Post on 28-Sep-2020
Be a Surgical “Multiplier” in MIGS Inspire Brilliance Through Teamwork
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Scientific Program ChairJubilee Brown, MD
Honorary ChairBarbara S. Levy, MD
PresidentMarie Fidela R. Paraiso, MD
SYLLABUSLate Breaking News
Professional Education Information
Target Audience This educational activity is developed to meet the needs of surgical gynecologists in practice and in training, as well as other healthcare professionals in the field of gynecology. Accreditation AAGL is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAGL designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. DISCLOSURE OF RELEVANT FINANCIAL RELATIONSHIPS As a provider accredited by the Accreditation Council for Continuing Medical Education, AAGL must ensure balance, independence, and objectivity in all CME activities to promote improvements in health care and not proprietary interests of a commercial interest. The provider controls all decisions related to identification of CME needs, determination of educational objectives, selection and presentation of content, selection of all persons and organizations that will be in a position to control the content, selection of educational methods, and evaluation of the activity. Course chairs, planning committee members, presenters, authors, moderators, panel members, and others in a position to control the content of this activity are required to disclose relevant financial relationships with commercial interests related to the subject matter of this educational activity. Learners are able to assess the potential for commercial bias in information when complete disclosure, resolution of conflicts of interest, and acknowledgment of commercial support are provided prior to the activity. Informed learners are the final safeguards in assuring that a CME activity is independent from commercial support. We believe this mechanism contributes to the transparency and accountability of CME. ANTI-HARASSMENT STATEMENT AAGL encourages its members to interact with each other for the purposes of professional development and scholarly interchange so that all members may learn, network, and enjoy the company of colleagues in a professional atmosphere. Consequently, it is the policy of the AAGL to provide an environment free from all forms of discrimination, harassment, and retaliation to its members and guests at all regional educational meetings or courses, the annual global congress (i.e. annual meeting), and AAGL-hosted social events (AAGL sponsored activities). Every individual associated with the AAGL has a duty to maintain this environment free of harassment and intimidation. Any individual covered by this policy who believes that he or she has been subjected to such an inappropriate incident has three (3) options for reporting:
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Table of Contents Course Description ........................................................................................................................................ 1 Disclosure ...................................................................................................................................................... 2
A Randomized Controlled Non-Inferiority Trial of Reduced Versus Routine Opioid Prescription after Prolapse Repair E.R.W. Davidson ........................................................................................................................................... 3
How Low Should We Go? Examining Low Quantities of Opioid Tablets After Ambulatory Gynecologic Laparoscopy: A Randomized Controlled Trial K.M. Plewniak................................................................................................................................................ 6
Postoperative Opioid Prescriptions Following Enhanced Recovery After Surgery (ERAS) Implementation in Minimally Invasive Gynecologic Surgery: A Retrospective Cohort Study L.A. Christianson ........................................................................................................................................... 9
UTERUS-11 Study: A Randomized Clinical Trial on Surgical Staging versus CT-Staging Prior to Primary Chemoradiation in Patients with FIGO2009 Stages IIB-IVA Cervical Cancer A.T. Tsunoda ............................................................................................................................................... 11
Laparoscopic Visual Contained In-Bag Morcellation versus Uncontained Conventional Morcellation of Fibroids and Large Uterus with Fibroids – a Research Study P.H. Trivedi ................................................................................................................................................. 14
Outcomes of Women Undergoing Trachelectomy After Supracervical Hysterectomy M.P. McHale ............................................................................................................................................... 16
Abnormal Pathology seen on Appendectomy in Patients with Predominant Right-Sided Pelvic PainK.Sisler ......................................................................................................................................................... 17
Molecular Characterization and Diagnosis of Endometriosis to Aid in Surgical Resection using Ambient Ionization Mass Spectrometry M.T. Breen .................................................................................................................................................. 18
Cultural and Linguistics Competency ......................................................................................................... 23
Late Breaking News
Moderator: Nutan Jain, Eric R. Sokol
Faculty: Michael T. Breen, Lee A. Christianson, Emily R.W. Davidson, Melissa P. McHale, Kari M. Plewniak, Katelin Sisler, Audrey T. Tsunoda, Prakash H. Trivedi
Discussant: Mauricio S. Abrao, Liane M. Belland Sean Dowdy, Stephanie N. Morris, Lois M. Ramondetta, Yukio Sonoda
Course Description The late breaking news session will highlight research that focuses on significant advancements, techniques, complications, new information and important findings as they exist within the field of minimally invasive gynecology and best practice.
Course Objectives At the conclusion of this activity, the participant will be able to: 1) Address late breaking news containing new information and important findings in the field of minimally invasive gynecology.
Course Outline
2:00 E.R.W. Davidson
2:05 K.M. Plewniak
2:10 L.A. Christianson
2:15 2:20 A.T. Tsunoda
2:28 P.H. Trivedi
2:36 M.P. McHale
2:44 K. Sisler
2:52
A Randomized Controlled Non-Inferiority Trial of Reduced Versus Routine Opioid Prescription after Prolapse Repair How Low Should We Go? Examining Low Quantities of Opioid Tablets After Ambulatory Gynecologic Laparoscopy: A Randomized Controlled Trial Postoperative Opioid Prescriptions Following Enhanced Recovery After Surgery (ERAS) Implementation in Minimally Invasive Gynecologic Surgery: A Retrospective Cohort Study Discussant for the first three papers: S. Dowdy UTERUS-11 Study: A Randomized Clinical Trial on Surgical Staging versus CT-Staging Prior to Primary Chemoradiation in Patients with FIGO2009 Stages IIB-IVA Cervical Cancer Discussant: L.M. Ramondetta Laparoscopic Visual Contained In-Bag Morcellation versus Uncontained Conventional Morcellation of Fibroids and Large Uterus with Fibroids – a Research Study Discussant: Yukio Sonoda Outcomes of Women Undergoing Trachelectomy After Supracervical Hysterectomy Discussant: L.M. Belland Abnormal Pathology seen on Appendectomy in Patients with Predominant Right-Sided Pelvic PainDiscussant: S.N. Morris Molecular Characterization and Diagnosis of Endometriosis to Aid in Surgical Resection using Ambient Ionization Mass Spectrometry Discussant: M.S. Abrao
M.T. Breen
Page 1
PLANNER DISCLOSURE The following members of AAGL have been involved in the educational planning of this workshop (listed in alphabetical order by last name). Art Arellano, Professional Education Director, AAGL* Linda D. Bradley, Medical Director, AAGL* Erin T. Carey Consultant: MedIQ Mark W. Dassel Contracted Research: Myovant Sciences Erica Dun* Adi Katz* Linda Michels, Executive Director, AAGL* Erinn M. Myers Speakers Bureau: Laborie Medical Technologies, Teleflex Medical Other: Unrestricted educational grant to support NC FPMRS Fellow Cadaver Lab: Boston Scientific Corp. Inc. Amy Park* Grace Phan, Professional Education Specialist, AAGL* Harold Y. Wu* Linda C. Yang Other: Ownership Interest: KLAAS LLC
SCIENTIFIC PROGRAM COMMITTEE Linda D. Bradley, Medical Director, AAGL* Jubilee Brown* Nichole Mahnert* Shanti Indira Mohling* Fariba Mohtashami Consultant: Hologic Marie Fidela R. Paraiso* Shailesh P. Puntambekar* Matthew T. Siedhoff Consultant: Applied Medical, Caldera Medical, CooperSurgical, Olympus Amanda C. Yunker Consultant: Olympus Linda Michels, Executive Director, AAGL*
FACULTY DISCLOSURE
The following have agreed to provide verbal disclosure of their relationships prior to their presentations. They have also agreed to support their presentations and clinical recommendations with the “best available evidence” from medical literature (in alphabetical order by last name). Mauricio S. Abrao Consultant: AbbVie, Chugai Pharmaceuticals, Johnson & Johnson Contracted Research: Myovant Other: Advisory Board: AbbVie, Applied Medical, Bayer Healthcare Corp. Liane M. Belland* Michael T. Breen* Lee A. Christianson* Emily R.W. Davidson* Sean Dowdy* Nutan Jain* Melissa P. McHale* Stephanie N. Morris* Kari M. Plewniak* Lois M. Ramondetta* Katelin Sisler* Eric R. Sokol Stock Ownership: Pelvalon Other: Grant funding to Stanford University: Acell, Coloplast, Cook MyoSite Other: Travel reimbursement: Contura Yukio Sonoda* Prakash H. Trivedi* Audrey T. Tsunoda Other: Honorarium for educational lectures: AstraZeneca, Roche
Content Reviewer has nothing to disclose.
Asterisk (*) denotes no financial relationships to disclose.
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A Randomized Controlled Non-Inferiority Trial of Reduced Versus Routine Opioid Prescription After Prolapse Repair
Emily R.W. Davidson, MDMarie Fidela R. Paraiso, MD; Mark Walters, MD; Katie Propst, MD; Beri Ridgeway, MD; Meng Yao, MS; Cecile A. Ferrando, MD MPH
Cleveland Clinic
Disclosures
• I have no financial relationships to disclose.
Objectives
• Recognize the reality of excess postoperativeprescribing
• Compare patient satisfaction after reducingpostoperative opioid quantities
• Evaluate prescribing practices consideringthe principle of opioid stewardship
Background
• Opioid epidemic is deadly - 130 deaths per day1
• Excess opioid prescribed after surgery2-5
- Gynecology patients use 10 of 30+ tabs prescribed2-5
• Risks – diversion, abuse, persistent use6
• …so why are we still overprescribing?
- Patient satisfaction concerns
Study Design• Hypothesis: There will be no difference in patient
satisfaction with postoperative pain control whenreducing postoperative opioid quantity.
• Two-arm, unmasked, single-center RCT of womenundergoing prolapse repair
• Primary outcome: satisfaction at postop visit
118 patients randomized
116 patients with follow-up
Reduced arm: 5 tablets of oxycodone 5mg (n=59)
Routine arm: 28 tablets of oxycodone 5mg (n=59)
All patients received multimodal pain therapy
Page 3
All Subjects (n=118)
Age 62 (±10.4)
Race• White• Black• Hispanic• Other
106 (91.4%)5 (4.3%)1 (0.9%)4 (3.4%)
Post-menopausal 99 (83.9%)
Surgery Type‐ Hyst + Native Tissue Repair‐ Vaginal Colpopexy‐ Hysteropexy‐ SCP
71 (60.2%)18 (15.3%)18 (15.3%)11 (9.3%)
No difference in smoking status, highest level of education, or household income.
Results: Primary Outcome
* = statistical analysis by Farrington-Manning score test for non-inferiority with a 15% margin
All 5 tabs 28 tabs p value
Satisfaction – Yes 108 (93.1%) 53 (93.0%) 55 (93.2%) 0.005*
Satisfaction with pain controlVery Satisfied Somewhat SatisfiedNeutralSomewhat Unsatisfied Very Unsatisfied
96 (82.8%)12 (10.3%)2 (1.7%)1 (0.9%)5 (4.3%)
47 (82.5%)6 (10.5%)1 (1.8%)0 (0%)3 (5.3%)
49 (83.1%)5 (10.2%)1 (1.7%)1(1.7%)2 (3.4%)
0.88
More than originally prescribed?
9 (8.3%) 8 (14.8%) 1 (1.9%) 0.01
Willing to destroy? 101 (95.3%) 50 (94.3%) 51 (96.2) 0.65
# used oxycodone tablets 2 (IQR 0-5.75) 1 (IQR 0-3) 3 (IQR 0-14) 0.03
# unused oxycodone tablets 5 (IQR 3-26) 4 (IQR 2-5) 26 (IQR 15-28) <0.01
Summary of Findings
• Significant opioid excess (1500 vs 230 tabs)
• Prescribing reduced opioids leads to:- Non-inferior satisfaction with pain control
- 15% incidence of needed refills
- Fewer opioid tablets used
- Fewer excess opioid tablets
Conclusions
• Opioid stewardship
• Be aware of the excess
• Surgeons may prescribe fewer opioids afterprolapse surgery without impacting patientsatisfaction- Consider 5-10 tabs for most patients- Recommend multimodal pain treatment
• Systems for disposal of excess opioid
References
1. The opioid epidemic: By the numbers [CDC Website].
2. Swenson CW, Kelley AS, Fenner DE, Berger MB. Outpatient narcotic use after minimally invasiveurogynecologic surgery. Female Pelvic Med Reconstr Surg. 2016;22(5):377-81.
3. Kendall CG, Nisse VC, Department of Gynecology B, et al. Opioid prescription and patient use after gynecologic procedures: A survey of patients and providers. Journal of Minimally Invasive Gynecology. 2018;0(0).
4. Hota LS, Warda HA, Haviland MJ, Searle FM, Hacker MR. Opioid use following gynecologic and pelvicreconstructive surgery. Int Urogynecol J. 2017.
5. Griffith KC, Clark NV, Zuckerman AL, Ferzandi TR, Wright KN. Opioid prescription and patient use after gynecologic procedures: A survey of patients and providers. J Minim Invasive Gynecol. 2017.
6. Bates C, Laciak R, Southwick A, Bishoff J. Overprescription of postoperative narcotics: A look at postoperative pain medication delivery, consumption and disposal in urological practice. J Urol. 2011;185(2):551-5.
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Patient Eligibility
Inclusion:
• Women 18 years of age or older undergoing a Urogyn procedure with an anticipated overnight hospital admission
- vaginal hysterectomy with vault suspension, sacrospinousligament fixation, hysteropexy, and minimally invasive sacrocolpopexy
Exclusion:
• Chronic pain
• Preoperative opioid use
• Intolerance to study medications
• Score >30 on Pain Catastrophizing Scale
Statistical Power and Analysis
• 59 patients per group, 118 patients- predicted satisfaction of 92%1
- 15% non-inferiority index
- 90% power, 0.05 alpha- 2 additional patients per group due to no-show rate
• Primary outcome: Farrington-Manning-test for non-inferiority; intention-to-treat analysis
• Other outcomes: Student’s t test, chi square, or Mann-Whitney U for nonparametric data
1. Crisp CC, Khan M, Lambers DL, et al. The Effect of Intravenous Acetaminophen on Postoperative Pain and Narcotic Consumption After Vaginal Reconstructive Surgery: A Double-Blind Randomized Placebo-Controlled Trial. Female Pelvic Med Reconstr Surg. 2017;23(2):80-85.
Strengths
• Among the first to study reduction of postoperative opioid use on satisfaction
• Patient population widely applicable to Urogynecology- Potential for extrapolation to other
populations
Limitations
• Inclusion/exclusion criteria- Minor surgeries, chronic pain, NSAIDs
• Protocol deviations- Same day discharge, medication
intolerance
• Patient compliance with surveys- Limits medication counts, daily activities
Acknowledgement
Marie Fidela R. Paraiso, MD; Mark Walters, MD;
Katie Propst, MD; Beri Ridgeway, MD; Meng Yao, MS;
Cecile A. Ferrando, MD MPH
Cleveland Clinic
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How Low Should We Go? Examining Low Quantities of Opioid Tablets After Ambulatory Gynecologic Laparoscopy: A Randomized Control Trial
Minimally Invasive Gynecologic SurgeryDepartment of Obstetrics & Gynecology and Women’s Health
Montefiore Health System
Kari M Plewniak, MD, FACOG
Disclosure
I have no financial relationships to
disclose.
Objectives
• Examine current practices for
postoperative prescriptions of opioids
• Examine whether prescribing 5 mg 5
tablets of oxycodone with acetaminophen
and ibuprofen adequately treats pain after
minor gynecologic laparoscopy
Background
SOURCE: CDC/NCHS, National Vital Statistics System, Mortality.
Patient comfort
Patient convenience
Excess pills
Avoiding urgent visits
Risks of new persistent use
Safe storage/ disposal
Expectation management
Lacking evidence-
based guidelines
New Persistent Opioid Use
Wright et al 2019
Page 6
Pills Prescribed and Taken After Laparoscopic Cholecystectomy
(Hill et al., 2017)
Study Design• Randomized single-blinded• Objective: to assess if 5 tablets is sufficient for post
operative analgesia
Study Design
• ≥ 18 years old
• Benign minor gynecologic laparoscopy
- (hysterectomy excluded)
• No contraindication to medications
• No chronic opioid use/ treatment for abuse ● Median taken 2.0 tablets and 2.5 tablets (5 vs 10 tab)● 31.8% and 28.3% took no oxycodone● 68.2% and 65.2% took 3 or less tablets
Tablets Used by Day 7
Unscheduled Patient Contact and Treatment Change Within 7 Days
Conclusions
• 5 tablets 5 mg oxycodone is likely sufficient for the
majority of patients
• Decreasing excess pills while still...
○ Keeping pain scores still low
○ Very few refills needed
Page 7
1. Hedegaard H, Miniño AM, Warner M. Drug overdose deaths in the United States, 1999–2017.
NCHS Data Brief, no 329. Hyattsville, MD: National Center for Health Statistics. 2018.
https://www.cdc.gov/nchs/products/databriefs/db329.htm
2. Wright JD, Huang Y, Melamed A, Tergas AI, St Clair CM, Hou JY, Khoury-Collado F, Ananth CV,
Neugut AI, Hershman DL. Use and Misuse of Opioids After Gynecologic Surgical Procedures. Obstet
Gynecol. 2019 Aug;134(2):250-260.
3. Hill MV, McMahon ML, Stucke RS, Barth RJ Jr. Wide Variation and Excessive Dosage of Opioid
Prescriptions for Common General Surgical Procedures. Ann Surg. 2017;265(4):709-714.
4. Eid AI, DePesa C, Nordestgaard AT, et al. Variation of Opioid Prescribing Patterns among Patients
undergoing Similar Surgery on the Same Acute Care Surgery Service of the Same Institution: Time
for Standardization? Surgery. 2018;164(5):926-930.
5. Hota LS, Warda HA, Haviland MJ, Searle FM, Hacker MR. Opioid use following gynecologic and
pelvic reconstructive surgery. Int Urogynecol J. 2018;29(10):1441-1445.
ReferencesEmily Kintzer MD, Ja Hyun Shin MD
Minimally Invasive Gynecologic Surgery
Department of Obstetrics & Gynecology and Women’s Health
Montefiore Health System
Acknowledgment
Page 8
Postoperative Opioid Prescriptions Following Enhanced Recovery After Surgery (ERAS)
Implementation in Minimally Invasive Gynecologic Surgery: A Retrospective Cohort Study
Lee A Christianson MD FACOGMinimally Invasive Gynecologic Surgery
University Medical PartnersStanford OB/GYN Partners for Health
*Research during FMIGS fellowship at Legacy Health, Portland, OR
Disclosure
I have no financial relationships to disclose
Objectives
● Compare surgeon postoperative opioid prescribing practices pre and post Enhanced Recovery After Surgery (ERAS) implementation following minimally invasive gynecologic surgery
● Observe the effect of ERAS implementation on filling additional opioid prescriptions in the 90 days following minimally invasive gynecologic surgery
● Examine persistent postoperative opioid use following minimally invasive gynecologic surgery
Opioid Epidemic
● Deaths from prescription opioids have more than quadrupled since 1999 1
● Opioids frequently prescribed for acute postoperative pain control following minimally invasive hysterectomy despite a lack of prescribing guidelines
● Surgeons prescribe four times the amount of opioids needed for minimally invasive hysterectomy 2
● Estimated 8.8 million oxycodone 5 mg tablets remain in medicine cabinets unused annually from hysterectomy alone 3
Enhanced Recovery After Surgery (ERAS)
● Multimodal, multidisciplinary approach to care of the surgical patient comprised of evidence-based perioperative care measures designed to reduce surgical stress and maintain normal physiologic function postoperatively. 4-6
● Promotes multimodal, non-opioid approach to analgesia 6-8
○ Acetaminophen○ NSAIDs○ Gabapentin
Methods
● Retrospective cohort study in large community-based healthcare system in Portland, OR
● Women undergoing minimally invasive gynecologic surgery in 2015 and 2017 by five high volume subspecialty gynecologic surgeons
● ERAS perioperative care was implemented system wide in April 2016
● Opioid prescription data was collected from the Oregon Prescription Drug Monitoring Program (PDMP) from 90 days preoperatively to 12 months postoperatively.
● Pre and postoperative opioid prescription data was utilized to classified patients as opioid naïve, exposed or tolerant. 9,10
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Results: Demographics and Surgical Characteristics
Total patients (n = 386) Pre ERAS (n = 177)
Post ERAS (n = 209)
p value
Age (mean) 55.4 59.5 0.08
BMI (mean) 31.1 29.7 0.66
Race, n(%) 0.36
Caucasian 158 (89.3) 186 (89.0)
Hispanic/Latino 5 (2.8) 11 (5.3)
Other 14 (7.9) 12 (5.7)
Smoking, n(%) 20 (11.3) 12 (5.7) 0.14
Insurance, n(%) 0.45
Commercial 95 (53.7) 103 (49.3)
Medicare/Medicaid 82 (46.3) 103 (49.3)
Other 1 (.6) 4 (1.9)
Anxiety, n(%) 19 (10.7) 40 (19.1) 0.03
Depression, n(%) 33 (18.6) 32 (15.3) 0.39
Gynecologic Malignancy, n(%)
61 (34.5) 89 (42.6) 0.13
BMI = Body mass index, ERAS = Enhanced Recovery After Surgery
Total patients (n = 386) Pre ERAS (n = 177)
Post ERAS (n = 209)
p value
Preoperative Opioid Classification, n(%)
0.38
Opioid Naïve 85 (48.0) 124 (59.3)
Opioid Exposed 59 (33.3) 61 (29.2)
Opioid Tolerant 2 (1.1) 4 (1.9)
Opioid History Unknown
31 (17.5) 20 (9.6)
Surgical Procedures, n(%)
Robotic assisted 150 (84.7) 184 (88.0) 0.42
Hysterectomy 114 (64.4) 146 (69.9) 0.30
Operative Time (minutes) 130 150 < 0.01
Length of Stay (days) 1.30 1.16 < 0.01
Postoperative Opioid Prescription OutcomesAll patients
(n=321)Pre ERAS (n = 140)
Post ERAS (n = 181)
p value
Filled surgical prescription*, n(%) 284 (88.5) 122 (87.1) 162 (89.5) 0.63Opioid amount, mean MME (IQ range) 265 (180-338) 296 (225-375) 242 (180-300) <0.001
Filled second prescription**, n(%) 91 (28.4) 39 (27.9) 52 (31.4) 0.96Total additional dispensed opioid amount***, mean MME (IQ range)
214 (0-150) 272 (0-191) 170 (0-150) 0.70
* Prescription dispensed closes to surgery date, corrected for opioid tolerance and unknown opioid history** Dispensed between surgical date and 90 days postoperatively, corrected for opioid tolerance and unknown opioid history*** All additional prescriptions to 90 days postoperatively, surgical prescription excluded, corrected for opioid tolerance and unknown opioid status ERAS = Enhanced Recovery After Surgery, MME = morphine milliequivalents, IQ = inner quartile
Persistent Postoperative Opioid UseAll opioid
naïve patients (n = 209)
Pre ERAS (n = 85)
Post ERAS (n = 124)
P value
Opioid Naïve with Persistent Postoperative Opioid Use, n (%)
8 (3.8%) 2 (2.4%) 6 (4.8%) 0.47
ERAS = Enhanced Recovery After Surgery
• Two large retrospective cohort studies of opioid naïve surgical patients estimated persistent postoperative opioid use ranges from 3.1% to 6.5% 11
• For minimally invasive hysterectomy specifically, one study estimated persistent postoperative opioid use in opioid naïve patients at 1.5% 12
Conclusion
● ERAS implementation reduced the mean opioid initially prescribed for postoperative pain management following minimally invasive gynecologic surgery without an increase in additional opioid filled up to 90 days post surgery.
● Trend towards a reduction in the mean MME for additional opioids prescriptions filled up to 90 days post surgery with ERAS implementation.
● Persistent postoperative opioid use is a potential risk for opioid naïve patients undergoing minimally invasive gynecologic surgery.
References1. Prevention, Center for Disease Control, Annual Surveillance Report of Drug-Related Risks and Outcomes - United States, 2017., U.S. Department for
Health and Human Services, Center for Disease Control and Prevention, Editor. 2017.
2. Wong, M., et al., Opioid use after laparoscopic hysterectomy: prescriptions, patient use, and a predictive calculator. Am J Obstet Gynecol, 2019. 220(3): p. 259 e1-259 e11.
3. Moulder, J.K., et al., Opioid Use in the Postoperative Arena: Global Reduction in Opioids After Surgery Through Enhanced Recovery and Gynecologic Surgery. Clin Obstet Gynecol, 2019. 62(1): p. 67-86.
4. Nelson, G., et al., Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS(R)) Society recommendations--Part II. Gynecol Oncol, 2016. 140(2): p. 323-32.
5. Nelson, G., et al., Guidelines for pre- and intra-operative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS(R)) Society recommendations--Part I. Gynecol Oncol, 2016. 140(2): p. 313-22.
6. Nelson, G., et al., Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations-2019 update. Int J Gynecol Cancer, 2019.
7. Kalogera, E. and S.C. Dowdy, Enhanced Recovery Pathway in Gynecologic Surgery: Improving Outcomes Through Evidence-Based Medicine. ObstetGynecol Clin North Am, 2016. 43(3): p. 551-73.
8. ACOG Committee Opinion No. 750 Summary: Perioperative Pathways: Enhanced Recovery After Surgery. Obstet Gynecol, 2018. 132(3): p. 801-802.
9. Edwards, D.A., et al., American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Management of Patients on Preoperative Opioid Therapy. Anesth Analg, 2019.
10. Kent, M.L., et al., American Society for Enhanced Recovery and Perioperative Quality Initiative-4 Joint Consensus Statement on Persistent Postoperative Opioid Use: Definition, Incidence, Risk Factors, and Health Care System Initiatives. Anesth Analg, 2019.
11. As-Sanie, S., et al., Opioid Prescribing Patterns, Patient Use, and Postoperative Pain After Hysterectomy for Benign Indications. Obstet Gynecol, 2017. 130(6): p. 1261-1268.
12. Clarke, H., et al., Rates and risk factors for prolonged opioid use after major surgery: population based cohort study. BMJ, 2014. 348: p. g1251.
Page 10
UTERUS-11 Study: A Randomized Clinical Trial on Surgical Staging versus CT-Staging
Prior to Primary Chemoradiation in Patients with FIGO2009 Stages IIB-IVA Cervical Cancer
Audrey T Tsunoda, MD, PhDGynecologic Oncology Department - Hospital Erasto Gaertner
Professor at Positivo University
Disclosure
Other: Honorarium for educational lectures: AstraZeneca, Roche
Objectives
● At the conclusion of this presentation, the audience will be able to estimate the results obtained in the first large RCT comparing clinical staging versus surgical staging for locally advanced cervical cancer
Co-authors
Marnitz S, Tsunoda A, Martus P, Vieira M, Affonso RJ,
Nunes JS, Budach V, Schneider A, Hertel H, Mustea A,
Sehouli J, Plaikner A, Ebert A, Köhler C.
simone.marnitz‐schulze@uk‐koeln.de
christhardt.koehler@uk‐koeln.de
atsunoda@gmail.com
Background and Rationale Clinical vs. Surgical Staging
•Considerable limitations of imaging (CT,MRI,PET-CT) with risk of under- and
overstaging (Ramirez P 2011)
•The only randomised trial failed due to imbalanced stages and high radiation
toxicity, and was terminated prematurely after 65 patients (Lai CH 2003)
•Different recommendations in national and international guidelines (NCCN
4.2019, ESGO Guidelines)
•Clear evidence: Surgical staging leads to upstaging in a relevant percentage
of patients with locally advcanced cervical cancer, but oncologic benefit has
been discussed controversially (Gouy S 2013, Marnitz S 2016)
Study Design Patients with histologically proven cervical cancer FIGO stages IIB‐IVA
Randomisation
Arm A:
Surgical staging (n=125)
Arm B: Clinical staging (n=125) including
CT‐Abdomen (± CT‐guided paraaortic FNAC/Bx)
Positive paraaortic
lymph nodes
Primary pelvic chemo‐radiation including extended field
5 y Follow‐up
Negative paraaortic lymph nodes
Positive paraaortic
lymph nodes
Primary pelvic chemoradiation
5 y Follow‐up
Primary pelvic chemo‐radiation including extended
field
5 y Follow‐up
Page 11
Endpoints and Study Design
•Prospective randomized, two arms, multicentric study (Charité Berlin, Barretos Cancer Center Brazil, 8 German study centers)
•Primary Endpoint
•PFS•Secondary Endpoints•OS•Local Control•Acute and Late Toxicity•Quality of Life, Sexuality
Arm A ‐ Surgical Staging Arm B – Clinical Staging P
Randomised Patients 130 125
Eligible Patients 121 119
Mean Age (years) 47.2 49.6 n.s.
BMI 26.2 26.2 n.s.
FIGO‐ Stage IIBIIIAIIIBIVA
70%3.5%24%2.5%
67%5%20%8%
n.s.
Removed pelvic nodes (median) 19 ‐‐ ‐‐
Removed paraaortic nodes (median) 17 ‐‐ ‐‐
Pelvic lymph node metastases (mean) 2.4 ‐‐ ‐‐
Paraaortic lymph node metastases (mean) 1.3 ‐‐ ‐‐
Patients´ Characteristics
Quality of the Surgical Procedure
• Laparoscopic approach 96.7%
•Conversion to open approach: n=1 (0.8%)
•due to obesity and severe adhesions
•Blood Loss >500 cc: n=2 (1.6%)
•Delay of primary chemo‐radiation: n=2
•4 and 5 days, respectively
• Intraoperative Mortality n=0
Köhler C, et al. Perioperative morbidity …Am J Obstet Gynecol 2015; 213;503.e1‐7
Upstaging after Surgical Staging
FIGO Stage IIB IIIA IIIB IVA IVB all Upstaging Arm A
IIB 64 0 0 4 17 85 21/85 (24.7%)
IIIA 0 2 0 0 2 4 2/4 (50%)
IIIB 0 0 14 4 11 29 15/29 (51.7%)
IVA 0 0 0 1 2 3 2/3 (66.6%)
All 64 2 14 9 32 121 40/121 (33%)
Tsunoda AT, Marnitz S, Soares Nunes J, Mattos de Cunha Andrade CE, Scapulatempo Neto C, Blohmer JU, Herrmann J, Kerr LM, Martus P, Schneider A, Favero G, Köhler C. Incidence of histologically proven pelvic and para‐aortic lymph node metastases and rate of upstaging in patients with locally advanced cervical cancer:
results of a prospective randomized trial. Oncology (Karger) 2017;92:213‐220
Clinical Arm (Arm B):patients with positive CT‐guided paraaortic punction: 7/114 (6%)
Chemo‐radiation related Toxicity
•Time Surgery to Chemo‐RT start: 7‐21 days
•Techniques: IMRT: 64% / 3D‐RT: 36%
•No grade 5 toxicity was observed during CRT
Marnitz S, Martus P, Köhler C, Stromberger C, Asse E, Mallmann P, Schmidberger H, Affonso R, Nunes JS, Sehouli J, Budach V. Role of surgical versus clinical staging in chemo‐radiated FIGO stage IIB‐IVA cervical cancer patients. Acute toxicity and treatment quality of the Uterus‐11 multicenter phase
III Intergroup trial of the German Radiation Oncology Group (ARO) and the Gynecologic Cancer Group (AGO). Int J Radiat Oncol Biol Phys 2016;94:243‐253
0 23 45 68 90
Week 8 GI Tox
Week 6 GI Tox
Week 4 GI Tox
Week 2 GI Tox
GI Toxicity Surgical Arm A
Grade 4 Grade 3
Grade 2 Grade 1
Grade 0
0 25 50 75 100
Week 8 GI Tox
Week 6 GI Tox
Week 4 GI Tox
Week 2 GI Tox
GI Toxicity Clinical Arm B
Grade 4 Grade 3
Grade 2 Grade 1
Grade 0
0 25 50 75 100
Week 8 GU Tox
Week 6 GU Tox
Week 4 GU Tox
Week 2 GU Tox
GU Toxicity Surgical Arm A
Grade 4
Grade 3
Grade 2
Grade 1
Grade 0
0 25 50 75 100
Week 8 GU Tox
Week 6 GU Tox
Week 4 GU Tox
Week 2 GU Tox
GU Toxicity Clinical Arm B
Grade 4
Grade 3
Grade 2
Grade 1
Grade 0
Marnitz S, Martus P, Köhler C, Stromberger C, Asse E, Mallmann P, Schmidberger H, Affonso R, Nunes JS, Sehouli J, Budach V. Role of surgical versus clinical staging in chemo‐radiated FIGO stage IIB‐IVA cervical cancer patients. Acute toxicity and treatment quality of the Uterus‐11 multicenter phase
III Intergroup trial of the German Radiation Oncology Group (ARO) and the Gynecologic Cancer Group (AGO). Int J Radiat Oncol Biol Phys 2016;94:243‐253
Chemo‐radiation related Toxicity
Page 12
Oncologic Results
p = 0.088n.s.
p = 0.068n.s.
p = 0.028significant
Median follow‐up 90 months in both arms
Progression‐free survival (PFS)
Overall survival (OS) Cancer‐specific survival (CSS)
Arm A (surgical staging)Arm B(clinical staging)
Arm A (surgical staging)Arm B(clinical staging)
Arm A (surgical staging)Arm B(clinical staging)
•Uterus‐11 is the only completed prospective
randomised trial on surgical staging
•nearly all surgical staging procedures done by
minimally invasive approach
•exclusively use of modern radiation techniques
• long‐term median follow‐up (90 months)
•high data completeness ‐ 6 pts. (2.5%) lost to
follow up
Strengths and Weaknesses•no PET‐CT included (no
recommendation‐no
reimbursement)
•FIGO stage IB2 (old FIGO) could not
be included
•Rate of para‐aortic nodes was too
optimistic
Conclusions
• Laparoscopic surgical staging is a safe procedure and lead to >30% upstaging rate
• Surgical staging does neither delay primary CRT nor increases complication rates
• We demonstrated a significant cancer‐specific survival benefit in favor for (laparoscopic)
staging compared to clinical staging
• With regard to survival, distant metastases are the most common cause of death in locally
advanced cervical cancer patients, there is an urgent need for more effective systemic
treatments
Acknowledgements
All patients and families
•Prof. Christhardt Kohler and Prof. Simone Marnitz for the mentorship
•Barretos Cancer Center Colleagues (Gyn Oncol, Medical Oncology, Radiation Oncology, Radiology) for recruiting >30% of the study patients
•Study Nurses Silvia B. (Charité Berlin) and Talita G. (Barretos)
References
• Ramirez PT, Jhingran A, Macapinlac HA, Euscher ED, Munsell MF, Coleman RL, et al: Laparoscopic extraperitoneal para-aortic lymphadenectomy in locally advanced cervical cancer: a prospective correlation of surgical findings with positron emission tomography/computed tomography findings. Cancer 2011; 117: 1928–1934Smits et al. 2014
• Lai CH, Huang KG, Hong JH, Lee CL, Chou HH, Chang TC, et al: Randomized trial of surgical staging (extraperitoneal or laparoscopic) versus clinical staging in locally advanced cervical cancer. Gynecol Oncol 2003; 89: 160–167
• Cervical Cancer NCCN 4.2019
• ESGO Guidelines for Cervical Cancer
• Gouy S, Morice P, Narducci F, Uzan C, Martinez A, Rey A, et al: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer
undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 2013; 31: 3026–
3033.
• Kohler C, Mustea A, Marnitz S, Schneider A, Chiantera V, Ulrich U, et al: Perioperative morbidity and rate of upstaging after laparoscopic staging for patients with locally advanced cervical cancer: results of a prospective randomized trial. Am J Obstet Gynecol 2015; 213: 503.e1–e7.
• Tsunoda AT, Marnitz S, Soares Nunes J, Mattos de Cunha Andrade CE, Scapulatempo Neto C, Blohmer JU, Herrmann J, Kerr LM, Martus P, Schneider A, Favero G, Köhler C. Incidence of histologically proven pelvic and para-aortic lymph node metastases and rate of upstaging in patients with locally advanced cervical cancer: results of a prospective randomized trial. Oncology (Karger) 2017;92:213-220
• Marnitz S, Martus P, Köhler C, Stromberger C, Asse E, Mallmann P, Schmidberger H, Affonso R, Nunes JS, Sehouli J, Budach V. Role of surgical versus clinical
staging in chemo-radiated FIGO stage IIB-IVA cervical cancer patients. Acute toxicity and treatment quality of the Uterus-11 multicenter phase III Intergroup trial of the
German Radiation Oncology Group (ARO) and the Gynecologic Cancer Group (AGO). Int J Radiat Oncol Biol Phys 2016;94:243-253
Page 13
Laparoscopic visual contained in-bag morcellation versus uncontained
conventional morcellation of fibroids and large uterus with fibroids –
A Research Study
Dr. Prakash TrivediMD, DNB, FCPS
Director : Trivedi’s Total Health Care Hospital , Mumbai, India
Disclosure
“I have NO financial relationships to disclose”
Objectives
● To evaluate the feasibilility & safety of visual contained laparoscopic power morcellationfor fibroids & large uterus with fibroids.
● To evaluate duration of surgery, blood loss, complications, histopathology & patient parameters during morcellation.
● Study of 426 cases of Laparoscopic visual contained bag morcellation of fibroids & large uterus with fibroid for > 4 years from 14th May, 2015
● Compared to 430 cases of uncontained conventional morcellation of over 4 years from 14th May 2011
● At Trivedi’s Total Health Care Centre- a tertiary referral centre for Fibroids in India
PROBLEMS OF POWER MORCELLATION
● Trauma
● Tissue Disruption
● Dispersion
What is the ONE STEP in myomectomy under our Control??
● Vasopression Infiltration/ Aquadissection● Myometrial Incision● Fibroid Enucleation● Myometrial Closure● Fibroids lying in peritoneal cavity during closure● NONE when spillage is concerned● ONLY STEP WE CAN CONTAIN IS
MORCELLATION
Page 14
Sample under observation
INSERT FILM HERE
Demographic and clinical characteristics of patientsParameters- Conventional Electromechanical morcellation
Parameters - Contained Electro- Mechanical Morcellation
RESULTS
• No case of leiomyosarcoma or mortality in either (856 cases over 8 years).
• No evidence of residual tumor/parasitic spread 6 months post-op on IMAGING MRI & USG
• In both conventional or contained bag morcellation the mean operating time and mean blood loss were comparable,
• For specimen weighing upto2200 grams, with multiple fibroids upto 17 in number and maximum diameter of 20 cms, contained bag morcellationwas feasible.
• Out of 426 cases of Visual Contained Morcellation, 5 Complications
• 2 Conversion to Conventional Morcellation due to uncorrectable Bag Twisting
• 1 Conversion to Open/Mini-Lap retrieval due to Large Calcified fibroid
• 2 Port-Site Wound Infection
Research to Question our Thinking…
● AHRQ-ACOG 1,36,195 cases-160 meta-analysis research reveals very low risk for leiomyosarcoma - 0.02-0.08%.1 Prevalence of leiomyosarcoma was 0.67% out of 10731 uteri morcellated.2
● Vienna Oncology hospitals revealed that out of 71 cases of leiomyosarcoma back traced, none started from fibroid.3
● Pathology text book mentions that leiomyosarcomas are due to a selective gene supressions, but fibroid is due to gene expression. Hence leiomyosarcoma developing from fibroid is a myth & unlikely.4
Scientific Debates & Arguments
● After all steps of Laparoscopic myomectomy are done just putting the specimen in bag, widening the port incision followed by blind cold knife morcellation with 9.2% bag puncture rate is not a safe option.5
● MRI guided FUS and uterine artery embolization are accepted in treatment for fibroid without tissue diagnosis.
● Also laparoscopic radical hysterectomy with lymphadenectomy is accepted, where we deal with proven cancer. Only morcellation becomes the culprit in cases of fibroid.
● Uncontained laparoscopic morcellation has liability of residual fibroids, port site fibroid & leiomyomatosis which can be reduced by contained visual bag morcellation.
Conclusion
Our study of 856 cases over 8 years of laparoscopic removal of fibroids clearly shows visual contained in bag morcellation reduces spillage and improves intraoperative patient’s parameters during morcellation & reduces residual or port site fibroid, becomes a step of extra care to give option of MAS surgery benefits in thousands of women, who deserve it.
References
1. Hartmann KE, Fonnesbeck C, Surawicz T, Krishnaswami S, Andrews JC, Wilson JE, et al. Management of uterine fibroids. Comparative Effectiveness Review No. 195,2017, AHRQ Publication No. 17(18)-EHC028-EF. Rockville (MD): Agency for Healthcare Research and Quality:ES 12
2. Bojahr B, De Wilde RL, Tchartchian G. Malignancy rate of 10,731 uteri morcellated during laparoscopic supracervicalhysterectomy (LASH). Arch Gynecol Obstet 2015;292:665–72.
3. Mayerhofer K, Obermair A, Windbichler G, Petru E, Kaider A, Hefler L, Czerwenka K, Leodolter S, Kainz C. Leiomyosarcoma of the uterus: a clinicopathologic multicenter study of 71 cases.Gynecol Oncol. 1999 Aug;74(2):196-201.
4. Quade BJ, Wang TY, Sornberger K, Dal Cin P, Mutter GL, Morton CC. Molecular pathogenesis of uterine smooth muscle tumors from transcriptional profiling. Genes Chromosomes Cancer. 2004 Jun;40(2):97-108.
5. Cohen SL, Morris SN, Brown DN, et al. Contained tissue extraction using power morcellation: prospective evaluation of leakage parameters. Am J Obstet Gynecol 2016;214:257.e1-6.
Page 15
Title: Outcomes of Women Undergoing Trachelectomy After Supracervical Hysterectomy Authors: McHale MP, Smith AJB, Wethington SL, Fader AN, Objective: Gynecologic surgical subspecialists are frequently consulted for trachelectomy after supracervical hysterectomy. We aimed to characterize the indications and complication rates of women who underwent trachelectomy after supracervical hysterectomy. Design and Subject Selection: We performed a retrospective cohort study of women undergoing trachelectomy after hysterectomy in the 2010-2014 National Inpatient Sample (n=230). ICD-9 codes were utilized to identify indications for trachelectomy and post-procedure pathology. We weighted the hospital-level data to obtain nationwide estimates of patient characteristics, surgical complications, and length of stay. Results: Nationwide, 1,140 women underwent trachelectomy after hysterectomy. The mean age was 49 (95%CI 47-50). The majority of women were white (57%, 95%CI 50-63) and privately-insured (64%, 95%CI 58-70). Fibroids were the most common indication for trachelectomy (35%, 95%CI 29-42) followed by prolapse (14%, 95%CI 9-18). Around 6% (95%CI 3-9) were performed for uterine cancer, 4% (95%CI 2-7) for cervical cancer, 4% (95%CI 1-6) for ovarian cancer, and 1% (95%CI 0-2) for other gynecologic cancers. Only 2% (95%CI 0-4) of trachelectomies were performed laparoscopically; the remainder were performed via an abdominal or vaginal approach. Five percent (95%CI 2-8) of women experienced a urogenital complication, most commonly a urinary tract infection (3%, 95%CI 1-6) or bladder injury (1%, 95%CI 0-2). The median length of stay was 3.7 days (95%CI 3.2-4.3). Conclusions: Women undergoing trachelectomy had high rates of complications and findings of cancer. Supracervical hysterectomy subjects patients to a second surgery for which a minimally invasive approach is often not performed and which carries an increased risk of urologic injury and prolonged hospital admission when compared to that reported for a total hysterectomy. Strong consideration should be given to removal of the cervix at the time of hysterectomy except under exceptional circumstances.
Page 16
Abnormal Pathology seen on Appendectomy in Patients with Predominant Right-Sided Pelvic Pain
Katelin Sisler, PGY4 Saint Louis University Ob/Gyn Study Objective: To determine the prevalence of abnormal pathology within the appendix in women with predominantly right-sided chronic pelvic pain (CPP) compared to generalized chronic pelvic pain. Design: A retrospective case-control study. Setting: Tertiary care center in St. Louis, MO. Patients: 220 women who underwent diagnostic laparoscopy and planned or incidental appendectomy for CPP and suspected endometriosis between January 2015 and December 2018. Interventions: None Results: No significant difference in abnormal appendix pathology was found between women with predominantly right-sided CPP (cases) and women without predominantly right-sided CPP (controls) (30.9% versus 34.5%, p=0.74, odds ratio = 0.85, 95% CI: (0.44, 1.62)). Regardless of where the patient had chronic pain, the incidence of abnormal pathology was found to be 30.6% in macroscopically normal appearing appendices and 37.5% in appendices with gross abnormalities. Conclusion: In this study, the presence of abnormal pathology within the appendix did not correlate with right-sided CPP or abnormal appearance of the appendix. However, performing routine appendectomy may be reasonable for any woman with CPP given the significant rates of abnormal pathology of the appendix found when removed. This study supports the practice of routine appendectomy for patients with CPP by general surgeons and gynecologists.
Page 17
Ambient Ionization Mass Spectrometry for Molecular Characterization of Surgical Diagnosis of Endometriosis
Michael T Breen, MD
AAGL 2019
University of Texas Dell School of Medical SchoolDirector Robotics and Minimally Invasive Surgery
I have no financial relationships to disclose.
2
Disclosure
Explore and evaluate novel technology (Mass Spectrometry) to characterize metabolic and proteomic markers in endometriosis patients using desorption electrospray ionization (DESI) and Mass Spectrometry Pen.
Identify diagnostic markers of endometriosis from ectopic tissue biopsies from endometriosis patients and unaffected patients.
Discuss the potential of Mas Spec Pen as an intraoperative tool for in vivo endometriosis detection in laparoscopic surgeries.
3
Objectives
4
10% of women have endometriosis
176 million women worldwide live with endometriosis – About 10x more people than the total number of people who are diagnosed with cancer each year
In 2017, the NIH allocated 6 million dollars of its 32.3 billion dollar budget to endometriosis research – the same amount allocated to seasonal allergy research
Pediatric and Adolescent gynecology literature focusing awareness toward physical and psychological effects of adenomyosis in adolescent patients.
www.cancer.gov/about-cancer/understanding/statistics
https://report.nih.gov/categorical_spending.aspx
www.mayoclinic.org/diseases-conditions/endometriosis/
Symptoms can include pelvic pain, abdominal distortion, and subfertility.
Currently, causes and pathogenesis of endometriosis is unclear and no proposed biomarkers have proven capable of disease diagnosis.
Diagnosis can take from 5-20 years
Typically, the best treatment option is laparoscopic removal of endometriosis lesions, although ~50% of patients see recurrence of lesions within five years.
Menarche to menopause can be relentless
5
Endometriosis is uncontrolled growth of endometrial tissue outside the uterus Current endometriosis diagnosis procedure
Pelvic Exam
Ultrasound
MRI
6
Challenges:
Non-specific symptoms and comorbidity
Large health care costs and risks
Hesitancy to establish a diagnosis in adolescent population
Page 18
Endometrial Stroma
Endometrial Glands
Hemosiderin
2 histological featured observed
Endometriosis diagnosis
Endometriosis histology
Challenges:
Healthy and endometriosis endometrial
glands/stroma are histologically
identical
Heterogeneity and size of lesions
Permanent pathology does not provide
information about margins or address
atypical lesions in real time.
7
Desorption electrospray ionization (DESI) mass spectrometry for disease characterization
Y
X Moving Stage
VSolvent
N2
Desorbed Ions
%
Rel
. Abu
ndan
ce (
%)
m/z
Rel
. Abu
ndan
ce (
%)
m/z
Rel
. Abu
ndan
ce (
%)
m/z
0 100 0 100 0 100% %
1 mm
5
Scan 1 Scan 2 Scan 3
Scan 1 Scan 2 Scan 3
Desorption electrospray ionization (DESI) mass spectrometry for disease characterization
Y
X Moving Stage
VSolvent
N2
Desorbed Ions
%
Rel
. Abu
ndan
ce (
%)
m/z
Rel
. Abu
ndan
ce (
%)
m/z
Rel
. Abu
ndan
ce (
%)
m/z
0 100 0 100 0 100% %
1 mm
Advantages:
Targeting of specific cellular environments
within heterogeneous samples
Excellent chemical specificity and detection of
relative abundance alterations
Easily translatable into the clinic
5
Perform DESI-MS imaging to analyze healthy endometrium and endometriosis lesions
Develop a tissue classification model to distinguish the endometrial glands and stroma from healthy endometrium and endometriosis lesions
Use mass spectrometry molecular data to evaluate biological differences between healthy endometrium and endometriosis that may give insights into potential pathogenesis and biomarkers of endometriosis.
Can ambient ionization MS help us detect and understand endometriosis?
8
Prospectively collected and sectioned 269 endometrium
and endometriosis samples from
89 patients
DESI-MS analysis in the negative ion
mode at 100 μm spatial
resolution
Pathological evaluation of samples for isolation of endometrial
stroma tissue
Statistical analysis of
molecular data
1) Differentiation between endometrium and
endometriosis stroma
2) Identify molecules showing significant
differences between tissue types
Our DESI-MS imaging workflow
9
2-3 endometriosis surgeries per week
Collection took ~2 years
DESI-MS metabolic profiles of endometrium and endometriosis stroma
Endometrium
1000100 200 300 400 500 600 700 800 900m/z
0
20
40
60
80
100
0
20
40
60
80
100
Re
lativ
e A
bu
nd
an
ce (
%)
PI 38:4885.549
FA 16:0255.233 FA 18:1
281.249 PE 38:4766.539
PS 36:1788.545
FA 20:4303.233
FA 18:1281.249
FA 20:4303.233FA 16:0
255.233
CL 72:8723.478
Endometriosis
Re
lativ
e A
bu
nd
an
ce (
%)
700 720 740 760 780 800 820 840 860 880 900m/z
0
20
40
60
80
100
0
20
40
60
80
100
PE 38:4766.539PE-P 36:4
722.513 PS 36:1788.545
PS 40:4838.560
ST 40:1888.566
PI 38:4885.549
ST 40:1888.566
PI 34:2833.518
Patient #30
PS 36:1788.545
PI 38:4885.549
CL 72:8723.478 PE 38:4
766.539
PS 36:1788.545
PI 38:4885.549
Metabolic profiles of healthy endometrium and endometriosis
Iodine126.905
Endometrium
Endometriosis
8
Page 19
En
do
met
riu
mE
nd
om
etri
osi
s
m/z 766.538PE 38:4
m/z 126.905Iodine
m/z 246.951m/z 788.545
PS 36:1m/z 279.233
FA 16:2m/z 885.549
PI 38:4
Relative A
bundance
0%
100%
1 mm 200 μm
500 μm 100 μm
1 mm 500 μm
1 mm 250 μm
H&E Stained Histology
DESI-MS ion images of healthy endometrium endometriosis
9
Statistical analysis of DESI-MS imaging data
m/z values
pixe
ls
Pathological diagnosis Molecular information
1 mm
%
100
0
~ 30,000 pixels
~ 500 m/z values per pixel
15 million data points!!!
Courtesy of Jonathan Young
12
100%
0%
Ion
inte
nsi
ty
Statistical classification of endometriosis by lasso
73 samples from 36 patients
Training Set
44 endometriosis (3,616 pixels)
15 endometrium (13,329 pixels)
Validation Set
11 endometriosis (1,330 pixels)
3 endometrium (3,886 pixels)
Test Set
21 endometriosis (2,369 pixels)
4 endometrium (4,263 pixels)
Sensitivity: 98.0%Specificity: 88.8%
Overall accuracy: 90.8%
Sensitivity: 99.5%Specificity: 99.3%
Overall accuracy: 99.3%
Sensitivity: 98.0%Specificity: 100.0%
Overall accuracy: 99.3%
14
25 samples from 14 patients
-70 -50 -30 -10 10 30 50 70 90
887.56
255.23
788.54766.54
479.36421.22331.26
307.27303.23
281.25279.23
246.96226.99
215.05201.04
187.04137.03
126.91
Selected m/z features
Ind
icative of E
nd
om
etrium
Ind
icat
ive
of
En
do
met
rio
sis
Lasso weight
Selected lasso features for distinguishing healthy endometrial and endometriosis tissue
m/z Identification
887.558 PI 18:0_20:4†
788.544 PS 18:1_18:0
766.538 PE 18:0_20:4
421.226 Dioctyl sulfosuccinate
331.264 FA 22:4
307.264 FA 20:2
303.233 FA 20:4
281.249 FA 18:1
279.233 FA 18:2
255.233 FA 16:0
226.997 Isocitric acid [M+Cl]
215.033 Hexose [M+Cl]
201.038 Lactate [2M-2H+Na]
137.036 Urocanic acid
126.905 Iodine
*Annotation XX:Y signifies (number of carbons):(level of unsaturation of the FA chains)† Indicates isotopic peak
15
Biological relevance of selected metabolites
m/z Identification
887.558 PI 18:0_20:3
788.544 PS 18:1_18:0
766.538 PE 18:0_20:4
421.226 Dioctyl sulfosuccinate
331.264 FA 22:4
307.264 FA 20:2
303.233 FA 20:4
281.249 FA 18:1
279.233 FA 18:2
255.233 FA 16:0
226.997 Isocitric acid [M+Cl]
215.033 Hexose [M+Cl]
201.038 Lactate [2M-2H+Na]
137.036 Urocanic acid
126.905 Iodine
Glycerophosphoethanolamine (PE) 18:0_20:4
Glycerophosphoserine (PS) 18:0_18:1
16
Chagovets, V. V. et al. Sci. Rep. 2017, 7, 2546.Dutta, M et al. J. Proteome Res. 2016, 15, 2626-2633.Leventis, P. A et al. Annu. Rev. Biophys. 2010, 39, 407-427.
Indicative of Endometriosis
Indicative of Endometrium
Biological relevance of selected metabolites
m/z Identification
887.558 PI 18:0_20:3
788.544 PS 18:1_18:0
766.538 PE 18:0_20:4
421.226 Dioctyl sulfosuccinate
331.264 FA 22:4
307.264 FA 20:2
303.233 FA 20:4
281.249 FA 18:1
279.233 FA 18:2
255.233 FA 16:0
226.997 Isocitric acid [M+Cl]
215.033 Hexose [M+Cl]
201.038 Lactate [2M-2H+Na]
137.036 Urocanic acid
126.905 Iodine
FA 18:1 (Oleic Acid)
FA 18:2 (Linoleic acid)
FA 22:4 (Adrenic Acid)
FA 20:4 (Arachidonic Acid)
Gazvani, M. R., et al. Fertil. Steril., 76, 717-722.Hopeman, M. M, et al. S. Reprod. Sci. 2015, 22, 1083-1087. 17
Indicative of Endometriosis
Indicative of Endometrium
Page 20
-70 -50 -30 -10 10 30 50 70 90
Glycerophosphoinisitol (38:3)
Linoleic acid
Glycerophosphoserine (36:1)
Glycerophosphoethanolamine (38:4)
Dioctyl sulfosuccinate
Palmitic acid
Isocitric acid
Hexose
Lactic acid
Selected m/z features
Ind
icative of E
nd
om
etrium
Ind
icat
ive
of
En
do
met
rio
sis
Lasso weight
15 identified, biologically relevant species that are different between healthy endometrium and endometriosis tissue
20
Adrenic acid
Arachidonic acid
Oleic acid
Eicosadienoic acid
Urocanic acid
Iodine
-70 -50 -30 -10 10 30 50 70 90
Glycerophosphoinisitol (38:3)
Linoleic acid
Glycerophosphoserine (36:1)
Glycerophosphoethanolamine (38:4)
Dioctyl sulfosuccinate
Palmitic acid
Isocitric acid
Hexose
Lactic acid
Selected m/z features
Ind
icative of E
nd
om
etriumIn
dic
ativ
e o
f E
nd
om
etri
osi
s
Lasso weight
15 identified, biologically relevant species that are different between healthy endometrium and endometriosis tissue
20
Adrenic acid
Arachidonic acid
Oleic acid
Eicosadienoic acid
Urocanic acid
Iodine
While healthy endometrium and endometriosis tissue are histologically
identical, our data suggests they are not molecularly identical!
Challenges associated with endometriosis surgery
Endometriosis lesions can have a variety of appearances, some of which can be difficult to identify.
Endometriosis can present as “invisible” microscopic lesions that are difficult for even expert surgeons to remove. Margins of excision can be unclear
Many women undergoing endometriosis surgery are doing so to increase fertility, making conservation of healthy tissue extremely important.
Dinic, S. P.-T. et al. Laparoscopic Surgery in the Treatment of Endometriosis. In Fertility-oriented Female Reproductive Surgery, Darwish, A., Rijeka, 2017; p Ch. 04.
16
The MasSpec Pen: A tool for mass spectral analysis
Biocompatible
Non-destructive
Capable of in vivo tissue analysis
Real-time automated feedback of disease state
17
Zhang, J. et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Science Translational Medicine 2017, 9 (406).
Page 21
Use of MS imaging to collect spatial and molecular information from healthy endometrium and endometriosis lesions has been validated.
Ability to distinguish between healthy endometrium and endometriosis glands and stroma with an overall accuracy of 99.3% per pixel on an independent test set of samples.
Identification of 15 species with altered abundances between healthy endometrium and endometriosis glands and stroma, suggesting them as possibly relevant for endometriosis pathogenesis and potential disease biomarkers.
Conclusions
21
Ongoing validation of Mass Spectrometry accuracy and utility in Endometriosis management.
Porcine in vivo studies for evaluation of technology in CO2 laparoscopic environment.
Future IRB submission for human in vivo intraoperative Mass Spectrometry analysis of endometriosis (in preparation).
Identification of adenomyosis unique Mass Spec Signature.
Extrapolation and validation to assist in adolescent endometriosis.
27
Future Applications
28
Acknowledgments
Dr. Livia S. EberlinMacArthur Foundation Fellow
UT Austin Chemistry Department
• Prof. Livia S. Eberlin• Spencer Woody• Dr. Jialing Zhang• Anna Krieger• Eberlin Research Lab• Clara Fielder
Dr. Michael T. Breen Dr. Suzanne LedetKatherine Sebastian
Acknowledgments
Eberlin Group
Clinical collaborators
External funding and resources
22
1. www.cancer.gov/about-cancer/understanding/statistics2. https://report.nih.gov/categorical_spending.aspx3. www.mayoclinic.org/diseases-conditions/endometriosis/4. Chagovets, V. V. et al. Endometriosis foci differentiation by rapid lipid profiling using tissue spray ionization and high resolution mass
spectrometry.Sci. Rep. 2017, 7, 2546.5. Dutta, M et al. Metabolomics Reveals Altered Lipid Metabolism in a Mouse Model of Endometriosis. J. Proteome Res. 2016, 15, 2626-2633.6. Leventis, P. A et al. The distribution and function of phosphatidylserine in cellular membranes. Annu. Rev. Biophys. 2010, 39, 407-4277. Gazvani, M. R., et al. High omega-3:omega-6 fatty acid ratios in culture medium reduce endometrial-cell survival in combined endometrial
gland and stromal cell cultures from women with and without endometriosis. Fertil. Steril., 2001,76, 717-722.8. Hopeman, M. M, et al. Serum Polyunsaturated Fatty Acids and Endometriosis. Reprod. Sci. 2015, 22, 1083-1087.9. Dinic, S. P.-T. et al. Laparoscopic Surgery in the Treatment of Endometriosis. In Fertility-oriented Female Reproductive Surgery, Darwish, A.,
Rijeka, 2017; p Ch. 04.10. Zhang, J. et al. Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system. Science
Translational Medicine 2017, 9 (406).11. Barbar G. et al. When love hurts. A systematic review on the effects of surgical and pharmacological treatments for endometriosis on female
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References
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CULTURAL AND LINGUISTIC COMPETENCY Governor Arnold Schwarzenegger signed into law AB 1195 (eff. 7/1/06) requiring local CME providers, such as
the AAGL, to assist in enhancing the cultural and linguistic competency of California’s physicians
(researchers and doctors without patient contact are exempt). This mandate follows the federal Civil Rights Act of 1964, Executive Order 13166 (2000) and the Dymally-Alatorre Bilingual Services Act (1973), all of which
recognize, as confirmed by the US Census Bureau, that substantial numbers of patients possess limited English proficiency (LEP).
California Business & Professions Code §2190.1(c)(3) requires a review and explanation of the laws
identified above so as to fulfill AAGL’s obligations pursuant to California law. Additional guidance is provided by the Institute for Medical Quality at http://www.imq.org
Title VI of the Civil Rights Act of 1964 prohibits recipients of federal financial assistance from
discriminating against or otherwise excluding individuals on the basis of race, color, or national origin in any of their activities. In 1974, the US Supreme Court recognized LEP individuals as potential victims of national
origin discrimination. In all situations, federal agencies are required to assess the number or proportion of LEP individuals in the eligible service population, the frequency with which they come into contact with the
program, the importance of the services, and the resources available to the recipient, including the mix of oral
and written language services. Additional details may be found in the Department of Justice Policy Guidance Document: Enforcement of Title VI of the Civil Rights Act of 1964 http://www.usdoj.gov/crt/cor/pubs.htm.
Executive Order 13166,”Improving Access to Services for Persons with Limited English
Proficiency”, signed by the President on August 11, 2000 http://www.usdoj.gov/crt/cor/13166.htm was the genesis of the Guidance Document mentioned above. The Executive Order requires all federal agencies,
including those which provide federal financial assistance, to examine the services they provide, identify any
need for services to LEP individuals, and develop and implement a system to provide those services so LEP persons can have meaningful access.
Dymally-Alatorre Bilingual Services Act (California Government Code §7290 et seq.) requires every
California state agency which either provides information to, or has contact with, the public to provide bilingual
interpreters as well as translated materials explaining those services whenever the local agency serves LEP members of a group whose numbers exceed 5% of the general population.
~
If you add staff to assist with LEP patients, confirm their translation skills, not just their language skills.
A 2007 Northern California study from Sutter Health confirmed that being bilingual does not guarantee competence as a medical interpreter. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2078538.
US Population
Language Spoken at Home
English
Spanish
AsianOther
Indo-Euro
California
Language Spoken at Home
Spanish
English
OtherAsian
Indo-Euro
19.7% of the US Population speaks a language other than English at home In California, this number is 42.5%
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