Advances in the Detection and Evaluation of Barrett's Esophagus:

Has a paradigm shift occurred?

New York Society for Gastrointestinal Endoscopy

December 18, 2015

Dr. Seth Gross

Overview of WATS3D

The Problem

Adenocarcinoma – A Disease with a Rapidly Increasing Incidence

AdenoCa Esoph

Melanoma

Prostate

Lung/Breast

Colon

Pohl H et al. J Natl Cancer Inst 2005;97:142-6.

Not Much Progress Being Made…

Incidence

Mortality

Pohl H et al. J Natl Cancer Inst 2005;97:142-6.

Trends in EAC

Kong CY et al, CEBP, 2014.

We are Losing the Battle Against Esophageal Adenocarcinoma

Most Presentation is Late-Stage

Schlansky B et al. Aliment Pharmacol Therap, 2006.

• Case-control study in the KP Bay Area population

• Cases: Pts with known BE who died of EAC, 1995-2009• Controls: Pts from the pop with BE who did not die of EAC

• Matched for age, sex, and duration of f/u

• Exposure: Surveillance endoscopy in 3 yrs prior to index date

• Basic idea is that those dying of CA should be less likely to have surveillance exam than those who did not die

“Since dysplasia has no distinctive gross features, endoscopists collect random samples of esophageal tissue for biopsy; thus sampling error is a major problem.

By the time biopsy specimens show high-grade dysplasia in patients with Barrett’s esophagus, approximately one third of patients have an invasive cancer. Extensive sampling can reduce this problem but cannot eliminate it…Despite its shortcomings, endoscopy with random sampling for dysplasia remains the clinical standard for managing Barrett’s esophagus.”

Spechler SJ. Clinical practice. Barrett's Esophagus. N Engl J Med 2002; 346

“Sampling error is a major problem”

Invasive cancerIntramucosal cancer

Dysplasia

Limitations of the Random Biopsy

in the Detection of Barrett’s Esophagus

“The distribution of goblet cells is patchy within the columnar lined distal esophagus. The yield of intestinal metaplasia on biopsies obtained from the columnar lined esophagus will depend on the length of columnar mucosa as well as the number of biopsies obtained.”

Prateek Sharma, Barrett’s Esophagus and Esophageal Adenocarcinoma, 2001

• Random biopsy yield of IM in VSSBE of less than 1cm (evidenced as an irregular Z-line) = 15%

• Random biopsy yield of IM in SSBE of less than 3cm = 58%

Wallner et al, Scan. J of Gastroenterology 2000

Limitations of the Random Biopsy

in the Detection of Barrett’s Esophagus

Dysplastic Very Short Segment Barrett’s Esophagus

15

Forceps biopsies were negative for both BE and dysplasia

Unlike Cytology, the WATS3D Biopsy Obtains a

Complete Transepithelial Tissue Sample of the

Entire Thickness of the Esophageal Mucosa

16

The wider surface area sampled by the transepithelial WATS

biopsy addresses this problem

Forceps biopsy has a significant

potential for sampling error

Why didn’t anyone think of this before?

• WATS transepithelial tissue samples are routinely over 100μ thick, 50X thicker than the 2μ thick cytology or histology sample.

• This uniquely thick specimen consists of a complex mixture of disaggregated 3D tissue fragments which needs to be exhaustively searched by the pathologist for evidence of abnormality.

Neural Network Based 3D Imaging Analyzes the 100µ Thick WATS3D Tissue Sample by Synthesizing 100, 1 Micron Optical Slices.

Three Dimensional Image Capture and Computer

Analysis – U.S. Pat. No. 8,199,997

EDF Image

Images captured at

different z-planes

EDF Processing

Limited DOF

XYBoth X+Y

objects are in

focus

A

B

C

X

Y

• Extended Depth of Field WATS3D computer analysis keeps all objects within the microscopic field of view in focus in 1 µ slices.

• Every 1 µ focal plane is captured up to a 100 μspecimen.

20

• Computer Analysis presents to the pathologist a 3D Image Synthesized from Multiple 1μ Optical Slices.

• 196 areas/sample in the 3D display image are highlighted for the pathologist by the neural network.

Detailed Scanner Architecture

Low

40X

Medium

10X

High

20X

Centroid

Coordinates

Slide Map ReAcquire

selected cells

DSP:

- Coverslip,

- Bubble,

- Empty

~10,000

centroids/

slide

~1000 med.

res. fields

Bayesian

Classifier:

Cell level

Slide level

DSP:

Preprocess

Math Morph.

Cluster NN

- Base

- Geometric

Color

Grouping

Color - HSI

K-means

Feature

Extraction

Segment

Nucleus size,

Nuc. IOD,

N/C ratio,

Moments,

Texture,

Curvature

Abnormality

Score

Neural Nets:

Single NN

- Base

- Specialized

Cell Selection

Focus Map Focus Map

Cluster

Geometry

Focus

21 743 5 6

Neural Net

• Training by back-propagation

• Iteratively adjust connection weights in the direction that moves the outputs towards the desired values

f1 f2 f3 f4 f5

h1 h2

o1

f6

h3 h4

w1 w2 w3 w4 w5 w6

o1

25

HG - Individual cells separating from the edge of the cluster

02-01-KC

HG- Pleomorphic cells

02-06-B-G

Carcinoma - Clusters of pleomorphic cells within lymphatic spaces

02-17-RM

HG - Multiple variations

02-23-PC

02 25-RM

HG - Multiple variations

Introduction to WATS3D Data

• Unless testing a specific, identified lesion or performing a complete microscopic analysis of an entire tissue specimen, “test sensitivity” is not a relevant metric.

• For techniques designed to increase the detection of additional occult abnormality, the primary statistical metric is “Added Yield”

• Added Yield = Additional detection of disease resulting from addition of adjunctive test /Detection without addition of the adjunctive test

WATS3D is an Adjunctive Test

• In all studies clinicians are advised to continue to use their FB to test those areas of the esophagus which appear most suspicious endoscopically and to use WATS3D to test additional tissue.

• WATS3D and FB results are expected to differ because the two biopsy techniques are being used to test different tissue areas.

• Contingency table/Confusion matrix therefore has limited value.

Dr. Nicholas J. Shaheen

DDW 2014 Presidential Plenary Session:

Esophageal Brush Biopsy With Computer-

Assisted Tissue Analysis Increases Detection

of Barrett’s Esophagus and Dysplasia In A

Multi-Site Community-Based Setting

Seth A. Gross1, Vivek Kaul2; Anthony Infantolino3; Michael S. Smith4

1.Medicine/Gastroenterology, New York University Medical Center, New York, NY, United States.

2.Medicine/Gastroenterology, University of Rochester School of Medicine, Rochester, NY, United States.

3.Medicine/Gastroenterology, Thomas Jefferson University, Philadelphia, PA, United States.

4.Medicine/Gastroenterology, Temple University School of Medicine, Philadelphia, PA, United States.

Aim

• The goal of this study of 2,559 patients was to assess the benefits of WATS3D in routine community practice.

Methods

• Retrospective review of prospectively collected data

• Multi-site: 28 community based gastroenterologists

• Patients had both FB and WATS3D

• FB and WATS3D samples were sent to a central laboratory (CDx DiagnosticsTM, Suffern, NY).

• Absolute yield of BE using FB alone = 15%

• Absolute yield of BE after addition of WATS3D = 25%

• Added yield of BE resulting from addition of WATS3D = 68.4% (95% CI 58%-80%)

• NNT = 9.6

BE FB + FB - Total

WATS3D + 194 258 462

WATS3D - 183 1863 2046

Total 377 2121 2498

Dysplasia FB + FB - Total

WATS3D + 11 11 22

WATS3D - 6 2470 2476

Total 17 2481 2498

• Absolute yield of dysplasia on FB alone = 0.24%• Absolute yield of dysplasia after adding WATS3D = 0.68%• Added yield of dysplasia resulting from the addition of

WATS3D = 64.7% (95% CI 25%-142%)

ACG 2014

Increased Detection of Barrett’s Esophagus and Dysplasia in Community Gastroenterology Practices Resulting From the Addition of Computer-Assisted Transepithelial Brush Biopsy to Forceps Biopsy

Seth Gross1, Vivek Kaul2, Michael S. Smith3

1.Medicine/Gastroenterology, New York Univ. Medical Center, New York, NY

2.Medicine/Gastroenterology, Univ. of Rochester School of Medicine, Rochester, NY

3.Medicine/Gastroenterology, Temple Univ. School of Medicine, Philadelphia, PA,

• A prospective registry with 19 New Community Practices undergoing screening or surveillance endoscopy with both FB and WATS3D

• 1655 patients, average age was 59 years (43% male)

• The indication for endoscopy was GERD in over 75% of patients

• In cases with suspected BE, segment length was less than 3 cm

• FB alone identified BE in 203 cases (12%), and dysplasia in 9 cases (0.54%)

• WATS3D identified an additional 203 cases of BE, increasing the absolute yield for BE to 25%.

• WATS3D also detected an additional 12 cases of dysplasia, increasing the absolute yield for dysplasia to 1.26%.

• Added Yields of 110% for BE and 133% for dysplasia.

ACG 2015

• Study of over 12,000 patients in community-based settings

• WATS3D Biopsy Oral Presentation

• Wednesday, October 21, 7:00 – 7:10 AM

• Kalakaua Ballroom A

• First author is Dr. Erkanda P. Ikonomi, Department of Internal Medicine, Temple University Hospital, Philadelphia, PA

• All adults with a history of BE undergoing surveillance upper endoscopy between June 2012 and October 2014 at two tertiary-care, high-volume Barrett’s centers

• Cases were included in the analysis if they had:

• Prior RFA or SCT for treatment of BE• No visual evidence of BE during surveillance endoscopy• WATS3D and FB both performed during the same session

with results available for review

WATS3D Is Beneficial When Used For Post-Ablation Surveillance

Iorio et al. DDW 2015 Presentation 345

IM/Dysplasia/ Neoplasia

Forceps BiopsyPositive

Forceps Biopsy Negative

Total

WATS3D Positive 15 24 39

WATS3D Negative 24 145 169

Total 39 (18.8%) 169 208

Dysplasia/ NeoplasiaForceps Biopsy

PositiveForceps Biopsy

NegativeTotal

WATS3D Positive 0 4 4

WATS3D Negative 7 197 204

Total 7 (3.4%) 201 208

• With the addition of WATS3D to FB, the rate of detecting any metaplasia or dysplasia increases by 11.5% (from 18.8 to 30.3%) with a relative yield increase of 61.5%

• For dysplasia alone, the incremental yield of adding WATS3D to FB is 1.9% (from 3.4 to 5.3%); the augmented yield is 57.1%

• NNT for any metaplasia or dysplasia is 8.7, and 52.6 for dysplasia alone

Adjunctive Benefit of WATS3D

following Barrett’s Ablation

42%

57.10%

39.8%42%

68.4%64.7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Anandasabapathy S et al. Kataria RD et al. Johanson JF et al. Gross S et al. Gross S et al. Gerson L et al.

Barr

ett

’s E

sophagus

Barr

ett

’s E

sophagus

Dyspla

sia

Dyspla

sia

Post-

Abla

tion B

arr

ett

’s E

sophagus

Barr

ett

’s E

sophagus a

nd

Dyspla

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Cross-Sectional Data - Added Yield of Barrett’s Esophagus and Dysplasia

Incre

ased D

iagnostic Y

ield

with

Ad

junctive U

se

of

WA

TS

3D

N = 1,266 N = 2,559 N = 2,559 N = 151 N = 31 N = 1,699

Meta-analysisSurveillance Screening

1. Anandasabapathy et al. Dig Dis Sci, e-pub

2. Kataria et al. American College of Gastroenterology Annual Meeting; October 11-16, 2013; San Diego, California. Abstract P23.

3. Johanson et al. Dig Dis Sci, e-pub

4. Gross et al. Digestive Disease Week; May 18-21, 2014; Chicago. Abstract Su1452.

5. Gerson et al. Digestive Disease Week; May 18-21, 2014; Chicago. Abstract Sa1833.

Summary of Cross-Sectional Data

• Adjunctive use of WATS3D has been shown in large studies to markedly increase the detection of both BE and dysplasia in both community screening and academic surveillance settings.

• While substitutive use was not directly tested in any study and is not recommended, contingency tables suggest an advantage to WATS3D for this use.

What’s Next: WATS3D Clinical Registry

• The efficacy of WATS3D in addressing the intrinsic sampling error of random esophageal biopsy has been well established by cross-sectional data.

• As a result WATS3D is now being incorporated as part of the routine standard of care in both community and academic GI practices.

• Collecting longitudinal data from this routine clinical use may determine if WATS3D can not only provide greater detection of disease, but also a more prognostically useful detection of disease.

WATS3D Clinical Registry

• Participation open to community and academic settings

• Goals:

• 1) Understand the utilization of WATS3D in real world settings

• 2) Understand the longitudinal outcomes of patients assessed with WATS3D

• 3) Understand the significance of pathologic findings detected by WATS3D

• Crypt Dysplasia - To of effacement of the normal honeycomb pattern of the non-dysplastic gland

• Non-goblet cell Intestinal Metaplasia – CDX2

Crypt dysplasia with surface maturation: a

clinical, pathologic, and molecular study

of a Barrett's esophagus cohort.

Lomo LC, Blount PL, Sanchez CA, Li X, Galipeau PC, Cowan DS, Ayub K, Rabinovitch PS, Reid BJ, Odze RD.

The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (BCDA) with surface maturation. BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or adenocarcinoma.

Standard Anatomic Pathology Practice - Fundamentally unchanged

since 1850 - An approx. 5mm deep tissue sample is cut into a few thin

(2μ) sections which are stained with H&E to show tissue architecture

Standard microscopy requires 2μsectioning, destroying the natural appearance of the glandular surface

The surface of the gland, not the histologic section,

may hold the most definitive evidence of LGD

The non- dysplastic glandular surface is a cellular honeycomb

WATS3D preserves and presents the en face view of the gland, allowing for appreciation of the normal honeycomb arrangement of cells and its dysplastic effacement. May allow elimination of “Indefinite for Dysplasia”

WATS3D en face view of non dysplastic BE cf. confocal microscopy

“Indefinite for dysplasia ” on H&E

03-13-RCB

WATS3D en face view of same case shows dysplastic effacement

03-13-RCB

Does CDX2 expression predict Barrett's metaplasia in oesophageal columnar epithelium without goblet cells?

Kerkhof M, Bax DA, Moons LM, van Vuuren AJ, van Dekken H, Steyerberg

EW, Kuipers EJ, Kusters JG, Siersema PD; Cybar Study

CDX2 expression in cardiac-type mucosa might be able to predict the presence of undetected intestinal metaplasia in columnar-lined oesophagus, and thus may be a putative marker for the presence of intestinal metaplasia in the absence of goblet cells.

WATS3D Detection of Non-goblet cell IM

WATS3D Registry Requirements

• Open to qualified endoscopists who are using WATS3D as part of their clinical standard of care.

• Single consent of patient required to utilize de-identified data

• Data submission with each endoscopy along with all path reports and a photograph of the most proximal area of BE or of the z-line.

• $125 for the enrollment endoscopy , $100 for each subsequent endoscopic or surgical intervention

Thank you