocellular carcinoma, who underwent a first therapeutic procedure- either radiofrequency ablation (RFA), transarterial chemoembolization (TACE) with doxorubicin and lipiodol or drug eluding beads, or initiation of Sorafenib. We performed CEUS at each of the following visits (at one, three, six and twelve months after the procedure). We assessed the patients for recurrence of HCC and the development of PVT and conformed the results either by CT scan (at 1 and 6 months) or abdominal MRI (at 3 and 12 months).

Results: Out of the 215 patients included, 30 patients underwent RFA, 100 patients underwent TACE, 85 patients received Sorafenib. Table 1 presents the comparison of CEUS versus CT or MRI in determining HCC recurrence in the follow-up period. Overall sensibility of CEUS for all time periods and all treatment options was 94.26%; specificity was 98.27%, positive predictive value was 99.32%, negative predictive value was 86.36%. CEUS revealed the development of malignant PVT in 46 out of 215 patients, confirmed by CT scan or MRI.

P-194 ESCALON: EARLY DIAGNOSIS AND MECHANISMS OF HEPATOBILIARY MALIGNANCIES IN SOUTH AMERICA

Jose Debes* 1, 2, Jesus Bañales3, Marco Arrese4, Juan Carlos Roa4, Domingo Balderramo5, Pablo Romagnoli5, Enrique Carrera6, Angelo Z. Mattos7, Jhon Prieto8, Juan Valle9, Bettina Hansen10, Arndt Vogel11, Andre Boonstra1

1Erasmus MC, Rotterdam, Netherlands, 2University Of Minnesota, Minneapolis, United States, 3Biodonostia Research Institute, San Sebastian, Spain, 4Pontificia Universidad Catolica de Chile, Santiago, Chile, 5Hospital Privado, Cordoba, Argentina, 6Universidad de San Francisco de Quito, Quito, Ecuador, 7UFCSPA, Porto Alegre, Brazil, 8CEHYD, Bogota, Colombia, 9NHS Christie, Manchester, United Kingdom, 10University of Toronto, Toronto, Canada, 11Hannover Medical University, Hannover, Germany

Introduction: Hepatobiliary malignancies represent a significant cause of mortality in Latin America. Indeed, Chile, Argentina, Colombia and Ecuador have some of the highest mortality rates in the world related to these cancers. Mortality from hepatobiliary tumors occurs primarily due to late detection, which precludes potentially curative surgical intervention.

Methods: We formed a consortium funded by the European Union Horizon 2020 scheme to tackle the current high morality of hepatobiliary malignancies in South America by searching biomarkers for early diagnosis, as well as defining mechanisms of carcinogenesis specific to the region that could lead to preventive interventions.

Results: ESCALON has 3 main objectives: a) Validate immune-related markers in serum to predict the occurrence of hepatocellular carcinoma (HCC) in South America and evaluate environmental, genetic and infectious factors associated to early HCC development; b) Define the utility of extracellular vesicles and their protein content as biomarkers for early diagnosis of cholangiocarcinoma (CCA) and determine genetic and infectious variables that increase the individual risk of this cancer and; c) Identify biomarkers for gallbladder cancer (GBC) and evaluate novel immune risk factors that affect the geographical impact of this tumor.In order to achieve these objectives, the ESCALON consortium created a network of specialized centers from five South American countries, four European countries and Canada that will collect samples cross-sectionally for HCC, CCA and GBC, and prospectively for HCC over the next 4 years. Sample analyses and experimental procedures will be performed both in Europe and South America.

Conclusions: Through our consortium we expect to create a first-of-its-kind biobank for HCC, CCA and GBC in South America that will undoubtedly lead to a better understanding of these tumors in the region, and will expose novel biomarkers to early diagnose these malignancies providing an opportunity for curative treatment when possible.


P-195 FIRST-LINE COMBINATION THERAPY WITH LENVATINIB PLUS PEMBROLIZUMAB FOR PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA: PHASE 3 LEAP-002 STUDY

Josep Llovet* 1, Masatoshi Kudo2, Ann-Lii Cheng3, Richard S. Finn4, Peter R. Galle5, Shuichi Kaneko6, Tim Meyer7, Shukui Qin8, Corina E. Dutcus9, Erluo Chen10, Leonid Dubrovsky10, Andrew X. Zhu11

1Icahn School of Medicine at Mount Sinai, New York, United States, 2Kindai University School of Medicine, Higashiosaka, Japan, 3National Taiwan University Hospital Cancer Center, Taipei, Taiwan, Province of China, 4David Geffen School of Medicine at UCLA, Los Angeles, United States, 5University of Mainz Medical Center, Mainz, Germany, 6Kanazawa University Hospital, Kanazawa, Japan, 7University College London Cancer Institute, London, United Kingdom, 8People’s Liberation Army 81 Hospital, Nanjing, China, 9Eisai Inc., Woodcliff Lake, 10Merck & Co., Inc., Kenilworth, 11Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States

Introduction: The potent multiple-receptor tyrosine kinase inhibitor lenvatinib, which selectively inhibits VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, is approved as monotherapy for the first-line treatment of unresectable hepatocellular carcinoma (HCC). This approval was based on the findings of the open-label phase 3 REFLECT study, which showed noninferiority of lenvatinib vs sorafenib in overall survival (OS) and significantly improved objective response rate (ORR), progression-free survival (PFS), and time to progression (TTP). The programmed death 1 inhibitor pembrolizumab is an approved monotherapy for the second-line treatment of advanced HCC in patients previously treated with sorafenib, based on a clinically meaningful survival benefit (median PFS, 4.9 months; median OS, 12.9 months) and manageable safety profile in the phase 2 KEYNOTE-224 study. The potential benefit of combining lenvatinib and pembrolizumab in patients with unresectable HCC was seen in the phase 1b KEYNOTE-524 trial, which showed that the combination was well-tolerated and conferred promising antitumor activity in these patients. LEAP-002 is a phase 3 study to evaluate the safety and clinical benefit of lenvatinib plus pembrolizumab in patients with previously untreated advanced HCC (NCT03713593).

Methods: Eligible patients are ≥18 years old with radiologically, histologically, or cytologically confirmed HCC; Eastern Cooperative Oncology Group performance status (ECOG PS) 0/1; Barcelona Clinic Liver Cancer stage C or stage B disease not amenable to locoregional therapy or curative therapy; Child-Pugh class A liver score ≤7 days before study day 1; and at least 1 measurable lesion

analyzed. Treatment response was assessed using Computed tomography (CT) image at 1 month, 3 month, 6 month and 12 month after treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria.

Results: Median age was 61.0 years (range 45.1-78.6 years) and 10 patients (83.3%) were related to HBV. Eleven patients (91.7%) had Child-Pugh score A, and three patients (25.5%) had extra hepatic metastases. Eight patients (66.7%) were treated with transarterial chemoembolization before SBRT. The median total dose was 40 Gy (range 36 – 60 Gy) with three to five fractions. Most common dose/fractionation was 40 Gy / 4 or 5 fractions. The median follow-up period was 19.8 months (range, 5.8-87.1). Median overall survial was 29.5 months (95% confidential interval 8.6-50.4 months) for all patients. The number of patients with partial response (PR) or complete response (CR) out of the evaluated patients was 7 /12 at 1 month, 9/12 at 3 month, 9/11 at 6 month and 8/9 at 12 month. The number of patients with CR was 1/12 at 1month, 2/12 at 4 month, 3/11 at 6 month and 3/9 at 12 month. The patients with response at 1 month had durable response until the last day of follow up. One patient (8.3%) experienced progressive disease (PD) at 6 month. No treatment related grade 3 or more toxicity reported.

Image:

Conclusions: SBRT to the tumor thrombosis of the HCC showed durable response. Hence, SBRT may enable patients to pursue further local or systemic therapy which result in improved survival benefit.

References: 1. Shui Y, Yu W, Ren X, Guo Y, Xu J, Ma T, et al. Stereotactic body radiotherapy based treatment

for hepatocellular carcinoma with extensive portal vein tumor thrombosis. Radiation Oncology. 2018;13(1):188.

2. Bujold A, Massey CA, Kim JJ, Brierley J, Cho C, Wong RK, et al. Sequential phase I and II trials of stereotactic body radiotherapy for locally advanced hepatocellular carcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(13):1631-9.


P-193 COST-EFFECTIVENESS ANALYSIS OF METAL VERSUS PLASTIC STENTS IN HEPATOCELLULAR CARCINOMA PATIENTS’ WITH OBSTRUCTIVE JAUNDICE, BASED ON A RANDOMIZED CONTROLLED TRIAL

Esam Elshimi* 1 and Wesam Morad

1Menoufia university, National Liver Institute, Shebeen Elkom, Egypt

Introduction: Biliary drainage in obstructive jaundice-caused by HCC-improves patent’s quality of life, ERCP and drainage with biliary stents is the least invasive procedure, however the optimal method of drainage remains unclear, and includes the possible endoscopic application of plastic stents and metal stents.

Methods: To complete a cost analysis based on a medical effectiveness of both procedures in randomized trial comparing plastic stents approach with metal stents approach in patients with obstructive jaundice caused by HCC.

Results: The management strategies were based on medical effectiveness trial of endoscopic biliary drainage using either metal stent or plastic stents in 90 patients overa12-month follow-up period. Direct and indirect costs were included, adopting a societal perspective. The cost values were expressed in 2018 Egyptian pounds.

Conclusions: Total per-patient direct costs were 40857.84 and 21802.62 Egyptian pounds for patients with plastic and metal stents respectively. Concerning the indirect costs; 888 and 454 Egyptian pounds were spent for every patient with plastic and metal stent approach, respectively. Causes for differences in direct costs and indirect costs included a more frequent second procedure, the greater mean number of hospital days and medications over the year in patients of plastic stent group. however, there existed a large amount of overlap when varying total cost estimates across a sensitivity analysis range based on observed resources utilization.

Conclusions: based on this cost analysis, it is suggested that the use of metal stents rather than plastic stents in biliary drainage for those group of patients.


P-191 CLINICAL STUDY OF APATINIB COMBINED WITH TACE IN ADVANCED HEPATOCELLULAR CARCINOMA

APATINIB COMBINED WITH TACE IN THE TREATMENT OF ADVANCED HEPATOCELLULAR CARCINOMA

Shuwei Wen* 1

1Interventional Department, Shanxi Tumour Hospital, Taiyuan, China

Introduction: Transcatheter arterial chemoembolization (TACE) is the first choice in unresectable advanced hepatocellular carcinoma. However, even though TACE achieve the ideal embolization effect, postoperative revascularization after TACE could lead to failure of operation, medical cost increases and the liver vascular condition deteriorates after repeatedly TACE. Therefore, it is necessary to add systemic anti-angiogenesis therapy. Apatinib is the latest VEGFR-TKI and has achieved good results in published clinical studies of hepatocellular carcinoma.Research team had good clinical expectations for the combined treatment for advanced hepatocellular carcinoma.

Keywords: hepatocellular carcinoma; TACE; VEGFR-TKI Apatinib

Methods: This prospective study enrolled advanced hepatocellular carcinoma pts who is treated by TACE combined with Apatinib. Pts received Appatinib in strat dose of 250 mg po qd, combined with TACE once every 28 days, and evaluation of efficacy before each operation.

Results: Since June 1,2016, 20 pts were enrolled in this study. From data analysis, we found that pts' average age was 60.5(± 9.04 years) and all in later stages of cancer: 100% of pts were in BCLC stage C; 25% (5/20) with PVTT type III, 20%(4/20) with PVTT type II, 5%(1/20) with PVTT type I; 35% (7/20) of lesions ≥10cm, and 35% (7/20) of 5-10cm. The most common adverse events were weakness(45% ), hypertension(30%), proteinuria(25%),and we also observed hand-foot syndrome(10%), Decreased heart rate (10%), gastrointestinal reaction(5%), and 1 case of allergy (5%),which were better after treatment. Till Jan 1, 2019, the half-year survival rate was 65%(13/20), 1-year survival rate was 55%(11/20), and 30% (6/20) of patients still survived at the submission date. The median progression-free survival was 5.2 months, and median overall survival was 13.2 months. 85% of pts were available evaluated, 0% (0/20) of them were CR 25%(5/20) were PR 55% (11/20) were SD 5% (1/20) were PD. The objective response rate ORR was 25% (5/20) and the disease control rate (DCR) was 80% (16/20). Compared with simple TACE, the majority of pts in this study have significant survival benefits.

Image:

Conclusions: The focus of this study was on the treatment of patients with large tumors, PVTT, and poor physical condition. The dose of Apatinib was 250mg, op, qd, and the treatment results were better than expected. After analysis, we found that the pts were in late stage, older, after multiple TACE, and prognosis was poor, which resulted in worse overall median survival than reference study (13.2m vs 17m), but there was still a significant extension (7.7m) compared with TACE only. In terms of safety, the adverse reactions in this study are basically consistent with previous reports.


P-192 DYNAMIC CHANGES OF THE TUMOR THROMBOSIS AFTER STEROTACTIC BODY RADIOTHERAPY OF HEPATOCELLULAR CARCINOMA

Kyung Su Kim* 1, Chul-won Choi2

1Radiation Oncology, Ewha Womans University College of Medicine, Seoul, 2Radiation Oncology, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea, Republic Of

Introduction: To report the dynamic changes of tumor thrombosis after stereotactic body radiotherapy (SBRT) of the hepatocellular carcinoma.

Methods: From July 2011 to December 2017, 12 hepatocellular carcinoma patients treated with SBRT to the tumor thrombosis of the portal vein or intrahepatic inferior vena cava were retrospectively

Posters Posters


P-200 TO IDENTIFY THE BENEFICIAL BODY MASS INDEX (BMI) FOR PATIENTS WITH HEPATOCELLULAR CARCINOMA TO ACHIEVE A LONGER SURVIVAL TIME AFTER CURATIVE MICROWAVE ABLATION

Jianping Dou* 1, Jie Yu1, Ping Liang1

1Interventional Ultrasound Department, Chinese PLA General Hospital, Beijing, China

Introduction: To identify the beneficial body mass index (BMI) for patients with hepatocellular carcinoma to achieve a longer survival time after curative microwave ablation.

Methods: This retrospective study evaluated a total number of 474 patients with solitary primary HCC who underwent microwave ablation. BMI at initial admission and other characteristics were collected. The associations of BMI and overall survival (OS) and disease-free survival (DFS) were analyzed by multiple models. The threshold effects of BMI and OS/DFS were further examined by using a smoothing function

Results: Quintile of BMI showed that patients with normal BMI range achieved better survival outcomes but similar DFS in multiple models. In the model with the adjustment of age, size, Charlson Score, patients with BMI ≤22.9 kg/m2 and with BMI ≤24.9 kg/m2 illustrated lower death rate than patients with BMI ≤18.5 kg/m2(P<0.05). The U-shaped relationships between BMI and OS were illustrated when BMI was set as a continuous variable. The prevalence of death decreased with the increasing of BMI up to the first turning point of 21.5 (HR:0.72, 95%CI: 0.57, 0.90) and increased with the increasing of BMI up to the second turning point of 23.1(HR:1.13, 95%CI: 1.02, 1.24). Threshold effect analysis showed that no turning point was selected in DFS results neither in crude model (p=0.28) nor in adjusted model (p=0.10)

Conclusions: The beneficial BMI level for solitary primary HCC patients after microwave ablation is 21.5 kg/m2 to 23.1 kg/m2, between which patients might be more likely to gain favorable survival outcome.


P-201 HEPATOCELLULAR CARCINOMA IN ETHIOPIA: SINGLE-CENTER ANALYSIS OF THERAPY AND OUTCOMES

Amir Sultan1, Marilia Campos Ulloa2, Abate Bane1, Jose Debes* 3

1Addis Ababa University, Addis Ababa, Ethiopia, 2HCMC, 3University of Minnesota, Minneapolis, United States

Introduction: Hepatocellular carcinoma (HCC) has a high frequency and high mortality in Africa. However, little is known about the tumor characteristics and therapeutic approach in the continent.

Methods: We performed a retrospective assessment of individuals that presented with HCC at a major referral clinic in Addis Ababa, Ethiopia from 2016 to 2018. Diagnosis of HCC was performed via biopsy or imaging criteria as established by international guidelines. Survival was determined as date of last visit, and calculated in days from initial diagnosis visit. Those individuals with initial and last visit of less than seven days were removed from survival analysis. Mann-Whitney test was used for survival assessment.

Results: A total of 46 individuals were included in the study. The median age was 54 years (IQR 45-62) and 50% were females. Forty-one percent of individuals had hepatitis B (HBV) as underlying liver disease, 45% had hepatitis C (HCV) and the rest were classified as “other”. Seventy-eight percent (N36) of cases had evidence cirrhosis on presentation. Median age of HCC diagnosis was 54 years (IQR 45-62) in all patients, and 48 years (IQR 19-38) in those infected with HBV. Median tumor size was 6.5cm (IQR 4.5-6.9) and median MELD score was 12 (IQR 8-17). The median survival in the entire cohort was 68 days (IQR 17-334). The most common treatment modalities were trans-arterial chemoembolization (TACE, 16%), Sorafenib (18%) and Palliative care (31%), with median survival being 351, 94 and 27 days, respectively. HBV-infected individuals had a median survival of 45 days (IQR 15-381), with those on HBV antiviral treatment having a trend to survival benefit (median of 45 vs 34 days) despite having larger tumor-size (median 7.3cm vs 6cm). Twenty percent of all individuals were treated with sorafenib (N:9). Median survival in this group was 92 days (IQR 24-121), despite almost all of them having AFP >400ng/ml. Over half of these patients (5/9) were HBV-positive. Interestingly, a neutrophil-to-lymphocyte ratio (NLR) of <2.5 correlated with better survival (109 days vs 68 days for those with NLR >2.5, p=0.01).

Conclusions: Our study describes characteristics and therapy of HCC in a single center in Ethiopia. We found younger diagnosis of HCC in individuals infected with HBV, and a trend towards better survival in those with HBV-antiviral treatment. A small sub-group of individuals treated with sorafenib showed a reasonable survival benefit with a positive correlation of survival with NLR.


Results: From January 2007 to December 2016, one hundred and forty-three patients were enrolled for analysis, including 90 patients underwent SR and 53 patients received TACE. The SR group were younger, higher hemoglobin level, higher serum albumin, higher BUN, and lower glucose level than the TACE group. After a median follow-up of 17.0 (interquartile range 7.3-36.9) months, 75 patients had died. The cumulative 1, 3, and 5-year OS rate were 93.7%, 73.6%, 52.2% for the SR group and 76.5%, 34.8%, 13.7% for the TACE group, respectively (p<0.001). A multivariate analysis showed that TACE (Hazard ratio, HR 2.764, 95% confidence interval, CI 1.707-4.475, p<0.001), serum AFP levels > 400 ng/ml (HR 2.065, 95% CI 1.283-3.322, p=0.003) and albumin-bilirubin grade > 1 (HR 1.688, 95% CI 1.033-2.759, p=0.036) were the independent risk factors associated with poorer OS. After propensity score matching analysis to adjust for baseline differences, 33 pairs of matched patients were selected from each treatment arm. Patients who underwent SR still had a significantly better survival than patients who underwent TACE (p=0.012).

Conclusions: SR provided a better long-term survival than TACE for patients with solitary huge (≥ 10 cm) HCC. SR is recommended as the therapeutic priority for these patients.

Disclosure of Interest: W.-Y. Kao: None Declared, C.-W. Su Conflict with: Advisory Board - Gilead Sciences, C.-Y. Wei: None Declared, P.-H. Chen: None Declared, Y.-H. Huang: None Declared, M.-C. Hou: None Declared, J.-C. Wu: None Declared

P-199 IMPACT OF BASELINE CHARACTERISTICS ON THE OVERALL SURVIVAL OF HCC PATIENTS TREATED WITH SORAFENIB: A TEN-YEAR EXPERIENCE IN FIELD-PRACTICE

Giulia Rovesti* 1, Giulia Orsi1, Luca Faloppi2, Laura Gramantieri3, Nicola Silvestris4, Giorgia Marisi5, Francesco Giuseppe Foschi6, Emiliano Tamburini7, Kalliopi Andrikou8, Eleonora Molinaro1, Maria Laura Riggi1, Mario Scartozzi2, Stefano Cascinu1, Andrea Casadei Gardini1

1University of Modena and Reggio Emilia, Modena, 2University of Cagliari, Cagliari, 3University of Bologna, Bologna, 4 IRCCS-Giovanni Paolo II, Bari, 5IRST-IRCCS, Meldola, 6ASL Romagna, Faenza, 7AUSL Rimini, Rimini, 8AOU Modena, Modena, Italy

Introduction: Sorafenib, an oral multi-tyrosin kinase inhibitor (VEGFR-1/2/3, PDGFR, Flt3, c-Kit, Raf kinases), has been established as the standard of care for patients with advanced HCC since 2007, on the basis of two landmark trials (SHARP and Asia-Pacific). Although its efficacy is not a matter of doubt, this drug is effective only in a proportion of patients and may cause adverse effects that negatively impact on patients’ quality of life. Ten years have already passed since sorafenib was introduced in healthcare practice and, despite lot of research in the field, still no validated prognostic markers are available for patients treated with this therapeutic agent. Moreover, much of what we know come from sub-analyses and pooled analyses of randomized controlled trials, rather than from real life. Therefore, we conducted a field-practice study aimed at identifying which baseline factors are associated with overall survival (OS) of patients affected by HCC and treated with sorafenib.

Methods: For every patient we collected 37 biological/clinical parameters the day before the start of the treatment. OS was estimated by the Kaplan-Meier method and curves were compared by the log-rank test. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model.

Results: Between June 7, 2007 and August 8, 2018, 398 patients diagnosed with HCC and treated with Sorafenib were included in our analysis; the study sample included 356 males (89.4%) and 42 females (10.6%) with a median age at diagnosis of 69 years (range 25–88). Median OS was 12.3 months (95% CI 11.1-14.6). AEs of any grade were reported in 273 patients (74.5%); 32.2% of patients reported hand foot skin toxicity (Grade 1: 27.9%; Grade 2: 50%; Grade 3: 20.3%). The disease control rate was 58.7% (CR 0.7%, PR 11.5%, SD 46.5%). Progression disease was observed in 129 patients (41.3%). 44.5% of patients received other treatments after sorafenib progression/intolerance. For basal characteristics the univariate analysis identified AFP(>400vs<400;HR:1.51; p=0.0066), Albumin(<35vs>35;HR:1.47;p=0.03), AST(>40vs<40;HR:1.92;p=0.001), Bilirubin (>1.2vs<1.2;HR:1.43;p=0.02), Child Pugh(BvsA;HR:1.57;p=0.02), ECOG(>0vs0;HR1.71; p<0.0001), SII(>360vs<360;HR1.36;p=0.04), ALBI grade(1vs2;HR:2.47;p=0.0008) and portal vein thrombosis (Yes vs No;HR:1.45;p=0.0065) as potential prognostic factors for poorer OS. Following adjustment for clinical covariates positive in univariate analysis, the multivariate analysis including AFP (cut off 400), Age (>vs<70 years), Aetiology (HBV, HCV and others), albumin (>vs<NV), AST (>vs<NV), bilirubin (>vs<NV), Child Pugh (A vs B), LDH as a continuous variable, PLR (>vs<16), ECOG (0vs>0), ALBI grade (1vs2), portal vein thrombosis (Yes vs No), SII (<360vs>360) and BCLC stage (B vs C) identified increase of LDH, Age >70 years, other aetiologies, ECOG>0, Albumin <35, ALBI grade 2 and AST >40 as prognostic factors for poorer OS based on the 5% significance level.

Conclusions: Our study provides insights into the impact of baseline characteristics on the OS of sorafenib-treated HCC patients in real life usual care, highlighting that hepatic function (ALBI grade, AST, albumin, LDH), patient-centered variables (ECOG, age) and aetiology, rather than tumor stage, AFP and immune inflammation indicators, have prognostic value. These information might have implications in terms of therapeutic decision-making and patient counseling.


Image:

Conclusions: With the data evaluation, we have observed that Child B, C patients and patients with alpha-fetoprotein levels higher than 244 ng/mL have shown a greater mortality in the first six months, which guides us to avoid using TACE in those patients. However, to improve survival rate we need to improve patient selection – our study also have shown that Child A patients have advantage on having TACE.

References: Hayakawa, K., Tanikake, M., Kirishima, T., Yoshinami, N., Shintani, H., Yamamoto, E., & Morimoto, T. (2014). The incidence of contrast-induced nephropathy (CIN) following transarterial chemoembolisation (TACE) in patients with hepatocellular carcinoma (HCC). European Radiology, 24(5), 1105–1111. doi:10.1007/s00330-014-3099-8Thorat A, Lee CF, Wu TH, Chan KM, Chou HS, Lee WC. Safety of transarterial chemoembolization as bridging therapy in HCC patients with hyperbilirubinemia on the waiting list for liver transplantation: a centre experience. Hepatogastroenterology. 2013;60:2076-2079.Garwood, Elisabeth R., Fidelman, Nicholas, Hoch, Sarah E., Kerlan, Robert K., Yao, Francis Y. Morbidity and mortality following transarterial liver chemoembolization in patients with hepatocellular carcinoma and synthetic hepatic dysfunction. Liver Transplantation. 2013; 19(2):164-173.


P-198 TREATMENT STRATEGY FOR PATIENTS WITH A SOLITARY HUGE (> 10CM) HEPATOCELLULAR CARCINOMA (HCC) – LIVER RESECTION IS BETTER THAN TRANSARTERIAL CHEMOEMBOLIZATION (TACE)

Wei-Yu Kao* 1, Chien-Wei Su2, Cheng-Yi Wei2, Ping-Hsien Chen3, Yi-Hsiang Huang2, Ming-Chih Hou2, Jaw-Ching Wu4

1Division of Gastroenterology and Hepatology, Department of Internal Medicine, 2Division of Gastroenterology and Hepatology, Department of Medicine, 3Endoscopy Center for Diagnosis and Treatment, 4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Province of China

Introduction: For patients with solitary huge (>10cm in size) hepatocellular carcinoma (HCC) and without vascular invasion, surgical resection (SR) and transarterial chemoembolization (TACE) are the common performed treatment modalities. However, the most suitable treatment for such patients is still controversial. We aimed to compare the long-term outcomes between SR and TACE for patients with solitary huge HCC.

Methods: We conducted a prospectively enrolled, retrospectively analyzed study. Patients who presented (1) treatment naïve, (2) solitary HCC with size more than 10cm, (3) absence of major portal vein invasion and distant metastases, and (4) had received SR or TACE treatment in our institution, were enrolled for analysis. Candidate factors in terms of overall survival were analyzed by multivariate analysis. Propensity scores matching (PSM) method was adopted to adjust baseline demographic differences for further analysis.

Table:

Total number of patients

Number of patients with HCC recurrence

1 month(CEUS/CT scan)

3 months(CEUS/ MRI)

6 months(CEUS/CT scan)

12 months(CEUS/CT scan)

RFA 30 0/0 0/0 0/0 2/2

TACE 100 2/3 15/18 18/19 42/42

Sorafenib 85 - 18/20 25/27 26/26

Conclusions: CEUS can be a reliable method in monitoring patients after HCC treatment for disease recurrence or progression. However, limitations given by particularities of anatomy, nodule location as well as possible artifacts are difficult to overcome. We suggest that CEUS should be performed prior to HCC treatment as a landmark evaluation and, if nodule visualization is correct, CEUS can be used as a follow-up alternative for more expensive imagistic methods.

References: 1. Michel Claudon M, Dietrich CF, Choi BI, Ultrasound in medicine & biology Guidelines and

good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver--update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultrasound in medicine & biology 39(2) DOI: 10.1016/j.ultrasmedbio.2012.09.002

2. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. Journal of Hepatology 2018 vol. 69 j 182–236


P-197 SURVIVAL RATE FOLLOWING TRANSARTERIAL CHEMOEMBOLIZATION (TACE) AS ONLY TREATMENT: DECREASED SURVIVAL MARKERS

André R. Miquelin1, Caroline A. Marcondes2, Nicole D. O. Mazzeto2, Laura F. Martines2, Carolina A. Marques* 2, Rita de Cássia M. A. da Silva3, Willian J. Duca3, Helen C. de Felício3, Renato da Silva1

1Unidade de Transplante Hospital de Base, 2FAMERP, 3Unidade de Transplante Hospital de Base, FUNFARME, São José Do Rio Preto, Brazil

Introduction: The aim of this study is to analyze and determine risk factors that decrease survival rate among intermediate stage hepatocellular carcinoma (HCC) patients after TACE. It was a single center study, with retrospective review of 52 patients’ medical records between Jan/2000 and Jul/2016.

Methods: Retrospective analysis of patients who underwent TACE as the only treatment for HCC. The study has not considered gender, ethnicity or age. The statistics were made based on Kaplan-Meier method and Gehan-Breslow-Wilcoxon test, with significance level to P <0.05.

Results: In the medical records selection, we have obtained 69 patients with HCC who underwent to TACE. We have also analyzed laboratorial data, such as total bilirubin, creatinine, RNI, alpha-fetoprotein and the Child-Pugh score of those patients. From these 69 patients we were able to define the Child-Pugh Score of 52. Before TACE, 29 patients were Child A, 20 were Child B and three were Child C.After TACE, 21 of the 29 Child A patients remained Child A, while 7 evolved to Child B and one evolved to Child C. 13 of the 20 Child B kept this score, but four turned Child A and three became Child C. Finally, two of the three Child C patients remained Child C while one turned to Child A. The average Child A survival rate was 870 days, Child B 238 days and Child C 10 days.When we evaluate only the survival rate curve from Child A e B patients who underwent to TACE, it seems significant (p=0,0097), and a confidence interval of 0,395666 (0,168957 to 0,926574), which means that TACE could not be beneficial for non-Child A patients.We have also analyzed some biological markers, such as total bilirubin, creatinine, RNI and alpha-fetoprotein. Creatinine could be a great marker for TACE contraindication, since its average level was increased after TACE (Before TACE levels: 0.4-3.7, After TACE levels: 0.5-5.9; p = 0.0003). However, despite this finding, no patient needed dialytic support, which depreciate creatinine as a biochemical marker that could contraindicate TACE (as shown by Hayakawa et al). Bilirubin vary, being statistically significant, since the TACE occludes local vasa leading to an inflammatory response. Nevertheless, we must remember that TACE can be performed in hiperbilirubenimic patients, for it does not decompensate hepatic disease (Thorat, 2013). RNI have not been statistically significant as biochemical marker.In the meantime, alpha-fetoprotein seems to be a good predictive biomarker. On the ROC curve for alpha-fetoprotein, the exam was useful for evaluation, since the specificity is high (0,875), as well as the positive predictive value. Thus, the death probability in who has the alpha-fetoprotein above 244 ng/mL is 96.1% (25/26). The under curve area was good though (0,727) (Image).

Posters Posters


Conclusions: Our study suggested that TGFa is upregulated in liver tumour transformation in patients with liver cirrhosis particularly for those with HBV aetiology. Elevated level of serum TGFa may potentially be used as an adjunctive tumour marker for HCC. Future studies with more patients including NAFLD related liver cirrhosis and HCC is needed to define the specific role of TGFa in hepatocarcinogenesis and its role as a clinical biomarker for HCC.


P-209 RISK STRATIFICATIONS AND VALIDATION OF 50-50 CRITERIA AND POST-HEPATECTOMY LIVER FAILURE (PHLF) SCORE IN PATIENTS WITH CIRRHOSIS UNDERWENT CURATIVE RESECTION FOR HCC

Esam Elshimi* 1, Asmaa Gomaa1 and Eman Abdelsameea, Aya Aman and Hazem Mohamed Zkaria

1Hepatology, menoufia university, National Liver Institute, Shebeen Elkom, Egypt

Introduction: Given the poor synthetic function of cirrhotic liver, the successful resection for patients with HCC necessitates the ability to achieve resections with tumor free margins while leaving behind sufficient liver volume to maintain patients' life. However, standardized predictors of liver decompensation after resection is lacking. Aim: we aimed to validate the 50-50 criteria and PHLF and to stratify risks in patients with cirrhosis who underwent curative liver resection for HCC.

Methods: between December 2010 and January 2017, 120 patients underwent curative resection for HCC in patients with cirrhosis were included in this study, the pre-operative, operative and post-operative factors were recorded to stratify patients' risks of decompensation and survival, 50-50 criteria and PHLF were also validated.

Results: the preoperative MELD score (OR=2.7, 95% CI: 1.2-5.7, p-value=0.013), tumor diameter (OR=5.4, 95% CI: 2-14.8, p =0.001) and duration of hospital stay (OR=2.5, 95% CI: 1.5-4.2, p=0.001) were significant independent predictors of hepatic decompensation after resection. While, the preoperative MELD score (HR=1.37, 95% CI: 1.16-1.62, p-value <0.001) and different grades of PHLF (grade A: HR=2.33, 95% CI [0.59-9.24]; Grade B: HR=3.15, 95% CI [1.11-8.95]; Grade C: HR=373.41, 95% CI [66.23-2105.43]; p <0.001) and HCC recurrence (HR=11.67, 95% CI: 4.19-32.52, p <0.001) were significant independent predictors for survival.

Conclusions: In patients with cirrhosis undergoing curative resection for HCC, the preoperative MELD score, tumor diameter and the duration of hospital stay were independent predictors of decompensation. While, preoperative MELD score, different grades of PHLF and HCC recurrence were independent predictors for survival.


P-210 POSTOPERATIVE HEPATOBILIARY SURGERIES' FUNGAL INFECTIONS EPIDEMIOLOGY (PREVALENCE AND RISK FACTORS)

Esam Elshimi* 1 and Wesam S. Morad, Amal El-Sharnoby, And Amr Mostafa Aziz


Introduction: Candidemia and disseminated candidiasis are major causes of morbidity and mortality in hospitalized patients especially in ICU, the incidence of invasive candidiasis is on a steady rise because of increasing use of multiple antibiotics and invasive procedures carried out in the ICUs. Risk factors for invasive candidiasis & candidaemia include prior antimicrobial therapy, central venous catheters, urinary catheters, ICU admission, parenteral nutrition, major surgery and immunosuppressive therapies. Candida species were the most frequently isolated organism from any sites and comprise 85% of total number of cultures.Aim of the Study: Assessing the rate of fungal infections after hepatobiliary surgery and identification of the risk factors associated with the development of fungal infections in such patients. Candidemia and disseminated candidiasis are major causes of morbidity and mortality in hospitalized patients especially in ICU, .Aim of the Study: Assessing the rate of fungal infections after hepatobiliary surgery and identification of the risk factors associated with the development of fungal infections in such patients.

Methods: A prospective cohort hospital based study was carried out at National Liver Institute. The studied group consisted of 210 patients. All of them were examined thoroughly, their data were registered and sampled at two times, one at day of admission to be sure that they are free of fungal infection and the second was after hepatobiliary surgery pre-designed questionnaire was used which include data about personal history, medical history and suggested risk factors for fungal infections.A prospective cohort hospital based study was carried out at National Liver Institute. The studied group consisted of 210 patients. All of them were examined thoroughly, their data were registered and sampled at two times, one at day of admission to be sure that they are free of fungal infection and the second was after hepatobiliary surgery pre-designed questionnaire was used which include data about personal history, medical history and suggested risk factors for fungal infections.

P-206 ASSESSMENT OF LIVER FUNCTION USING ALBI SCORE IN PATIENTS TREATED WITH LENVATINIB FOR HEPATOCELLULAR CARCINOMA

Akio Moriya* 1, Hiromichi Kawaji1, Soichiro Mashima1, Masaharu Ando1

1Department of Gastroenterology, Mitoyo General Hospital, Kanonji, Japan

Introduction: Lenvatinib acts as a multiple kinase inhibitor against the VEGFR, FGFR, PDGFRα, RET, and KIT. It attracted attention for the high response rate in the clinical trial for hepatocellular carcinoma (HCC) [1]. On the other hand, the influence on liver function is also important to continue treatment. We aimed to evaluate the longitudinal change in liver function after administration of lenvatinib using ALBI score, which was recently proposed as a replacement of the conventional evaluation method, Child-Pugh score [2].

Methods: We analyzed 12 patients with advanced or TACE-refractory HCC treated with lenvatinib (9 men and 3 women; median age, 80 years old). Changes in ALBI scores during the treatment with lenvatinib in comparison to the value at baseline were evaluated. They were also separately evaluated according to the treatment effect assessed by modified RECIST.

Results: There were 3 patients of ALBI grade 1, 8 patients of grade 2, and 1 patient of grade 3. The median (interquartile range) of ALBI score at baseline was -2.221 (0.807). At the time of treatment discontinuation or the latest follow-up (median observation period, 95 days; range, 5-279 days), the change from baseline in ALBI score was + 0.2624 (0.5130). The longitudinal changes in ALBI score at 1 week (n = 12), 2 weeks (n = 9), 3-4 weeks (n = 9), 6-8 weeks (n = 9), 10-12 weeks (n = 7), 17-24 weeks (n = 6), and 28-40 weeks (n = 4) were +0.2394 (0.2682), +0.2098 (0.3610), +0.3814 (0.5854), +0.0523 (0.5950), +0.0850 (0.3819), +0.0927 (0.4460), and +0.1315 (0.6142), respectively. Although there was no significant change from the value of baseline during the treatment, ALBI score seemed aggravated until 4 weeks after the lenvatinib initiation and then recovered to some extent. It was similar when cases with less than 12 weeks of treatment were excluded. The response rate was 33% and the disease control rate was 83%. At the time of treatment discontinuation or the latest follow-up, the change from baseline in ALBI score was + 0.2675 (0.3781) in PR group and +0.2499 (0.7352) in SD/PD group; there was no significant difference between them (P = 0.8081).

Conclusions: In cases where lenvatinib for HCC can be administered for 4 weeks or more, liver function may recover after it worsened once.

References: [1] Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable

hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163-73.[2] Johnson PJ, et al. Assessment of liver function in patients with hepatocellular carcinoma: a new

evidence-based approach-the ALBI grade. J Clin Oncol. 2015;33:550-8.


P-208 SERUM TRANSFORMING GROWTH FACTOR ALPHA (TGFa) AS A BIOMARKER FOR HEPATOCELLULAR CARCINOMA (HCC)

Ngai M Law* 1

1Gastroenterology & Hepatology, Changi General Hospital, Singapore, Singapore

Introduction: Transforming Growth Factor Alpha (TGFa) has been found to be an important cytokine involved in liver cirrhosis (LC) associated hepatocellular carcinoma (HCC). Its exact role as a mitogen in liver tumour transformation from various causes of liver cirrhosis remained unclear. In addition, elevated serum TGFa may be a useful biomarker in detecting early HCC.

Methods: We analysed the serum level of TGFa in patients with LC and HCC. The diagnosis of LC was based on clinical features, imaging studies and biochemical profiles. Aetiology of LC and HCC were determined by alcohol consumption history (ALC) and specific virology tests for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). LC was staged by Child-Pugh staging system. HCC was staged by BCLC staging. Serum AFP level was done as a routine blood tests for all LC and HCC patients. Serum TGFa was measured by standard ELISA technique.

Results: The study recruited 26 LC patients (14 HBV, 9 ALC and 3 HCV) and 33 HCC patients (22 HBV, 8 ALC and 3 HCV). The mean ages of LC and HCC patients were 60.9 years and 61.8 years respectively. Serum TGFa was detected in 11/26 (42%) of LC patients (9 HBV, 2 ALC and 0 HCV) versus 20/30 (61%) of HCC patients (15 HBV, 4 ALC and 1 HCV). The serum level of TGFa was significantly different between HBV related LC and HCC (64.08±36.27 pg/ml vs 286.11 ±30.38 pg/ml, p=0.039) but not between ALC related LC and HCC (26.76±7.45 pg/ml vs 169.44±132.00, p=0.22). One out of 3 HCV related HCC patients had detectable serum level of TGFa versus none in all 3 HCV LC patients. No significant correlation was established between level of serum TGFa and other parameters including Child-Pugh scores, BCLC staging and serum AFP level.

Introduction: The clinical manifestation of patients with Hepatocellular carcinoma (HCC) have changed significantly in the last decades in countries that have adopted screening tests. In developing countries due to the rarity of surveillance/screening programs coupled with diagnostic challenges of Hepatocellular carcinoma most patients present late. We therefore evaluate the clinical manifestations, staging and prognostic factors for HCC in Gambian patients.

Methods: All patients with suspected HCC who were referred to the main liver clinic In Medical research Council, Gambia Unit (MRCG) were recruited between December 2015 to January 2019. The diagnostic criteria was based on ultrasound demonstration of liver mass ≥2 cm with or without clinical features combined with alpha-fetoprotein (AFP) level of ≥200ng/ml and/or histopathology confirmation. Clinical, radiological, fibroelastrography and laboratory data were collected in all patients. The performance status, Child-Pugh and BCLC stages were determined for each patient. Kaplan -Meier, univariate and multivariate cox regression analysis were used to assess factors related to survival in these patients.

Results: Two hundred and sixty patients were recruited into the study. The mean age of HCC patient was 40 years and mostly males (80.7%).The majority were rural born (74.4%), of the wollof tribe (26.2%) and farmer/gardener (42%). The most common constitutional symptoms were weight loss (92.3%), easy fatiguability (91.9%) while the most common gastrointestinal symptoms were early satiety (89.1%) and abdominal pain (88.7%). The most common signs were hepatomegaly (83.7%) and abdominal tenderness (44%).Multi-focal lesions were the most common on ultrasound scan (67.2%) compared to single lesions, and the median fibroelastography score was 75kpa in these patients. HBsAg carriage was present in 66.4% of HCC patients with a median AFP of 3895 ng/ml. WHO performance status 3, BCLC stage C and Child-Pugh score stage B were most common among this patient group. HBsAg-positive patients with HCC were mostly males, much younger, most likely to have abdominal pain, jaundice, dark urine, abdominal tenderness, raised transaminases and decreased platelet counts as compared to patients with HCC who are HBsAg-negative. Patients diagnosed with HCC who were HBsAg-negative tended to be older, more likely to be hypertensive and had a much better median survival ( 45 days vs 31 days). Both prognostic staging systems had good stratification of survival and the median survival of these patients was 35 days.Independent factors that affect survival were (i) Patient related, (sex, M vs F:p=0.022), (ii) tumour related (abdominal pain:p=0.020, oedema:p=0.003, jaundice:p=0.040, ascites: p=0.012), (iii) disease stage at presentation (child pugh scoring system,AB vs C: p=0.025) and Biochemical indices(AFP,≥200ng/ml:P=0.001,sodium:p=0.008, glucose p=<0.001, AST:p=<0.001 and albumin:p=0.001).

Conclusions: HBV is a significant factor in HCC in The Gambia. Young males who are the main work-force are disproportionately affected, are more likely to be symptomatic and have much shorter survival. In resource limited countries were screening programmes and therapeutic interventions are limited, the prognosis and survival of patients with HCC is poor, emphasizing the need for early preventive strategies.


P-205 THE CLINICAL AND HISTOPATHOLOGIC CHARACTERISTICS OF HEPATOCELLULAR CARCINOMA OF DIFFERENT ETIOLOGIES

Cheng-Ting Hsu* 1, Po-Yao Hsu1, Chia-Yen Dai1, 2, Ming-Lung Yu,1, 2, Jee-Fu Huang1, 2, Wan-Long Chuang1, 2

1Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, 2Hepatobiliary Division, Department of Internal Medicine,, Kaohsiung, Taiwan, Province of China

Introduction: Hepatocellular carcinoma (HCC) of non-viral etiology (NBNCHCC) is an increasing trend in the past decades. The clinical manifestations of NBNCHCC remains elusive. We aimed to explore the clinical features and the histopathological characteristics of NBNCHCC in those patients who received surgical intervention. The difference between HCC of viral origin and NBNCHCC was also compared.

Methods: Between June 2014 and August 2018, we consecutively enrolled 434 HCC patients who received curative tumor resection in a referral medical centre in Taiwan. We analyzed the clinical profiles and the histopathological features among those hepatitis B virus (HBV)-infected (HBVHCC), hepatitis C virus (HCV)-infected (HCVHCC), and those NBNCHCC, respectively.

Results: Those 143 HBVHCC patients had significantly younger mean age (61.9 ± 11.1 years) than those 107 HCVHCC (67 ± 8.8 years) and those 58 NBNCHCC patients (68.4 ± 10.6 years) (p<0.001). One hundred and thirteen (79%) HBVHCC patients were males, which was significantly higher than than other 2 groups (56.9% of NBNCHCC and 54.2% of HCVHCC, p<0.001). Besides having a significantly higher ALT levels, Patients with HCVHCC also had a significantly higher FIB-4 index (2.81, 95% CI=1.95-4.15] than HBVHCC group (2.25, 95% CI= 1.55-3.18), and NBNCHCC group (2.25, 95% CI= 1.55-3.18) (p= 0.002). The NBNCHCC had a significantly larger mean tumor size (3.70 cm, 95% CI=2.37-6.50) than HBV HCC group (3.20 cm, 95% CI=2.00-5.50), and HCVHCC (2.50 cm, 95%CI=1.80-4.10), respectively (P=0.002). The NBNCHCC patients had a significantly higher proportion of BCLC stage B/C (63.8%) than HBVHCC group (46.2%), and HCVHCC group (45.8%), respectively (P= 0.02).

Conclusions: The clinical features and disease severity of HCC are diverse in different etiologies. Patients with NBNCHCC had a more advanced disease stage than viral etiologies.


P-203 VITAMIN B12 SUPPLEMENTATION IS ASSOCIATED WITH LOWER RATES OF HEPATOCELLULAR CANCER

Zhibin Zhu1, Michelle Godbee2, Costica Aloman1, Donald Jensen1, Sheila L. Eswaran* 1

1Hepatology, 2Internal Medicine, Rush University Medical Center, Chicago, United States

Introduction: Increased serum cobalamin level (vitamin B12) is associated with hematological malignancies, such as leukemias, due to enhanced production of transcobalamin (1). Acute hepatitis, liver cirrhosis, and hepatocellular carcinoma have been also associated with increased circulating cobalamin due to cobalamin release during hepatic cytolysis and/or decreased cobalamin clearance by hepatocytes. Vitamin B12 supplementation is indicated to treat and prevent vitamin B12 deficiency, however often used over the counter for a myriad of ailments, despite insufficient data. Recent reports concluded that B12 supplements are associated with increased risk of in lung and colorectal cancer (2, 3). There is limited data evaluating B12 levels (4) and supplements in patients with liver cirrhosis and HCC.

Methods: This is a single institution retrospective case control study of cirrhotic patients without HCC (control) and with HCC (HCC case). We collected demographic data (gender, race), etiology of liver disease, vitamin B12 levels, and whether patient was taking B12 containing supplement. Chi-square, Fischer exact test and relative risk were used for categorical variables and t-Test for continuous variables to determine statistical significance.

Results: 579 subjects were included (201 control, 378 HCC). Between two groups there was no difference in distribution of gender (male 403, female 176; p=0.600), race (White 276, Hispanic 109, African American 138, Asian 31, other 19, unknown 6; p=0.965) or the cause of liver cirrhosis (alcohol 145, NASH 73, HCV 243, HBV 44, AIH/PBC/PSC 34, other 8, unknown 32; p=0.965). Forty five percent (258/579) had B12 levels recorded. HCC subjects had a lower B12 levels than controls (mean 1239 v 1310), but the difference was not statistically significant (p = 0.105). The rate of HCC in patients on receiving vitamin B12 containing supplements was 39% compared to 63% of those not on supplements (p=0.003) and reflected in a relative risk reduction of 38% and absolute risk reduction of 0.24. These data suggests that 4 treated patients with cirrhosis are needed in order to prevent one HCC case.

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Conclusions: Our data supports protective effect of vitamin B12 on HCC risk. Prospective interventional trials of vitamin B12 should be considered to validate this hypothesis.

References: 1. Ermens AA, Vlasveld LT, Lindemans J. Significance of elevated cobalamin (vitamin B12) levels in

blood. Clin Biochem. 2003 Nov;36(8):585-90. Review.2. Brasky TM, White E, Chen CL. Long-Term, Supplemental, One-Carbon Metabolism-Related

Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol. 2017 Oct 20;35(30):3440-3448

3. Oliai Araghi S, Kiefte-de Jong JC, Dijk SCV, Swart KMA, van Laarhoven HW, Schoor NMV, de Groot LCPGM, Lemmens V, Stricker BHC, Uitterlinden AG, Velde NV. Folic acid and vitamin-B12 supplementation and the risk of cancer: long-term follow-up of the B-vitamins for the Prevention Of Osteoporotic Fractures (B-PROOF) trial. Cancer Epidemiol Biomarkers Prev. 2018 Oct 19.

4. Lian-Hua Cui, Zhen-Yu Quan, Jin-Mei Piao, Ting-Ting Zhang, Meng-Hui Jiang, Min-Ho Shin, andJin-Su Choi. Plasma Folate and Vitamin B12 Levels in Patients with Hepatocellular Carcinoma. Int J Mol Sci. 2016 Jul; 17(7): 1032.


P-204 CLINICAL MANIFESTATION, STAGING AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA IN GAMBIAN PATIENTS

Sheikh O. Bittaye* 1, Abubacarr Kambi2, Muhammed Tekanyi2, Tamba Saydiba1, Yusupha Bah1, Momodou musa Sisawo1, Lamin Sanneh1, Abdoulie Jatta1, Sarjo Koita1, Jallow Awa1, Gibril Fatty1, Momodou S. Jallow3, Behnoush Abedi-Ardekani4, Ramou Njie1, 4

1Disease control and Elimination (DCE), MRC Unit, The Gambia, 2Internal Medicine Department, 3Pathology Department, Edward Francis Small Teaching Hospital, Banjul, Gambia, 4International agency for Research on Cancer, Lyon, France

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Methods: We retrospectively enrolled patients with treatment-naïve HCC and with EGV who underwent TACE from 2007 to 2012. The diagnosis of EGV was established by esophagogastroduodenoscopy. The prognostic factors were analyzed by Cox proportional hazards model.

Results: Among the 120 enrolled patients, the mean age was 67.0 years and 91 (75.8%) were males. Hepatitis B virus infection (52.5%) and hepatitis C virus infection (35.8%) were the major etiologies. After the initial TACE, 33 patients had a progressive disease (PD) by modified Response Evaluation Criteria in Solid Tumors. After a median follow-up of 16.9 months (25-75 percentiles 6.1-35.5 months), 97 patients died. The median overall survival (OS) time was 16.2 (95% confidence interval CI, 6.89-25.52) months. The cumulative 1-, 3-, and 5-year OS rates were 56.7%, 28.9% and 13.0%, respectively. A multivariate analysis disclosed that presence of ascites (hazard ratio, HR 1.980, 95% CI 1.253-3.125, p= 0.003), size of maximal tumor > 5cm (HR 3.469, 95% CI 2.263-5.317, p< 0.001), and progressive disease (PD) (HR 2.404, 95% CI 1.490-3.891, p< 0.001) were the independent risk factors correlated with poor OS after TACE. Stratified by the status of ascites, the median (95% CI) OS time were 8.6 (2.8-14.4) months and 27.2 (17.1-37.3) months for patients with and without ascites, respectively.

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Conclusions: For HCC patients with EGV and underwent TACE, presence of ascites, tumor size > 5cm and PD were associated with a poorer prognosis.

Disclosure of Interest: C.-Y. Wei: None Declared, C.-W. Su Conflict with: Advisory Board - Gilead Sciences, P.-H. Chen: None Declared, W.-Y. Kao: None Declared, Y.-H. Huang: None Declared, M.-C. Hou: None Declared, J.-C. Wu: None Declared

P-216 THE CHALLENGE OF HEPATOCELLULAR CARCINOMA MANAGEMENT IN THE ERA OF INDIVIDUALIZED THERAPY: THE EXPERIENCE OF A GREEK TERTIARY CENTER IN THE MIDDLE OF A FINANCIAL CRISIS

Chrysanthos D. Christou1, Andreas Tooulias* 1, Alexandros Tsolakidis1, Eleni Athanasiadou1, Bozidaria Pianetcki-Tsiantzi2, Vassilis Papayiannis3, Georgios Tsoulfas1, Vasileios Papadopoulos1

1First General Surgery Department, 2Anesthesiology Department, 3Radiology Department, Papageorgiou General Hospital, Thessaloniki, Greece

Introduction: The treatment of hepatocellular carcinoma (HCC) in the era of individualized therapy is a challenge. Treatment selection is based on the stage of the disease. The most prominent staging system is the Barcelona Clinic Liver Cancer (BCLC). Our study aims to record and analyze the course of these patients in a Greek tertiary care center during a financial crisis.

Methods: We conducted a retrospective analysis between 3/1/2010 and 12/31/2018 of patients with HCC admitted to our department. For each of these patients we collected information regarding demographics, comorbidities, radiological and laboratory characteristics of the disease and as an extension staging of the disease at the time of diagnosis, therapeutic procedures and overall survival. Patients were allocated to different treatment strategies based on the size and number of the lesion(s) and the existing comorbidities of the patient. All patients were discussed in a multidisciplinary tumor board with input from different specialties. Following data collection, we analyzed the data using statistical analysis software package SPSS version 25.0. Statistically significant was considered any test with a p value smaller than 0.05. Regarding survival, it was analysed using Kaplan – Meier survival curves and survival tables, censoring patients who are still alive. Finally, survival curves were compared using log rank test.

Results: The study population was 63 patients(N=63). Based on laboratory and radiological results, 52 patients(82.5%) were staged at Child-Pugh Class A and 11(17.5%) at Class B. Considering BCLC, patients were divided as follows: Very Early-5 patients(8.2%), Early-38 patients(62.3%), Intermediate-14 patients(23%), Advanced-4 patients(6.5%). Considering therapeutic approach, 32 patients(50.8%) were treated with surgery and 28 patients(44.4%) with locoregional treatments. Out of the 32 surgical patients, 13 patients(40.6%) received locoregional treatments post-operatively for recurrence. In the locoregional group (N=28), 19 patients(67.9%) were treated with

of 77.1%, NPV of 73.3%, AUC= 0.8 and p <0.0005. They also had serum AFP level ≥394.5 with PPV of 89.3%, NPV of 72.7%, AUC= 0.81 and P<0.0005. Serum fibrinogen level had no significant correlation with HCC grade.

Conclusions: Circulating D-dimer level is positively correlated with HCC grade in BCLC stage C and D HCC patients .It is significantly higher in HCC cases beyond Milan criteria than those within. It is diagnostic of HCC cases beyond Milan criteria with cutoff value ≥300 ng/ml. More studies are recommended to confirm the importance of circulating D dimer level measurement in evaluation of HCV related HCC cases before treatment.

References: 1. Edwards RL, Rickles FR, Moritz TE, et al. Abnormalities of blood coagulation tests in patients with

cancer. Am J Clin Pathol. 1987;88(5):596-602. 2. Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res

Clin Haematol. 2009;22(1): 49-60. 3. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small

hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334:693– 699.


P-214 SAFETY AND EFFICACY OF YTTRIUM-90 RADIOEMBOLIZATION FOR ADVANCED HCC PATIENTS: A 35 PROCEDURES CASE-SERIES

Hadar Meringer1, Yoram Menachem* 1, Isaac Kori2, Oren Shibolet1

1Hepatology unit, 2Radiology unit, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel

Introduction: Transarterial Radioembolization (TARE) using yttrium-90 microspheres is been investigated in patients with Hepatocellular Carcinoma (HCC) and its utility continues to expand. TARE is considered as a safe and effective therapy. It is used mainly in the treatment of unresectable HCC or as a bridge for liver transplantation. We aimed to report patients characteristics, outcomes and safety of TARE as performed in our center.

Methods: We searched our prospectively acquired database for patients treated with TARE from August 2014 through December 2018. Patients files were retrospectively reviewed for baseline characteristics, treatment characteristics and outcomes including complications following the procedure and imaging response.

Results: Twenty-nine HCC patients treated with TARE were identified in our database. Mean age was 63 years (Range 29-78), 79% were males and viral hepatitis was the most common liver disease etiology (80%). Solitary HCC was seen in only 14% of patients, the largest tumor size median was 5.75 cm (IQR 3.3-11) and portal vein thrombosis (PVT) occurred in 11/29 (38%). According to the BCLC Staging system patients were classified into early A, intermediate B or advanced stage C in 7%, 45% and 38%, respectively. Child-Pugh (CP) class A in 86% of patients and class B in 14%. A total of 35 radioembolization treatments were performed. Hepatic decompensation was seen after 12/35(34%) procedures during a 6 weeks follow-up and re-admission was required in 92% of them. 10 patients out of 12 with hepatic decompensation recovered after 2-4 weeks. Disease control (DC) was achieved in 45% of patients and in 6/9(67%) patients with baseline PVT and available assessment after 3 months. Median survival time was 9.5 months [IQR 3.25-18.25]. No difference in survival with and without PVT. Twelve radioembolizations were performed as part of a two staged procedure in 6 patients. No differences in the rate of complications or decompensation were found between patients who were treated in one stage procedure compared with two staged procedure, although progressive disease was seen more often after two staged procedures.

Conclusions: Radioembolization can serve as a safe and effective treatment especially in HCC patients with tumor PVT. One third of patients experienced decompensation, but most of them recovered. TARE was safe also when done in a two-stage procedure.


P-215 TUMOR SIZE, PRESENCE OF ASCITES, AND TREATMENT RESPONSE DETERMINED THE PROGNOSIS OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND WITH ESOPHAGOGASTRIC VARICES AFTER TRANSARTERIAL CHEMOEMBOLIZATION

Cheng-Yi Wei* 1, Chien-Wei Su1, Ping-Hsien Chen2, Wei-Yu Kao3, Yi-Hsiang Huang1, Ming-Chih Hou1, Jaw-Ching Wu4

1Division of Gastroenterology and Hepatology, Department of Medicine, 2Endoscopy Center for Diagnosis and Treatment, 3Division of Gastroenterology and Hepatology, Department of Internal Medicine, 4Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, Province of China

Introduction: The treatment efficacy of transarterial chemoembolization (TACE) for patients with hepatocellular carcinoma (HCC) and with esophagogastric varices (EGV) is still obscure. This study aimed to investigate the outcomes of patients with HCC and EGV following TACE.

P-212 DIABETES INCREASED THE RISKS OF DISTANT METASTASIS IN HCC PATIENTS WITH TRANSARTERIAL CHEMOEMBOLIZATION

Ming-Chin Yu* 1, Wen-Hui Chan2, Chao-Wei Lee 1, Tsung-Han Wu1, Chien-Fu Hung2, Kuan-Tse Pan2

1Surgery, 2Medical Imaging And Intervention, Chang Gung Memorial Hospital, Taoyuan, Taiwan, Province of China

Introduction: Hepatocellular carcinoma (HCC) is a common gastrointestinal cancer globally, and conventional transarterial chemoembolization (cTACE) is one of the first treatment choices for advanced HCC. However, diabetes have been seldom reported in the impact on the long-term outcomes.

Methods: We have identify the independent risks factors for cTACE: includingα-fetoprotein (AFP) > 200 ng/ml, advanced HCC, aspartate transaminase > 68 U/L, albumin < 3 g/dl, and presence of diabetes. This retrospective cohort study was aimed at long-term outcome of diabetes patients and the end-points were the liver function status , tumor status, and distant metastasis.

Results: This study included 444 HCC patients who underwent cTACE-based therapy in 2010–2012. The mean age was 62.1 ± 12.5 years, with 74.3% males. There was no significant difference between the diabetes group and the control group, concerning the liver function variables. But diabetes patients had significant increased the distant metastasis rates from 14.3% to 23.1% in the first and fourth years, whereas the control group had decreased from 13.6% to 9.9%. (p=0.843 and 0.005, respectively)

Conclusions: Our data supported HCC patients with DM had high risks to develop extrahepatic spreading but the liver function status was comparable to HCC patients without DM. Further work will be aimed at the anti-diabetic treatment.

References: Takayasu K. Transarterial chemoembolization for hepatocellular carcinoma over three decades: current progress and perspective. Japanese journal of clinical oncology 2012; 42: 247-255. 2012/03/13. DOI: 10.1093/jjco/hys020.Zhou YY, Zhu GQ, Liu T, et al. Systematic Review with Network Meta-Analysis: Antidiabetic Medication and Risk of Hepatocellular Carcinoma. Scientific reports 2016; 6: 33743


P-213 CIRCULATING D DIMER LEVEL CORRELATES WITH TUMOR GRADE IN CHRONIC HEPATITIS C RELATED HEPATOCELLULAR CARCINOMA

Hany R. Shabana* 1, Sahar A. EL.Gharabawy1, Ashraf A. E. Elfakhry2, Ghada M. Rabea3, Hanan A. Azzam4

1Internal Medicine, Hepatology and Gastroenterology Unit, 2Internal Medicine,Hepatology and Gastroenterology Unit, Specialized Medical Hospital, Mansoura University, Mansoura, 3Internal Medicine, Hepatology and Gastroenterology Unit, Damietta Liver Hospital, Damietta, 4Clinical Pathology Department, Faculty of Medicine,Mansoura University, Mansoura, Egypt

Introduction: Systemic activation of blood coagulation and pro-coagulant changes in the hemostatic system have frequently been observed in cancer patients, even in the absence of venous thromboembolism (VTE). Moreover, coagulation activation, in particular thrombin generation and fibrin formation and dissolution, have been implicated in angiogenesis, tumor cell invasion, tumor progression, and metastatic spread (1, 2). D-dimer is a biomarker that globally indicates the activation of hemostasis and fibrinolysis. Aim: To study the correlation of circulating D-dimer level with the grade of HCV related HCC.

Methods: HCC was diagnosed by noninvasive method according to EASL criteria using contrast enhanced abdominal CT and or MRI. Chromic HCV was diagnosed by 4th generation ELIZA for HCV antibody and confirmed by quantitative PCR for HCV RNA. HCC grade was described as grade one if it was within Milan criteria, grade three if it was metastatic (vascular invasion, lymph node metastasis, distant metastasis) and grade two if it was beyond Milan criteria but non –metastatic (3). BCLC staging depending on HCC burden, Child Turcotte Pugh (CTP) class and ECOG performance status, was done for all studied cases. Circulating D dimer level, serum fibrinogen level and serum AFP level were measured for all studied cases. Patients with history of any treatment for HCC or recent benign thrombo-embolic disorder were excluded.

Results: Fifty chronic HCV related HCC cases in BCLC stage C (N=20) and D (N=30), 43 males and 7 females with age 62.2±7.4 years, CTP class A (N=4), B (N=16) and C (N=30) were included. There was statistically significant positive correlation between circulating D-dimer level and largest HCC size and HCC grade (r =0.35, P = 0.012, r =0.33, P = 0.016 respectively). It also showed higher circulating D-dimer level in HCC cases beyond Milan criteria (G2, G3) (31patients) than those within (G1) (19 patients) (P<0.0005). There was also statistically significant positive correlation between circulating D-dimer and serum AFP level (r =0.45, P =0.001). Circulating D-dimer level also showed significant positive correlation with ECOG performance status (r =0.42, P = 0.002). HCC cases beyond Milan criteria (G2, G3) had serum level of circulating D-dimer ≥300 ng/ml with PPV

Results: In the present study the incidence rate of fungal infection among patients undergone hepatobiliary surgeries in NLI is (45.2%) and the main predictors of fungal infection were age (p-value 0.001), antibiotic use (p-value 0.05), liver disease (p-value 0.006), CVC (p-value 0.043), urinary catheter (p-value 0.05), and ICU hospitalization more than 48 hours (p-value 0.000008).In the present study the incidence rate of fungal infection among patients undergone hepatobiliary surgeries in NLI is (45.2%) and the main predictors of fungal infection were age (p-value 0.001), antibiotic use (p-value 0.05), liver disease (p-value 0.006), CVC (p-value 0.043), urinary catheter (p-value 0.05), and ICU hospitalization more than 48 hours (p-value 0.000008).

Conclusions: High incidence of fungal infection after hepatobiliary surgeries may reach 45% due to type of patient doing such surgeries. The great prevalence of fungal colonization inside ICU which is easily transmissible emphasizes very strongly on the importance of infection- control guidelines.High incidence of fungal infection after hepatobiliary surgeries may reach 45% due to type of patient doing such surgeries. The great prevalence of fungal colonization inside ICU which is easily transmissible emphasizes very strongly on the importance of infection- control guidelines.


P-211 ADJUVANT CHEMOTHERAPY FOR RESECTED INTRAHEPATIC CHOLANGIOCARCINOMA: IS THERE STILL A ROLE FOR GEMCITABINE?

Andrea Palloni* 1, Giorgio Frega1, Francesca Abbati1, Emanuele Forcesi2, Alessandro Rizzo1, Giovanni Brandi1

1Department of Experimental, Diagnostic and Speciality Medicine, Sant’Orsola Malpighi Hospital, University of Bologna, 2Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy

Introduction: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and its incidence is increasing worldwide in the last decades. Surgical resection is the only potentially curative treatment but, even after radical surgery, prognosis is poor due to the high recurrence rate. The rationale for use of adjuvant chemotherapy is to reduce the risk of relapse and potentially improve long-term outcome. To date there is no clear consensus about the optimum adjuvant strategy in resected patients. The aim of our study is to investigate the putative role of adjuvant gemcitabine in patients undergoing radical resection for ICC.

Methods: We retrospectively analyzed the outcome of all consecutive patients who underwent curative intent surgery for ICC in our institution between January 2000 and December 2017. Patients who underwent exploratory laparotomy or palliative surgery (R2), and those who underwent radical surgery (R0/R1) but were deemed unfit to start adjuvant therapy, were excluded from the analysis. We compared clinical outcome of patients who received adjuvant chemotherapy (gemcitabine 1000 mg/m2 on days 1, 8, 15 of a 28-days cycle for 6 cycles) with respect to those who underwent only surveillance after surgery. Survival has been estimated by Kaplan-Meier method. Multivariate analysis on prognostic factors was performed according to Cox proportional hazard model.

Results: A total of 115 patients who underwent surgical resection for ICC were included in the analysis. Clinicopathological characteristics of patients, compared by Pearson's chi-square test, were balanced between the two groups. After a median follow-up of 23.5 months, median disease-free survival (mDFS) was 15.0 months in the treatment group and 11.2 months in the control group and the difference was statistically significant (HR 0.58, p=0.028). Patients undergoing adjuvant chemotherapy also had a significantly greater overall survival (OS) as compared to patients who underwent only surveillance (mOS 42.1 vs 21.9 months, respectively; HR 0.55, p=0.035). At univariate analysis, negative lymph nodes status (p<0.001) was also significantly associated with a reduced risk of recurrence. The multivariate analysis confirms these two parameters as the only independent prognostic factors for DFS.

Conclusions: Even after radical surgery, the prognosis of ICC patients remains poor. The putative role of adjuvant chemotherapy is to reduce the high risk of relapse and potentially improve long-term outcome. To date there is a no a worldwide accepted adjuvant strategy for ICC patients, despite recent results of the large randomized BILCAP trial could define a new standard of care1. Gemcitabine is one of the most active agents against cholangiocarcinoma and it is widely used in advanced disease, but its role in the adjuvant setting is still unclear. Recent adjuvant gemcitabine-based randomized trials failed to demonstrate a survival benefit of gemcitabine, alone or in combination with oxaliplatin, over surveillance2,3. Despite the limitations of a retrospective analysis, our study showed that gemcitabine monotherapy could reduce the risk of relapse in resected ICC patients and potentially improve survival.

References: 1 Primrose JN et al. Lancet Oncol. 2019. Mar 25. pii: S1470-2045(18)30915-x.2 Edeline J et al. J Clin Oncol. 2019. Mar 10;37(8):658-667.3 Ebata T et al. Br J Surg. 2018 Feb;105(3):192-202.

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weakness and palpable abdominal mass. We report this rare and aggressive tumor in a 28-year-old male who presented with acute pancreatitis which is a rare presenting feature of this rare tumor.

Methods: Case report: A 28-year-old male presented with a two-week history of left upper quadrant abdominal pain and vomiting. Initial laboratory tests revealed deranged liver function tests and an elevated lipase suggestive of acute pancreatitis. Computed tomography of the abdomen demonstrated multiple enlarged abdominal lymph nodes suggesting possibility of lymphoma. Further work up showed elevated alpha-fetoprotein (AFP) and β-human chorionic gonadotropin raising the possibility of an underlying germ cell tumor. However, testicular ultrasound was unremarkable. He underwent three ERCP procedures with 4 stents and a cholecystotomy drain placed by IR. During these procedures, he had gastric and duodenal biopsies, along with supraclavicular lymph node excision consistent with poorly differentiated carcinoma, with hepatoid features dispersed in signet ring adenocarcinoma cells. Upper endoscopy showed gastric and duodenal ulcers, which were biopsied, and immunohistochemical stains returned positive for adenocarcinoma.

Results: There is no proven chemotherapy for hepatoid adenocarcinoma and treatment decision is usually based on the evidences from case reports and case series. Patient was treated with chemotherapy including FLOT (docetaxel, oxaliplatin, and fluorouracil/leucovorin) and Trastuzumab.

Conclusions: HAC is a highly aggressive tumor that portends a poor prognosis with short median overall survival time (6 months), and low three-year survival rate (22.6%) . It typically originates from endodermal and urogenital mucosal cells. The most commonly involved primary organs include stomach, ovaries, lungs, bladder, pancreas, and uterus. The nomenclature was derived from the morphologic similarity to hepatocellular carcinoma. HAC is challenging to differentiate from HCC morphologically as many patients present with liver metastases. Like HCC, cells of HAC are immunoreactive with AFP, polyclonal carcinoembryonic antigen, cytokeratin-8 and cytokeratin-18. The characteristic feature of these adenocarcinomas is hepatoid differentiation of cancer cells and the characteristic production of large amounts of AFP. All HAC does not produce AFP and about 46% of HAC demonstrate negative AFP levels by IHC staining, however our case was focally positive for AFP. This case report represents one of the youngest patients known in the literature with hepatoid adenocarcinoma.

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References: 1. Inagawa S, Shimazaki J, Hori M, Yoshimi F, Adachi S, Kawamoto T, Fukao K, Itabashi M. Hepatoid

adenocarcinoma of the stomach. Gastric Cancer. 2001;4:43–52. [PubMed]2. Shen Z, Liu X, Lu B, et al. Hepatoid adenocarcinoma of the stomach: A case report of a rare type

of gastric cancer. Oncol Lett, 2016,11(2):1077–10803. Zeng XY1, Yin YP1, Xiao H2, Zhang P1, He J3, Liu WZ1, Gao JB1, Shuai XM1, Wang GB1, Wu

XL4, Tao KX5. Clinicopathological Characteristics and Prognosis of Hepatoid Adenocarcinoma of the Stomach: Evaluation of a Pooled Case Series. Curr Med Sci. 2018 Dec;38(6):1054-1061. doi: 10.1007/s11596-018-1983-1. Epub 2018 Dec 7.

4. Min-Feng Ye, Feng Tao, Fang Liu, and Ai-Jing Sun. Hepatoid adenocarcinoma of the stomach: A report of three cases. World J Gastroenterol. 2013 Jul 21; 19(27): 4437–4442. Published online 2013 Jul 21. doi: [10.3748/wjg.v19.i27.4437]


Conclusions: Our study suggests that nivolumab can be relatively effective and safe strategy as both 2nd and 3rd line therapy in HCC patients refractory for sorafenib treatment. A further well controlled, large scaled study to prove survival benefit is recommended.


P-218 HOW TO IMPROVE RESPONSE TO SORAFENIB? A SINGLE TERTIARY CENTER EXPERIENCE

Yoram Menachem* 1, Reicher Reli1, Oren Shibolet1

1Hepatology unit, Tel Aviv Sourasky Medical Center, Tel-Aviv, Israel

Introduction: Sorafenib is a first-line systemic therapy for advanced HCC. Its approval and use were based on the SHARP and Asia-Pacific trials. These pivotal trials and additional real-world data had also shown significant side-effect profile that may disrupt treatment time due to intolerance.

Methods: The cohort included advanced HCC patients treated with Sorafenib from 2015 to 2019. Evaluation, treatment, and follow up were conducted by a dedicated MDT. Data included demographics, liver disease characteristics including CPS, tumor characteristics including BCLC, duration of treatment, cause for cessation and reported adverse effects. The patients were assessed periodically by CT/MRI and AFP levels for disease progression/stability. Overall survival was calculated from the time of Sorafenib initiation and cases were censored at the date of last follow up. Kaplan-Meier curves were used to evaluate the prognostic significance of various clinical variables.

Results: 27 patients that were treated with Sorafenib. Mean dose was 600 mg/d. Patients were evaluated weekly by a dedicated oncology-nurse and monthly by hepatologist-oncologist team. 23 out of 27 patients (85%) were males with an average age at diagnosis of 63.7 years (range 31-80). 74% of patients underwent previous treatments for HCC. Fourteen (52%) had loco-ablative therapies, seven patients (26%) underwent an operation and three (11%) underwent external radiotherapy. One patient underwent OLT. Seven patients (26%) were treated with Sorafenib as first-line treatment for HCC. 11/27 patients (41%) were graded BCLC B and sixteen patients (59%) were graded BCLC C. All patients were CPS A at time of Sorafenib treatment initiation. The etiology for liver disease was HCV infection in 13 of patients (48%), NASH in nine (33%), and HBV in four (15%). One patient had Fibrolamellar HCC. 17 out of 27 patients (63%) had extrahepatic spread. Concordance between radiologic response and biochemical response was good. 22 out of 27 patients (81%) had elevated AFP levels at presentation, of which seven (32%) responded to Sorafenib treatment with declining levels of AFP (biochemical response) and with radiological response as well. 14/22 patients with elevated AFP had a level >400 IU/ml, of which only 4 patients responded to Sorafenib. Radiological response was demonstrated in 10/27 patients (37%), with or without elevated AFP. Side effects occurred in almost all patients treated with Sorafenib (26/27), with subjective weakness and weight loss being the most prevalent, affecting 44% and 37% of patients respectively. Ten patients (37%) were affected by Hand-Foot-Skin-Reaction (HFSR). Diarrhea, neutropenia and hypertension were experienced by 2 patients each (7%). Seventeen patients (63%) had grade 1-2 side effects while ten (37%) experienced grade 3-4 adverse effects. Eventually the reason for Sorafenib treatment cessation was HCC progression and/or cirrhosis decompensation in sixteen patients (59%), and treatment intolerance in three (11%). Eight patients (30%) are on active Sorafenib treatment according to last follow up.

Conclusions: Sorafenib is a well-known treatment option for advanced HCC patients. When choosing carefully and monitoring them well, we demonstrate a 32% biochemical response and a 37% radiological (with good concordance), far more than the accepted 10-15%. Moreover, AFP levels of more than 400 IU/ml were considered to predict a negative response to Sorafenib. Only a minority of our patients stopped treatment due to intolerance, and it could be related to the close surveillance that they experienced.


P-219 A CASE OF HEPATOID ADENOCARCINOMA PRESENTING AS ACUTE PANCREATITIS AND ELEVATED AFP AND B-HCG- FIRST REPORTED CASE OF HEPATOID ADENOCARCINOMA IN A VICENARIAN

Rahul B. Chaudhari* 1, Frederick A. Nunes1, Mitul Modi1, Patricia Ford1

1Medicine, University of Pennsylvania Health System, Philadelphia, United States

Introduction: Hepatoid adenocarcinoma (HAC) is a rare and extremely aggressive type of adenocarcinoma and the reported incidence is approimately 0.38–0.73%. It is morphologically similar to hepatocellular carcinoma (HCC) due to the presence of hepatoid features in the adenocarcinoma cells and is challenging to differentiate from HCC. Mutation and amplification in HER2 gene along with p53 mutation, has been proposed as the etiology of this rare tumor. The diagnosis is usually made by H&E and immunohistochemical staining and is usually difficult due to its close resemblance to HCC. This carcinoma usually involves elderly with the reported median age of 65.5. The reported presenting symptoms include upper abdominal pain, hemetemesis, back pain,

20. Ishizawa T, et al: Neither multiple tumors nor portal hypertension are surgical contraindications for hepatocellular carcinoma, Gastroenterology: 134(7):1908–1916, 2008.

21. Torzilli G, et al: Hepatectomy for stage B and stage C hepatocellularcarcinoma in the Barcelona Clinic Liver Cancer classification: results of a prospective analysis, Arch Surg 143(11):1082–1190, 2008.

22. Torzilli G, et al: A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations? An observational study of the HCC East-West study group, Ann Surg 257(5):929–937, 2013.

23. Inoue Y, et al: Is there any difference in survival according to the portal tumor thrombectomy method in patients with hepatocellular carcinoma?, Surgery 145(1):9–19, 2009.

24. Llovet JM, et al: SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma, N Engl J Med 359(4):378–390, 2008

25. Kokudo T, et al: Surgical treatment of hepatocellular carcinoma associated with hepatic vein tumor thrombosis, J Hepatol 61(3):583–588,2014.

26. Parikh ND, et al: Downstaging hepatocellular carcinoma: A systematic review and pooled analysis, Liver Transpl. 2015 Sep;21(9):1142-52.

27. Han K, et al: Transarterial chemoembolization in hepatocellular carcinoma treatment: Barcelona clinic liver cancer staging system, World J Gastroenterol. 2015 Sep 28;21(36):10327-35.

28. Sapisochin G , et al: Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis. J Hepatol. 2017 Jul;67(1):92-99.

29. Kim JY, et al: Transcatheter arterial chemoembolization confers survival benefit in patients with a spontaneously ruptured hepatocellular carcinoma, Eur J Gastroenterol Hepatol 24:640–645, 2012.

30. Liao M, et al: Adjuvant transarterial chemoembolization for patients after curative resection of hepatocellular carcinoma: a meta-analysis. Scand J Gastroenterol. 2017 Jun - Jul;52(6-7):624-634.

31. Xu XL, et al: Radiofrequency Ablation versus Hepatic Resection for Small Hepatocellular Carcinoma: Systematic Review of Randomized Controlled Trials with Meta-Analysis and Trial Sequential Analysis. Radiology. 2018 May;287(2):461-472.

32. Fan ST, et al: Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths, Ann Surg 229(3):322–330, 1999.

33. Jarnagin WR, et al: Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade, Ann Surg 236(4):397–406, discussion 406-407, 2002.

34. European Association for the Study of the Liver; European Organization for Research and Treatment of Cancer: EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma,J Hepatol 56(4):908–943, 2012

35. Reig M, et al: Systemic therapy for hepatocellular carcinoma: the issue of treatment stage migration and registration of progression using the BCLC-refined RECIST, Semin Liver Dis 34(4):444–455,201.


P-217 NIVOLUMAB (ANTI PROGRAMMED DEATH 1 INHIBITOR) IN PATIENTS WITH PROGRESSION AFTER SORAFENIB CAN BE EFFECTIVE AS BOTH GROUP (2ND LINE AND 3RD LINE)

Sang Youn Hwang* 1, Jung Woo Im1, Seon Mi Lee1, Ki Jung Jeon1

1Internal Medicine, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea, Republic Of

Introduction: Nivolumab (anti PD-1 inhibitor) is approved as second line therapy in patients with progression after sorafenib in hepatocellular carcinoma (HCC) patients, however the study about efficacy of nivolumab as third line therapy. We aimed to evaluate the efficacy and safety of nivolumab in patients with advanced HCC with progressive disease after sorafenib therapy; 2nd line (2L) vs 3rd line (3L)

Methods: Eligible advanced HCC patients with documented radiological evidence of disease progression with sorafenib treatment were recruited in our hospital from 2017 to 2018. All patients received nivolumab 240mg as fixed starting dose every 2 weeks for unlimited cycles untile radiologic progression. Response assessments using both RECIST and modified RECIST criteria were performed after 2 or 3 cycles of therapy

Results: Eleven patients (2L group; 4 patients, 3L group; 7 patients) were enrolled in the study. The median level of AFP was 2248 ng/mL (4.7-77705) in 2L group, 4957 ng/mL (2.2-60481) in 3L group, that of PIVKA was 94 mAU/Ml (6-24891) in 2L group, 7375 mAU/mL (14-81813) in 3L group and tumor markers in both groups were not different significantly (p-value=0.290). The median OS was 2 months (range 0.75-5) in 2L group, 3 months (range 0.75-12) in 3L group and the median PFS was 1.5 months (range 0.75-5) in 2L group, 1.5 months (range 0.75-4) in 3L group. The OS and PFS in IR group & PN group were not different significantly (OS; p-value=0.768, PFS; p-value=0.648). In 2L group, 1 patients achieved partial response (complete response in intrahepatic lesion), and 3 patients had progression disease (PD) and in 3L group, 1 patients had stable disease, 6 patients had PD. No adverse reaction was noted.

transarterial-chemoembolization (TACE), 6 patients(21.4%) with radiofrequency-ablation(RFA) and 3 patients(10.7%) with RFA and TACE combination. The percentage of conversion to resectable cancer after locoregional therapy was 9.68%. Considering survival, the 1year-, 3years-, and 5years survival rates were 87.5%, 56.3%, and 30.3% in the surgery group vs. 64.3%, 30.6%, and 6.4% in the locoregional treatment group. In the surgery group, the median overall survival of the patients treated with surgery alone was 16.04(0.66-24.62) months, compared with 42.23(26.27-54.35) months for the patients treated with surgery followed by locoregional therapy.

Image:

Conclusions: Despite being challenged by locoregional therapy, hepatic resection remains the gold standard, as it provides higher survival rates than locoregional therapy(p<0.05). Locoregional therapy following surgery, increases survival compared with patients treated with surgery alone (p=0.01), and thus defining its proper place in the management of these patients is critical.

References: 1. Ferlay J, et al: Cancer incidence and mortality worldwide: sources, methods and major patterns

in GLOBOCAN 2012, Int J Cancer136(5):E359–E386, 2014.2. Ferlay J, et al:, Cancer incidence and mortality patterns in Europe: Estimates for 40 countries

and 25 major cancers in 2018. European Journal of Cancer.3. Sandhu, D, et al: Treatment options for hepatocellular carcinoma. Expert Review of

Gastroenterology & Hepatology, 2(1), 81–92.4. El-Serag, H. B., et al: Hepatocellular Carcinoma. New England Journal of Medicine, 365(12),

1118–1127, 2011.5. Bruix J, Sherman M: Management of hepatocellular carcinoma. Hepatology 2005;42:1208–1236.6. Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology

2011;53:1020–1022.7. Gadaleta-Caldarola G, et al: Sorafenib: the gold standard therapy in advanced hepatocellular

carcinoma and beyond. Future Oncol. 2015;11(16):2263-6.8. Bruix J, et al: Regorafenib for patients with hepatocellular carcinoma who progressed on

sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Jan 7;389(10064):56-66.

9. Lee VH et al: Yttrium-90 radioembolization for advanced inoperable hepatocellular carcinoma. Onco Targets Ther. 2015 Nov 20;8:3457-64.

10. Lo CM, et al: Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma, Hepatology 35:1164–1171, 2002.

11. Llovet JM, et al: Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial, Lancet 359:1734–1739,2002.

12. Lewandowski RJ, et al: Chemoembolization for hepatocellular carcinoma: comprehensive imaging and survival analysis in a 172-patient cohort, Radiology 255:955–965, 2010.

13. Ryder SD: Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults, Gut 52(Suppl 3):iii1–iii8, 2003.

14. Delis SG, et al: Model for end-stage liver disease (MELD) score, as a prognostic factor for post-operative morbidity and mortality in cirrhotic patients, undergoing hepatectomy for hepatocellular carcinoma, HPB (Oxford) 11(4):351–357, 2009.

15. Sørensen JB, et al: Performance status assessment in cancer patients. An inter-observer variability study, Br J Cancer 67(4):773–775, 1993.

16. Forner A, et al: Current strategy for staging and treatment: the BCLC update and future prospects, Semin Liver Dis 30(1):61–74, 2010.

17. Wei AC, et al: Risk factors for perioperative morbidity and mortality after extended hepatectomy for hepatocellular carcinoma, Br J Surg: 90(1):33–41, 2003.

18. Kokudo N, et al: Evidence-based clinical practice guidelines for hepatocellular carcinoma: the Japan Society of Hepatology 2013 update (3rd JSH-HCC Guidelines), Hepatol Res 45(2), 2015.

19. Ho MC, et al: Liver resection improves the survival of patients with multiple hepatocellular carcinomas, Ann Surg Oncol 16:848–855,2009.

Posters Posters


Conclusions: These results suggest that regorafenib provides a clinically meaningful survival benefit to HCC patients suffering recurrence after LT as compared to the outcome of patients who discontinued sorafenib after radiologic progression under sorafenib. Hence, regorafenib appears as a safe and an efficacious second line option is this population where large scale trials are unfeasible.

Disclosure of Interest: M. Iavarone Conflict with: Bayer, Gilead Science, Janssen, BTG, Abbvie, MSD, Conflict with: BTG, F. Invernizzi: None Declared, S. Mazza: None Declared, C. Zavaglia: None Declared, C. Czauderna: None Declared, M. Sanduzzi Zamparelli Conflict with: Bayer, S. Bhoori Conflict with: Bayer, G. Amaddeo: None Declared, M. Manini: None Declared, M. Fraile Lopez: None Declared, M. Anders: None Declared, M. Pinter Conflict with: Bayer, BMS, Lilly, Conflict with: Bayer, BMS, Eisai, MSD, Conflict with: Bayer, BMS, Ipsen, Eisai, Lilly, M. J. Blanco Rodriguez: None Declared, M. R. Cristobal: None Declared, G. A. Soteras: None Declared, F. Pinero Conflict with: Bayer, G. E. Villadsen: None Declared, A. Weinmann Conflict with: Bayer, Leo Pharma, G. Crespo: None Declared, V. Mazzaferro Conflict with: Terumo, Ipsen, Conflict with: Terumo, Ipsen, H. Regnault Conflict with: BTG, M. De Giorgio: None Declared, M. L. Gonzalez Dieguez Conflict with: Abbvie, Novartis, Gilead, Conflict with: Gilead, M. F. Donato: None Declared, M. Varela Conflict with: Bayer, Conflict with: Bristol-Myers-Squibb, Sirtex, BTG, IPSEN and Bayer, M. Worns Conflict with: Abbvie, Bayer, Bristol-Myers Squibb, Celgene, Gilead, Incyte, Ipsen, MSD, Norgine, Conflict with: Abbvie, Bayer, Bristol-Myers Squibb, Eisai, Gilead, Ipsen, Norgine, Roche, J. Bruix Conflict with: Bayer, BTG, Conflict with: Bayer-Shering Pharma, BTG, Eisai, Terumo, Sirtex, Ipsen, Conflict with: Arqule, Bayer-Shering Pharma, Novartis, BMS, BTG-Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, Merck, Sirtex, Ipsen, Astra- Medimmune, Incyte, Quirem, Adaptimmune, Lilly, P. Lampertico Conflict with: Bristol-Myers Squibb, Roche, Gilead, GSK, AbbVie, MSD, Arrowhead, Alnylam, and Janssen, Conflict with: Bristol-Myers Squibb, Roche, Gilead, GSK, AbbVie, MSD, Arrowhead, Alnylam, and Janssen, M. Reig Conflict with: Bayer Shering Pharmaceuticals, Conflict with: Bristol Meyer Squibb, Eli Lilly, Gilead, Conflict with: Roche, Ipsen, Astrazeneca, Eli Lilly

P-224 OUTCOMES OF LIVER TRANSPLANTATION FOR NASH-ASSOCIATED HEPATOCELLULAR CARCINOMA

Matthew L. Holzner* 1, Parissa Tabrizian1, Sander Florman1, Myron E. Schwartz1

1Liver Cancer Program, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, United States

Introduction: Nonalcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is the second leading cause of liver transplantation (LT) done for HCC. Despite this, little is known about the clinical characteristics and post-transplant outcomes of NASH-HCC.

Methods: Patients who underwent LT for HCC from 2001 to 2017 were reviewed. Clinical characteristics and outcomes of NASH-HCC (n=51) were compared to other etiologies of HCC including hepatitis C (HCV; n=429), hepatitis B (HBV; n=104), and alcoholic liver disease (ALD; n=51). Outcomes of NASH-HCC were also compared to outcomes of HCV-HCC in the direct acting antiviral (DAA) era (2014-2017).

Results: Patients with NASH-HCC were significantly older (median age 65 vs. 60 years, P<0.001), more likely to be White (54.5% vs. 38.9%, P=0.025), and more likely to have a maximum pre-transplant AFP <20 (78.4% vs. 42.1%, P<0.001) compared to other etiologies of HCC. The 1-, 3-, and 5-year survival of NASH-HCC was 92%, 86%, and 80%, respectively. There were no significant differences in pre-transplant tumor characteristics between the NASH-HCC and the other causes of HCC. On explant, NASH-HCC demonstrated more viable tumors but had similar maximum tumor dimeter and tumor features compared to the non-NASH group (Table 1). Overall survival of NASH-HCC was not significantly different compared to HCV (P=0.055), HBV (P=0.064), or ALD (P>0.99) (Figure 1). Tumor recurrence was similar among the different etiologies of HCC (P=0.345). Underlying NASH was not predictive of survival or tumor recurrence. Compared to HCV-associated HCC in the DAA era, NASH-HCC had comparable post-LT survival (3-year survival 87% vs. 86%, P=0.870) (Figure 2).

TABLE 1. Clinicopathologic Characteristics

Characteristic NASH (n=51) Non-NASH (n=584) P

Within Milan criteria at diagnosis 43 (84.3) 485 (83.8) 0.919

Maximum pre-LT AFP <20 40 (78.4) 246 (42.1) <0.001

Pretransplant MELD 15 (11-21) 13 (9-18) 0.021

Number of viable tumors 3 (1-4) 1 (1-3) <0.001

Maximum viable tumor diameter, cm 2 (1.4-3) 2.1 (1.1-3) 0.084

Poor tumor differentiation 5 (9.8) 53 (9.1) 0.396

Vascular invasion (micro or macro) 22 (43.1) 262 (45) 0.934

1Division of Gastroenterology and Hepatology, CRC a.M. e a. Migliavacca Center for Liver Diseases Fondazione Irccs Ca’ Granda Ospedale Maggiore Policlinico, Università Degli Studi Di Milano, Milan, Italy, 2Asst Grande Ospedale Metropolitano Niguarda Gastroenterology and Hepatology , Milan, Italy, 3University Medical Centre of the Johannes Gutenberg-University, Mainz, Germany Department of Internal Medicine I, Mainz, Germany, 4Hospital Clínic, Idibaps, Ciberehd, University of Barcelona, Spain Barcelona Clinic Liver Cancer (BCLC) Group. Liver Unit , Barcelona, Spain, 5Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy G.I. Surgery and Liver Transplantation Unit, Milan, Italy, 6Hopital Henri Mondor, Equipe 18, Inserm U955, Virus Immunité Cancer, Créteil, France Service d’Hepatologie, Creteil, France, 7Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy Gastroenterology, Hepatology and Transplant Unit, Departement of Specialty and Transplant Medicine, Bergamo, Italy, 8Hospital Universitario Central De Asturias, Oviedo, Spain Liver Unit, Oviedo, Spain, 9Hospital Aleman, Buenos Aires, Argentina Unidad De Hepatología y Trasplante Hepático, Buenos Aires, Argentina, 10Medical University of Vienna, Austria Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Vienna, Austria, 11Hospital De Jerez, Spain, Jerez, 12Gregorio Marañón Hospital, Madrid, Spain Liver Department, Madrid, Spain, 13Sanatorio De La Trinidad Mitre, Argentina, 14Hospital Universitario Austral, School of Medicine. Argentina. Latin American Liver Research Educational and Awareness Network (Lalrean), Argentina, Argentina, 15Aarhus University Hospital, Aarhus C, Denmark Department of Hepatology and Gastroenterology, Aarhus, Denmark, 16Hospital Clínic, Idibaps, Ciberehd, University of Barcelona, Spain Liver Transplant Unit, Liver Unit, Barcelona, Spain, 17Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy, 18CRC a.M. e a. Migliavacca Center for Liver Diseases Fondazione Irccs Ca’ Granda Ospedale Maggiore Policlinico, Università Degli Studi Di Milano, Milan, Italy Division of Gastroenterology and Hepatology, Milan, Italy

Introduction: We have recently shown the safety and applicability of regorafenib (REGO) as second-line treatment for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). The aim of this study was to evaluate the impact of REGO on overall survival (OS) and describe the outcome of REGO-treated patients compared to best supportive care (BSC), in two cohorts of liver-transplanted sorafenib-treated patients with HCC recurrence after LT

Methods: The active cohort (multicentric study) included 28 LT-patients treated with regorafenib after HCC progression under sorafenib (SOR) treatment. The control cohort (Milan cohort) included 40 patients receiving BSC after SOR-discontinuation since REGO was not yet available: 21 were excluded due to SOR-intolerance and 19 were finally analysed (SOR-tolerant progressors). Disease outcome was investigated in terms of OS from SOR-discontinuation.

Results: At SOR-discontinuation, the two groups were comparable (Table 1). All the 28 patients treated with REGO (treatment duration 6.3 months) had at least 1 adverse event patients (grade 3/4: fatigue in 7 and dermatological reaction in 5). Median follow-up (in months) since SOR-discontinuation was 13.2 (2.0-44.3) for the multicentric-cohort and 4.5 (0.6-22.3) for the Milan-cohort (p=0.004). At data-lock, 64% patients had died in the REGO-cohort and 100% in the BSC-cohort. Symptomatic tumor progression was the main cause of death. The median OS from SOR-discontinuation was 13.4 mos (95%CI:0.31-0.68) for the REGO-group compared to 4.79 mos (95%CI:0.20-0.62) for the BSC-group (p=0.0003). Moreover, the OS from SOR-start was 27.26 mos (95%CI:0.34-0.71) for the SOR-REGO sequence compared to 18.68 mos (95%CI:0.20-0.62) for the SOR-BSC sequence (p=0.0012). Finally, excluding those patients with a survival ≤60 days after SOR-discontinuation in both groups, the OS in the 27 patients treated with REGO was 13.4 mos (95%CI:0.33-0.70) vs 9.37 mos (95%CI:0.18-0.66) for the 14 patients in control group (p=0.004).

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P-222 A NEW PROTOCOL OF GADOXETIC ACID-ENHANCED LIVER MAGNETIC RESONANCE IMAGING MINIMIZES RESPIRATORY ARTIFACT AND IMPROVE IMAGE QUALITY

Celia del Caño* 1, Debora Vizcaino2, Rafael Menéndez de Llano2, Alicia Mesa2, Andrés Castaño1, Carmen Alvarez-Navascués1, Maria Luisa González-Diéguez1, Valle Cadahia1, Lissa Franco1, Manuel Rodríguez1, Maria Varela1

1Liver Unit, 2Radiology, Hospital Universitario Central De Asturias, Oviedo, Spain

Introduction: The aim of the study were to objectively evaluate the artifacts after contrast injection and to assess its potential impact on image quality in gadoxetic acid-enhanced magnetic resonance imaging performed under a double arterial phase protocol.

Methods: From Dec 12th 2017 to Jul 19th 2018 consecutive patients were submitted to characterize focal liver lesions by using gadoxetic acid enhanced-liver-MRI (0.025 mmol/Kg at 1.5 mL/sec followed by 25 mL of saline flush intravenously), with double arterial phase at a 3 Tesla equipment. The acquisition of the double arterial phase was performed with bolus detection system in the aorta, delay of 5 seconds and sustained inspiration (2 acquisitions in a single apnea of 16-20 seconds). The studies were independently reviewed by 2 radiologists with experience in liver pathology and a scale of 0 to 3 was established (0: no artifact, 1: minimum, 2: quite a lot and 3: not evaluable) depending on the quality of the images obtained. The presence of arterial enhancement of focal liver lesions was also assessed in each of the two phases.

Results: 81 patients / 89 studies: 64% men, median age 63 years, 28 studies in obese patients (BMI > 30 Kg/m2), 30 in patients with cirrhosis [17 alcohol, 6 hep C, 3 hep B, 3 NAFLD, 1 Wilson, 2 cholestatic; median elastography 24.9 Kpa (IQR 14.7-36.2). Child Pugh 5, MELD 9]. Concordance between both observers in the assessment of respiratory artefact was very good (Kappa Index > 0.81). 86% of the studies have no artefact or it was minimal in the first arterial phase. In the second arterial phase, the percentage improved to 98.9%. The arterial phase 2 increased no-artefact-studies (grade 0) from 55 to 81 (30%). There were 8 studies in which enhancement was observed only in the arterial phase 2, that meant an increase in the detection of hyperenhanced lesions by 10%.

Conclusions: The acquisition with double arterial phase decreased the number of invalid studies due to transient respiratory artefact and increased the sensitivity in the detection of hypervascular lesions, independently of obesity or liver dysfunction.

Disclosure of Interest: C. del Caño: None Declared, D. Vizcaino: None Declared, R. Menéndez de Llano Conflict with: BAYER, A. Mesa: None Declared, A. Castaño: None Declared, C. Alvarez-Navascués: None Declared, M. L. González-Diéguez: None Declared, V. Cadahia: None Declared, L. Franco: None Declared, M. Rodríguez: None Declared, M. Varela Conflict with: Bayer, Ipsen, BTG, Gilead, BMS

P-223 TREATMENT OF RECURRENT HEPATOCELLULAR CARCINOMA AFTER LIVER TRANSPLANTATION: REGORAFENIB PROVIDES SURVIVAL BENEFIT AS COMPARED TO BEST SUPPORTIVE CARE

Massimo Iavarone* 1, Federica Invernizzi1, Stefano Mazza1, Claudio Zavaglia2, Carolin Czauderna3, Marco Sanduzzi Zamparelli4, Sherrie Bhoori5, Giuliana Amaddeo6, Matteo Manini7, Miguel Fraile Lopez8, Margarita Anders9, Matthias Pinter10, Maria Jose Blanco Rodriguez11, Mario Romero Cristobal12, Gabriel Aballay Soteras13, Federico Pinero14, Gerda Elisabeth Villadsen15, Arndt Weinmann3, Gonzalo Crespo16, Vincenzo Mazzaferro17, Helene Regnault6, Massimo De Giorgio7, Maria Luisa Gonzalez Dieguez8, Maria Francesca Donato18, Maria Varela8, Marcus Worns3, Jordi Bruix4, Pietro Lampertico1, Maria Reig4

P-220 CLAUSENIDIN INDUCES A G0/G1 AND G2/M CELL CYCLE ARREST IN HEPG2 CELLS

Peter M. Waziri* 1, Rasedee Abdullah2, Jemimah Saidu1

1Biochemistry, Kaduna State University, Kaduna, Nigeria, 2Veterinary microbiology, University of Putra Malaysia, Selangor, Malaysia

Introduction: Clausena excavata Burm f. is a medicinal shrub from the Rutaceae family that is commonly used in Malaysia and Thailand for the treatment of cancers. The use of this plant in traditional medicine is based on hearsay and previous experience and with little or no scientific evidence supporting its therapeutic uses. Clausenidin is one of the compounds identified as an anti-cancer agent that contributes to the therapeutic effect of C. excavata. Therefore, the current study aims to evaluate the mechanism of action of clausenidin on liver (HepG2) cells

Methods: Clausenidin was isolated and characterized in our previous study. The IC50 of the pure clausenidin crystals at 72 hours was determined via cell viability assay. We also carried out cell cycle assay and gene expression studies in the clausenidin-treated HepG2 cells.

Results: Clausenidin induced a G0/G1 and G2/M cell cycle arrest in the HepG2 cells. The percentage of cells in the resting G0/G1 phase decreased significantly (p<0.05) while there was significant (p<0.05) increase in the proportion of apoptotic cells with clausenidin treatment. Clausenidin treatment significantly increased the expression of cyclin D, p21 and p53 mRNAs. The p53-dependent activation of p21 gene is presumed to be responsible for the cell cycle arrest observed at the G0/G1 phase of cell cycle. The cell cycle arrest halted the proliferation of the HepG2 cells and ultimately led to apoptotic cell death as observed in proportion of cells in the sub G0/G1 phase after 72 hours

Conclusions: Clausenidin can be potentially used for the treatment of liver cancer

References: 1. Arbab, I. A., Abdul, A. B., Sukari, M. A., Abdullah, R., Syam, S., Kamalidehghan, B., Ibrahim, M. Y.,

Taha, M. M. E., Abdelwahab, S. I. and Ali, H. M. (2013). Dentatin isolated from Clausena excavata induces apoptosis in MCF-7 cells through the intrinsic pathway with involvement of NF-κB signalling and G0/G1 cell cycle arrest: a bioassay-guided approach. Journal of Ethnopharmacology, 145, 343-354.

2. Waziri, P. M., Abdullah, R., Yeap, S. K., Omar, A. R., Kassim, N. K., Malami, I., How, C. W., Etti, I. C. and Abu, M. L. (2016a). Clausenidin induces caspase-dependent apoptosis in colon cancer. BMC Complementary and Alternative Medicine, 16, 256


P-221 FEASIBILITY AND EFFICACY OF RADIOFREQUENCY-ASSISTED ALPPS UNDER LAPAROSCOPY IN PATIENTS WITH LIVER TUMORS

Zhe Tang* 1, Kezhong Tang1

1The second affiliated hospital of zhejiang university, Hangzhou, China

Introduction: It‘s still controversial about associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) because of high morbidity and mortality. To overcome the shortage of ALPPS, a modification of ALPPS (radiofrequency-assisted ALPPS under laparoscopy, L-RALPPS) were evaluated in patients with liver tumors in the study.

Methods: Patients diagnosed with liver tumors and considered to have insufficient future liver remnant (FLR) were contained in the study, including 7 patients with Hepatocellular carcinoma, 1 patient with intrahepatic cholangiocarcinoma, and 1 with colon carcinoma liver metastasis. In stage I, radiofrequency ablation was used to form a coagulum avascular area along the planned resection plane pre-operation. One of the main branch of portal vein was ligated depending on the location of tumors. When the FLR reached above 0.8% of patients’ weight, we performed hepatectomy in stage II along the coagulum area. Changes of liver function, operative morbidity, mortality, increase of FLR, operative time and blood loss were obtained in the study.

Results: 9 patients with liver tumors were treated with L-RALPPS from May 2017 to September 2018. The median FLR before stage I was 30%, which increased to 46% before stage II after a median interval of 34 days. The median operative time was 178 min in stage I and 330 min in stage II. The median blood loss was 50 mL in stage I and 800 mL in stage II. There were no severe complications (Clavien-Dindo ≥IIIb) in stage I. 3 patients failed to receive operation after stage I because of intrahepatic metastasis. The incidence of severe complications was 33.3% (2/6) with one biliary leakage and one post-hepatectomy liver failure (PHLF).

Conclusions: L-RALPPS has a significant advantage in serious complications, operative time and blood loss compared with classic ALPPS, especially in stage I. At the same time, L-RALPPS can achieve a similar effect of increase of FLR with a longer interval time.

Authors Index

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 1 1 3

Name Abstract Name Abstract

Posters

I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S 1 1 2

Image:

Conclusions: In this large single-center experience of NASH-HCC, we demonstrates that NASH-HCC has favorable outcomes following LT comparable to other common etiologies of HCC.


P-225 CLINICAL CHARACTERISTICS AND SURVIVALS IN HUGE(≥8CM) ADVANCED HEPATOCELLULAR CARCINOMA

Min Woo Chung* 1, Dae Seong Myung1, Chung Hwan Jun1, Sung Bum Cho1, Wan Sik Lee1, Young Eun Joo1, Sung Kyu Choi1

1Internal Medicine, Chonnam National University Medical School, Gwangju, Korea, Republic Of

Introduction: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality and has a very poor prognosis, especially if it is not curable by ablation or resection. Many staging systems exist, and each of them has limitations. BCLC (Barcelona clinic liver cancer) staging system is the most widely used, but there is no mention of the size of HCC. Clinically, huge HCC (≥8cm) is often encountered and in the case of a single large cancer, there is a treatment of choice which is surgical resection. However, when it is not resectable by surgery, the prognosis and treatment methods of huge HCC are rarely studied.

Methods: The clinical characteristics of the patients diagnosed with huge HCC (largest size is more than 8cm) in advanced or terminal stage (BCLC C or D) were reviewed, retrospectively. In one tertiary medical center in South Korea, 4,513 patients diagnosed with HCC from 2011 to 2012 were screened and 370 patients had HCC of more than 8cm in size. 29 patients whose survival could not be confirmed were excluded and total 341 patients were analyzed.

Results: Mean survival of 341 patients was 9.1 months and median survival was 4 months, which showed very poor prognosis. Among them, 78 patients survived for more than one year, of which 41 patients were treated with transarterial chemoembolization (TACE), 10 were sorafenib, 4 were hepatic arterial infusion chemotherapy (HAIC), and 10 patients were treated with best supportive care. Although not statistically significant, TACE group showed better outcome compared to sorafenib group in trend.

Conclusions: Patients with huge HCC had a very poor prognosis (especially median survival), compared to those in same BCLC stage. In these patients, TACE seems to be preferred as a first-line treatment and the treatment response rate seemed to have better outcome, but further studies are needed.


Abbati, Francesca ............................................................................................................ P-211Abdel-Rahman, Mohamed ..................................................................................... P-095, P-125Abdullah, Heba ..................................................................................................................O-32Abdullah, Rasedee ........................................................................................................... P-220Abedi-Ardekani, Behnoush ............................................................................................... P-204Abou-Alfa, Ghassan ................................................................................................O-14, P-029Abreu, Phillipe ...........................................................................................P-042, P-086, P-138Abugabal, Yehia .................................................................................................................O-02Acevedo-Moreno, Lou-Anne .................................................................................. P-045, P-149Acosta-López, Silvia .............................................................................................. P-143, P-148Acosta-Rivera, Mirelis.........................................................................................................O-13Adam, Rene .......................................................................................................... P-073, P-176Agopian, Vatche ......................................................................................................O-18, P-091Ahn, Keun Soo ...................................................................................................... P-096, P-179Ahn, Sang Hoon ..............................................................................P-074, P-117, P-136, P-187Ahsen, Mehmet ............................................................................................................... P-010Ajmera, Veeral ................................................................................................................ P-014Akamatsu, Nobuhisa ........................................................................................................ P-106Akarca, Ayse .................................................................................................................... P-071Akers, Nicholas ............................................................................................................... P-034Akiba, Jun .........................................................................................................................O-33Alban, Tyler ...................................................................................................................... P-149Albenmousa, Ali .................................................................................................... P-137, P-167Albillos, Agustin ............................................................................................................... P-036Alencar, Regiane .............................................................................................................. P-185Alexopoulos, Sophoclis .......................................................................................................O-16Alhamoudi, Waleed .......................................................................................................... P-137Al-Hamoudi, Waleed ......................................................................................................... P-167Alkhouri, Naim ................................................................................................................. P-014Allard, Marc Antoine ......................................................................................................... P-176Allegra, Sarah ....................................................................................................................O-33Allende, Daniela .................................................................................................... P-045, P-149Allette, Kimaada ............................................................................................................... P-010Allison, James ...................................................................................................................O-02Aloia, Thomas ....................................................................................................................O-02Aloman, Costica ............................................................................................................... P-203Alonso, Cristina ..................................................................................................................O-28Al-osaimi, Abdullah .......................................................................................................... P-167Alqahtani, Saleh .............................................................................................................. P-167Alsina, Angel ......................................................................................................... P-020, P-029Alsuhaibani, Hamad ......................................................................................................... P-167Álvarez-Navascués, Carmen .................................................................................. P-067, P-132Alves, Venancio ..................................................................................................................O-09Amaddeo, Giuliana ................................................................................................ P-025, P-052Amemiya, Fumitake.......................................................................................................... P-046Amorim, Nadia ...................................................................................................................O-30An, Jihyun ....................................................................................................................... P-018Anders, Margarita ......................................................................................P-026, P-048, P-134Andersen, Jesper .......................................................................................... O-05, O-28, P-051Anderson, Jeffrey ....................................................................................................O-13, P-016Ando, Masaharu .............................................................................................................. P-206Andreu-Oller, Carmen .........................................................................................................O-09Andrikou, Kalliopi ............................................................................................................. P-199Arai, Makoto ......................................................................................................... P-039, P-061Arai, Yasuaki .................................................................................................................... P-131Araya, Juan ..................................................................................................................... P-051Ardalani, Hamisha ............................................................................................................ P-090Arenas, Isabel .................................................................................P-026, P-048, P-089, P-134Arenas, Juan Ignacio ........................................................................................................ P-070Argemi, Josepmaria ......................................................................................................... P-005Arita, Junichi ................................................................................................................... P-106Armengol, Carolina ........................................................................................................... P-034Arrese, Marco .................................................................................................................. P-194Arretxe, Enara ....................................................................................................................O-28Arufe, Diego ......................................................................................................... P-089, P-134Asgharpour, Amon ............................................................................................................ P-010Ashraf, Taha .................................................................................................................... P-063Assenat, Eric ................................................................................................................... P-066Astorgues-Xerri, Lucile .......................................................................................... P-181, P-183Athanasiadis, Dimitrios .......................................................................................................O-16Athanasiadou, Eleni .......................................................................................................... P-216Atorrasagasti, Catalina ..................................................................................................... P-005

Atsukawa, Masanori ......................................................................................................... P-039Aubuchon, Sean.................................................................................................................O-19Aucejo, Federico ................................................................................................... P-045, P-149Audureau, Etienne ..............................................................................................................O-03Augustine, Mathew ......................................................................................................... P-084Avellini, Claudio................................................................................................................ P-071Avril, Norbert.................................................................................................................... P-113Awa, Jallow ..................................................................................................................... P-204Ayoub, Walid .................................................................................................................... P-088Ayuso, Carmen ................................................................................................................ P-047Azad, Adiba ..................................................................................................................... P-003Azemoto, Ryosaku ............................................................................................................ P-039Azzam, Hanan .................................................................................................................. P-213Bae, Si Hyun ...................................................................................P-085, P-144, P-161, P-190Bae, Sun Hyun ................................................................................................................. P-035Bah, Yusupha .................................................................................................................. P-204Bai, Dou-Sheng................................................................................................................ P-140Baiev, Islam ..................................................................................................................... P-142Baio, Gianluca .................................................................................................................. P-021Balderramo, Domingo ....................................................................................................... P-194Balmer, Matias ................................................................................................................. P-089Banales, Jesus........................................................................................................O-28, P-194Bañares, Rafael ............................................................................................................... P-036Bane, Abate ..................................................................................................................... P-201Bao, Yongxing .................................................................................................................. P-159Barrabino, Martín ............................................................................................................. P-026Barry, Anna ...................................................................................................................... P-121Bartlet, Adam ................................................................................................................... P-174Bassaganyas, Laia ........................................................................................................... P-006Bastian, Ingmar ................................................................................................................ P-002Basu, Bristi ........................................................................................................................O-23Bauer, Kelly...................................................................................................................... P-142Bayard, Quentin ............................................................................................................... P-069Bayh, Inga ....................................................................................................................... P-037Bayik, Defne .................................................................................................................... P-149Bayo, Juan ...................................................................................................................... P-005Beaufrère, Aurélie ..............................................................................................................O-22Beecroft, Robert .............................................................................................................. P-138Beg, Muhammad ..............................................................................................................O-27Behary, Jason ....................................................................................................................O-30Beltrán, Oscar .................................................................................................................. P-026Belz, Christine .................................................................................................................. P-083Bemanian, Amin ............................................................................................................... P-158Ben Bouallègue, Fayçal .................................................................................................... P-025Benzaghou, Fawzi ........................................................................................................... P-072Bergeat, Damien .............................................................................................................. P-068Bermejo, Justo ................................................................................................................. P-051Bermúdez, Carla .............................................................................P-026, P-048, P-089, P-134Bes Maijo, Marta ............................................................................................................. P-083Besa, Cecilia ......................................................................................................................O-04Beyer, Kirsten................................................................................................................... P-158Bhat, Mamatha .................................................................................................... P-042, P-138Bhatt, Deepak .................................................................................................................. P-051Bilbao, Itxarone ................................................................................................................ P-057Bilbao, Jose Ignacio ......................................................................................................... P-070Bioulac-Sage, Paulette ..................................................................................................... P-069Bittaye, Sheikh ................................................................................................................. P-204Bizzari, Jean-Pierre .......................................................................................................... P-182Black, James ................................................................................................................... P-019Blanc, Jean-Frederic ..............................................................................................O-14, P-021Blando, Jorge ....................................................................................................................O-02Blum, Steven ................................................................................................................... P-016Bocobo, Andrea ............................................................................................................... P-142Boffetta, Paolo ...................................................................................................................O-09Boin, Ilka ........................................................................................P-026, P-048, P-089, P-134Boland, Jade.................................................................................................................... P-104Boldorini, Renzo ............................................................................................................... P-019Bonnin, Philippe ............................................................................................................... P-100Boonstra, Andre .................................................................................................... P-099, P-194Borgman, Anne ............................................................................................................... P-072Bouattour, Mohamed ..........................................................................................................O-01Boudjema, Karim ............................................................................................................. P-068

Authors Index Authors Index

B O O K O F A B S T R A C T S - I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 1 1 5I L C A A N N U A L C O N F E R E N C E , 2 0 1 9 - B O O K O F A B S T R A C T S1 1 4

Name Abstract Name AbstractName Abstract Name Abstract

de Felício, Helen .............................................................................................................. P-197de Gramont, Armand ........................................................................................................ P-100de Koning, Leanne ........................................................................................................... P-069De La Torre, Manuel ...................................................................................P-047, P-070, P-108de Navarro Armando, Leandro .......................................................................................... P-048Dean, Michael .................................................................................................................. P-051Debes, Jose ...............................................................................................P-099, P-194, P-201Deng, Jing ....................................................................................................................... P-001Deng, Yangyang .................................................................................................................O-19Desbois-Mouthon, Christèle ...............................................................................................O-08Dhanasekaran, Renumathy ............................................................................................... P-014Dhillon, Dilshan ................................................................................................................ P-011Di Tommaso, Luca ..............................................................................................................O-33Díaz Bethencourt, Dacil ......................................................................................... P-143, P-148Díaz Beveridge, Roberto ................................................................................................... P-157Dieterich, Douglas ............................................................................................................ P-010Dinicola, Caroline ............................................................................................................. P-142Diot, Thomas .....................................................................................................................O-03Dogra, Navneet ................................................................................................................ P-010Dominguez, Dana ............................................................................................................. P-121Dominguez, Luciana ......................................................................................................... P-005Dommann, Noëlle ............................................................................................................ P-094Donadon, Matteo ...............................................................................................................O-33Dong, Haidong ................................................................................................................. P-008Dongfeng, Tan....................................................................................................................O-02Dou, Jianping ....................................................................................................... P-087, P-200Doxtader, Katelyn ............................................................................................................. P-118Doyle, Adam ................................................................................................................... P-138Du, Qiang ....................................................................................................................... P-093Duarte, Pablo ................................................................................................................... P-073Duarte-Rojo, Andres ......................................................................................................... P-014Dubrovsky, Leonid ............................................................................................................ P-195Duca, Willian .................................................................................................................... P-197Duclos Vallee, Jean Charles .............................................................................................. P-073Duffin, Bret ...................................................................................................................... P-090Dufour, Jean-François ........................................................................................................O-09Dumitru, Radu ................................................................................................................. P-196Dupuy, Evelyne................................................................................................................. P-100Dutcus, Corina ...........................................................................................P-020, P-029, P-195 Duvoux, Christophe .................................................................................................O-31, P-048Dweik, Raed .................................................................................................................... P-045Dyke, Alison ..................................................................................................................... P-051Ebbinghaus, Scot ...............................................................................................................O-01Edeline, Julien ................................................................................. O-01, P-025, P-068, P-139Ehsan, Nermine ............................................................................................................... P-180EI-Omar, Emad ................................................................................................................. P-104Eizaguirre, Emma ...............................................................................................................O-28EL.Gharabawy, Sahar ....................................................................................................... P-213El-Azab, Dina ................................................................................................................... P-095Elfakhry, Ashraf ................................................................................................................ P-213El-Goday, Shereen ............................................................................................................ P-125Elkhadragy, Lobna ............................................................................................................ P-007El-Khoueiry, Anthony ..................................................................................... O-13, O-14, P-016Elmer, Sidney .....................................................................................................................O-26El-Omar, Emad ...................................................................................................................O-30El-Rayes, Bassel .....................................................................................................O-13, P-016Elshimi, Esam ..................................................................... P-116, P-171, P-193, P-209, P-210Enomoto, Nobuyuki .......................................................................................................... P-046Erdman, Lauren .............................................................................................................. P-086Erinjeri, Joseph ................................................................................................................ P-131Escobedo-Calvario, Alejandro ............................................................................................ P-102Estambale, Benson .......................................................................................................... P-162Esteban-Fabró, Roger ....................................................................................................... P-006Esteller, Manel ................................................................................................................. P-009Estrade, Florian ................................................................................................................ P-139Eswaran, Sheila ................................................................................................... P-014, P-203Evangeliou, Alexandros .......................................................................................................O-16Evans, TR Jeffry ...........................................................................................O-23, P-020, P-029Eveno, Clarisse ................................................................................................................ P-100Factor, Valentina .................................................................................................................O-05Faivre, Sandrine .........................................................................................P-100, P-181, P-183Faloppi, Luca ..........................................................................................................O-15, P-199

Fan, Jia ....................................................................................................P-023, P-064, P-140Farazi, Paraskevi .............................................................................................................. P-147Farbstein, Motti ..................................................................................................................O-27Fatty, Gibril ...................................................................................................................... P-204Fauda, Martín ............................................................................................P-026, P-048, P-134Febles González, Ángel .................................................................................................... P-143Feng, Gen-Sheng ...............................................................................................................O-25Fernandez, Inmaculada .................................................................................................... P-036Ferreccio, Catterina .......................................................................................................... P-051Ferrer, Teresa ................................................................................................................... P-157Figueroa, Rodrigo ...........................................................................P-026, P-048, P-089, P-134Finn, Richard .............................................................. O-01, O-18, P-029, P-066, P-091, P-195Fiore, Esteban .................................................................................................................. P-005Fishman, Pnina ..................................................................................................................O-27Fix, Oren.......................................................................................................................... P-014Fleming, Bryan ................................................................................................................. P-119Flores, Avegail.................................................................................................................. P-014Florez, Pablo ......................................................................................................... P-067, P-132Florio, Andrea ....................................................................................................................O-21Fontana, Andrea ............................................................................................................... P-073Forcesi, Emanuele ............................................................................................................ P-211Ford, Patricia ................................................................................................................... P-219Forgues, Marshonna ........................................................................................................ P-121Fornari, Francesca .............................................................................................................O-15Fornaro, Lorenzo ................................................................................................................O-15Foschi, Francesco Giuseppe ....................................................................................O-15, P-199Fraile-López, Miguel ......................................................................................................... P-067Franch-Expósito, Sebastià ................................................................................................ P-006Fraser, Raphael ................................................................................................................ P-158Frega, Giorgio .................................................................................................................. P-211Frenette, Catherine .......................................................................................................... P-014Friedman, Scott .................................................................................................................O-09Fu, Pei-Yao ........................................................................................................... P-023, P-140Fu, Yizhen ........................................................................................................................ P-112Gaba, Ron ....................................................................................................................... P-007Gadano, Adrian ...............................................................................P-026, P-048, P-089, P-134Galle, Peter ...............................................................................................P-064, P-066, P-195Galvin, Zita .......................................................................................................... P-042, P-138Gamble, Jennifer .............................................................................................................. P-104Gane, Edward .................................................................................................................. P-174Gao, MengDan ................................................................................................................. P-123Gao, Yu-Tang ................................................................................................................... P-051Garcia, Mariana ............................................................................................................... P-005García Paredes, Beatriz .................................................................................................... P-157García Solo de Zaldívar, Javier .......................................................................................... P-143Garcia-Lezana, Teresa ........................................................................................... P-009, P-010Garcia-Samaniego, Javier ................................................................................................. P-036Garcia-Sanchez, Araceli .................................................................................................... P-036Garin, Etienne ............................................................................................P-025, P-068, P-139Garrido, Marcelo ................................................................................................................O-01Gavini, Jacopo ................................................................................................................. P-094Ge, Yongsheng ................................................................................................................. P-173Gea, Francisco ................................................................................................................. P-036Geller, David ...........................................................................................................O-16, P-093Gerona, Solange ........................................................................................P-026, P-048, P-134Ghanekar, Anand .................................................................................................. P-042, P-138Ghassan, Abou-Alfa .......................................................................................................... P-021Gil, Octavio ...................................................................................................................... P-134Ginesta, Alexandra ................................................................................................ P-026, P-048Giovannucci, Edward ........................................................................................................ P-050Girard, Lauren ....................................................................................................................O-02Giurini, Eileena ................................................................................................................. P-007Gnjatic, Sacha....................................................................................................................O-04Godard, Cécile ...................................................................................................................O-08Godbee, Michelle ............................................................................................................. P-203Goldenberg, Anna ........................................................................................................... P-086Goldin, Robert .................................................................................................................. P-071Goldstein, Alisa ................................................................................................................ P-051Golse, Nicolas ....................................................................................................... P-073, P-176Gomaa, Asmaa ..................................................................................................... P-180, P-209Gomez, Carlos ................................................................................................................. P-070Gomez-Da fonseca, Leonardo ........................................................................................... P-070

Bourien, Héloïse ............................................................................................................... P-068Bracci, Paige ................................................................................................................... P-142Braiteh, Fadi ................................................................................................................... P-072Brandi, Giovanni ................................................................................................... P-066, P-211Breder, Valeriy .........................................................................................................O-01, P-029Bresnahan, Erin .................................................................................................................O-12Brodie, Tess ..................................................................................................................... P-094Broering, Dieter ............................................................................................................... P-167Bronk, Steve .................................................................................................................... P-003Brown, J. ......................................................................................................................... P-149Brown, Mark .................................................................................................................... P-045Bruix, Jordi ................................................................................................P-013, P-047, P-108Buendia, Marie ............................................................................................................... P-034Bundchen, Cristiane ......................................................................................................... P-073Burlone, Michela .............................................................................................................. P-019Busuttil, Ronald .......................................................................................................O-18, P-091Byun, Hwa Kyung .................................................................................................. P-126, P-154Byun, Kwan Soo .............................................................................................................. P-062Bzeizi, Khalid ........................................................................................................ P-137, P-167Cabellos, Laia .................................................................................................................. P-006Cadahía, Valle ....................................................................................................... P-067, P-132Caetano-Oliveira, Rui ..........................................................................................................O-05Cagnot, Carole ...................................................................................................................O-03Cairo, Stefano .................................................................................................................. P-034Calatayud, Anna-Line ............................................................................................ P-053, P-069Calderaro, Julien ........................................................................................P-052, P-053, P-069Calleja, Jose Luis .......................................................................................P-036, P-047, P-108Campbell, Peter ....................................................................................................O-21 , P-050Campillo-Gimenez, Boris .................................................................................................. P-025Campos Ulloa, Marilia ....................................................................................................... P-201Camps, Jordi ................................................................................................................... P-006Candinas, Daniel .............................................................................................................. P-094Carmagnani, Roberto .........................................................................................................O-02Carrera, Enrique ............................................................................................................... P-194Carrilho, Flair .............................................................O-09, P-026, P-048, P-089, P-134, P-185Carrillo-Reixach, Juan ...................................................................................................... P-034Caruso, Stefano ......................................................................................................O-22, P-069Carvalho, Heloisa ............................................................................................................. P-185Casadei Gardini, Andrea ..........................................................................................O-15, P-199Cascinu, Stefano .....................................................................................................O-15, P-199Cassidy, Laura ................................................................................................................. P-158Cassinotto, Christophe...................................................................................................... P-025Castaing, Denis ..................................................................................................... P-073, P-176Castaño-García, Andrés ......................................................................................... P-067, P-132Cattral, Mark ........................................................................................................ P-042, P-138Cejas Dorta, Luis .............................................................................................................. P-143Chagas, Aline ...................................................................... P-026, P-134, P-048, P-089, P-185Chaim Correia, Maria ....................................................................................................... P-048Chaki, Sulalita .................................................................................................................. P-007Chalaye, Julia .................................................................................................................. P-025Chaman, José ....................................................................................................... P-026, P-048Chan, Andrew .................................................................................................................. P-050Chan, Anthony W.H. .......................................................................................................... P-098Chan, Henry .................................................................................................................... P-083Chan, Lo-Kong ................................................................................................................. P-060Chan, Stephan ............................................................ O-01, O-14, P-020, P-066, P-098, P-131Chan, Wen-Hui ................................................................................................................ P-212Chandna, Shaun .............................................................................................................. P-014Chang, Ah Ram ................................................................................................................ P-035Chang, Charissa ................................................................................................................O-09Chang, Jeng-Shou .............................................................................................................O-07Chang, Michael ..................................................................................................................O-19Chang, Sung Won ........................................................................................................... P-062Chang, U Im.......................................................................................................... P-085, P-161Chang, Young .................................................................................................................. P-038Chanock, Stephen ............................................................................................................ P-051Chao, Yee ..........................................................................................................................O-01Chaudhari, Rahul ............................................................................................................. P-219Chaudhry, Arvind ............................................................................................................. P-072Chee, Cheng ......................................................................................................................O-23Chen, Andre..................................................................................................................... P-185Chen, Erluo ..................................................................................................O-01, P-111, P-195

Chen, Hanna .................................................................................................................... P-007Chen, Jiancong ................................................................................................................ P-112Chen, Jie ......................................................................................................................... P-151Chen, Jinbiao ................................................................................................................... P-104Chen, Jinbin .................................................................................................................... P-112Chen, Minshan................................................................................................................. P-112Chen, Pin Jung .......................................................................................................O-18, P-091Chen, Ping-Hsien ............................................................................P-030, P-133, P-198, P-215Chen, Rongxin ................................................................................................................. P-150Chen, Shiguang ............................................................................................................... P-109Chen, Tao ........................................................................................................................ P-151Chen, Vincent .................................................................................................................. P-081Chen, Xin................................................................................................................O-11, P-004Chen, Xinyan ................................................................................................................... P-004Cheng, Ann-Lii ................O-01, O-14, P-020, P-021, P-029, P-037, P-064, P-072, P-111, P-195Cheng, Jason.....................................................................................................................O-17Cheng, Ngan.................................................................................................................... P-104Cheong, Jae Youn ............................................................................................................ P-117Cherciu, Nelly ...................................................................................................................O-27Cherouveim, Panagiotis ......................................................................................................O-16Cherqui, Daniel ..................................................................................................... P-073, P-176Chiba, Tetsuhiro .................................................................................................... P-039, P-061Chin, Steve ..................................................................................................................... P-064Chiu, David Kung-Chun ......................................................................................................O-29Chiu, Elley ....................................................................................................................... P-060Cho, Eun Ju ..................................................................................................................... P-038Cho, Hyo Jung ................................................................................................................. P-117Cho, Jai Young ................................................................................................................. P-188Cho, Kyungjoo.................................................................................................................. P-124Cho, Mong ....................................................................................................................... P-117Cho, Sung Bum ............................................................................................................... P-080Cho, Sung Won ............................................................................................................... P-117Cho, Yong Kyun ............................................................................................................... P-160Choi, Chul Won ..................................................................................................... P-035, P-192Choi, Hong Jun ................................................................................................................ P-074Choi, Jong Young .......................................................................................P-085, P-161, P-190Choi, Moon Seok .............................................................................................................. P-117Choi, Sang Wook .............................................................................................................. P-161Chon, Young Eun .............................................................................................................. P-117Chong, Charing ................................................................................................................ P-098Chong Menéndez, Ricardo ...............................................................P-026, P-048, P-089, P-134Choo-Wosoba, Hyoyoung ................................................................................................. P-051Christou, Chrysanthos ...................................................................................................... P-216Chu, Francis ......................................................................................................................O-30Chuang, Wan-Long .............................................................................................. P-175, P-205Chun, Yun Shin ..................................................................................................................O-02Chung, Andrew ................................................................................................................ P-097Chung, Jin Wook .............................................................................................................. P-038Ciacio, Oriana .................................................................................................................. P-176Ciuleanu, Tudor-Eliade .......................................................................................................O-27Cleary, Sean ................................................................................................................... P-064Coll, Susana .................................................................................................................... P-157Colnot, Sabine ...................................................................................................................O-08Cosse, Cyril ..................................................................................................................... P-176Costentin, Charlotte ............................................................................................................O-31Couchy, Gabrielle ....................................................................................................O-22, P-069Court, Colin ...........................................................................................................O-18, P-091Craig, Amanda ...................................................................................................... P-009, P-010Croitoru, Adina ...................................................................................................................O-27Cubillo, Antonio ................................................................................................................ P-016Cui, Xiao .......................................................................................................................... P-093D’Avola, Delia .................................................................................................................. P-010Da Fonseca, Leonardo ........................................................................................... P-047, P-108da Silva, Renato ............................................................................................................... P-197da Silva, Rita de Cássia .................................................................................................... P-197Dadduzio, Vincenzo .................................................................................................. O-14, O-15Dahman, Bassam ...............................................................................................................O-19Dai, Chia-Yen ........................................................................................................ P-175, P-205Dang, Hien ...................................................................................................................... P-121Daniele, Bruno .............................................................................................O-01, P-020, P-021de Ataide, Elaine ................................................................................................... P-048, P-089de Baère, Thierry.............................................................................................................. P-025




Jeon, Mi Young ................................................................................................................ P-136Jeon, Woo Kyu ................................................................................................................. P-160Jepsen, Peter .................................................................................................................. P-032Jia, Wei-Dong .................................................................................................................. P-140Jiang, Xiao-Tao ..................................................................................................................O-30Jiang, Z. Gordon .............................................................................................................. P-014Jiménez-Agüero, Raúl ........................................................................................................O-28Jo, Sunmi ........................................................................................................................ P-035John, Binu ..............................................................................................................O-19, P-014John, Smitha .....................................................................................................................O-19Jones, Patricia ................................................................................................................. P-015Jou, Janice ...................................................................................................................... P-014Ju, Michelle ..................................................................................................................... P-084Jung, Jinhong ....................................................................................................... P-018, P-028Jung, Young Kul ................................................................................................... P-062, P-080Kabashima, Ayano ............................................................................................................ P-092Kachura, John ................................................................................................................ P-138Kadokura, Makoto ............................................................................................................ P-046Kagan, Sofia .................................................................................................................... P-014Kaldas, Fady ...........................................................................................................O-18, P-091Kaldate, Rajesh .................................................................................................................O-14Kambi, Abubacarr ............................................................................................................ P-204Kanayama, Kengo ................................................................................................. P-039, P-061Kanda, Tatsuo .................................................................................................................. P-039Kaneko, Shuichi ............................................................................................................... P-195Kaneko, Shun .................................................................................................................. P-163Kang, Jun Hyuk ................................................................................................................ P-049Kang, Koo Jeong ................................................................................................... P-096, P-179Kang, Min Kyu ................................................................................................................. P-117Kang, Wonseok ................................................................................................................ P-117Kang, Yoon-Koo .....................................................................................................O-13, P-066Kanogawa, Naoya ................................................................................................. P-039, P-061Kanoko, Junichi ............................................................................................................... P-106Kanzaki, Hiroaki .................................................................................................... P-039, P-061Kao, Wei-Yu ....................................................................................P-030, P-133, P-198, P-215Kapuria, Devika ................................................................................................................ P-014Karam, Vincent ................................................................................................................ P-073Karbhari, Nishika .............................................................................................................. P-084Karin, Michael .................................................................................................................. P-002Kasai, Kazuhiro ................................................................................................................ P-169Kaseb, Ahmed ...................................................................................................................O-02Kato, Naoya .......................................................................................................... P-039, P-061Katsumi, Tomohiro ........................................................................................................... P-003Kaur, Randeep ................................................................................P-011, P-079, P-130, P-155Kawaji, Hiromichi ............................................................................................................. P-206Kay, Chul-Seung ................................................................................................................O-17Kayali, Zeid ...................................................................................................................... P-072Ke, Qiao ............................................................................................................... P-110, P-156Kelley, Robin Kate ............................................................................ O-14, P-021, P-072, P-142Kenyon, Jonathan ............................................................................................................ P-113Khallafi, Hicham ............................................................................................................... P-015Khatib, Subreen ............................................................................................................... P-121Kim, Chang-Min ............................................................................................................... P-065Kim, Beom Kyung................................................................ P-074, P-136, P-187, P-117, P-177Kim, Bo Hyun ........................................................................................................ P-049, P-065Kim, Byung Ik .................................................................................................................. P-160Kim, Chang Wook .................................................................................................. P-085, P-161Kim, Do Young ...................................P-074, P-080, P-117, P-124, P-126, P-136, P-154, P-187Kim, Eun Seog ................................................................................................................. P-035Kim, Hee Yeon....................................................................................................... P-085, P-161Kim, Hong Joo ................................................................................................................. P-160Kim, Hwi Young ..................................................................................................... P-038, P-117Kim, Hyo-Cheol ................................................................................................................ P-038Kim, Hyun Ju ........................................................................................................ P-126, P-154Kim, Hyung Joon ............................................................................................................. P-080Kim, Irene ........................................................................................................................ P-088Kim, Ji Hoon ......................................................................................................... P-062, P-080Kim, Jin Sook................................................................................................................... P-101Kim, Jong Hoon .................................................................................................... P-018, P-028Kim, Kang Mo .................................................................................................................. P-018Kim, Kyung Su ................................................................................................................. P-192Kim, Kyung-Tae................................................................................................................ P-101

Kim, Mi Na ...................................................................................................................... P-117Kim, Mi-Sook ................................................................................................................... P-035Kim, Moon Young ............................................................................................................ P-080Kim, Nalee .........................................................................................................................O-17Kim, Nam Hee.................................................................................................................. P-160Kim, Sehwa .................................................................................................................... P-062Kim, Seoung whan ........................................................................................................... P-168Kim, Seung Up ................................................................................P-074, P-117, P-136, P-187Kim, So Yeon ........................................................................................................ P-018, P-028Kim, Soon Sun ................................................................................................................. P-117Kim, Sun Woong .............................................................................................................. P-038Kim, Tae Hun ................................................................................................................... P-117Kim, Tae-Seok.................................................................................................................. P-096Kim, Tae-You .....................................................................................................................O-13Kim, Woochul ................................................................................................................... P-035Kim, Yong Hoon ................................................................................................................ P-096Kim, Yoon Ah ................................................................................................................... P-187Kim, Yoon Jun .................................................................................................................. P-038Kimura, Tomoki ..................................................................................................................O-17King, Michael .....................................................................................................................O-04Kiyono, Soichiro .................................................................................................... P-039, P-061Knight, Lucy .................................................................................................................... P-121Knox, Jennifer .............................................................................................. O-01, O-13, P-064Kobayashi, Kazufumi ............................................................................................. P-039, P-061Koh, Kwang Cheol ............................................................................................................ P-117Koh, Soo Jeong ................................................................................................................ P-065Koh, Young Hwan ............................................................................................................ P-065Köhler, Bruno .................................................................................................................. P-083Kohonen-Corish, Maija ..................................................................................................... P-104Koita, Sarjo ...................................................................................................................... P-204Kokudo, Norihiro ............................................................................................................. P-064Kokudo, Takashi .............................................................................................................. P-106Komiyama, Hitomi ............................................................................................................ P-046Kondo, Takayuki .................................................................................................... P-039, P-061Konjeti, Venkata Rajesh ......................................................................................................O-19Kori, Isaac ....................................................................................................................... P-214Kosari, Kambiz ................................................................................................................. P-088Koshiol, Jill ...................................................................................................................... P-051Kotler, Honore .................................................................................................................. P-088Kotoh, Yurika......................................................................................................... P-059, P-164Kraglund, Frederik ............................................................................................................ P-032Kramer, Jennifer .............................................................................................................. P-033Krishnan, Anuradha .......................................................................................................... P-003Kuchuk, Olga ................................................................................................................... P-034Kudo, Masatoshi .........................................................O-01, O-13, P-013, P-016, P-020, P-029, .......................................................................................... P-037, P-066, P-111, P-131, P-195Kulik, Laura ..................................................................................................................... P-014Kuo, Alexander ................................................................................................................. P-088Kuo, Wei-Lang ...................................................................................................................O-07Kuroda, Hidekatu ............................................................................................................. P-169Kurosaki, Masayuki .......................................................................................................... P-163Kusakabe, Yuko..................................................................................................... P-039, P-061Kweon, Young Oh ............................................................................................................. P-117Kwon, Jung Hyun .................................................................................................. P-085, P-161La Bella, Tiziana ......................................................................................................O-10, P-069Labgaa, Ismail ................................................................................................................. P-010Lachenmayer, Anja .............................................................................................................O-09Ladfil, Fouad .................................................................................................................... P-100Laface, Ilaria ......................................................................................................................O-04Lafdil, Fouad .................................................................................................................... P-052Laffont, Sophie................................................................................................................. P-025Lai, Changliang ................................................................................................................ P-135Lai, Michelle ................................................................................................................... P-050Lai, Renchun ................................................................................................................... P-112Lalazar, Gadi .................................................................................................................... P-056Lanigan, Christopher ........................................................................................................ P-149Lathia, Justin ................................................................................................................... P-149Latt, Nyan ........................................................................................................................ P-014Lau, Lawrence ................................................................................................................. P-086Laud, Purushottam ........................................................................................................... P-158Lauko, Adam ................................................................................................................... P-149Laurent, Alexis ................................................................................................................. P-052

Gomez-Martin, Carlos....................................................................................................... P-020Gomez-Quiroz, Luis ......................................................................................................... P-102Gong, Jun ........................................................................................................................ P-088Gong, Lan ..........................................................................................................................O-30Gong, Liansheng .............................................................................................................. P-152Gonzalez Campaña, Ariel .................................................................................................. P-089González-Diéguez, Maria Luisa .............................................................................. P-067, P-132Gonzalez-Kozlova, Edgar ................................................................................................... P-009Gordan, John ..........................................................................................................O-06, P-142Gordana, Vlahovic ............................................................................................................ P-131Gordon, Cohen ................................................................................................................. P-131Gores, Gregory ...........................................................................................P-003, P-008, P-092Gorgen, Andre............................................................................................P-042, P-086, P-138Gougelet, Angélique ...........................................................................................................O-08Goyal, Lipika .................................................................................................................... P-142Graeber, Thomas .............................................................................................................. P-091Gramantieri, Laura ..................................................................................................O-15, P-199Grant, David ......................................................................................................... P-042, P-138Grasl-Kraupp, Bettina ....................................................................................................... P-069Grasu, Mugur................................................................................................................... P-196Gregori, Josep ................................................................................................................. P-057Greig, Paul ........................................................................................................... P-042, P-138Greten, Tim ..................................................................................................................... P-119Groothuismink, A. Zwier .................................................................................................... P-099Grove, David .................................................................................................................... P-045Groza, Doina .....................................................................................................................O-27Guerrero-Garcia, Antonio ...................................................................................... P-047, P-108Guicciardi , Maria E .......................................................................................................... P-003Guiu, Boris ....................................................................................................................... P-025Gupta, Barkha .................................................................................................................. P-053Gutierrez-Ruiz, Maria ........................................................................................................ P-102Guzman, Grace ................................................................................................................ P-007Gwak, Geum-Youn ........................................................................................................... P-117Ha, Yeonjung .................................................................................................................... P-117Haber, Philipp .................................................................................................................. P-034Habib, Nagy .......................................................................................................................O-23Hack, Steve .......................................................................................................................O-32Haga, Yuki ....................................................................................................................... P-039Hainaud, Patricia .............................................................................................................. P-100Hall, Matthew................................................................................................................... P-119Ham, Cheol Bae ............................................................................................................... P-160Hammoudeh, Rawan ........................................................................................................ P-063Han, Kwang-Hyub ..............................P-074, P-117, P-124, P-126, P-136, P-154, P-177, P-187Han, Nam Ik .......................................................................................................... P-085, P-161Han, Seungmoon ............................................................................................................. P-168Hanje, James ................................................................................................................... P-014Hannan, Lindsay .............................................................................................................. P-142Hansen, Bettina .........................................................................................P-042, P-138, P-194Hara, Takanobu ................................................................................................................ P-078Harouaka, Ramdane ......................................................................................................... P-081Harpaz, Zivit.......................................................................................................................O-27Harris, William.................................................................................................................. P-142Hart, James .......................................................................................................................O-26Hasegawa, Kiyoshi ........................................................................................................... P-106He, Aiwu Ruth ....................................................................................................................O-32He, Ning .......................................................................................................................... P-107He, Wei ........................................................................................................................... P-112He, Yukai ...........................................................................................................................O-34Hectors, Stefanie ................................................................................................................O-04Heikenwälder, Mathias........................................................................................................O-09Helal, Thanaa ................................................................................................................... P-180Hendifar, Andrew .............................................................................................................. P-088Henriquez, Victor .............................................................................................................. P-048Heo, Nae-Yun .................................................................................................................. P-117Hernaez, Ruben .................................................................................................... P-014, P-033Hernandez-Meza, Gabriela ..................................................................................... P-009, P-010Hester, Caitlin .................................................................................................................. P-084Hézode, Christophe .......................................................................................................... P-052Higashi, Takaaki .................................................................................................................O-04Higuera, Monica ............................................................................................................... P-057Hildesheim, Allan ............................................................................................................. P-051Hiriart, Jean-Baptiste ....................................................................................................... P-066

Ho, Daniel ........................................................................................................................ P-060Ho, Mitchell ..................................................................................................................... P-119Hobeika, Christian ............................................................................................................ P-100Hoff, Paulo ....................................................................................................................... P-185Holden, Andrew................................................................................................................ P-174Hong, Young Mi ................................................................................................................ P-117Hoshida, Tomomi ............................................................................................................. P-059Hoshida, Yujin ....................................................................................................................O-04Hoteit, Maarouf ................................................................................................................ P-014Hou, Jiajie ....................................................................................................................... P-146Hou, Ming-Chih ...............................................................................P-030, P-133, P-198, P-215Hou, Ming-Mo ...................................................................................................................O-13Hou, Shuang ...........................................................................................................O-18, P-091Hou, Yuli .......................................................................................................................... P-123Hoyos Duque, Sergio ......................................................................P-026, P-048, P-089, P-134Hsieh, Sen-Yung ................................................................................................................O-07Hsing, Ann ....................................................................................................................... P-051Hsu, Cheng-Ting ................................................................................................... P-175, P-205Hsu, Chih-Hung ................................................................................................................O-32Hsu, Chiun .........................................................................................................................O-13Hsu, Po-Yao .......................................................................................................... P-175, P-205Hsu, Yanzhi ..................................................................................................................... P-066Hu, Bo .................................................................................................................. P-023, P-140Hu, Caixia ........................................................................................................................ P-107Huang, Jee-Fu ...................................................................................................... P-175, P-205Huang, Jian ..................................................................................................................... P-002Huang, Kai-Wen .................................................................................................................O-23Huang, Peixin................................................................................................................... P-165Huang, Wen-Yen ................................................................................................................O-17Huang, Yi-Hsiang ............................................................................P-030, P-133, P-198, P-215Humbert, Magali .............................................................................................................. P-094Hung, Chien-Fu ............................................................................................................... P-212Husain, Abdullah .............................................................................................................. P-060Hwang, Sang Youn ............................................................................................... P-080, P-217Hwang, Seong Gyu ........................................................................................................... P-117Ichida, Akihiko ................................................................................................................. P-106Ielasi, Luca ........................................................................................................................O-15Ikoma, Naruhiko .................................................................................................................O-02Iliescu, Laura ................................................................................................................... P-196Ilieva, Rumyana .................................................................................................................O-27Im, Jung Woo .................................................................................................................. P-217Imagawa, Naoto ............................................................................................................... P-046Imbeaud, Sandrine ..................................................................................................O-10, P-069Iñarrairaegui, Mercedes .................................................................................................... P-070Inoue, Masanori ............................................................................................................... P-039Ioanitescu, Simona ........................................................................................................... P-196Ioannou, George............................................................................................................... P-014Iracheta, Alexis................................................................................................................. P-026Irene, Ng ......................................................................................................................... P-120Ishizawa, Takeaki ............................................................................................................ P-106Itakura, Jun ..................................................................................................................... P-163Itobayashi, Ei ................................................................................................................... P-039Itoh, Yoshito ..................................................................................................................... P-016Itokawa, Norio ................................................................................................................. P-039Iwamoto, Takuya .............................................................................................................. P-059Iyer, Renuka ..................................................................................................................... P-113Izumi, Namiki ........................................................................................................ P-020, P-163Jackson , Whitney ............................................................................................................ P-014Jalal, Prasun .................................................................................................................... P-014Jallow, Momodou ............................................................................................................. P-204Jang, Byoung Kuk ........................................................................................................... P-080Jang, Eun Sun ................................................................................................................ P-080Jang, Jae Young .............................................................................................................. P-080Jang, Jeong Won .................................................................................................. P-085, P-161Jang, Se Young ................................................................................................................ P-117Jang, Wonil ...................................................................................................................... P-035Janin, Eric ....................................................................................................................... P-182Jarmel, Melissa................................................................................................................ P-056Jatta, Abdoulie ................................................................................................................. P-204Jebeili, Hazem ...................................................................................................................O-30Jensen, Donald ................................................................................................................ P-203Jeon, Ki Jung ................................................................................................................... P-217




Mazzolini, Guillermo ......................................................................................................... P-005Mazzotta, Alessandro ....................................................................................................... P-068McCall, John ................................................................................................................... P-174McCallister, Katharine ...................................................................................................... P-033McCaughan, Geoffrey ....................................................................................................... P-104McCluskey, Samantha ...................................................................................................... P-042McCluskey, Sydney .......................................................................................................... P-042McCormack, Lucas ....................................................................................P-048, P-089, P-134McGilvray, Ian ...................................................................................................... P-042, P-138McGlynn, Katherine ................................................................................................O-21, P-050Medova, Michaela ............................................................................................................ P-094Mehta, Neil ...................................................................................................................... P-014Meinhardt, Gerold ............................................................................................................ P-013Melero, Ignacio ..................................................................................................................O-13Menachem, Yoram ................................................................................................ P-218, P-214Menéndez, Josemaría .....................................................................P-026, P-048, P-089, P-134Meng, Zhi Qiang .............................................................................................................. P-166Menna, Jose .................................................................................................................... P-048Merad, Miriam ...................................................................................................................O-04Mercan-Stanciu, Adriana .................................................................................................. P-196Meringer, Hadar ............................................................................................................... P-214Merle, Philippe ................................................................................ O-01, P-013, P-029, P-066Mesa, Alicia .......................................................................................................... P-067, P-132Meunier, Léa .................................................................................................................... P-069Meyer, Tim .................................................................................................... O-14, O-23, P-195Miller-Atkins, Galen .......................................................................................................... P-045Milwee, Steven ............................................................................................................... P-072Mineo, Takashi ................................................................................................................. P-071Mínguez, Beatriz .............................................................................. O-09, P-047, P-057, P-108Miquelin, André ................................................................................................................ P-197Misir, Soamnauth .................................................................................................. P-020, P-029Mizumoto, Hideaki ............................................................................................................ P-039Modi, Mitul ...................................................................................................................... P-219Moeini, Agrin ..........................................................................................................O-09, P-006Molinaro, Eleonora ........................................................................................................... P-199Molina-Sanchez, Pedro .......................................................................................................O-12Mollon, Patrick ................................................................................................................. P-021Montero, Jose .................................................................................................................. P-157Montironi, Carla ......................................................................................................O-09, P-034Moon, Andrew ................................................................................................................. P-014Moon, Hyuk .......................................................................................................... P-124, P-177Morales, Ivan ................................................................................................................... P-063Morgan, Shethah .................................................................................................. P-064, P-131Morgenstern, Dave ........................................................................................................... P-083Moriya, Akio ..................................................................................................................... P-206Muaddi, Hala .................................................................................................................. P-138Mulé, Sebastien ............................................................................................................... P-052Muñoz Espinosa, Linda ....................................................................P-026, P-048, P-089, P-134Mur, Juan ........................................................................................................................ P-083Murphy, Caitlin ........................................................................................................O-20, P-015Mylonas, Konstantinos ........................................................................................................O-16Nadeu, Ferran .................................................................................................................. P-006Nahon, Pierre .....................................................................................................................O-03Nakajima, Keiko ............................................................................................................... P-037Nakamoto, Shingo ................................................................................................. P-039, P-061Nakamura, Masato ................................................................................................ P-039, P-061Nakanishi, Hiroyuki ........................................................................................................... P-163Nam, Hee Chul................................................................................................................. P-190Nam, Jun Yeol .................................................................................................................. P-038Nam, Soon Woo .................................................................................................... P-085, P-161Nam, Yunsun .................................................................................................................. P-118Natošević, Sladjana ...........................................................................................................O-27Nault, Jean-Charles ......................................................................................................... P-069Neely, Jaclyn......................................................................................................................O-13Nelson, Walter ..................................................................................................... P-086, P-138Nepal, Chirag ..........................................................................................................O-05, P-051Ng, Irene .............................................................................................................. P-060, P-153Ng, Irene Oi-Lin .................................................................................................................O-29Nguyen, Cong Trung ......................................................................................................... P-052Nissen, Nicholas .............................................................................................................. P-088Nita, Amedeia ...................................................................................................................O-27Njie, Ramou ..................................................................................................................... P-204

Nonell, Lara ..................................................................................................................... P-034Notarpaolo, Andrea ............................................................................................................O-31Noureddin, Mazen ............................................................................................................ P-088Nowak, Anna .....................................................................................................................O-26Numata, Kazushi .....................................................................................................O-32, P-016Nunes, Frederick .............................................................................................................. P-219Nunez, Julio ..................................................................................................................... P-176O'Rourke, Colm ......................................................................................................O-05, P-051O'Brein, Daniel ................................................................................................................. P-179Obu, Masamichi ............................................................................................................... P-039Odewole, Mobolaji ............................................................................................................ P-014Ogasawara, Sadahisa ...................................................................................O-01, P-039, P-061Oikawa, Takayoshi ............................................................................................................ P-169Okabe, Shinichiro ............................................................................................................. P-039Okuwaki, Tetsuya ............................................................................................................. P-046Oliveira, Claudia .................................................................................................................O-09Oloruntoba, Omobonike .................................................................................................... P-014Ongati, Omolo .................................................................................................................. P-162Onorato, Agostina ............................................................................................................ P-005Ooka, Yoshihiko ..................................................................................................... P-039, P-061Orr, David ....................................................................................................................... P-174Orsi, Giulia ..............................................................................................................O-15, P-199Ortiz, Cynthia ................................................................................................................... P-033Ortiz-Pedraza, Yunuen ...................................................................................................... P-102Orujov, Mushfig ................................................................................................................ P-149Osterlund, Pia .................................................................................................................. P-029Otedo, Amos .................................................................................................................... P-162Ouine, Bérengère ............................................................................................................ P-069Ozgurdal, Kirhan .............................................................................................................. P-013Padilla-Machaca, Martín ..................................................................P-026, P-048, P-089, P-134Paik, Eun Kyung ............................................................................................................... P-035Paik, Seung Woon ............................................................................................................ P-117Paik, Yong-Han ................................................................................................................ P-117Palard, Xavier .................................................................................................................. P-025Palloni, Andrea ................................................................................................................. P-211Palmer, Daniel .............................................................................................O-23, P-029, P-066Pan, Kuan-Tse ................................................................................................................. P-212Pan, Yangxun ........................................................................................................ P-027, P-112Papadopoulos, Vasileios ................................................................................................... P-216Papayiannis, Vassilis......................................................................................................... P-216Paradis, Valérie ............................................................................................O-22, P-100, P-182Pareja, Maria .....................................................................................................................O-28Parente García, Jose ........................................................................................................ P-134Parikh, Neehar ...................................................................................................... P-014, P-081Park, Chan Hyuk .............................................................................................................. P-031Park, Hae Jin ................................................................................................................... P-035Park, Hee Hyun ................................................................................................................ P-028Park, Ji Hee .................................................................................................................... P-065Park, Jin-hong ................................................................................................................. P-028Park, Joong-Won .................................................................O-14, P-049, P-064, P-065, P-101Park, Jun Yong .................................................................... P-074, P-117, P-124, P-136, P-187Park, Jung Gil .................................................................................................................. P-117Park, Jung Won ............................................................................................................... P-179Park, Seung Ha ................................................................................................................ P-117Park, Soo Young ............................................................................................................... P-117Park, Wonhyeong ............................................................................................................. P-168Park, Young ......................................................................................................................O-33Park, Young Hee ............................................................................................................... P-035Parks, Anna ..................................................................................................................... P-142Pascual, Sonia ................................................................................................................. P-157Pastan, Ira ....................................................................................................................... P-119Patel, Nayan .................................................................................................................... P-014Paul, Ananya ......................................................................................................................O-26Pawlotsky, Jean Michel .................................................................................................... P-052Payao, Fabio .................................................................................................................... P-185Peck-Radosavljevic, Markus ............................................................................................. P-037Pecora, Irene .....................................................................................................................O-15Pedrono, Maud ................................................................................................................ P-139Peix, Judit .........................................................................................................................O-09Péneau, Camille ......................................................................................................O-10, P-069Perales Reges, Simone ......................................................................................... P-089, P-134Perelló, Christie .........................................................................................P-036, P-047, P-108

Law, Ngai M .................................................................................................................... P-208Layese, Richard .................................................................................................................O-03Le Sourd, Samuel.................................................................................................. P-068, P-139Lee, Boram ...................................................................................................................... P-188Lee, Chao-Wei ..................................................................................................... P-145, P-212Lee, Cheol-Hyung ............................................................................................................ P-038Lee, Danbi ....................................................................................................................... P-018Lee, Donghyuk ................................................................................................................. P-051Lee, Ha Seok .................................................................................................................. P-062Lee, Hae Lim ........................................................................................................ P-085, P-161Lee, Han Ah ..................................................................................................................... P-136Lee, Han Chu .............................................................................................P-018, P-028, P-037Lee, Hye ...........................................................................................................................O-33Lee, Hyo Young ................................................................................................................ P-038Lee, Hyun Woong .................................................................................................. P-031, P-080Lee, Jae Seung ...............................................................................P-074, P-136, P-117, P-187Lee, Jeong-Hoon .................................................................................................. P-038, P-080Lee, Jieun ....................................................................................................................... P-141Lee, Jin .............................................................................................................................O-25Lee, Joo Ho ..................................................................................................................... P-117Lee, Joon Hyeok .............................................................................................................. P-117Lee, Ju Hee .................................................................................................................... P-065Lee, Kyung-Hun .................................................................................................................O-32Lee, Michael ......................................................................................................................O-32Lee, Min Woo ................................................................................................................... P-031Lee, Minjin....................................................................................................................... P-062Lee, Minjong .................................................................................................................... P-049Lee, Miran ....................................................................................................................... P-168Lee, Rheun-Chuan ........................................................................................................... P-030Lee, Sangheun ................................................................................................................. P-031Lee, Seon Mi ................................................................................................................... P-217Lee, Sung Won ..................................................................................................... P-085, P-161Lee, Victor ........................................................................................................................O-17Lee, Young-Sun..................................................................................................... P-062, P-080Lee, Yun Bin .................................................................................................................... P-038Lee, Zhenghong ............................................................................................................... P-113Lei, Song ......................................................................................................................... P-051Leise, Michael.................................................................................................................. P-014Lencioni, Riccardo ................................................................................................ P-064, P-131Lescure, Céline ................................................................................................................ P-139Letouzé, Eric .................................................................................................................... P-069Lewinska, Monika ..............................................................................................................O-28Lewis, Sara ........................................................................................................................O-04Li, Jia .............................................................................................................................. P-104Li, Kang ................................................................................................................ P-178, P-107Li, Lin .............................................................................................................................. P-118Li, Wenxin ........................................................................................................................ P-151Li, Yuxin ........................................................................................................................... P-021Liang, Binyong ...................................................................................................................O-11Liang, Ping ........................................................................................................... P-087, P-200Lièvre, Astrid .................................................................................................................... P-068Lilly, Les .............................................................................................................. P-042, P-138Lim, Howard .................................................................................................................... P-020Lim, Ho-Yeong ...................................................................................................................O-01Lim, Huat Chye ..................................................................................................................O-06Lim, Huiju ........................................................................................................................ P-153Lim, Jin Hong .................................................................................................................. P-031Lim, Tae Seop .................................................................................................................. P-136Lim, Young-Suk ..................................................................................................... P-018, P-028Lin, Albert ........................................................................................................................ P-029Lin, Chen-Chun ..................................................................................................................O-07Lin, Joseph ...................................................................................................................... P-115Lin, Nanping ......................................................................................................... P-128, P-129Lin, Xue-jia ...................................................................................................................... P-002Lin, Yu-Hsuan .................................................................................................................. P-054Lindblad, Katherine ............................................................................................................O-12Lindenmeyer, Christina ..................................................................................................... P-014Lisy, Marcus-Rene ........................................................................................................... P-083Liu, Bo ..............................................................................................................................O-32Liu, Haohan ..................................................................................................................... P-135Liu, Jingfeng ......................................................................................................... P-128, P-129Liu, Ken ........................................................................................................................... P-104

Liu, Xuan ........................................................................................................................ P-064Liu, Zhiwei ...................................................................................................................... P-051Lledó, Jose Luis ..............................................................................P-047, P-070, P-108, P-157Llop, Elba ........................................................................................................................ P-036Llovet, Josep ..........................................O-09, O-12, O-27, P-006, P-009, P-034, P-066, P-195 Loeuillard, Emilien ........................................................................................................... P-008Lok, Anna ........................................................................................................................ P-081Lonardi, Sara .....................................................................................................................O-15Long, Jiang...................................................................................................................... P-107Longerich, Thomas ........................................................................................................... P-119Lorente, Sara ................................................................................................................... P-070Losic, Bojan ...............................................................................................P-009, P-010, P-034Louie, Brent .......................................................................................................................O-26Love, Eleanor .....................................................................................................................O-19Lu, Shelly ........................................................................................................................ P-088Lu, Xiaoyun ...................................................................................................................... P-112Luciani, Alain ................................................................................................................... P-052Luedtke, Gregory ...............................................................................................................O-26Lujambio, Amaia ................................................................................................................O-12Lum, Pek ...........................................................................................................................O-26Luu, Michael ................................................................................................................... P-088Lyu, Ning ......................................................................................................................... P-001Ma, Min ........................................................................................................................... P-150Ma, Xiaolu ............................................................................................................ P-058, P-114Ma, Yanan ....................................................................................................................... P-050Ma, Yuk-Ting .....................................................................................................................O-23Maccali, Claudia ............................................................................P-026, P-048, P-089, P-134Machou, Camilia .............................................................................................................. P-052Macias, Rocio ....................................................................................................................O-28Macshut, Mahmoud ......................................................................................................... P-125Maeda, Masaki ................................................................................................................ P-059Maeda, Takahiro ................................................................................................... P-039, P-061Maille, Pascale ................................................................................................................. P-052Malhotra, Usha ................................................................................................................ P-111Mallat, Ariane................................................................................................................... P-052Mallo, Mar ....................................................................................................................... P-034Malvicini, Mariana ............................................................................................................ P-005Mami, Iadh ........................................................................................................................O-10Mann, Helen ........................................................................................................ P-131, P-064Manojlovic, Nebojsa ..........................................................................................................O-27Mansour, John ................................................................................................................. P-084Mantry, Parvez ................................................................................................................. P-014Mao, Kai .................................................................................................................O-24, P-135Marafioti, Teresa .............................................................................................................. P-071Maraschio, Martín ......................................................................................P-048, P-089, P-134Marcellin, Patrick ...............................................................................................................O-03Marciano, Sebastián .......................................................................,P-026, P-048, P-089, P-134Marcondes, Caroline ........................................................................................................ P-197Marinca, Mihai ..................................................................................................................O-27Marisi, Giorgia ........................................................................................................O-15, P-199Markby, David ....................................................................................................................O-14Marquardt, Jens .............................................................................................................. P-102Marques, Carolina ............................................................................................................ P-197Márquez, Laura .........................................................................................P-047, P-070, P-108Marrero, Jorge ................................................................................................................. P-014Martin, Ana ...................................................................................................................... P-036Martin, Sean .................................................................................................................... P-121Martines, Laura ................................................................................................................ P-197Martinet, Matthieu ......................................................................................P-181, P-182, P-183Martinez-Quetglas, Iris ..................................................................................................... P-034Maruta, Susumu ................................................................................................... P-039, P-061Maruyama, Hitoshi ................................................................................................ P-039, P-061Mashima, Soichiro ........................................................................................................... P-206Massengill James, Brandon .............................................................................................. P-095Matilla, Ana ....................................................O-13, P-016, P-036, P-047, P-070, P-108, P-157Matsumoto, Toshihiko ....................................................................................................... P-059Matter, Matthias .................................................................................................................O-05Mattera, Juan ................................................................................P-026, P-048, P-089, P-134Mattos, Angelo ................................................................................................................. P-194Mauri, Francesco .................................................................................................. P-019, P-071Mazzaferro, Vincenzo..................................................................................P-006, P-009, P-034Mazzeto, Nicole ................................................................................................................ P-197




Seki, Atsuyoshi................................................................................................................. P-039Selim, Ranya....................................................................... P-011, P-063, P-079, P-130, P-155Selzner, Markus ................................................................................................... P-042, P-138Selzner, Nazia ...................................................................................................... P-042, P-138Sen, Suvajit .......................................................................................................................O-14Sengupta, Srikumar ......................................................................................................... P-090Sensui, Miyuki ................................................................................................................. P-061Seo, Yeon Seok ..........................................................................................P-062, P-080, P-136Seong, Jinsil ................................................................................................O-17, P-126, P-154Serbinowski, Emily .......................................................................................................... P-149Sergeev, maxim ............................................................................................................... P-113Sergeeva, Olga ................................................................................................................ P-113Serrano, Trinidad .............................................................................................................. P-157Sexton, Sandra ................................................................................................................ P-113Shaban , Mohammad ...................................................................................................... P-125Shabana, Hany................................................................................................................. P-213Shalapour, Shabnam ........................................................................................................ P-002Shang, Runze .................................................................................................................. P-004Sharma, Padmanee ............................................................................................................O-02Sharma, Rohini ..................................................................................................... P-019, P-071Shawkat, Mohamed ......................................................................................................... P-137Shen, Jialing .................................................................................................................... P-120Shen, Yun .........................................................................................................................O-13Shen, Zhewei .....................................................................................................................O-26Shi, Bingchao ....................................................................................................................O-24Shibolet, Oren ....................................................................................................... P-214, P-218Shim, Ju Hyun ................................................................................................................. P-018Shimamura, Naruki .......................................................................................................... P-046Shin, Seoungmok ............................................................................................................. P-168Shin, Sunyeong ..................................................................................................... P-177, P-124Sia, Daniela .......................................................................................O-09, O-12, P-006, P-034Siddique, Abdul ................................................................................................................ P-071Siegel, Abby ............................................................................................................O-01, P-111Silva, Marcelo ...................................................................... O-31, P-026, P-048, P-089, P-134, Silveira Bello Stucchi, Raquel ............................................................................................ P-026Silver, Daniel ................................................................................................................... P-149Silverman, Michael .............................................................................................................O-27Silvestris, Nicola ......................................................................................................O-15, P-199Simbiri, Kenneth .............................................................................................................. P-162Simon, Sanford ................................................................................................................ P-056Simon, Tracey ................................................................................................................. P-050Simon-Coma, Marina ....................................................................................................... P-034Simoni-Nieves, Arturo ....................................................................................................... P-102Singal, Amit ..........................................................................O-20, P-014, P-015, P-033, P-084Singh, Shalini .....................................................................................................................O-02Sinha, Rajni .................................................................................................................... P-072Sinn, Dong-Hyun ................................................................................................... P-038, P-117Sisawo, Momodou Musa .................................................................................................. P-204Smoot, Rory ..................................................................................................................... P-092Soares Lima, Agnaldo ......................................................................P-026, P-048, P-089, P-134Sodergren, Mikael ..............................................................................................................O-23Sohn, Won ............................................................................................................ P-031, P-160Soliman, Elwy .................................................................................................................. P-137Song, Do Seon ...................................................................................................... P-085, P-161Sørensen, Henrik.............................................................................................................. P-032Soria, Maria ..................................................................................................................... P-057Soza, Alejandro ................................................................................................................ P-134Spahn, Jessica ..................................................................................................................O-32Spalding, Duncan ...............................................................................................................O-23Spina, Paolo .................................................................................................................... P-019Stein, Stacey......................................................................................................................O-32Stemmer, Salomon .............................................................................................................O-27Stephens, Carlie .................................................................................................................O-30Stewart, Matthew ............................................................................................................. P-007Stolovitzky, Gustavo .......................................................................................................... P-010Stroka, Deborah ............................................................................................................... P-094Sturdevant, Mark ............................................................................................................. P-167Su, Chien-Wei .................................................................................P-030, P-133, P-198, P-215Suehiro, Yutaka ................................................................................................................ P-059Sugiura, Nobuyuki ............................................................................................................ P-039Suh, Sang Jun ................................................................................................................ P-062Sui, Jing .......................................................................................................................... P-050

Sukeepaisarnjaroen, Wattana ............................................................................................ P-083Sukhun, Rajaa ...................................................................................................................O-26Sulpice, Laurent ............................................................................................................... P-068Sultan, Amir ..................................................................................................................... P-201Sultan, Mervat ................................................................................................................. P-125Sun, Jianping .............................................................................................P-107, P-123, P-178Sun, Qi-Man .................................................................................................................... P-023Sundaram, Latha ...............................................................................................................O-19Sundaram, Vinay .............................................................................................................. P-088Sung, Max ............................................................................................................ P-020, P-029Sung, Pil Soo ..................................................................................P-085, P-144, P-161, P-190Suzuki, Eiichiro ..................................................................................................... P-039, P-061Sweed, Dina ..............................................................................................P-095, P-125, P-180Swiatek-De Lange, Magdalena.......................................................................................... P-083Sze, Karen ............................................................................................................ P-060, P-153Tabrizian, Parissa ............................................................................................................. P-010Tacher, Vania ................................................................................................................... P-025Tak, Won Young................................................................................................................ P-117Takami, Taro ......................................................................................................... P-059, P-164Takami, Yuko .............................................................................................P-078, P-184, P-189Takikawa, Yasuhiro ........................................................................................................... P-169Talmon, Geoffrey .............................................................................................................. P-147Tamaki, Nobuharu ............................................................................................................ P-163Tamburini, Emiliano .......................................................................................................... P-199Tani, Claudia .................................................................................................................... P-185Tanwandee, Tawesak........................................................................................................ P-083Taouli, Bachir .....................................................................................................................O-04Tateishi, Ryosuke ............................................................................................................. P-020Tatum, James ....................................................................................................................O-19Tawada, Akinobu ................................................................................................... P-039, P-061Taylor, Fiona..................................................................................................................... P-016Tebbutt, Niall.................................................................................................................... P-029Tekanyi, Muhammed ....................................................................................................... P-204Terroir-Cassou-Mounat, M ................................................................................................ P-025Testillano, Milagros........................................................................................................... P-070Thamer, Mae ................................................................................................................... P-015Therapondos, George ....................................................................................................... P-015Thomas, Faith .................................................................................................................. P-007Thompson, Gwilym ........................................................................................................... P-016Thomson, James ............................................................................................................. P-090Thongsawat, Satawat ....................................................................................................... P-083Thung, Swan .....................................................................................................................O-09Thung, Swang....................................................................................................................O-04Tijeras-Raballand, Annemilaï ............................................................P-100, P-181, P-182, P-183Todo, Tsuyoshi ................................................................................................................. P-088Toma, Letitia .................................................................................................................... P-196Toma, Mihai ..................................................................................................................... P-196Tomasini, Michael ............................................................................................................ P-056Tomlinson, James ...................................................................................................O-18, P-091Ton, Phuongnga .................................................................................................................O-05Tong, Joanna ................................................................................................................... P-098Toniutto, Pierluigi ............................................................................................................. P-071Tooulias, Andreas ............................................................................................................. P-216Torner Simó, Maria .....................................................................................P-047, P-108, P-132Torrecilla, Sara ........................................................................................................O-09, P-006Torrens, Laura....................................................................................................... P-006, P-034Torrens, Maria.................................................................................................................. P-057Torres, Ferrán .................................................................................................................. P-047Torres-Martin, Miguel .........................................................................................................O-09Tovoli, Francesco ...............................................................................................................O-13Trivedi, Pritesh ................................................................................................................. P-019Tsai, Chi-Neu .................................................................................................................. P-145Tschan, Mario .................................................................................................................. P-094Tselikas, Lambros ............................................................................................................ P-025Tseng, Hsian-Rong ..................................................................................................O-18, P-091Tsolakidis, Alexandros ..................................................................................................... P-216Tsoulfas, Georgios ..................................................................................................O-16, P-216Tsuchiya, Kaoru ............................................................................................................... P-163Tsui, Yu-Man ................................................................................................................... P-060Tzeng, Ching-Wei ...............................................................................................................O-02Um, Soon Ho ................................................................................................................... P-136Urban, Daniel ................................................................................................................... P-119

Pérez Hernández, Francisco Andrés ........................................................................ P-143, P-148Perumalswami, Ponni ....................................................................................................... P-014Petrick, Jessica ......................................................................................................O-21, P-050Petrov, Petar .....................................................................................................................O-27Pianetcki-Tsiantzi, Bozidaria ............................................................................................. P-216Pilet, Jill .......................................................................................................................... P-069Pillai, Anjana .................................................................................................................... P-014Pinato, David James .............................................................................................. P-019, P-071Piñero, Federico ....................................................................O-31, P-026, P-048, P-089, P-134Pinheiro, Paulo ................................................................................................................. P-015Pinter, Matthias ................................................................................................................ P-029Pinyol, Roser ...........................................................................................................O-09, P-006Piratvisuth, Teerha ............................................................................................................ P-083Pirisi, Mario ..................................................................................................................... P-019Pittau, Gabriella ............................................................................................................... P-176Plata-Bello, Julio .................................................................................................. P-143, P-148Plummer, Elizabeth .............................................................................................................O-23Pocard, Marc ................................................................................................................... P-100Pol, Stanislas .....................................................................................................................O-03Polanco, Patricio .............................................................................................................. P-084Pomyen, Yotsawat ............................................................................................................ P-121Poniachik, Jaime .............................................................................P-026, P-048, P-089, P-134Pons, Monica ........................................................................................................ P-047, P-108Porembka, Matthew ......................................................................................................... P-084Portela, Anna ................................................................................................................... P-009Poté, Nicolas......................................................................................................................O-22Pracht, Marc .................................................................................................................... P-139Prasad, Debi .................................................................................................................... P-174Prieto, Amador ................................................................................................................. P-132Prieto, Jhon ..................................................................................................................... P-194Prokunina-Olsson, Ludmila .............................................................................................. P-051Protter, Andrew ..................................................................................................................O-26Purcell, William .................................................................................................................O-27Puscas, Ioana ...................................................................................................................O-27Putra, Juan ........................................................................................................................O-04Qazi, Aisha ...................................................................................................................... P-007Qin, Ling............................................................................................................... P-123, P-178Qin, Shukui ........................................................................................................... P-131, P-195Quer, Josep ..................................................................................................................... P-057Quiñonez, Emilio ............................................................................P-026, P-048, P-089, P-134Rabea, Ghada .................................................................................................................. P-213Raffa, Pía......................................................................................................................... P-026Raghav, Kanwal .................................................................................................................O-02Rakoski, Mina .................................................................................................................. P-014Rangnekar, Amol .............................................................................................................. P-014Raoul, Jean-Luc ............................................................................................................... P-037Raposo, Anita.....................................................................................................................O-30Rau, Kun-Ming ................................................................................................................. P-020Raymond, Eric.................................................................................P-100, P-181, P-182, P-183Real, Alejandrina .............................................................................................................. P-005Rebouissou, Sandra .............................................................................................. P-053, P-069Reeves, Helen ....................................................................................................................O-09Regnault, Hélène .............................................................................................................. P-052Reig, Maria .....................................................................................P-013, P-047, P-070, P-108Rekik, Samia.................................................................................................................... P-069Reli, Reicher .................................................................................................................... P-218Remiro Azocar, Antonio ..................................................................................................... P-021Ren, Min.......................................................................................................................... P-029Ren, Qiu Ping ................................................................................................................... P-105Ren, Zhenggang .................................................................................................. P-131, P-165Renne, Salvatore ................................................................................................................O-33Riby, Diane ...................................................................................................................... P-068Rich, Nicole ..................................................................................... O-20, P-014, P-033, P-084Riggi, Maria Laura ............................................................................................................ P-199Rimassa, Lorenza ...................................................................................................O-14, P-072Rimola, Jordi ....................................................................................................... P-047, P-108Rizvi, Sumera ................................................................................................................... P-008Rizzato, Mario Domenico ....................................................................................................O-15Rizzo, Alessandro ............................................................................................................. P-211Rizzo, Manglio.................................................................................................................. P-005Ro, Weonsang ....................................................................................................... P-124, P-177Roa, Juan Carlos ................................................................................................... P-051, P-194

Robert, Corentin ............................................................................................................... P-025Roberts, Lewis ................................................................................................................. P-179Rocha, Manoel ................................................................................................................. P-185Rodrigues, Aurélie ................................................................................................. P-052, P-100Rodriguez, Marcelo .......................................................................................................... P-005Rodríguez, Manuel ................................................................................................ P-067, P-132Rodríguez-Frías, Francisco................................................................................................ P-057Roessler, Stephanie ............................................................................................................O-09Rohr-Udilova, Nataliya ...................................................................................................... P-069Rolland, Yan ...............................................................................................P-025, P-068, P-139Rolny, Vinzent .................................................................................................................. P-083Romagnoli, Pablo ............................................................................................................. P-194Roncalli, Massimo ..............................................................................................................O-33Rosenblatt, Russell ........................................................................................................... P-014Rotroff, Daniel .................................................................................................................. P-045Rousseau, Benoit ............................................................................................................. P-100Roversi, Gustavo .............................................................................................................. P-149Rovesti, Giulia .........................................................................................................O-15, P-199Royo, Laura ..................................................................................................................... P-034Rudini, Noemi ....................................................................................................................O-33Ruiz de Galarreta, Marina ...................................................................................................O-12Ruth He, Aiwu ....................................................................................................................O-13Ryoo, Baek-Yeol ..............................................................................................O-01, O-14, O-32Ryu, Tomoki ...............................................................................................P-078, P-184, P-189Sa Cunha, Antonio................................................................................................. P-073, P-176Sadeghi, Saeed .......................................................................................................O-18, P-091Saeian, Kia ...................................................................................................................... P-158Saeki, Issei ........................................................................................................... P-059, P-164Safar, Bandar ................................................................................................................... P-167Said, Adnan ..................................................................................................................... P-014Said, Daniela .....................................................................................................................O-04Saidu, Jemimah ............................................................................................................... P-220Saito, Tomoko ....................................................................................................... P-039, P-061Saitsu, Hideki ........................................................................................................ P-184, P-189Sakaida, Isao ........................................................................................................ P-059, P-164Sakamuri, Divya .................................................................................................................O-02Sala, Margarita ................................................................................................................ P-034Salas-Silva, Soraya........................................................................................................... P-102Salaverria, Itziar ............................................................................................................... P-006Salcedo, Maria ................................................................................................................. P-057Salgia, Reena........................................................... P-011, P-014, P-063, P-079, P-130, P-155Salih, Isam....................................................................................................................... P-137Salih, Issam ..................................................................................................................... P-167Samaka, Rehab................................................................................................................ P-125Samant, Hrishikesh .......................................................................................................... P-014Samuel, Didier ................................................................................................................. P-073Sanceau, Julie ...................................................................................................................O-08Sánchez-Taltavull , Daniel ................................................................................................. P-094Sangro, Bruno .................................................. O-13, O-28, P-016, P-047, P-070, P-108, P-131 Sanneh, Lamin ................................................................................................................. P-204Santini, Daniele ..................................................................................................................O-15Santoro, Armando ...................................................................................................O-13, P-016Santos, Luisa ............................................................................................P-048, P-089, P-134Santos-Laso , Alvaro ..........................................................................................................O-28Sanyal, Arun ......................................................................................................................O-09Sapena, Victor....................................................................................................... P-047, P-108Sapisochin, Gonzalo ..................................................................................P-042, P-086, P-138Sarker, Debashis ................................................................................................................O-23Sarrias, Maria Rosa .......................................................................................................... P-034Sasaki, Shin .......................................................................................................... P-184, P-189Satapathy, Sanjaya ........................................................................................................... P-014Sawara, Kei ..................................................................................................................... P-169Saydiba, Tamba................................................................................................................ P-204Scaglione, Steven............................................................................................................. P-014Scartozzi, Mario ......................................................................................................O-15, P-199Schachtschneider, Kyle ..................................................................................................... P-007Schaeffer, Samantha ........................................................................................................ P-053Schelman, William ........................................................................................................... P-066Schirmacher, Peter .............................................................................................................O-09Schook, Lawrence ............................................................................................................ P-007Schwartz, Myron ..........................................................................................O-04, P-009, P-010Sebra, Robert................................................................................................................... P-010



Name Abstract

Zhang, Zhe ...................................................................................................................... P-098Zhao, Ming ...................................................................................................................... P-001Zhao, Peng ...................................................................................................................... P-107Zhao, Yan ............................................................................................................. P-107, P-123Zhao, Yanan .......................................................................................................... P-107, P-178Zhao, Yang ...................................................................................................................... P-104Zhao, Zhiying ................................................................................................................... P-165Zheng, Elizabeth .............................................................................................................. P-014Zhou, Jian ......................................................................................P-023, P-064, P-111, P-140Zhou, Qianlei .....................................................................................................................O-24Zhou, Zhonggo ................................................................................................................ P-112Zhu, Andrew .........................................................................O-01, P-066, P-072, P-111, P-195Zhu, Bin .......................................................................................................................... P-051Zhu, Hao ...................................................................................................P-054, P-097, P-118Zhu, Mary ....................................................................................................................... P-042Zhu, Yazhen .......................................................................................................................O-18Zhu, Zhen Feng ............................................................................................................... P-166Zhu, Zhibin ...................................................................................................................... P-203Ziogas, Ioannis ...................................................................................................................O-16Zucman-Rossi, Jessica.......................................................................O-10, O-22, P-053, P-069

Name Abstract

Uzilov, Andrew....................................................................................................................O-09Vadas, Mathew ................................................................................................................ P-104Valcheva, Velichka ............................................................................................................ P-021Valle, Juan ....................................................................................................................... P-194Vanwolleghem, Thomas .................................................................................................... P-099Varela, Maria ...................................................................... P-047, P-067, P-070, P-108, P-132 Vargas-Accarino, Elena .................................................................................................... P-057Varón, Adriana ................................................................................P-026, P-048, P-089, P-134Vasconcelos, Karina ......................................................................................................... P-185Vasudevan, Anupama ....................................................................................................... P-033Vauthey, Jean ....................................................................................................................O-02Vence, luis .........................................................................................................................O-02Venook, Alan .................................................................................................................... P-142Vera-Torres, Cristian ......................................................................................................... P-002Verdure, Lucas ................................................................................................................. P-068Vergara Sandoval, Rodrigo ...............................................................P-026, P-048, P-089, P-134Verret, Wendy ....................................................................................................................O-32Vibert, Eric ............................................................................................................ P-073, P-176Victor, Stephane ............................................................................................................... P-019Viganò, Luca ......................................................................................................................O-33Vila-Casadesús, Maria ...................................................................................................... P-006Vilatoba, Mario ................................................................................P-026, P-048, P-089, P-134Villadsen, Gerda ............................................................................................................... P-032Villanueva, Augusto ............................................................................................... P-009, P-010Vilstrup, Hendrik............................................................................................................... P-032Vivaldi , Caterina ................................................................................................................O-15Vlahovic, Gordana ........................................................................................................... P-064Vlock, Elizabeth ................................................................................................................ P-147Vogel, Arndt ...............................................................................................P-111, P-029, P-194von Felden, Johann ............................................................................................... P-009, P-010Wada, Yoshiyuki .........................................................................................P-078, P-184, P-189Wan, Wang ...................................................................................................................... P-163Wang, Chunxiao .............................................................................................................. P-066Wang, Dan ...................................................................................................................... P-122Wang, Difei ...................................................................................................................... P-051Wang, Haichuan .................................................................................................................O-11Wang, Huan .......................................................................................................................O-09Wang, Jie ...............................................................................................................O-24, P-135Wang, Juncheng .............................................................................................................. P-112Wang, Kui ........................................................................................................................ P-140Wang, Lei ............................................................................................................. P-128, P-129Wang, Pan ....................................................................................................................... P-004Wang, Qi ......................................................................................................................... P-107Wang, Sam ...................................................................................................................... P-084Wang, Xiaohui .................................................................................................................. P-112Wang, Xicheng ................................................................................................................. P-151Wang, Xin ........................................................................................................................ P-121Wang, Xining ................................................................................................................... P-151Ward, Stephen ...................................................................................................................O-04Watkins, Neil.................................................................................................................... P-104Waziri, Peter .................................................................................................................... P-220Wei, Cheng-Yi ................................................................................P-030, P-133, P-198, P-215Wei, Yonglong .................................................................................................................. P-118Weidong, Jia ...................................................................................P-017, P-041, P-170, P-172Wei-Qiang, Leow................................................................................................................O-09Wen, Liang ........................................................................................................................O-25Wen, Shuwei ................................................................................................................... P-191Wenjing, Yang ....................................................................................................... P-024, P-103Were, Vincent .................................................................................................................. P-162Werneburg, Nathan .......................................................................................................... P-092West, Joe ........................................................................................................................ P-032Wicha, Max ..................................................................................................................... P-081Widau, Ryan ................................................................................................................... P-066Wilson, W. David ................................................................................................................O-26Winograd, Paul ..................................................................................................................O-18Wisniewski, Tami .............................................................................................................. P-016Wolff, Robert ......................................................................................................................O-02Won, Kyoung Sook ........................................................................................................... P-096Wong, Carmen Chak-Lui ..............................................................................O-29, P-060, P-120Wong, Ching .................................................................................................................... P-071Wong, Chun Ming ............................................................................................................ P-120Wong, Nathalie ................................................................................................................ P-098

Wong, Robert ........................................................................................................ P-014, P-015Woo, Ha ............................................................................................................................O-33Wu, Jaw-Ching ...............................................................................P-030, P-133, P-198, P-215Wu, Tsung-Han ............................................................................................................... P-212Xia, Jinglin ....................................................................................................................... P-165Xia, Qiang ........................................................................................................................ P-140Xiao, Feng Ming ............................................................................................................... P-105Xiao, Lei .......................................................................................................................... P-159Xiao, Yao ......................................................................................................................... P-152Xiao, Zhiyu..............................................................................................................O-24, P-135Xin, Bing ............................................................................................................................O-25Xin, Wei ........................................................................................................................... P-113Xiong, Yi .......................................................................................................................... P-159Xu, Dabo ......................................................................................................................... P-081Xu, Li .............................................................................................................................. P-112Xu, Li Tao ........................................................................................................................ P-166Xu, Meng ......................................................................................................................... P-004Xu, Yang ............................................................................................................... P-023, P-140Yamada, Hiroyuki ............................................................................................................. P-179Yamasaki, Takahiro ............................................................................................... P-059, P-164Yamashita, Tatsuya ........................................................................................................... P-020Yan, Yongcong ........................................................................................................O-24, P-135Yang, Hyun ........................................................................................................... P-190, P-144Yang, Jin Mo ......................................................................................................... P-085, P-161Yang, Jingchun ............................................................................................................... P-008Yang, Ju Dong ...................................................................................................... P-014, P-088Yang, Wanshui ................................................................................................................. P-050Yang, Xiaozhen ................................................................................................................ P-107Yang, Xin ......................................................................................................................... P-159Yano, Hirohisa ....................................................................................................................O-33Yao, James ........................................................................................................................O-02Yao, Shen ..........................................................................................................................O-04Yasui, Shin ............................................................................................................ P-039, P-061Yasui, Yutaka ................................................................................................................... P-163Yau, Thomas ............................................................................ O-01, O-13, O-14, P-021, P-111Yen, Chia Jui ......................................................................................................... P-029, P-066Yeon, Jong Eun ............................................................................................................... P-062Yim, Hyung Joon .................................................................................................. P-062, P-080Yoo, Kwon ....................................................................................................................... P-117Yoo, Sun Hong ...................................................................................................... P-085, P-161Yoon, Jun Sik ................................................................................................................... P-038Yoon, Jung ...................................................................................................................... P-118Yoon, Jung-Hwan ............................................................................................................. P-038Yoon, Ki Tae .......................................................................................................... P-080, P-117Yoon, Sang Min ..................................................................................................... P-018, P-028Yoon, Seung Kew ................................................................ P-031, P-085, P-144, P-161, P-190Yopp, Adam ............................................................................................................O-20, P-084Yousif, Sarra ......................................................................................................... P-137, P-167Yu, Jie .................................................................................................................. P-087, P-200Yu, Min-Cheng ................................................................................................................. P-023Yu, Ming-Chin ....................................................................................................... P-145, P-212Yu, Ming-Lung ...................................................................................................... P-175, P-205Yu, Su Jong ..................................................................................................................... P-038Yujin, Kwon ...................................................................................................................... P-188Zagonel, Vittorina ...............................................................................................................O-15Zanaga, Leticia ................................................................................................................ P-026Zang, Chaoran ...................................................................................................... P-107, P-178Zapata, Rodrigo ..............................................................................P-026, P-048, P-089, P-134Zeh III, Herbert ................................................................................................................. P-084Zekry, Amany .....................................................................................................................O-30Zeng, Yongyi ......................................................................................................... P-128, P-129Zeng, Zhao-Chong .............................................................................................................O-17Zhang, Fan ...................................................................................................................... P-104Zhang, He........................................................................................................................ P-146Zhang, Honghai ............................................................................................................... P-107Zhang, Jianlong ............................................................................................................... P-135Zhang, Kai ...................................................................................................................... P-121Zhang, Meizhuo ............................................................................................................... P-013Zhang, Xuehong ......................................................................................................O-21, P-050Zhang, Yaojun ....................................................................................................... P-027, P-112Zhang, Yifan .................................................................................................................... P-113Zhang, Yonghong .......................................................................................P-107, P-123, P-178

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