serrated polyps - american college of...

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Risk of Metachronous High‐Risk Adenomas and Large (> 1 cm) Serrated Polyps in Individuals With Serrated Polyps on Index Colonoscopy: Longitudinal Data From

the New Hampshire Colonoscopy Registry

Joseph C. Anderson, M.D. Lynn F. Butterly, M.D. , Director of NHCRJulia E. Weiss, M.S.Christina M. Robinson, M.S.Christopher I Amos, PhDAmitabh Srivastava, M.D.

Serrated Polyps• Serrated polyp pathway may account for up to 30% of CRC

• Common, detected in up to 21% of all screening patients

• Surveillance of these polyps is an important issue

• Serrated polyps include:– Sessile serrated polyps (SSP); dysplastic potential

– Traditional serrated adenomas (TSA); dysplastic potential

– Hyperplastic polyps (HP); no dysplastic potential

• HPs can be difficult to distinguish from SSP (Anderson JCG 2017)

• Use size or histology to guide surveillance?

• Little data exist to support guideline recommendations

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Surveillance of conventional and serrated polyps High risk adenoma

on indexSerrated polyp

on index

Serrated polyp and HRAon index

High risk adenomaon surveillance

Size?< vs > 1cm

Histology?SSP or TSAvs HP

Good datato support

Little data

Higher risk?

Surveillance of conventional and serrated polyps

Size?< vs > 1cm


High risk adenomaon index

Serrated polypon index


Serrated polypon surveillance

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Goal

We used the population based New Hampshire Colonoscopy Registry (NHCR) to examine the risk of metachronous large (> 1 cm) SPs and HRA associated with

serrated polyps (SPs) on index colonoscopy as characterized by SP size or

histology

NHCR at a glance

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Analytic Plan• Included adults in NHCR with index and surveillance colonoscopy

• 2 separate schemes to stratify adults by index SPs– Size: < 1 cm vs > 1cm

– Histology: SSP or TSA vs hyperplastic polyps (HP)

• SP groups further stratified by presence or absence of synchronous HRA (adenoma > 1cm, villous, HGD, multiple (> 2), cancer)

• Reference group had normal exams

• Logistic regression, adjusted for age, sex, BMI, smoking and follow up time to calculate metachronous risk of: – 1) HRA;

– 2) Large SPs (> 1cm).

Results • 4,616 adults with 2 colonoscopies (6/2004‐6/2015)

• Median time to surveillance: 4.9 yrs

• Median (IQR) age was 59 (53 ‐ 66) years and 47.5% male

• 28 participating endoscopy facilities

• Risk for metachronous HRA was 6.3% and for large SP was 1.2%

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Index Findings N Risk of metachronous HRA

*Adjusted OR (95% CI)

SP < 1 cm alone (NO HRA) 724 0.69 (0.40-1.20)

SP > 1 cm alone (NO HRA) 87 0.87 (0.21-3.65)

NO SP AND NO HRA (reference) 2396 1.0

HRA AND SP > 1 cm 18 5.61 (1.72-18.28) ⬆

HRA AND SP < 1 cm 140 4.78 (2.93-7.81) ⬆

Metachronous HRA risk when serrated polyps are classified by size

HRA alone (NO SP) 603 3.86 (2.77-5.39) ⬆



HP alone (NO HRA) 698 0.69 (0.42-1.14)

SSP/TSA alone (NO HRA) 153 0.84 (0.26-2.73)


HRA AND HP 186 3.51 (2.17-5.68) ⬆

HRA AND SSP/TSA 28 16.04 (6.95-37.00) ⬆⬆

Metachronous HRA risk when serrated polyps are classified by histology

HRA alone (NO SP) 603 3.86 (2.77-5.39) ⬆

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Index Findings N Risk of metachronous large SP


HP alone 698 1.85 (0.79-4.36)

SSP/TSA alone 153 9.70 (3.63-25.92) ⬆


SP < 1 cm alone 452 1.14 (0.38-3.45)

SP > 1cm alone 87 14.34 (5.03-40.86) ⬆

Metachronous large SP risk

HRA alone (NO SP) 603 0.98 (0.31-3.07)



SP > 1 cm alone 65 0.83 (0.20-3.49)

SSP/TSA alone 104 0.83 (0.26-2.70)

NO SP AND NO LRA (reference) 2396 1.0

SSP/TSA Plus LRA 49 2.88 (1.67-7.13) ⬆

SP > 1cm Plus LRA 22 1.83 (0.41-8.11)

Metachronous HRA risk for index LRA

LRA alone (NO SP) 272 1.93 (1.41-2.62) ⬆

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Metachronous HRAHigh risk adenoma


on index


Size?< vs > 1cm


High risk adenomaon surveillance

OR=3.86

OR=16.04 with SSPOR=0.87 SP > 1cmOR=0.84 SSP

Metachronous Large SPsHigh risk adenoma


on index

Size?< vs > 1cm


Serrated polypon surveillance

OR=0.98 OR=9.70 SSPOR=14.34 SP > 1cm


OR=17.45

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Summary of findings and implications• SPs alone do not predict conventional HRA

– Our large database provides good estimate of minimal risk due to large sample of participants with only SSP/TSA (N=152) or large SPs (N =87) (no HRA) at index exam

• Serrated polyps predict future large SPs– Large SPs, rather than HRA, may be better surveillance outcome in patients with index

SPs– Do large ORs reflect field effect, or inadequate detection and/or resection (Pohl CARE

2013)?– Since participants with large SPs may have increased long term (> 10 years) risk for

CRC, (Holme et al GUT 2015; Errischson et al 2015 Gastro) these patients require surveillance

• Increased risk of HRA risk in patients with HRAs and SSP/TSA– Further study is needed regarding risk factors and CRC risks in these patients

Questions?

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Index colonoscopy findings Follow up colonoscopy findings

High risk Conventional Adenoma AND

Sessile Serrated Adenoma/polyp

Large (>1cm) Serrated Polyp OR

Sessile Serrated Adenoma/polyp

High risk Conventional Adenoma

High risk Conventional Adenoma

Large (>1cm) Serrated Polyp

OR = 16.04

OR = 3.86

SSA/P OR = 9.70

Large SP OR = 14.34

XOR = 1.00

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Enhanced Recovery in Acute Pancreatitis (RAPTor):

A Randomized-Controlled Trial

Elizabeth Dong MD, Jonathan I. Chang MD, Dhruv Verma MD, Michael Batech DrPH, Cecia Villarin, Karl K. Kwok MD, WanSu Chen PhD,

Bechien U. Wu MD, MPH

Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA

ACUTE PANCREATITIS (AP)

o One of the most common reasons for hospitalization1.

o Annual estimated cost - $2.6 billion1.

o Treatment remains supportive:

Analgesia

Intravenous fluid resuscitation

Bowel rest

1. Peery AF, Crockett SD, Barritt AS, et al. Burden of Gastrointestinal, Liver, and Pancreatic Diseases in the United States. 2015. doi:10.1053/j.gastro.2015.08.045.

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BACKGROUND

o Barriers to recovery:

Analgesia > opioid medications delay gut motility

Bowel rest > delays restoration of gut function

o Enhanced Recovery After Surgery (ERAS): reduced

complications and care time in surgery2

o ERAS principles:

o Early re-feeding

o Early ambulation

o Adjunctive non-opioid analgesia

2. Ljungqvist O, Scott M, Fearon KC, et al. Enhanced Recovery After Surgery. JAMA Surg. 2017;152(3):292. doi:10.1001/jamasurg.2016.4952.

STUDY AIM

To evaluate impact of an enhanced recovery

protocol versus standard care on restoration of

gut function in patients with mild acute

pancreatitis.

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METHODSo Design: prospective, single-blind, randomized-controlled trial

o Dates: July 2016 – April 2017

o Population:

Diagnosis of AP confirming 2 of 3 criteria:

Typical epigastric abdominal pain

Amylase/lipase ≥ 3 times normal

Confirmatory features on cross-sectional imaging

Enrolled within 12 hours of admission

o Exclusion criteria: active SIRS, organ failure, chronic opioid use

METHODS Primary endpoint - time to successful oral re-feeding

Tolerance of solid diet without:

o Nausea

o Vomiting

o Abdominal pain

Secondary endpoint – pancreatitis activity scores (PASS)3

o SIRS

o Organ failure

o Pain scale

o Morphine equivalents

o Oral intake3. Wu BU, Batech M, Quezada M, et al. Dynamic Measurement of Disease Activity in Acute Pancreatitis: The Pancreatitis Activity Scoring System. Am J Gastroenterol. 2017

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SAMPLE SIZE

o Feasibility: estimate willingness to undergo enhanced protocol

o Efficacy: 46 patients (23 per arm) to achieve a 24 hour reduction

in time to successful oral re-feeding from average 4 days to 3,

with 80% power, alpha = 0.05

o Safety:

Worsening of pancreatitis: necrosis, organ failure, mortality

30 day re-admissions

Feeding intolerances, length of stay

METHODS

AP

RANDOMIZE

STANDARD

ENHANCED

Physician directed dietLactated Ringer’s 3mL/kg/hr x 24 hours; 1.5mL/kg/hrHydromorphone 0.2, 0.4, 0.6mg IV q2h PRN pain

Low-fat solid diet; patient directed intakeLactated Ringer’s 3mL/kg/hr x 24 hoursAcetaminophen 1g IV q6h x 24 hoursKetorolac 30mg IV q6h PRN mild-moderate painMorphine 2mg IV q4h pRN severe painOndansetron 4mg IV q6h x 24 hoursOut of bed, ambulate 5x a day with nursingNasal cannula 2L/min x 24 hours

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METHODS

AP

RANDOMIZE

STANDARD

ENHANCED



METHODS

AP

RANDOMIZE

STANDARD

ENHANCED



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METHODS

AP

RANDOMIZE

STANDARD

ENHANCED



Assessed for Eligibility

(N = 172)

Excluded (N = 126)

•Declined to participate, 11

•SIRS/organ failure, 35

•Active malignancy, 9

•Not hospitalized, 25

•Chronic/recent opioid use, 18

•Alternate diagnosis, 24

Randomized

(N = 46)

Standard

(N = 22)

Enhanced

(N = 24)

Analyzed

(N = 22)

Analyzed

(N = 24)

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RESULTSTABLE 1 – BASELINE DEMOGRAPHICS

Standard Enhanced Total P-value

22 (47.8%) 24 (52.2%) 46

Mean Age (Years) (SD) 56.7 (19.71) 49.7 (16.93) 53.1 (18.44) 0.17

Female Sex 13 (59.1%) 12 (50%) 25 (54.3%) 0.54

Race/Ethnicity

White, non-Hispanic 4 (18.2%) 4 (16.7%) 8 (17.4%)

0.20Black, non-Hispanic 0 (0%) 3 (12.5%) 3 (6.5%)

Hispanic 13 (59.1%) 16 (66.7%) 29 (63%)

Asian, non-Hispanic 4 (18.2%) 1 (4.2%) 5 (10.9%)

Other, non-Hispanic 1 (4.5%) 0 (0%) 1 (2.2%)



22 (47.8%) 24 (52.2%) 46

Mean Age (Years) (SD) 56.7 (19.71) 49.7 (16.93) 53.1 (18.44) 0.17

Female Sex 13 (59.1%) 12 (50%) 25 (54.3%) 0.54

Race/Ethnicity



Hispanic 13 (59.1%) 16 (66.7%) 29 (63%)



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22 (47.8%) 24 (52.2%) 46

Mean Age (Years) (SD) 56.7 (19.71) 49.7 (16.93) 53.1 (18.44) 0.17

Female Sex 13 (59.1%) 12 (50%) 25 (54.3%) 0.54

Race/Ethnicity



Hispanic 13 (59.1%) 16 (66.7%) 29 (63%)



RESULTS

TABLE 2 – DISEASE ETIOLOGY


22 (47.8%) 24 (52.2%) 46

Gallstones 15 (68.2%) 13 (54.2%) 28 (60.9%)

0.28Alcohol 2 (9.1%) 5 (20.8%) 7 (15.2%)

Hypertriglyceridemia 4 (18.2%) 2 (8.3%) 6 (13%)

Other 1 (4.5%) 4 (16.7%) 5 (10.9%)

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RESULTS

TABLE 2 – DISEASE ETIOLOGY


22 (47.8%) 24 (52.2%) 46

Gallstones 15 (68.2%) 13 (54.2%) 28 (60.9%)

0.28Alcohol 2 (9.1%) 5 (20.8%) 7 (15.2%)

Hypertriglyceridemia 4 (18.2%) 2 (8.3%) 6 (13%)

Other 1 (4.5%) 4 (16.7%) 5 (10.9%)

RESULTS – Time to Oral Re-FeedingA = StandardB = Enhanced

Median time to oral re-feeding:Standard 124.8 hours

versus Enhanced 13.8 hours Log-rank P < 0.001

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0

10

20

30

40

50

60

70

80

90

0-<3 days 3-<5 days 5 days or more

Mea

n P

AS

S S

core

acr

oss

Day

s of

Adm

issi

onRESULTS – PASS

Standard

Enhanced

Standard 80.0 (40.0, 110.0) vs Enhanced 60.0 (25.0,95.0)

Fischer exact P < 0.01

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0-<3 days 3-<5 days 5 days or more

Mea

n M

orph

ine

Equ

ival

ents

RESULTS – Morphine EquivalentsStandard, 3.29

Enhanced, 1.35 Fischer exact P < 0.01

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OUTCOMES AND ADVERSE EVENTSStandard Enhanced P-value

N = 22 (47.8%) N = 24 (52.2%)

Median Length of Stay 3 days, (2.0, 4.2) 3 days, (2.5, 4.1)

30-day Re-Admission 2 (9.1%) 1 (4.2%) 0.51

Pancreatic Necrosis 2 (9.1%) 1 (4.2%) 0.51

Organ Failure 0 0

Mortality 0 0

Adverse Events2 (9.1%) dizziness after

hydromorphone

1 (4.5%) enteral feeding

1 (4.2%) diarrhea

LIMITATIONS

o Small sample size

Pilot study to assess feasibilty

o Excluded patients with severe disease, organ failure

o Large proportion of biliary disease

Length of stay

Inpatient cholecystectomy prior to discharge

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SUMMARYWith enhanced recovery protocol:

Patients tolerated solid diet earlier

Decreased PASS scores during recovery

Decreased morphine equivalents without increased pain

o No differences in:

Length of stay

30-day re-admissions

Adverse events

CONCLUSION

Enhanced recovery strategies appear safe in

mild acute pancreatitis and may allow for

earlier restoration of gut function.

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Functional Obstructive Gastroparesis:Effect of laparoscopic pyloroplasty on symptoms, gastric

emptying and gastric myoelectrical activity after successful endoscopic pyloric therapies

Jennifer Wellington, DO

Paula Stuart, PA‐C

Kenneth L. Koch, MD

Wake Forest School of Medicine

Section on Gastroenterology

Winston‐Salem, North Carolina

Background:

Gastroparesis associated symptoms are very difficult to treat in many patients.

Pyloric therapies have been tried in the past but patients were not selected on the basis of gastric myoelectrical activity (GMA).

We hypothesized that patients with gastroparesis, 3 cycle per minute (cpm) GMA and normal upper endoscopy, had functional obstructive gastroparesis and would respond to pyloric therapies.

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Aims:

To determine the effect of pyloroplasty on symptoms, weight and gastric emptying in patients with gastroparesis and normal 3 cycle per min (cpm) GMA.

Methods:

Patient selection:

– Gastroparesis

• defined by 4 hour gastric emptying study

– Normal 3cpm GMA

• Electrogastrography with water load test (WLT)

– Normal endoscopy

• Excluded pyloric stenosis

– Patients had failed medical treatment for gastroparesis

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Methods, continued

Patient selection:

‐Endoscopy with botulinum toxin A injection and/or balloon dilation of pylorus

‐For patients with symptom relief after at least 2 endoscopic pyloric therapies, pyloroplasty was offered

Measures Before and After Pyloroplasty:

1. Weight and major symptoms

2. EGG and 4 hour gastric emptying

Pyloroplasty Patients

• Pyloroplasty, N=10

– 9 women, 1 man

– Average age 36 years

– 7 with idiopathic GP

– 3 with diabetic GP

• Pyloroplasty operations performed:

– Finney (4), Jaboulay (1), Heineke‐Mikulicz (5)

– Procedure type determined by surgical colleagues

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Results:

• Clinical assessment performed 6 months after pyloroplasty

– 90% of patients reported improved symptoms

• Nausea

• Fullness

– Average weight increased 6.4 lbs (p = 0.04)

Gastric Retention Before and After Pyloroplasty

Average % retained at 4 hr decreased from 47% to 16% (p<0.01)

0

20

40

60

80

100

Baseline 4hr retention Post‐op 4hr retention

Percent Meal Retained

Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Patient 7

Patient 8

Patient 9

Patient 10

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RSA and EGG in Patient with Functional Obstructive Gastroparesis

3 cpm GMA and WLT: Before and After Pyloroplasty

Gastric Myoelectrical Activity (% distribution of time

in 3 cpm range)

Baseline Post‐Pyloroplasty p value

Before WLT 53 ± 12% 17 ± 11% *p <0.01

10 minutes 49 ± 13% 29 ± 12% p = 0.26

20 minutes 55 ± 14% 16 ± 10% *p = 0.03

30 minutes 58 ± 13% 27 ± 12% *p = 0.04

Water Load Test (WLT) Volumes 430ml ± 180ml 473ml ± 195ml p <0.06

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3 cpm GMA and WLT: Before and After Pyloroplasty

Gastric Myoelectrical Activity (% distribution of power

in 3 cpm range)

Baseline Post‐Pyloroplasty p value

Before WLT 31 ± 5% 19 ± 5% *p <0.01

10 minutes 33 ± 6% 26 ± 4% p = 0.31

20 minutes 37 ± 6% 25 ± 7% *p = 0.04

30 minutes 34 ± 5% 23 ± 5% *p = 0.01

Water Load Test (WLT) Volumes 430ml ± 180ml 473ml ± 195ml p <0.06

GMA and WLT: % Distribution 3 cpm PowerBefore and After Pyloroplasty

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Conclusions

1. After two or more successful endoscopic pyloric treatments, pyloroplasty in GP patients with 3 cpmGMA improved gastric emptying and decreased 3 cpmGMA, consistent with relief of functional gastric outlet obstruction.

2. Pyloric neuromuscular dysfunction is a key factor in delayed emptying in patients with GP and normal 3 cpmGMA and represents a GP subtype— functional obstructive gastroparesis

Thank you

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A Prospective Validation of Deep-Learning for

Automatic Polyp Detection during Colonoscopy

Pu, Wang1 M.D. and Xiao, Xiao2 Ph.D. et al.1Sichuan Academy of Medical Sciences and Sichuan Provincial

People’s Hospital2Shanghai Wision AI Co., Ltd

Notice

We present the most updated results of our study.

• According to the review advice from a prestigious medicaljournal, we excluded images of polyps without biopsy in theoriginal validation set ( that’s why the statistic numbers areslightly better than those in the abstract ).

• We finished a prospective Real-time Video Validation this July,the results of which were not yet ready when submitting the abstract.

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Objective

• To validate clinical applicability of deep-learning for automaticpolyp detection during colonoscopy.

Source: https://www.health.harvard.edu/diseases-and-conditions/they-found-colon-polyps-now-what

Background

• Colonoscopy is the gold standard for screening colorectal cancer1, one of the leading causes of cancer deaths in the United States2

and China3.

• Evidence has shown that each 1.0% increase in adenoma detection rate (ADR) predicted a 3.0% decrease in the risk of interval colorectal cancer4.

• However, significant adenoma miss rate (AMR) ranging from 6–27% and depends on a variety of polyp and operator characteristics5. Reference:

1. Zauber AG, et al. Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med. 2012; 366:687–96.2. Siegel R, et al. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11–30. 3. Chinese Society of Gastroenterology. Chinese consensus: screening,early diagnosis and treatment, comprehensive prevention of large bowel cancer[J]. Chin J Gastroenterology Hepatology, 2011,20(11):979-995.4. Corley D A, Jensen C D, Marks A R. et al. Adenoma detection rate and risk of colorectal cancer and death[J]. N Engl J Med. 2014; 370:1298–13065. Ahn SB, Han DS, Bae JH et al. The miss rate for colorectal adenoma determined by quality-adjusted, back-to-back colonoscopies. Gut Liver 2012;6:64–70.

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Background

• There are two independent reasons for a missed polyp6:

I. Never in the visual field;II. In the visual field but Not

Recognized. Observation of the video monitor by nurses or gastroenterology trainees have been shown to obviously increase polyp detection rate7,8,9;

Reference:6. Jorge B, et al. Comparative Validation of Polyp Detection Methods in Video Colonoscopy: Results From the MICCAI 2015 Endoscopic Vision Challenge. IEEE Transactions on Medical Imaging 2017; 36:1231-1249.2. Siegel R, et al. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11–30. 7. Aslanian HR, Shieh FK, Chan FW et al. Nurse observation during colonoscopy increases polyp detection: a randomized prospective study. Am J Gastroenterol 2013;108:166–72.8. Lee CK, Park DI, Lee SH et al. Participation by experienced endoscopy nurses increases the detection rate of colon polyps during a screening colonoscopy: a multicenter, prospective, randomized study. GastrointestEndosc 2011;74: 1094–102. 9. Buchner AM, Shahid MW, Heckman MG et al. Trainee participation is associated with increased small adenoma detection. Gastrointest Endosc 2011;73:1223–31.

Background

• Deep learning has achieved some success in real-lifeimage/video detection10, including medical imaging11,12.

• Ideally, an automatic polyp detection system with performanceclose to an endoscopist could serve as an effective ‘extra set of eyes’ on all aspects of the video data13.

Reference:10. Yann leCun, et al. Deep Learning, Nature, 2015: 521, 436-44411. Varun Gulshan, et al, Development and Validation of a Deep Learning Algorithm for Detection of Diabetic Retinopathy in Retinal Fundus Photographs, JAMA, 2016: 316(22):2402-241012. Andre Esteva, et al. Dermatologist-level classification of skin cancer with deep neural networks, Nature 2017: 542, 115–11813. Nadim M, et al. Computer vision and augmented reality in gastrointestinal endoscopy. Gastroenterology Report, 3(3), 2015, 179–184

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Algorithm Derivation

• Development Data: 5,545 images acquired during colonoscopy procedures performed between January 2007 and December 2015, among 1290 polyp patients.

• Image Annotation: Endoscopists were asked to outline the boundaries of any polyps present in the image of developmentdata.

Algorithm Derivation

• Deep Learning System: The specific neural network used in this study is SegNet architecture14. Data flow is from left to right.(Test our algorithm at )

Reference:14. Vijay Badrinarayanan, Alex Kendall, Roberto Cipolla. SegNet: A Deep Convolutional Encoder-Decoder Architecture for Image Segmentation. ArXiv. 2015

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Prospective Validation

Scenario Description

• Still-frame Analysis: In this scenario, the algorithm predicted polyp presence in each validation image;

• Simulated Real-time Video Analysis: In this scenario, real-life colonoscopy video streams were simulated, and in real-time the system acquired the video stream, processed with the detection algorithm and displayed the results.

• Exclusion Criteria: 1. Polyps without Histology; 2. Unqualified Intestinal Preparation; 3. Giant CRC Mass (> 2cm).

Prospective Validation:Dataset Baseline I

Purpose Still-Frame Validation Simulated Real-time Video Validation

Acquired Time

Jan - Dec 2016 May - Jul 2017

Content 27,113 colonoscopy images,5,541 with polyps

289 colonoscopy videos(156,337 frames, 60,914 with polyps)

PatientDemographics

1,138 patients with polyps;421 (36.99%) female;Age, mean (SD): 57.37 (12.83).

151 patients with polyp history;63 (41.72%) female;Age, mean (SD): 56.74 (12.50).

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Prospective Validation:Dataset Baseline II

Purpose Still-Frame Validation Simulated Real-time Video Validation

PolypHistology

Total polyp number 1,495 (100%);Carcinomatous 57 (3.81%);Adenomatous 1,044 (69.83%);Hyperplastic 200 (13.38%);Inflammatory 184 (12.31%);Others 10 (0.67%).

Total polyp number 138 (100%);Carcinomatous 0 (0%);Adenomatous 77 (55.80%);Hyperplastic 36 (26.09%);Inflammatory 21 (15.22%);Others 4 (2.90%).

PolypCharacteristics

Small (<=0.5 cm) 983 (65.75%);Isochromatic 807 (53.98%);Flat (Yamada I) 540 (36.12%).

Small (<=0.5 cm) 84 (60.87%);Isochromatic 99 (71.74%);Flat (Yamada I) 37 (26.81%).

Performance Metrics6

• True Positive (TP): A polyp with correct detection;

• False Positive (FP): A detection that falls outside any polyp;

• False Negative (FN): A polyp without any detection;

• True Negative (TN): An image without polyp and with nodetection;

• Precision: Prec = TP / (TP + FP);

• Recall (Sensitivity): Rec = TP / (TP + FN);

• Specificity: Spec = TN / (FP + TN);

• F1-measure: F1 = 2*Prec*Rec / (Prec + Rec).

Reference:6. Jorge B, et al. Comparative Validation of Polyp Detection Methods in Video Colonoscopy: Results From the MICCAI 2015 Endoscopic Vision Challenge. IEEE Transactions on Medical Imaging 2017; 36:1231-1249.2. Siegel R, et al. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11–30.

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Results I: Still-Frame (Unpublished)Image Group Total

No. of Images

TP FP FN TN Precision[%]

Recall(Sensitivity)[%]

Specificity[%]

F1[%]

Images with only

isochromatic polyps of

Yamada I, and size <= 0.5 cm

1,208 1,296 41 118 NA 96.93 91.65 NA 94.22

All Images 27,113 5,663 1,255 337 20,691 81.86* 94.38 94.28 87.68*

* The values of Precision and F1-measures are dependent on the ratio of positive samples to negative samples. Small ratio of positive samples leads to small Precision value.

Result I: Still-Frame (Unpublished)

• Receiver Operating Characteristic (ROC curves) for All Images, and the area under the receiver operating characteristic curve (AUC) was 0.991.

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Case Demo: Still-Frame

Performance Metrics6: Video Additional

• Detection Rate (DR): Measured as the percentage of polyps detected in at least one frame out of the total of polyps present in the testing videos;

• Detection Latency (DL): The delay in frames between the first appearance of the polyp in the video sequence and the first actual detection of the polyp.

• Temporal Coherence (TC): A metric to assess detection stability in consecutive frames;

• Refresh Rate (RR): How many frames can be processed every second by the real-time detection system.

Reference:6. Jorge B, et al. Comparative Validation of Polyp Detection Methods in Video Colonoscopy: Results From the MICCAI 2015 Endoscopic Vision Challenge. IEEE Transactions on Medical Imaging 2017; 36:1231-1249.2. Siegel R, et al. Cancer statistics, 2013. CA Cancer J Clin. 2013; 63:11–30.

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Results II: Simulated Real-time Video(Unpublished)

Precision[%]

Recall(Sensitiv

-ity)[%]

Specificity[%]

F1[%]

Detection Rate[%]

Latency [frames]

mean(SD)

TempC[%]

mean(SD)

Refresh Rate [fps]mean(SD)

AlgorithmProcessing

Time forEach

Frame[ms]mean(SD)

94.21 91.64 96.30 92.91 100.001.36

(1.61)88.93

(22.62)26.86(0.72)

43.28(4.00)

Case Demo: Simulated Real-time Video

• Conventional Case

-A Small Isochromatic Polyp of Yamada I under SwayingCamera

• Adaptability

-Under NBI

-Melanosis Coli

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Limitations:

• False Alarms: on waterbubbles and annular vessels.

• Flat/Depressed Cancer notincluded: this deep-learningalgorithm is built for polypsspecifically.

• Pre-clinical Validation: thevalidation was not in real-worldclinical setting, although usingreal-world clinical data.

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Looking Forward

• Achieve Higher Performance.

• Validate in Real-world Clinical Setting:

I. Real-time visual assistant during colonoscopy;

II. Re-examination on colonoscopy images/videos after colonoscopy.

• Handle More: Flat/depressed cancer.

Thank you

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Effectiveness of endoscopic therapy in patients with Barrett’s esophagus (BE) with early cancer is comparable to that of BE

with high-grade dysplasia (HGD): Results from an international, multi-center consortium

Rajesh Krishnamoorthi, Sreekar Vennelaganti, Alessandro Repici, Vani Konda, Irving Waxman, Stefan Seewald, Matthew Stier, Rehan Haidry,

Daniel Buckles, Neil Gupta, Ajay Bansal, Sharad Mathur, Mojtaba Olyaee, Michael Bourke, Gary Falk, Prateek Sharma, Andrew Ross

1. Virginia Mason Medical Center, Seattle, WA, United States2. University of Kansas, Kansas City, KS, United States3. Kansas city VA medical center, MO, United States4. University of Chicago, Chicago, IL, United States5. Hirsladen, Zurich, Switzerland6. Loyola University, Maywood, IL, United States7. University college London Hospital, London, UK8. University of Sydney, Westmead, NSW, Australia9. Instituto Clinico Humanitas, Milan, Italy10. University of Pennsylvania, Philadelphia, PA, United States

Background

BE – ND/LGD

E AC

BE ‐ HGD

BE ‐ IMC

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Background

BE – ND/LGD

E AC

BE ‐ HGD

BE ‐ IMC

Surgery

Endoscopic Rx

Endoscopic Rx

Surgery

• Endoscopic therapy is the current treatment of choice for

Barrett’s esophagus (BE) patients with HGD

• Endoscopic therapy is a noninvasive alternative to surgery for

treatment of BE with intra-mucosal cancer (IMC)

• There are limited data comparing the outcomes of endoscopic

therapy in BE patients with IMC and HGD

• recommend consideration of endoscopic therapy (ET) for BE with low-grade dysplasia (BE-LGD) Use of ET is expected to increase

Background

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• To compare the rates of complete eradication of intestinal

metaplasia (CE-IM) and complete eradication of dysplasia (CE-

D) between patients with IMC and HGD undergoing endoscopic

therapy

• recommend consideration of endoscopic therapy (ET) for BE with low-grade dysplasia (BE-LGD) Use of ET is expected to increase

• Goal of endoscopic therapy needs to individualized – CEIM vs CED

• Define clinical goal: Risk reduction of cancer vs Eradication of BE?

Aim

EET Database: Multicenter Database

• Prospective database of BE and early esophageal adenocarcinoma (EAC)• University of Kansas Medical Center, Kansas City, KS, USA

• Virginia Mason Medical Center, Seattle, WA, USA

• Kansas City VA Medical Center, Kansas City, MO, USA• Loyola University, Maywood, IL, USA

• University of Chicago Medical Center, Chicago, IL, USA

• University of Pennsylvania, Philadelphia, PA, USA• Instituto Clinico Humanitas, Milan, Italy

• University College London Hospital, London, UK

• Gastrozentrum Hirslanden, Zurich, Switzerland• University of Sydney, Westmead, NSW, Australia

• 708 subjects undergoing endoscopic therapy

• Recruitment: April 2012 - Oct 2017 (ongoing)

• Records of demographic details, endoscopic and histologic findings

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Methods

• Endoscopic therapy

• Endoscopic mucosal resection (EMR) of visible lesions Mucosal

ablation of flat BE

• Inclusion criteria• Subjects with HGD or IMC undergoing endoscopic therapy• Completed at least four EGDs with endoscopic therapy

• Exclusion criteria• Subjects who discontinued endoscopic therapy• Subjects with missing data

Methods

Definitions

• CE-IM- Histologic absence of intestinal metaplasia

• CE-D- Histologic absence of dysplasia

• Re-IM- Histologic evidence of BE ( IM, dysplasia or EAC) after achieving CEIM

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Methods

BE – ND/LGD

E AC

BE ‐ HGD

BE ‐ IMC

Endoscopic Rx

Endoscopic Rx

Surgery

Are the outcomes similar or different?

Methods- Analysis

• Rates of CEIM, CED and Re-IM were calculated in the 2 study groups -IMC and HGD

• Cox proportional hazards models• If the success rate of endoscopic therapy (CEIM & CED) was different

between the 2 groups – IMC vs HGD• If the rate of Re-IM was different between the 2 groups – IMC vs HGD

• Confounders adjusted for• Age• Sex• BE length

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• 276 BE subjects (70 with IMC and 206 with HGD) were included

• The median (IQR) age was 66.0 (58.0, 73.0) years

• 232 (84.1%) were males

• Median BE segment (IQR) length was 6 cm (3.0, 10.0)

Results

IMCn=70

Endoscopic Rx

CED62 (88.6%)

CEIM 57 (81.4%)

Re‐IM 25

Results

HGDn=206

CED185 (81.4%)

CEIM 173 (84.0%)

Re‐IM 60

Study subjectsn= 276

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Results

13

Baseline Characteristics

IMCn = 70

HGDn = 206

p value

Age (IQR) Yrs 68.0 (63.0, 74.0) 65.0 (58.0, 72.0) 0.06

Male 55 ( 78.6% ) 177 ( 85.9% ) 0.14

BE length[cm‐median (IQR)]

5.5 (3.0, 10.0) 6.0 (3.0, 10.0) 0.42

Results

14

EndotherapyOutcomes

IMCn = 70

HGDn = 206

p value

CE‐ IM 57 ( 81.4% ) 173 ( 84.0% ) 0.62

CE‐ D 62 ( 88.6% ) 185 ( 89.8% ) 0.77

Re‐ IM 25 ( 43.9% ) 60 ( 34.7% ) 0.21

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• Multivariate analysis

• Rate of CE-IM in HGD vs IMC

• Hazards Ratio: 1.15, 95% CI 0.38 – 3.51, p= 0.81

• Rate of CE-D in HGD vs IMC

• Hazards Ratio: 1.21, 95% CI 0.31-4.66, p= 0.79

Results - Analysis

Limitations

• Relatively small number of patients in each study group

• Patients lost to follow-up were excluded

• Observational study : Confounders (unknown and known)

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• In this large well-defined cohort of BE patients, effectiveness of endoscopic therapy in IMC is comparable to that of HGD

• Consideration of endoscopic therapy in BE patients with early cancer could reduce the need for invasive surgery

Conclusion

Thanks

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ClinicalTrials.gov Identifier: NCT02651532

In vivo Detection of Colonic Mucosa Microinflammation by Confocal Laser

Endomicroscopy Probe (CLE) in patients withIrritable Bowel Syndrome

Carlos Robles‐Medranda, MD; Manuel Valero, MD; Miguel Soria, MD, Miguel Puga‐Tejada, MD, MSc; Jesenia Ospina‐Arboleda, MD, MSc, Haydee Alvarado‐Escobar, MD; Guillermo Muñoz‐Jurado, MD;

Roberto Oleas, MD; Hannah Pitanga‐Lukashok, MD.

Instituto Ecuatoriano de Enfermedades Digestivas (IECED)

Guayaquil – Ecuador


BACKGROUND

• Irritable bowel syndrome (IBS) is one of the most common gastrointestinaldisorders (prevalence of 5‐20%), however many patients remain undiagnosed.

• Diagnosis is based on the Rome III criteria. However, combination of the Rome IIIcriteria have a sensitivity, specificity, PPV and NPV of 65%, 100%, 100% and 76%.

• Current tests commonly fail to obtain an objective diagnosis. There are no reliablebiomarkers and no specific endoscopic findings that can discriminate IBS patientsfrom healthy patients.

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BACKGROUND

• Most colonoscopies are performed to rule out other etiologies in IBSand > 50% are normal being considered as a “functional disease”.

• It has been previously described and impaired intestinal barrierfunction with mucosal inflammation in the small intestine of thesepatients.

• However, in the colonic mucosa this fact have not been evaluated.


AIM

•To determine utility of Confocal LaserEndomicroscopy (CLE) identifying colorectalmucosa micro‐inflammation in patients withIBS.

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METHODS: Study design

• A prospective, controlled, non‐randomized and simple blinddiagnostic trial was performed from Jan‐2016 to Mar‐2017 atInstituto Ecuatoriano de Enfermedades Digestivas (IECED), a referralcenter in digestive disease care.

• The study was in accordance with the Declaration of Helsinki, and wasapproved by the Institutional Review Board (IRB) of IECED.

• Every enrolled patient signed the corresponded written informedconsent.


METHODS: Patients

Inclusion criteria:

• Patients with IBS according to RomaIII criteria (IBS group), and healthypatients who underwent to screeningfor colorectal cancer (control group).

• Prior to enrolment to IBS group, labtests, serial coproparasitaryexamination and coproculture wereperformed in each potential patient,in order to confirm Roma III criteria.

• Both groups underwent colonoscopyusing CLE with target‐biopsy of eachcolorectal section.

Exclusion criteria:

• Patients receiving NSAIDs, corticosteroids or antibiotics;

• Heart, kidney, liver or severe metabolic disease, bacterial overgrowth, gastrointestinal bleeding

• History of: colitis, colonic obstruction, colectomy, allergy to fluorescein.

• Pregnancy

• Poor bowel preparation.‐ Boston Bowel Preparation Scale (BBPS) < 6.

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METHODS: Sample size

• Sample size was performed considering a margin of error of 1% (typeI and type II errors), and micro‐inflammation changes prevalence inIBS and control group of 62.5% and 11.1%, considering CLE diagnosticaccuracy of gap density for IBS previous established.

Turcotte et. al. Gastrointest Endosc. 2013 Apr;77(4):624‐30.

(62.5%) (11.1%)


METHODS: Technical procedure

• All colonoscopies were performed after standard bowel preparationusing polyethylene glycol‐electrolyte solution in all patients.

• After deep sedation using intravenous propofol, a routinecolonoscopy with white light was performed in IBS and healthycontrol patients, using a Pentax high definition scope (Pentax EC‐3890LZi, Tokyo, Japan) with great care to avoid damage theepithelium.

• The Boston Bowel Preparation Scale (BBPS) was evaluated.

• If patients had a good bowel preparation, an intravenous injection of5 ml of fluirescein was done.

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METHODS: Technical procedure

• Finally, a confocal laser endomicroscopy evaluation was done in eachcolonic segment, using the pCLE probe (Cellvizio; Mauna Kea Technology,Paris, France), through the accessory channel of the scope. The probe wasgently placed in contact with the mucosa to avoid trauma.

• Immediately after CLE evaluation, and before proceeding to the next colonsegment, targeted biopsies will be taken from the mucosal area evaluated.

• Altered crypt architecture, epithelial gaps with fluorescein leaks and dilatedand prominent branching vessels were the considered CLE criteria forinflammation.

• Following Geboes Scale was used to evaluated the histological aspects by asingle pathologist blinded to endoscopic findings.


HEALTHY COLONIC MUCOSA

Dark goblet cellsRound cryptstructures

Regular, narrow vessels surrounding

crypts

Case No. 52 Case No. 59 Case No. 61

Li CQ, et. al. Am J Gastroenterol. 2010 Jun;105(6):1391-6.

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INFLAMMATION CRITERIA

Cellular infiltrationpresent, fluorescein leaks

into the crypt lumen

Differences in shape, size and distribution of crypts; increased distance between crypts, focal

crypt distribution.

Mild to moderate increase of capillaries, dilated and distorted

capillaries

Normal Mucosa

Case No. 1 Case No. 6 Case No. 9 Case No. 11

Li CQ, et. al. Am J Gastroenterol. 2010 Jun;105(6):1391-6.


Geboes K, et. al. Gut. 2000 Sep;47(3):404‐9.Lemmens B,| et. al. Inflamm Bowel Dis. 2013 May;19(6):1194‐201.

Geboes Scale: Disease severity of ulcerative colitis

Grade 0: Structural (architectural changes)

No abnormality 0.0

Mild abnormality 0.1

Mild or moderate diffuse or multifocal abnormalities 0.2

Severe diffuse or multifocal abnormalities 0.3

Grade 1: Chronic inflammatory infiltrate

No increase 1.0

Mild but unequivocal increase 1.1

Moderate increase 1.2

Marked increase 1.3

Grade 2: Lamina propria neutrophils and eosinophils

2A Eosinophils

No increase 2A.0

Mild but unequivocal increase 2A.1

Moderate increase 2A.2

Marked increase 2A.3

2B Neutrophils

No increase 2B.0

Mild but unequivocal increase 2B.1

Moderate increase 2B.2

Marked increase 2B.3

Grade 3: Neutrophils in epithelium

None 3.0

< 5% crypts involved 3.1

< 50% crypts involved 3.2

> 50% crypts involved 3.3

Grade 4: Crypt destruction

None 4.0

Probable ‐ local excess of neutrophils in parto of crypt 4.1

Probable ‐marked attenuation 4.2

Unequivocal crypt destruction 4.3

Grade 5: Erosion or ulceration

No erosion, ulceration or granulation tissue 5.0

Recovering epithelium + adjacent inflammation 5.1

Probable erosion ‐ focally stripped 5.2

Unequivocal erosion 5.3

Ulcer or granulation tissue 5.4

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Data analysis

• Continuous and categorical variables were compared by Student t‐Test, x2 or Fisher exact test as appropriate.

• Relationship between study group and presence of micro‐inflammation at CLE was determined through Odds Ratio.

• Overall diagnostic accuracy were determined by sensitivity, specificity,PPV, NPV, observed and inter‐rater agreement (Cohen kappa).

• A p value <0.05 was considered to be statistically significant.

• Statistical methods were reviewed by the IECED institutionalBiostatistician

• Statistical analysis was performed in SPSS software suite v.22.


RESULTS: Baseline characteristicsIBS group

(n=37)

Control group

(n=37)

Total

(n=74)p value

Age, mean ± SD 50.62 ± 15.9 55.51 ± 12.3 53.07 ± 14.3 0.143a

Sex (female), n (%) 29 (78.4) 19 (51.4) 48 (64.9) 0.015b

Symptoms, n (%)

Abdominal pain with diarrhea

(IBS‐D)11 (29.7) 0 11 (29.7) n/a

Abdominal pain with constipation (IBS‐C) 21 (56.8) 0 21 (56.8) n/a

Abdominal pain with alternating diarrhea

and constipation (IBS‐M)5 (13.5) 0 5 (13.5) n/a

Boston Bowel Preparation Scale (BBPS), mode (range min – max)

Right colon 2 (2 – 3) 3 (2 – 3) 3 (2 – 3) 0.165c

Transverse colon 3 (2 – 3) 3 (2 – 3) 3 (2 – 3) 0.119c

Left colon 3 (2 – 3) 3 (2 – 3) 3 (2 – 3) 0.784c

TOTAL 6 (6 – 9) 8 (6 – 9) 8 (6 – 9) 0.066c

a. Student’s t‐test b. Chi‐squared test c. Mann‐Whitney U test

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CASE Nº 32: IBS WITH CONSTIPATIONCecum Right colon Sigmoid colon RectumTransverse colon Left colon


CASE Nº 32: IBS WITH CONSTIPATIONCecum Right colon Sigmoid colon RectumTransverse colon Left colon

Geboes 5 Geboes 5 Geboes 5 Geboes 5Geboes 5 Geboes 0

10x 10x 10x

40x 40x 40x

10x 10x 10x

40x 40x 40x

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RESULTS: CLE inflammation findings between IBS and control group

There was a significant increased number of inflammatory lesions at p‐CLE in the IBS group (65.8%) compared

with control group (23.4%) (OR 6.28; 4.14 – 9.52; p<0.001).

0

5

10

15

20

25

30

Cecum Right colon Transversecolon

Left colon Sigmoid Rectum

IBS group Control group

p=0.003* p=0.002* p=0.003*p<0.001* p<0.001* p<0.001*

25/37 (67.6%)

12/37 (32.4%)

28/37 (75.7%)

7/37 (18.9%)

23/37 (62.2%)

10/37 (27.0%)

18/37 (48.6%)

6/37 (16.2%)

26/37 (70.3%)

8/37 (21.6%)

9/37 (24.3%)

26/37 (70.3%)

*Chi‐squared test


Histological findings compatible with inflammation according to Geboes Scale, by each colon segments and rectum.

0

5

10

15

20

25Cecum

Right colon

Transverse colon

Left colon

Sigmoid

Rectum

Geboes 0 Geboes 1 Geboes 2


0

5

10

15

20

25

30Cecum

Right colon

Transverse colon

Left colon

Sigmoid

Rectum



IBS group Control group

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RESULTS: Overall diagnostic accuracy of CLE forinflammatory findings in IBS, considering CLE target biopsy* as gold standard (%, CI 95%).

Cecum Right colonTransverse

colonLeft colon Sigmoid Rectum TOTAL

Sensitivity87.5

(73.2 – 95.8)

82.1

(66.5 – 92.5)

88.6

(73.3 – 96.8)

78.3

(56.3 – 92.5)

88.2

(72.6 – 96.7)

96.0

(79.7 – 99.9)

86.7

(81.2 – 91,2)

Specificity94.1

(80.3 – 99.3)

91.4

(76.9 – 98.2)

94.9

(82.7 – 99.4)

88.2

(76.1 – 5.6)

90.0

(76.3 – 97.2)

77.6

(63.4 – 88.2)

88.7

(84.1 – 92.4)

PPV94.6

(81.9 – 98.5)

91.4

(78.2 – 97.0)

93.9

(80.0 – 98.4)

75.0

(59.7 – 86.2)

88.2

(76.4 – 95.0)

68.6

(56.3 – 78.7)

85.9

(81.0 – 89.6)

NPV86.5

(73.7 – 93.6)

82.1

(69.9 – 90.0)

90.2

(78.6 – 95.9)

90.0

(80.5 – 95.2)

90.0

(78.1 – 95.8)

97.4

(84.7 – 99.6)

89.4

(85.5 – 92.4)

Observed

agreement90.5 86.5 91.9 91.9 89.2 83.8 87.8

Inter‐rater

agreement

81.1

(67.8 – 94.4)

73.1

(57.6 – 88.5)

83.7

(71.2 – 96.2)

65.7

(47.2 – 84.2)

78.2

(64.0 – 92.5)

67.0

(50.6 – 83.4)

75.4

(69.2 – 81.5)

* 1/74 (1.4%) from the IBS group corresponded to eosinophilic colitis.


RESULTS: Overall diagnostic accuracy of CLE forinflammatory findings in IBS, considering CLE target biopsy as gold standard (%, CI 95%).

There was not statistically difference in overall accuracy between each bowel portion, according to pooled sensitivity and specificity: p=0.4680 and p=0.1427, respectively.

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Conclusion

• CLE proved to be a reliable method for detecting colorectal mucosamicro‐inflammation in patients with IBS, showing that patients withIBS have 6 times more prevalence of mucosal colorectalmicroinflammatory than healthy patients.

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Signature of Circulating microRNA (miR) Detected by NextSeq Differentiates Non-alcoholic Fatty Liver Disease (NAFLD) Patients With Higher

Percentage Hepatic Collagen: A Potential Role for a Prognostic Biomarker

Younossi, Zobair M.1, 2; Karrar, Azza1; Tokarz, Kira3; Ulyanov, Anatoly3; Stepanova, Maria4; Younoszai, Zahra1; Jeffers, Thomas1; Felix, Sean1; Tan, Daisong2;; Moin Ahmad3; Iyer, Ramaswamy K.3; Deeken, John3;

Goodman, Zachary2

1. Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States.2. Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, United States.

3. Inova Translational Medicine Institute (ITMI), Inova Fairfax Hospital, Falls Church, VA, United States. 4. Center for Outcomes Research in Liver Disease, Washington, DC, United States.

.

No Steatosis Steatosis Steatohepatitis (NASH) NASH/Fibrosis

NAFLD is considered the hepatic manifestation of metabolic syndrome

Liver biopsy remains the gold standard to diagnose NASH and to accurately stage fibrosis

Fibrosis is the only predictor of mortality in patients with NASH

There is no validated non-invasive SERUM biomarker for NASH-related fibrosis

Background

• Nalbantoglu IL, World J Gastroenterol, 2014 Jul 21;20(27):9026-37

• Kleiner DE, Bedossa P. Gastroenterology, 2015 Nov;149(6):1305-8

• Sanyal AJ, Hepatology 2015; 61:1392-1405

• Matteoni CA, Younossi ZM, Gastroenterology 1999 Oct; 66(9):529-30

• Younossi ZM, Hepatology 2016;64:73-84

• Chalasani N, Younossi Z, Hepatology 2012;55:2005-2023

• Mccullough, A. Journal of Clinical Gastroenterolog, 2006 Mar;40 Suppl 1:S17-29

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DNA

mRNA

miRNAProtein

X

What are microRNAs (miR )?

Circulating microRNAs (miRs) are

Short, single-stranded RNA

Excellent candidates for human serum biomarkers

Stable in secretions and serum

May be reliable mechanistic biomarkers for monitoring liver disease

• Hornby RJ,.Expert Rev Clin Pharmacol 2014;7(3):349–362• Yamada H, Clin Chim Acta 2013; 424:99–103• Bala S,. Hepatology2012;56(5):1946–1957• Bandiera S., Journal of Hepatology 2015; 62:448-57• Laterza OF., Biomarker Med 2013;7:205-10

• Szabo, G. & Bala, S. (2013) , Nat. Rev. Gastroenterol. Hepatol.doi:10.1038/nrgastro.2013.87

• DiStefano Jk, Expert Review Gastroenterology Hepatolgy, 2016; 161-3• Yamada H, Clin Chim Acta 2013; 424:99–103• Pirola CJ, Gut 2015 May;64(5):800-12.• Marco MD, Semin Liver Dis 2015;35:43–54• Szabo G., Dig Dis Sci 2016; 61:1314-24• Vincent R, Curr Pathobiol Rep 2014;2:109–116

Szabo, G. & Bala, S. (2013) MicroRNAs in liver diseaseNat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2013.87

miRs May Regulate Hepatic Fibrogenesis

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Aims

Assess differential miR serum signature which is associated with fibrosis in NAFLD

Biopsy proven NAFLD (n=67)

All liver biopsies were evaluated by one hepato-pathologist (Zachary Goodman MD)

Hepatic fibrosis can be staged semi-quantitatively by Ishak or metavir scores

Hepatic collagen quantified by computerized morphometry (CAM) is more accurate

NAFLD patients : high % collagen (upper quartile) and low % collagen (lower quartile)

Next generation sequencing (NGS) technology was used to sequence (~2200 miR)

Circulating miR signature score was calculated using Random Forests (RF) package

Further analyses were carried out using multiple regression and pathway analysis

Methodology

• Goodman ZD.. Clin Liver Dis 2014;18:33-40.• Bedossa P. Dig Dis Sci 2016;61:1348-1355.

% collagen quantification

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Results

Demographic and Clinical Characteristics of NAFLD Cohort

NASH

(43)

Non-NASH

NAFLD (24)

All

(67)

p-value

Male 16 (37.2%) 6 (25.0%) 22 (32.8%) 0.31

Diabetes 28 (65.1%) 8 (33.3%) 36 (53.7%) 0.0124

Fibrosis ≥2 34 (79.1%) 7 (29.2%) 41 (61.2%) <0.0001

Age (years) 47.2 +/- 10.3 45.1 +/- 10.7 46.5 +/- 10.4 0.43

BMI (kg/m2) 48.9 +/- 10.5 48.7 +/- 9.2 48.9 +/- 10.0 0.91

ALT (IU) 51.2 +/- 35.0 34.0 +/- 18.3 45.0 +/- 31.0 0.0234

AST (IU) 40.6 +/- 24.9 23.4 +/- 13.0 34.3 +/- 22.8 0.0006

Collagen % 4.71 +/- 3.28 2.79 +/- 1.74 4.04 +/- 2.97 0.0219

Fat % 18.64 +/- 8.47 12.91 +/- 7.55 16.64 +/- 8.56 0.0076

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miRs Sera Signature Associated with Higher % Hepatic Collagen

• The miRNA signature was generated using importance function from R-package Random Forests (RF)

• For each score, the ability to discriminate between two groups was characterized by the receiveroperating characteristic (ROC) curve, and the area under the ROC curve (AUC) was calculated using thepROC R-package

miR-1245a, miR-3124-3p,miR-4760-3p, miR-3613-5p, miR-4488

AUC, p-value: 0.9335,<0.0001

Independent miR Predictors of Higher % Hepatic Collagen

Predictor Beta SE p-value

miR-3169 0.54395 0.23057 0.0216

miR-4792 -1.98389 0.34902 <.0001

• The multiple logistic regression (bi-directional stepwise selection), determined the followingmiRNA to be independently (p≤0.05) associated with higher % collagen.

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Ingenuity Pathway Analysis (IPA)

From the serum miR signature, miR-3124-3p and miR-4488

are regulators for genes regulating stellate cell activation and

fibrosis progression

Additionally, miR-4792 is the direct regulator of pathways

involved in the outcomes of hepatic fibrosis

Discussion and Summary

We have identified clinically relevant serum miR signature

that can segregate NAFLD patients according to the

presence of high and low hepatic % collagen deposition

(fibrosis)

These results indicate the potential role of serum miRs as

non-invasive biomarkers to predict significant fibrosis, the

most important prognostic factor in NAFLD

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Acknowledgment

• Principal Investigator: Dr. Zobair YounossiPathology Team

• Dr. Zack Goodman

• Lakshmi Alaparthi

• Fanny Monge

• Tan, Daisong

ITMI Team:

• Moin Ahmad

• Iyer, Ramaswamy

• John Deeken

Data Team & Bioinformatics

• Andrei Racila

• Maria Stepanova

• Kira Tokarz

• Ulyanov, Anatoly

Clinical data and Specimen Collection Team

• Hussain Allawi

• Thomas Jeffers

• Zahra Younoszai

• Sean Felix

THANK YOU!

Inova Fairfax Hospital, Falls Church, VA

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WCOG@ACG2017October 13‐18Orlando, Florida

1Carol A. Burke, MD, FACG, 2Christina M. Surawicz, MD, MACG, 3Amy S. Oxentenko,MD, FACG, 1Rocio Lopez, MS, MPH, 1Shashank Sarvepalli, MD, 4Joseph C. Anderson,MD, MHDCS, FACG, 5Kenneth R. DeVault, MD, FACG, 6Costas H. Kefalas, MD, MMM,FACG, 7Daniel J. Pambianco, MD, FACG, 8Sarah Richman, BA, 9Harry E. Sarles, MD,FACG, 8Anne‐Louise B. Oliphant, MPP, 10 Ronald J. Vender, MD, FACG

1Cleveland Clinic, Cleveland, OH, 2University of Washington, Seattle, WA, 3 Mayo Clinic, Rochester, MN, 4

Dartmouth College, Hanover, NH, 5 Mayo Clinic, Jacksonville, FL, 6 Akron Digestive Disease Associated, Akron, OH, 7 Charlottesville Gastroenterology Associates, 8 American College of Gastroenterology, Bethesda, MD, 9,

Digestive Health Associates, Rockwall, TX, 10 Yale University, New Haven, CT


Introduction

Burnout has been reported in up to 50% of physicians

Burnout is a syndrome characterized by

Emotional exhaustion

Depersonalization: cynicism and lack of compassion for patients/peers

Diminished sense of personal accomplishment

The prevalence and factors associated with burnout in gastroenterology not previously studied

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Aim

To determine the prevalence of burnout (BO) in gastroenterologists

To assess factors associated with BO


Methods 60 item survey emailed to ACG members in 2014‐2015

Demographics, employment setting , location, compensation type

Hours at work, % clinic, hospital, endoscopy, research

Time allotted for each visit type

Ease of use of EMR, typing skills

Hours spent on domestic activities, performing patient related work at home

Call, vacation and CME days taken

Spouse/Partner: Employment status, hours at work and in domestic chores, satisfaction with relationship

Wellness: % meals eaten, exercise, BMI, volunteerism

Maslach Burnout Inventory

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Methods The 22 item Maslach Burnout Inventory (MBI) was used to measure BO

Personal Accomplishment

Depersonalization

Emotional Exhaustion

Scoring Personal Accomplishment

Emotional Exhaustion

Depersonalization

High 0‐31 > 27 > 13

Moderate 32‐38 17‐26 7‐13

Low > 39 0‐16 0‐6

http://education.med.ufl.edu/files/2010/10/3455-mbi-scoring-key-2.pdf


Methods MBI subscales of emotional exhaustion (EE) and depersonalization (DP) used as indicators of burnout

Burnout defined as “High” EE and or DP scores

Univariable analysis assessed differences between respondents who had low/moderate BO scores and those who had high BO scores

Multivariable logistic regression analysis evaluate factors associated with BO. An automated stepwise selection method performed on 1000 bootstrap samples to choose the final model

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Results Surveys sent to 11080 ACG members; 1021 (9.2%) response rate

754 completed all MBI questions and used for the analysis


Results:Demographicand PracticeResponses

No BurnoutN=382

BurnoutN=372

P value

GenderFemaleMale

35.6%54.3%

64.4%45.7%

<0.001

Age, yrs 50.4 ± 9.2 <0.001

EmploymentPart timeFull time

61.7%50.3%

38.3%49.7%

0.13

Practice TypePrivateAcademiaVeteransOther

49.9%52.1%45.5%56.4%

50.1%47.9%54.5%43.6%

0.72

Practice LocationUrbanSuburbanRural

54.7%48.0%44.1%

45.3%52.0%55.9%

0.090

Compensation TypeSalary onlySalary & incentiveOther

43.9%50.8%60.9%

56.1%49.2%39.1%

0.084

EMR UseUser friendlyNot user friendlyDo not use

54.1%44.2%65.1%

45.9%55.8%34.9%

0.002

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Results:Socialand FamilyResponses

No Burnout Burnout P value

AVERAGE HOURS SPENT PER WEEK

• Domestic chores 6.0[4.0,10.0] 8.0[5.0,10.0] <0.001

• Caring for children 0.00[0.00,7.0] 2.0[0.00,10.0] 0.015

ADDITIONAL HOURS SPENT EACH DAY

• Performing patient‐related tasks at home 1.00[0.00,1.00] 1.00[0.00,2.00] 0.019

• Performing non‐patient work‐related tasks at home 1.00[0.00,1.00] 1.00[0.00,1.00] 0.40

SPOUSE EMPLOYMENT 0.011

. Single 38.2% 61.8%

. Spouse/Partner unemployed 47.1% 52.9%

. Spouse/Partner employed 56.3% 43.7%HOURS/WEEK EMPLOYED SPOUSE SPENDS

• At work or in employment related activities 40.0 [20.0,50.0] 40.0 [30.0,50.0] 0.003

• On domestic chores 12.0 [7.0,20.0] 12.0 [10.0,20.0] 0.86

• Caring for children 5.0 [0.00,20.0] 5.5 [0.00,20.0] 0.28

SATISFACTION WITH RELATIONSHIP <0.001

. Neutral/Dissatisfied 35.1% 64.9%

. Somewhat/Extremely satisfied 54.3% 45.7%

AGE OF YOUNGEST CHILD 0.006

. No children 39.7% 60.3%

. <10 years 47.5% 52.5%

. 11‐15 years 43.0% 57.0%

. 16+ years 57.0% 43.0%

AGE OF OLDEST CHILD <0.001

. <10 years 49.3% 50.7%

. 11‐15 years 30.8% 69.2%

. 16+ years 56.2% 43.8%

Median [25th and 75th ]


Results:Healthand Impactof BO

NoBurnout

Burnout P value

Moderate Exercise0‐120 min/wk>120 min/wk

50.4%51.8%

49.6%48.2%

0.75

Work days eating breakfast and lunch0‐50%> 50%

46.9%54.6%

53.1%45.4%

0.038

Satisfaction with Spouse/PartnerNeutral, somewhat/extremely dissatisfiedSomewhat or extremely satisfied

35.1%54.3%

64.9%45.7%

<0.001

Planning retirement earlier/Leaving practice within 2 years

35.8% 64.2% <0.001

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Thoughts of Early Retirement: 46%


ResultsMULTIVARIABLE ANALYSIS OR (95% CI) P value

Age (1 yr increment) 0.94 (0.92,0.96) < 0.001

EMR User friendly vs not 0.56 (0.29,1.09) 0.089

Domestic chores/wk (3 hour increment) 1.09 (1.01, 1.06) 0.036

Relationship SatisfactionSomewhat/Extremelyvs Neutral or Dissatisfied

0.53 (0.35, 0.83) 0.005

Oldest child < 10 yrs vs No children 0.56 (0.29, 1.1) 0.094

11‐15 yrs vs No children 1.5 (0.68, 3.3) 0.31

> 15 yrs vs No children 1.2 (0.61, 2.2) 0.63

Eating Breakfast and Lunch > 50% days vs Not 0.75 (0.54, 1.04) 0.088

Early Retirement/Leaving Practice in 2 yrs vs Not 3.5 (2.5, 4.9) <0.001

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Conclusions

Nearly 50% of gastroenterologist respondents report burnout

More related to work life balance issues than employment factors

Higher rates of burnout reported in: Younger gastroenterologists, those spending more time doing domestic chores

Physicians neutral or dissatisfied with their partner/spouse

Those planning to leave their practice early

Burnout has serious implications on the GI workforce

Strategies and Resources to address success in a physician’s personal and professional life are needed and requested

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Evolving Trends in the epidemiology of IBD in the 21st Century: A Systematic Review of Population‐Based Studies

Siew Ng ‐ Chinese University of Hong Kong, Hai Yun Shi ‐ Chinese University of Hong Kong, Nima Hamidi ‐University of Calgary, Fox Underwood ‐ University of Calgary, Whitney Tang ‐ Chinese University of Hong Kong,

Eric Benchimol – University of Ottawa, Remo Panaccione ‐ University of Calgary, Subrata Ghosh ‐University of Birmingham, Justin CY Wu ‐ Chinese University of Hong Kong, Francis Chan ‐ Chinese University

of Hong Kong, Joseph Sung ‐ Chinese University of Hong Kong, Gilaad Kaplan ‐ University of Calgary

E‐publication on October 16, 2017 in The Lancet

1930 1950 1960 1980 1990 2000

Western World

Molodecky, Soon, Rabi, Ghali, Ferris, Chernoff, Benchimol, Panaccione, Ghosh, Barkema, and Kaplan GG. Increasing Incidence of Inflammatory Bowel Disease with Time and Among Regions, Based on Systematic Review. Gastroenterology. 2012 Jan; 142(1): 46‐54

Background: The incidence of IBD skyrocketed during the 20th Century in the Western World.

Inciden

ce per 100,000

2 4 6 8 10

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Objective

We conducted a systematic review of population‐based studies reporting the incidence of IBD since 1990 across the world and performed temporal

trend analyses of incidence rates.

Methods•Systematic Review

• 2 Independent Teams: Calgary & Hong Kong• Population‐based studies reporting the incidence or prevalence of IBD after 1990

• Excluded pediatric‐onset IBD• 1990 to 2010 from prior systematic review1

• Systematic review (Embase/Medline) 2010‐2016

•Choropleth maps for incidence of CD or UC•Maps were divided into 5 colours corresponding to incidence quintiles defined by prior systematic review1

1. Molodecky, et al. Gastroenterology. 2012 Jan; 142(1): 46‐54

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Methods•Scatter Plots

• Scatter plots for studies reporting annual incidence of Crohn’s disease or ulcerative colitis from 1990‐2016

•Temporal Analysis• Joinpoint regression assessed annual percent change (APC) in incidence with 95% confidence interval (CI)

• Assessed stable, decreasing or increasing incidence

Results: A total of 119 studies reported the incidence of Crohn’s disease or ulcerative colitis.

11170 citations from 2010‐2016

226 full text reviews

147 Studies

119 Incidence

69 Prevalence

95 studies from prior systematic

review

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Results: Global Incidence of IBD from 1990 to 2016

Global Incidence of Crohn’s Disease Global Incidence of Ulcerative Colitis

Incidence exceeds 6.4 per 100,000 Incidence exceeds 7.7 per 100,000

Prevalence of IBD exceeds 0.3% in most countries of the Western World

73% of Crohn’s disease studies in Western World have stable or decreasing incidence

83% of ulcerative colitis studies in Western World have stable or decreasing incidence

Incidence per 100,000

1990 1995 2000 2005 2010 2015 1990 1995 2000 2005 2010 2015

0 5 10 15 20 25 30

0 5 10 15 20 25 30

2015 2020 2025 2030 2035 2040 2015 2020 2025 2030 2035 2040

Will the incidence of IBD in newly industrialized countries mirror the progression of IBD in the western world during the 20th century?

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Results: Rapid rise in the incidence of IBD in newly industrialized countries of Asia and South America

Brazil (1990 to 2012)

CD: APC = +11.1; 95% CI: 4.8, 17.8

UC: APC = +14.9; 95%: CI 10.4, 19.6

Taiwan (1998 to 2008)

CD: APC = +4.0; 95% CI: 1.0, 7.1

UC: APC = +4.8; 95% CI: 1.8, 8.0

South Korea (1991 to 2005)

CD: APC = +13.8; 95% CI: 8.7, 19.0

UC: APC = +9.5; 95% CI: 2.7, 16.7

Limitations

•No meta‐analyses due to heterogeneity between studies• Approach to surveillance of incidence• Quality of studies• Access to healthcare

• Variation in reporting of incidence• Crude versus adjusted• Age of population (e.g. studies reporting only pediatric‐onset IBD were excluded)

• Time periods

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Conclusion: IBD is a Global Disease1. Paradigm shift in the incidence of IBD at the turn of the 21st Century

2. Since 1990, the incidence of IBD in most Western countries has stabilized or decreased

3. Newly industrialized countries have rising incidence analogous to trends observed in the Western world during the latter part of the 20th century

4. Future research should identify environmental factors associated with westernization of society that prevent the development of IBD

Acknowledgements

Fox UnderwoodNima HamidiRemo PanaccioneGil Kaplan

Eric Benchimol Subrata Ghosh

Siew NgHai Yun ShiWhitney TangJustin WuFrancis ChanJoseph Sung

E‐publication on October 16, 2017 in The Lancet

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RISK OF ALCOHOL ABUSE IS INCREASED AFTER BARIATRIC SURGERY:

A Systemic Review and Meta‐analysisPraneet Wander, M.D.1

Daniel Castaneda, M.D.2

Joanna Dognin, PsyD.3

Christopher C. Thompson, M.D., M.H.E.S.4

Violeta B. Popov, M.D., Ph.D.3,5

1Hofstra Northwell, Northshore LIJ Hospital, New York2Mount Sinai St Luke’s and West Hospital, New York

3NY VA Harbor Healthcare System, New York NY4Brigham & Women’s Hospital; Harvard Medical School, Boston

5NYU School of Medicine, NYU Langone Medical Center, New York

BACKGROUND

• Bariatric surgery is associated with improvement of obesity related co‐morbidities

• Some studies suggest that post‐bariatric patients may be susceptible to alcohol abuse, although data is inconsistent

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BACKGROUND• Alcohol is metabolized differently after bariatric surgery:

– Alcohol levels increase after RYGB • Accelerated alcohol absorption• Higher maximum alcohol concentration• Longer time to eliminate alcohol

– Physiologic alterations after surgery• Rapid emptying of liquids from the gastric pouch may accelerate absorption of alcohol in the small intestine

• The stomach, a main source of alcohol dehydrogenase, is bypassed, thus facilitating rapid absorption

• Undiagnosed depression or substance use

Klockhoff H, Näslund I, Jones AW. Br J Clin Pharmacol 2002Woodard GA, Downey J, Hernandez‐Boussard T, Morton JM. J Am Coll Surg 2011

Horowitz M, Collins PJ, Harding PE, Shearman DJ. Int J Obes 1986

AIM

• To assess the impact of bariatric surgery on high‐risk alcohol use in a meta‐analysis of the published data

4

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METHODS: DATA SOURCES

• MEDLINE and Embase databases searched through 1/16

• MeSH terms ”alcohol”, “substance abuse”, “outcomes”, “bariatric surgery”

• Review of title/abstracts, full text

• Data extraction were performed independently by 2 authors

5

METHODS: STUDY DESIGN

• INCLUSION CRITERIA– Retrospective or prospective cohort studies of Roux‐en‐Y gastric bypass (RYGB), sleeve gastrectomy, laparoscopic adjustable gastric banding (LAGB)

– long‐term outcomes (>12 months) after bariatric procedures

– >100 patients in a cohort– alcohol use as per the AUDIT, dSCID criteria and data from inpatient alcohol treatment

6

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METHODS: ANALYSIS• Study Population:

– Obese patients that have undergone a bariatric surgery procedure

• Comparator:– Same population prior to surgery– Appropriate control group: age‐ and BMI‐matched

• Statistical analysis:– Random effects meta‐analysis– Heterogeneity by Cochrane’s Q‐test and I2

OUTCOME MEASURES

• PRIMARY OUTCOMES

– Pooled event rate and 95% confidence interval (95% CI) of significant alcohol use before and after surgery

– Pooled odds ratio for new‐onset significant alcohol use in studies that compared alcohol use before and after bariatric surgery, or with a control group

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RESULTS: STUDY SELECTION

RESULTS

• Total subjects: 15,714• 12 prospective • 16 retrospective or cross‐sectional• Study origin: Brazil, Canada, Portugal, Sweden, Spain, United

States of America

• The studies evaluated ETOH by: • dSCID and other substance use (n= 11) • AUDIT (n= 21) • inpatient admissions (n= 4)

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RESULTS

• Average follow‐up: 2.6 years (6 months ‐ 12 years)

• Age range: 43.4 years (26.5 ‐ 50 years)

• Female: 76.8%

• Type of procedure:– Roux‐en‐Y gastric bypass : 23 studies

– Laparoscopic gastric banding: 12 studies

– Restrictive procedures: 8 studies

ALCOHOL USE PRIOR TO BARIATRIC SURGERY

Study name Statistics for each study Event rate and 95% CI

Event Lower Upper rate limit limit Z-Value p-Value

Burgos, 2015 0.07 0.06 0.10 -16.97 0.00Alfonsson, 2014 0.14 0.09 0.21 -7.16 0.00Mitchell, 2015 0.33 0.27 0.40 -4.63 0.00Engel, 2015 0.08 0.02 0.28 -3.25 0.00Lent, 2013 0.47 0.39 0.55 -0.83 0.40Conason, 2013 0.61 0.53 0.69 2.79 0.01King, 2012 0.07 0.06 0.09 -29.16 0.00Sogg, 2011 0.35 0.30 0.41 -5.34 0.00Ertelt, 2008 0.09 0.04 0.18 -5.54 0.00de Amorium, 2015 0.03 0.01 0.08 -6.25 0.00Suzuki, 2012 0.35 0.23 0.49 -2.07 0.04Wiedemann et al., 2013 0.37 0.25 0.51 -1.80 0.07Mitchell, 2001 0.13 0.07 0.22 -5.66 0.00Tedesco et al., 2013 0.21 0.16 0.28 -7.63 0.00Tae 2014 0.38 0.23 0.55 -1.40 0.16Ertelt et al. 2008 0.09 0.04 0.18 -5.54 0.00Spadola 2016 0.17 0.10 0.28 -4.91 0.00Wee, 2014 0.15 0.11 0.19 -11.23 0.00

0.19 0.12 0.28 -5.49 0.00

-1.00 -0.50 0.00 0.50 1.00Pooled Event Rate 19% (0.12, 0.28)N studies=18, n= 4,697 subjects, I2 =97%, Tau2 =1.1

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SIGNIFICANT ALCOHOL ABUSE AFTER BARIATRIC SURGERY

Study name Statistics for each study Event rate and 95% CI


Burgos, 2015 0.03 0.02 0.05 -15.26 0.00Alfonsson, 2014 0.08 0.04 0.14 -7.52 0.00Mitchell, 2015 0.08 0.05 0.13 -9.39 0.00King, 2015 0.11 0.09 0.12 -28.91 0.00Engel, 2015 0.83 0.63 0.94 2.94 0.00Lent, 2013 0.61 0.53 0.69 2.79 0.01Conason, 2013 0.63 0.47 0.77 1.60 0.11Cuellar, 2013 0.23 0.13 0.37 -3.40 0.00Sogg, 2011 0.41 0.36 0.46 -3.24 0.00Saules, 2010 0.61 0.48 0.73 1.62 0.11Suzuki, 2012 0.12 0.05 0.24 -4.64 0.00Wiedemann et al., 2013 0.76 0.63 0.86 3.57 0.00Mitchell, 2001 0.08 0.03 0.16 -5.85 0.00Tae 2014 0.19 0.09 0.36 -3.24 0.00Reslan 2014 0.04 0.02 0.09 -7.46 0.00Ivezaj et al. 2014 0.27 0.21 0.35 -5.22 0.00Ertelt et al. 2008 0.10 0.05 0.20 -5.51 0.00Spadola 2016 0.22 0.14 0.33 -4.39 0.00Wee, 2014 0.13 0.10 0.17 -11.56 0.00

-1.00 -0.50 0.00 0.50 1.00Pooled Event Rate 23% (0.12, 0.28)N studies=19, n= 4,552 subjects, I2 =97%, Tau2 =1.5

NEW‐ONSET ALCOHOL ABUSE AFTER BARIATRIC SURGERY

Model Study name Statistics for each study Event rate and 95% CI


Mitchell, 2015 0.06 0.04 0.11 -9.32 0.00

Lent, 2013 0.06 0.04 0.12 -8.18 0.00

King, 2012 0.08 0.07 0.09 -29.22 0.00

Spadola 2016 0.04 0.01 0.13 -5.24 0.00

Wee, 2014 0.08 0.05 0.11 -12.00 0.00

Fixed 0.08 0.07 0.09 -34.30 0.00

Random 0.08 0.07 0.09 -34.30 0.00

-1.00 -0.50 0.00 0.50 1.00

Pooled Event Rate 8% (0.07, 0.09)N studies=5, n= 2,698 subjects, I2 =0%

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ODDS OF SIGNIFICANT ALCOHOL USE AFTER SURGERY COMPARED TO BEFORE SURGERY

Model Study name Statistics for each study Odds ratio and 95% CI

Odds Lower Upper ratio limit limit p-Value

Mitchell, 2015 0.64 0.45 0.91 0.01Engel, 2015 55.00 14.97 202.11 0.00Lent, 2013 1.81 1.32 2.49 0.00Conason, 2013 1.08 0.64 1.82 0.76King, 2012 1.53 1.30 1.79 0.00Sogg, 2011 1.28 1.03 1.60 0.03Wiedemann et al., 2013 5.47 2.97 10.09 0.00Tae 2014 0.59 0.25 1.36 0.21Ertelt et al. 2008 1.19 0.53 2.66 0.68Spadola 2016 1.32 0.72 2.40 0.36Wee, 2014 0.86 0.63 1.17 0.34

Random 1.50 1.07 2.11 0.02

0.01 0.1 1 10 100

Decreases ETOH Increases ETOH

Pooled Odds Ratio 1.5 (1.07, 2.11), p=0.02N studies=11, n= 3,370 subjects, I2 =89%, Tau2 =0.3

LIMITATIONS

• No randomized controlled data available and few good quality prospective studies

• Follow up time varied between studies

• Studies originated in various countries with different cultural norms, thus affecting attitudes towards alcohol use

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CONCLUSION

• Bariatric surgery is associated with increase in moderate to high‐risk alcohol use/abuse with a new‐onset incidence of 8% and increased odds of alcohol abuse after surgery

• 19% of patients overall reported problem drinking prior to surgery

• Screening for high‐risk behaviors may help better patient selection

• After bariatric surgery, patients require close follow‐up and evaluation for psychiatric illness and substance abuse

• More prospective data is needed

THANK YOU

Email: [email protected]

18

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Integrated Efficacy and Safety of Glecaprevir/Pibrentasvir to Treat HCV Genotype 1‐6 Infection in Patients without Cirrhosis Including HIV Co‐Infection

David E. Bernstein1, Graham R. Foster2, Douglas E. Dylla3, Stefan Mauss4, David R. Nelson5, Tarik Asselah6, Steve L. Flamm7, Curtis Cooper8, Ran Liu3, Rolando Viani3, Stanley Wang3, Federico J. Mensa3, Mark S. Sulkowski9

World Congress of Gastroenterology at ACG 2017• Orlando, FL, USA • 16 October 2017

1Department of Medicine, Zucker School of Medicine at Hofstra Northwell, Manhasset, NY 2Queen Mary University of London, Barts Health, London, United Kingdom. 3AbbVie Inc. North Chicago, IL 4Center for HIV and Hepatogastroenterology, Düsseldorf, Deutschland. 5Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL. 6Hopital Beaujon, Clichy, France. 7Northwestern Feinberg School of Medicine, Chicago, IL. 8Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada. 9Johns Hopkins University School of Medicine, Baltimore, MD.

Disclosures

DE Bernstein: Research support: AbbVie, BMS, Gilead, Merck; Consultant/Speaker: AbbVie, BMS, Gilead, Merck.GR Foster: Grant: AbbVie, BMS, Merck, Roche/Genentech, Gilead, Novartis, Janssen, Consultant: AbbVie, Vertex, BMS, Merck, Roche/Genentech, Gilead, GSK, Janssen, Virco, Novartis. S Mauss: Consultant: AbbVie, BMS, Gilead, Janssen, MSD, ViiV; Sponsored Lectures: AbbVie, BMS, Gilead, Hexal, Janssen, MSD. DR Nelson: Grant/Research Support: AbbVie, Bristol‐Myers Squibb, Gilead, Merck, Janssen. T Asselah: Advisor/Speaker/Investigator: AbbVie, Bristol‐Myers Squibb, Gilead, Janssen, Merck, Roche. S Flamm: Grant: AbbVie, Gilead, Merck, Consultant: AbbVie, Gilead, Merck. C Cooper: grants, speaker, advisor‐ ABV, GS, MK. DE Dylla, R Liu, R Viani, S Wang, F Mensa are employees of AbbVie, Inc. and may hold stock or stock options. MS Sulkowski: Consultant/advisor: AbbVie, Gilead, Janssen, Trek; Data safety monitoring board: Gilead (funds paid to Johns Hopkins University); Grant/research support: AbbVie, Gilead, Merck (paid to Johns Hopkins University).

AbbVie sponsored the studies (NCT02604017, NCT02243293, NCT02640157, NCT02243280, NCT02738138), contributed to their design, participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of this publication.

Medical writing support was provided by Daniel O’Brien, PhD, of AbbVie.

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Integrated Efficacy and Safety of Glecaprevir/Pibrentasvir to Treat HCV Genotype 1‐6 Infection in Patients without Cirrhosis Including HIV Co‐Infection ACG 16 Oct 2017

G/P is Approved for Patients with HCV GT1‐6 Infection

G/P is dosed once daily as three pills for a total dose of 300 mg/120 mgGlecaprevir was identified by AbbVie and Enanta

Glecaprevirpangenotypic NS3/4Aprotease inhibitor

Pibrentasvirpangenotypic NS5A

inhibitor

Coformulated: G/P

GLE PIB

• Overall SVR12 rate of 98% across GT1–6 in more than 2200 patients1

• 8 week duration approved for all treatment naïve patients without cirrhosis2

• Favorable safety profile irrespective of baseline factors such as compensated liver cirrhosis or advanced renal disease

• Potent against common polymorphisms (eg, Y93H in NS5A and Q80K in NS3)

1. Grebely et al, INHSU, 08 Sept 20172. MAVYRET / MAVIRET [US package insert / EU SmPC]. AbbVie. 2017

100% SVR4 and Favorable Safety of ABT‐493 + ABT‐530 Administered for 12 Weeks in Non‐Cirrhotic Patients with GT4‐6 Infection (SURVEYOR‐I) | DDW | 23 May 2016 4Integrated Efficacy and Safety of Glecaprevir/Pibrentasvir to Treat HCV Genotype 1‐6 Infection in Patients without Cirrhosis Including HIV Co‐Infection ACG 16 Oct 2017

G/P Approved Indications in the United States*Without Cirrhosis

With Compensated Cirrhosis

HCV Genotype Prior Treatment Experience Duration

1, 2, 3, 4, 5, 6 Naïve 8 Weeks 12 Weeks

1, 2, 4, 5, 6 PRS 8 Weeks 12 Weeks

3 PRS 16 Weeks 16 Weeks

1NS3/4A PI Only 12 Weeks 12 Weeks

NS5A Inhibitor Only 16 Weeks 16 Weeks

PI, protease inhibitor; PRS, regimens containing interferon, pegylated interferon, ribavirin and/or sofosbuvir (no experience with NS3/4A PI or NS5A inhibitors)*MAVYRET [US package insert ]. AbbVie. 2017†AASLD guidelines updated in September 2017. h p://hcvguidelines.org/sites/default/files/full‐guidance‐pdf/HCVGuidance_September_21_2017_c.pdf

• Dosage and durations are also applicable to:

– Patients with HIV/HCV co‐infection

– All degrees of renal impairment, including patients on dialysis

• No baseline restrictions for viral load, race, or HIV co‐infection for 8‐week G/P therapy, which are not recommended by the AASLD Guidelines for 8‐week LDV/SOF therapy†

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Objective

• Evaluate SVR12 rates from pooled datasets of GT1‐6 treatment‐naïve and GT1, 2, 4‐6 PRS treatment‐experienced non‐cirrhotic patients treated with G/P for 8 weeks and GT3 PRS‐experienced non‐cirrhotic patients treated for 16 weeks

• Evaluate whether baseline factors impact achievement of SVR12 among non‐cirrhotic patients

• Evaluate safety and adverse events in non‐cirrhotic patients treated with G/P

PRS, treatment‐experienced with interferon (IFN) or pegIFN ± ribavirin (RBV), or sofosbuvir (SOF) plus RBV ± pegIFN.


Study Design

Data were pooled from arms of five Phase 2 or 3 studies*, in patients without cirrhosis receiving G/P†

*Patients without cirrhosis were pooled from the phase 2 SURVEYOR‐I and SURVEYOR‐II Part 2 and Phase 3 SURVEYOR‐II Parts 3‐4, ENDURANCE‐1, ENDURANCE‐3, and EXPEDITION‐2 studies†Phase 3 studies involved coformulated tablets of G/P whereas the Phase 2 studies had GLE and PIB as separate tablets‡GT3 patients must have been treatment naïve only to receive 8 week treatment

N = 965GT1‐6 TN/TE‡ without cirrhosis

Day 0 Wk 20Wk 8

G/P†8 weeks

SVR12 assessment

G/P16 weeks

N = 22GT3 TE

without cirrhosis

Wk 16 Wk 28

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• Adults with chronic HCV GT 1, 2, 3, 4, 5 or 6 infection (HCV RNA > 1000 IU/mL)

• Age ≥ 18 years

• BMI ≥ 18 kg/m2

• HCV treatment‐naïve or PRS‐experienced (experienced with interferon (IFN) or pegylated IFN ± ribavirin (RBV), or sofosbuvir (SOF) plus RBV ± pegIFN)

• Absence of cirrhosis (based on liver biopsy, Fibroscan®, or Fibrotest® and APRI)

• No prior HCV treatment experience with a DAA other than SOF

• Absence of hepatitis B virus co‐infection

• For HIV‐infected patients: naïve to treatment with any antiretroviral therapy (ART) OR on a stable, qualifying HIV‐1 ART regimen* for at least 8 weeks

Key Eligibility Criteria

*ART regimens that were not allowed in the study were atazanavir, efavirenz, tipranavir/ritonavir, etravirine, nevirapine. Darunavir/ritonavir and lopinavir/ritonavir were not permitted in cirrhotic patients.


Endpoints

• ITT and mITT SVR12 (HCV RNA < LLOQ at post‐treatment week 12)

• On‐treatment virologic failure and post‐treatment relapse

Additional assessments

• Impact of > 20 baseline variables on SVR, including HIV co‐infection

• Adverse events (AEs) and laboratory abnormalities

ITT, intent‐to‐treat population includes all patients that received at least one dose of study drug mITT, modified intent‐to‐treat population excludes patients with non‐virologic failure

Endpoints and Assessments

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Characteristic8‐week G/P

N = 965

16‐week G/P (GT3 PRS)

N = 22

Male, n (%) 537 (56) 14 (64)

Race, n (%)

White 794 (82) 20 (91)

Asian 87 (9) 2 (9)

Black 65 (7) 0

Age, ≥ 65 years, n (%) 92 (10) 3 (14)

BMI, ≥ 30, n (%) 174 (18) 6 (27)

Genotype 1/2/3/4/5/6, n 474/206/208/62/2/13 0/0/22/0/0/0

Subtype 1a, n/N (%) 244/474 (51) N/A

Subtype 1b, n/N (%) 229/474 (48) N/A

HCV treatment‐experienced, n (%) 197 (20) 22 (100)

IFN‐based 187 (95) 13 (59)

SOF‐based 10 (5) 9 (41)G/P, glecaprevir/pibrentasvir; BMI, body mass index; HCV, hepatitis C virus; IFN, interferon; SOF, sofosbuvir

Baseline Demographics and Disease Characteristics


Characteristic8‐week G/P

N = 965


N = 22

HCV RNA, median (range), log10 IU/mL 6.2 (0.7 – 7.6) 6.1 (4.7 – 7.3)

HCV RNA level, IU/mL, n (%)

< 1,000,000 392 (41) 10 (45)

≥ 1,000,000 573 (59) 12 (55)

< 6,000,000 734 (76) 15 (68)

≥ 6,000,000 231 (24) 7 (32)

Fibrosis score, n/N (%)

F0‐F2 856 (89) 17 (77)

F3 106 (11) 5 (23)

HIV‐1 co‐infected, n (%) 152 (16) 0

Concomitant PPI use, n (%) 72 (7) 2 (9)

On stable opiate substitution, n (%) 73 (8) 0

History of injection drug use*, n (%) 427 (44)* 13 (59)G/P, glecaprevir/pibrentasvir; PPI, proton pump inhibitor*In 8 week treatment group, 23 patients reported injection drug use within last 12 months, while 253 patients reported injection drug use more than 12 months ago; data was missing from n = 320 patients


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% Patients with SVR12

Efficacy: SVR12, ITT Analysis

ITT, intention‐to‐treat. TN, treatment naïve. TE, treatment experienced.*One GT6 patient initially with missing SVR12 data was subsequently found with undetectable HCV RNA and is considered an SVR12 by backward imputation.

10 virologic failures (1%) among 987 patients treated

Reason for non‐response, n

Breakthrough 2 1 1Relapse 8 2 5 1Discontinuation 5 2 2 1Lost to follow‐up 7 1 4 2



Efficacy: SVR12, mITT Analysis*

mITT, modified ITT (excludes patients with non‐virologic failure). TN, treatment naïve. TE, treatment experienced*One GT6 patient initially with missing SVR12 data is excluded from this analysis.

Reason for non‐response, n

Breakthrough 2 1 1Relapse 8 2 5 1

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Subgroup Analyses in 8‐week G/P arms, mITT*

mITT, modified ITT (excludes patients with non‐virologic failure).*One GT6 patient initially with missing SVR12 data is excluded from this analysis.


0 20 40 60 80 100

Treatment nonadherent

Treatment adherent

Not on opiate substitution therapy

On opiate substitution therapy

No history of injection drug use

History of injection drug use

No use of PPI

Use of PPI

F3

F0-F2 fibrosis

HCV RNA 6000000 IU/ML

HCV RNA <6000000 IU/ML

HCV RNA 1000000 IU/ML

HCV RNA <1000000 IU/ML


99

99

99

99

98

386/387

557/565

720/725

223/227

841/846

99/103 96

70/70 100

873/882

72/72

99

871/880

100

99

% SVR12

832/840

111/112

99

99

414/418

529/534

99

99

Subgroup Analyses in 8‐week G/P arms, mITT*

mITT, modified ITT (excludes patients with non‐virologic failure).*One GT6 patient initially with missing SVR12 data is excluded from this analysis.

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Summary of Safety

Event, n (%)8‐week G/P

N = 965


N = 22

Any AE 610 (63) 17 (77)Serious AE 15 (2) 1 (5)DAA‐related serious AE 0 0AE leading to D/C 1 (0.1)* 0AEs occurring in ≥10% of patients

Headache 152 (16) 4 (18)Fatigue 125 (13) 4 (18)

Laboratory abnormalitiesALT, grade ≥3 (>5 ULN)† 0 0Total bilirubin, grade ≥3 (>3 ULN) 5 (0.5)‡ 0

AE, adverse event; DAA, direct‐acting antiviral; D/C, discontinuation; ALT, alanine aminotransferase.*Pancreatic adenocarcinoma not related to DAA based on clinical assessment.†The grade of post‐nadir ALT value must be more extreme than the grade of the nadir ALT value.‡All pa ents had bilirubin eleva ons at baseline; the grade 3 eleva ons were primarily indirect, with no associated post‐nadir ALT elevations by grade.


Summary

G/P regimen achieved an overall SVR12 rate 98% (ITT) and 99% (mITT) in patients with HCV GT 1–6 infection without cirrhosis

GT3‐infected, non‐cirrhotic patients with prior PRS treatment experience treated for 16 weeks achieved a 95% SVR12 rate

• G/P was highly efficacious regardless of baseline patient and viral factors

• Relapse rate < 1% for the 8‐week treatment duration

G/P was well‐tolerated regardless of treatment duration

• No serious drug‐related AEs

• No drug‐related discontinuations

PRS, treatment‐experienced with interferon (IFN) or pegIFN ± ribavirin (RBV), or sofosbuvir (SOF) plus RBV ± pegIFN.

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Conclusion

These data support the US and EU labeling for G/P as a pangenotypic8‐week regimen for patients without cirrhosis, with no baseline restrictions such as viral load, prior PRS treatment experience (other than GT3), and HIV co‐infection


Acknowledgement

The authors would like to express their gratitude to the patients who participated in these studies, as well as their families, study investigators and their staff

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10/27/2017

1

Degree of Estimated Fibrosis in AsymptomaticSubjects With Non‐Alcoholic Fatty Liver DiseaseCorrelates With Higher Cardiovascular Risk

María Cristina Moreno‐del Castillo*, Alain Sánchez‐Rodríguez*, Javier José Hernández‐Buen Abad**, José Ramón Mena‐Ramírez*, Ricardo García‐Buen Abad***, Jonathan Salazar‐Segovia***, María Emilia Mendizábal‐Álvarez*,

Natalie Atkinson‐Ginsburg*, Ignacio García‐Juárez****

*Department of Internal Medicine American British Cowdray, Medical Center

**Department of Preventive Medicine American British Cowdray, Medical Center

***Department of Radiology American British Cowdray Medical Center

****Department of Gastroenterology American British Cowdray Medical Center

Mexico City, Mexico

Introduction• Mexico has one of the highest obesity and Metabolic

Syndrome rates worldwide that ultimately lead tocardiovascular disease and death

• It has been previously reported that in Mexico 8 out of 10individuals with the Metabolic Syndrome have some degreeof Non‐alcoholic fatty liver disease (NAFLD)

‐Alegre‐Díaz, et al. Diabetes and Cause Specific Mortality in Mexico City NEJM, 2016,1961‐1971‐Castro‐Martínez et al. Prevalencia de hígado graso no alcohólico en individuos con síndrome metabólico Cir Cir, 2012,128‐133

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Introduction

• Fibrosis stage has been shown to be an independentpredictor of cardiovascular mortality in propective studies

• Moreover, it seems cardiovascular events are the maincause of death in patients with NAFLD.

Ekstedt M, et al. Fibrosis stage is the strongest predictor for disease‐specific mortality in NAFLD after up to 33 years of follow‐up. Hepatology, 2015, 1547–1554.

Introduction• The NAFLD fibrosis score (NFS) has been validated as a

powerful tool to estimate fibrosis

• Framingham risk score (FRS) and ACC/AHA are known to havestrong prediction capability for cardiovascular events

‐Angulo P, et al. The NAFLD Fibrosis Score: A Noninvasive System That Identifies Liver Fibrosis in Patients with NAFLD. Hepatology. 2007, 846‐854‐D'Agostino, et al. General cardiovascular risk profile for use in primary care: the Framingham HeartStudy. Circulation 2008, 117:743. ‐Goff DC, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of theAmerican College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014, 129:S49.

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Objective

Estimated 10-year atherosclerotic

cardiovascular risk scores (ASCVD) in

patients with NAFLD

Degree of estimated fibrosis by Non-

alcoholic fatty liver disease (NAFLD)

fibrosis score (NFS).

?

Methods

NAFLD was diagnosed by ultrasound.

Cross-sectional observational study from a single center in Mexico in asymptomatic outpatients.

Estimated 10-year ASCVD risk:✧(2013 ACC/AHA) risk equation✧Framingham risk score for coronary heart disease (FRS-CHD)

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Methods• We included all patient records with sufficient data to

calculate risk equations

• Patients excluded:

– significant alcohol consumption (defined by >30 gr/day in men, >20 g/day in women)

– Active cancer, acute illness

MethodsHigh ASCVD riskwas defined:

✧ 2013 ACC/AHA>= 7.5%

✧ Framingham> =20%

NFS was stratified into three groups:

✧<-1.455: F0-F2

✧>=-1.455-≤ 0.675: indeterminate

score

✧>0.675: F3-F4

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Results• We included data from 495 patients

• 62% were male

• BMI of 25.9 (SD ± 3.9) Kg/m2

• 45 (SD ± 11.5) years old.

• 141 patients had NAFLD by ultrasound (prevalence 28.4%)

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Results

• NAFLD vs. Non‐NAFLD patients had higher mean cardiovascular risk.

FRS: 7.1 vs 4.1%(p=0.05) and 2013 ACC/AHA: 5.7 vs 4.4% (p=0.05)

• Global 10‐year ASCVD risk was in the NAFLD group:

for ACC/AHA 5.7% (CI: 95% 4.6‐6.9), FRS‐CHD 7.1% (CI: 95% 6.1‐8.2)

ResultsFRS (=>10%) NAFLD

[OR = 5.05 (95% CI 2.1 – 11.9, p<0.01)]

FRS (=> 20%) F3‐F4 fibrosis [OR = 9.8 (95% CI 1.17 – 81, p=0.011)].

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Results

Higher degree of fibrosis by NAFLD fibrosis score correlated with higher Framingham risk score

Results

NAFLD Fibrosis Score

F0‐F2<‐1.455

Indeterminate

>=‐1.455‐≤ 0.675

F3‐F4

>0.675

Framingham

Risk Score

3.5% (IQR 1.3‐7.5)

3.9%

(IQR 2.0‐5.7)

8.7%

(IQR 5.3‐13.1)

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Results

Pearson’s r: 0.49, (p<0.001).

CH

DF

RS

F0-F2

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5-5

0

5

10

15

20

25

30

35

40

Indeterminado

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5

F3-F4

-6 -5 -4 -3 -2 -1 0 1 2 3 4 5-5

0

5

10

15

20

25

30

35

40

F0 - F2: r = 0.19, p = 0.25Indeterminado: r = 0.30, p < 0.01F3 - F4: r = 0.36, p < 0.01

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Discussion• NAFLD patients have higher ASCVD risk than healthy

subjects.

• Higher estimated fibrosis by NAFLD score correlated with higher 10‐year ASCVD risk in asymptomatic patients with ultrasonographic fatty liver disease.

Discussion

• ASCVD and NAFLD could share physiopathological pathways that may explain the correlation between two scores.

• Therefore, the presence of one may be able to predict the other

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Discussion

• Higher estimated NFS in fatty liver disease shouldprompt cardiovascular risk assessment and intervention.

• We need further prospective studies in patients withNAFLD to readjust our equations in order to preciselypredict cardiovascular outcomes in Hispanics

María Cristina Moreno del Castillo, MD

Internal Medicine ResidentAmerican British Cowdray, Medical Center

Mexico City, Mexico

E‐mail: [email protected]

THANK YOU

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10/27/2017

1

Validity of Non-Invasive Fibrosis Scores to Detect Advanced Fibrosis in Patients With

Type 2 Diabetes With Suspected Non-Alcoholic Fatty Liver Disease

Amandeep Singh1, Rocio Lopez1, Eric Lawitz2, Fred Poordad2, Naim Alkhouri2

Cleveland Clinic1, Texas Liver Institute2

Background• Nonalcoholic Fatty Liver disease (NAFLD) affects up to 75% of

patients with type 2 diabetes (T2D)

• Diabetes is a risk factor for the aggressive form of nonalcoholic steatohepatitis (NASH) and advanced fibrosis

• Patients with advanced fibrosis (F3- 4) have the highest risk of progression to cirrhosis and end-stage liver disease

• Recent guidelines from EASL recommended case finding of advanced disease in patients with type 2 diabetes (T2D)

1. Singh et al. J Clinical Gastroenterol, 20172. EASL–EASD–EASO Clinical Practice Guidelines. J Hepatol 2016

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Diagnosis of Advanced NAFLD in T2D

• Liver biopsy is the “gold standard” to diagnose advance fibrosis in NAFLD patients:

- High cost, sampling error

• New noninvasive imaging tests (e.g. MRE) are promising to diagnose advanced fibrosis

- Costly, limited availability for large scale testing

Noninvasive Fibrosis Scores in NAFLD

• Due to the high prevalence of NAFLD in diabetics, inexpensive noninvasive fibrosis scores have been developed

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Aim

• To assess the accuracy of commonly used noninvasive scores to predict the presence of advanced fibrosis (stage 3- 4) in a large cohort of type-2 diabetics with biopsy-proven NAFLD

MethodsInclusion Criteria

1. Patients with diagnosis of T2DM in the Cleveland Clinic system who had liver biopsy for suspected NAFLD

2. Age 18-80 years

Exclusion Criteria

1. Patients with incomplete medical records to calculate the scores

2. Patients with secondary causes of hepatic steatosis (hepatitis C, Wilson disease, parenteral nutrition, medications)

3. Alcohol consumption more than 30 g of alcohol per day for males or more than 20 g per day for females

10/27/2017

4

• Fibrosis stage was reported as F0-F4 according to the NASH-CRN criteria.

• Cutoffs for advanced fibrosis (F3-4)- AST to platelet ration index (APRI): > 1.5 and < 1- FIB-4 index: > 2.67 and < 1.45 - NAFLD fibrosis score (NFS): > 0.676 and < -1.455

• Sensitivity, specificity, and area under the ROC curve (AUC) were calculated to predict the overall accuracy of each score

Methods

Results

• Patient included in the study (n) = 1,157

• Mean age (yrs) at NAFLD diagnosis - 54.7

• 60% Females

• 94% Caucasians

• 94% Overweight or obese

• 60% Hyperlipidemia

• CKD in 22%

• Mean HbA1c - 6.9%

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Demographics and Patient Characteristics

Fibrosis 0-2 Fibrosis 3-4Factor (N=790) (N=367) p-valueAge at NAFLD diagnosis (yrs.) 49.5±11.3 54.7±11.3 <0.001Race <0.001

Caucasian 658(85.8) 330(94)African-American 90(11.7) 10(2.8)Other 19(2.5) 11(3.2)

BMI 35.7±7.7 35.1±8.8 0.26Hypertension 604(76.5) 258(70.3) 0.025Hyperlipidemia 596(75.4) 223(60.8) <0.001CKD 55(7) 81(22.1) <0.001Oral Hypoglycemic agents 574(72.7) 236(64.3) 0.004Insulin 256(32.4) 155(42.2) 0.001

Laboratory DataFibrosis 0-2 Fibrosis 3-4

Factor (N=790) (N=367) p-value

Platelets ( k/uL) 237.7±74.0 174.2±84.6 <0.001

Albumin (g/dL) 4.3±0.96 3.9±0.90 <0.001

Total Cholesterol (mg/dL) 172.3±42.9 157.6±43.8 <0.001

HDL (mg/dL) 49.1±16.7 42.4±16.8 <0.001

LDL (mg/dL) 94.6±35.5 85.8±35.1 <0.001

HbA1c (%) 6.7±1.4 6.9±1.7 0.039

AST (U/L) 24.0[19.0,35.0] 36.0[25.0,52.0] <0.001

ALT (U/L) 27.0[18.0,43.0] 33.0[20.0,52.0] <0.001

ALP (U/L) 78.0[64.0,98.0] 91.0[73.0,122.0] <0.001

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Performance of APRI Score in Predicting Advanced Fibrosis

Test Sensitivity Specificity PPV NPV

APRI > 1.5 16.5 (12.6, 20.3) 97.4 (96.3, 98.5) 74.7 (65.1, 84.3) 71.7 (68.9, 74.4)

APRI ≥ 1 27.9 (23.3, 32.6) 94.7 (93.1, 96.3) 70.9 (63.4, 78.4) 74.0 (71.3, 76.7)

Fibrosis 0-2 Fibrosis 3-4

0.190.280.45

0.320.551.09

Q1Median

Q3

AP

RI

0.0

1.0

0.5

2.0

2.5 p = 0.018

1.5

Per

cen

t

0

20

40

60

80

100

N 993< 1

621 – 1.5

79> 1.5

Fibrosis 0-2Fibrosis 3-4

APRI

74% 75%

25%

66%

34%26%

Performance of FIB-4 Score in Predicting Advanced Fibrosis


FIB-4 > 2.67 44.1 (39.0, 49.3) 93.0 (91.3, 94.8) 74.5 (68.7, 80.4) 78.3 (75.6, 81.0)

FIB-4 ≥ 1.45 72.6 (68.0, 77.2) 64.4 (61.1, 67.8) 48.5 (44.3, 52.7) 83.6 (80.6, 86.6)

p = 0.007


0.351.171.70

1.392.294.07

Q1Median

Q3

FIB

-4 S

core

0

2

4

6

8

Per

cen

t

0

20

40

60

80

100

N 598< 1.45

3241.45 – 2.67

212> 2.67


FIB-4

16%

69%

31%25%

75%84%

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Performance of NFS in Predicting Advanced Fibrosis


NFS > 0.676 63.7 (58.5, 68.8) 70.0 (66.7, 73.4) 49.8 (45.0, 54.5) 80.5 (77.4, 83.6)

NFS ≥ -1.455 94.6 (92.2, 97.1) 16.9 (14.2, 19.7) 34.7 (31.6, 37.8) 87.1 (81.6, 92.7)

p < 0.001


-1.03-0.000.84

0.051.292.54

Q1Median

Q3

NF

S

-5

0

5

Per

cen

t

0

20

40

60

80

100

N 140< -1.455

486-1.455 – 0.676

431> 0.676


NFS

87%

13%

79%

21%

50% 50%

Validity of Fibrosis Scores in Subjects with Diabetes Type II and NAFLD

Sen

siti

vity

1 - Specificity

APRI: 0.74 (0.71, 0.77)FIB-4: 0.77 (0.74, 0.80)NFS: 0.72 (0.69, 0.75)

0.00.0 0.2 0.4 0.6 0.8 1.0

0.2

0.4

0.6

0.8

1.0

10/27/2017

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Conclusions

• APRI >1.5 and FIB-4 >2.67 have high specificity to rule in advanced fibrosis but lack sensitivity

• NFS ≥ -1.455 has high sensitivity but very low specificity

• Combining scores with high sensitivity (NFS ≥ -1.455 ) and those with high specificity (APRI >1.5 ) might provide better diagnostic accuracy

• In diabetics with NAFLD, the development of reliable fibrosis scores suitable for large scale screening is urgently needed

10/27/2017

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Safety and Efficacy of Long‐Term Treatment with Ozanimod, an Oral S1P Receptor Modulator, in Moderate to Severe Ulcerative

Colitis: TOUCHSTONE Extension 2‐year Follow‐Up

W. J. Sandborn1, B. Feagan2, G. D’Haens3, S. Hanauer4, D. Wolf5, S. Vermeire6, S. Ghosh7, C. Li8, D. Penenberg8, A. Petersen8, R. Aranda8, A.Olson8

1 University of California San Diego, La Jolla, CA, USA;2 Robarts Research, Western University, London, Canada;3 Academic Medical Center, Amsterdam, Netherlands;

4 Feinberg School of Medicine, Chicago, IL, USA;5 Atlanta Gastroenterology Associates, Atlanta, GA, USA;

6 University of Leuven, Leuven, Belgium;7 University of Calgary, Alberta, Canada;

8 Receptos, San Diego, CA, USAClinicalTrials.gov: NCT01647516

This study was sponsored by Celgene Corporation

WOCG at ACG Orlando, Florida

Monday, 16 October 201716:30‐16:40

Disclosures

• Support provided by Celgene Corporation.

• William J. Sandborn reports grants/research support from AbbVie, Amgen, Receptos/Celgene International, Genentech, Janssen, Pfizer, Prometheus Laboratories, Takeda. He has been a consultant for AbbVie, Actavis, Amgen, Receptos/Celgene International, Genentech, Jansen, Pfizer, Prometheus Laboratories, Salix, Shire, Takeda, and UCB Pharma.

2

10/27/2017

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Ozanimod Overview

• Ozanimod, an oral, once daily immunomodulator that selectively target S1P1R and S1P5R, has

demonstrated clinical efficacy in ulcerative colitis (UC)1

• Ozanimod down‐regulates S1P1R, resulting in the

retention of autoreactive T and B cells2,3

• Following treatment cessation, lymphocyte

counts return to the normal range4

3

1. Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016; 374(18): 1754‐1762.2. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine‐1‐phosphate receptor‐1 (S1P1) and receptor‐5 (S1P5) agonist with autoimmune disease‐modifying activity. Br J Pharmacol. 2016; 173(11):

1778‐1792.3. Förster R, Davalos‐Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008; 8: 362‐371.4. Olson A, Hartung J, Timony G, et al. Safety and tolerability of orally administered RPC1063, a novel S1P1 receptor modulator, in healthy adult volunteers, results of a Phase 1 study. Neurology. 2013; 80(7): Supplement

P01.178.

Ozanimod Overview (continued)

• TOUCHSTONE was a randomized, double‐blind, placebo‐controlled phase 2 trial, in patients with moderate to severe UC1

• Designed to assess the efficacy and safety of ozanimod 0.5 mg and 1 mg versus placebo during induction and maintenance

• TOUCHSTONE established that ozanimod induced and maintained clinical remission (CR), clinical response, endoscopic mucosal healing, and histologic remission (HR) through weeks 8 and 32

41. Sandborn WJ, Feagan BG, Wolf DC, et al. Ozanimod induction and maintenance treatment for ulcerative colitis. N Engl J Med. 2016; 374(18): 1754‐1762.

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TOUCHSTONE OLE: Study Design and Objective

• Objective: To evaluate the long‐term safety and efficacy of daily ozanimod 1 mg in patients with moderate to severe UC who had initially participated in the TOUCHSTONE trial for up to 32 weeks.

• Of the initial 197 patients (65 on 0.5 mg arm, 67 on 1 mg, and 65 on placebo) randomized, 170 (86%) entered the OLE and received daily ozanimod 1 mg.

• As of the data cut‐off in March 2017, 100 (58.8%) patients had efficacy evaluations reported through Week 92; of these, 94 (55.3%) had received ozanimod 1 mg/day in the OLE for ≥2 years. 5

Extension

OLE Week 92 (N=100)

ozanimod 1 mg

Non-responders at the end of induction

Completed maintenance

Lost response during Maintenance

Entry into OLE(N=170)

+4 +8 +20 +32 +44

OLE Visit

Treatment for up to 32

weeks in the main study prior to OLE

Induction & Maintenance

+80+56 +68 +92

Eligibility Criteria

• Patients with moderate to severe UC (including Mayo score 6‐12 with endoscopic subscore of ≥2) enrolled into the main study could enter the OLE and receive treatment with 1 mg ozanimod daily if they:

• Were non‐responders at the end of the initial 8‐week induction period

• Lost their response during the subsequent 24‐week maintenance period

• Completed maintenance treatment

6

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OLE PopulationTotalN=170

Age (years), mean (SD) 40.4 (11.8)

Male, % 57.6

Years since UC diagnosis, mean (SD) 5.9 (5.3)

Mayo Score at Baseline by central reader, mean (SD) 8.6 (1.52)

Partial Mayo Score (pMS) at Baseline, mean (SD) 6.0 (1.3)

Physician Global Assessment (PGA) 0 or 1, n (%) 3 (1.8)

Rectal bleeding subscore (RBS) 0 or 1, n (%) 79 (46.5)

Blood in stools, n (%) 157 (92.4)

7

Mean Partial Mayo Score (pMS) by OLE Visit Through Week 92

8Bars indicate standard error.pMS mean change from OLE Baseline was determined in the safety population using the last‐observation‐carried‐forward methodology.

• At entry into the OLE, the pMS for patients on placebo, ozanimod 0.5 mg, and 1 mg was 4.6, 4.5, and 3.3 respectively, which improved significantly by OLE Week 8, with the greatest improvement reported in patients who had received placebo or ozanimod 0.5 mg in the TOUCHSTONE trial

0

1

2

3

4

5

6

7

Mean Partial M

ayo Score (±SE)

OLE Week

Placebo (N=55)

Ozanimod 0.5 mg (N=56)

Ozanimod 1 mg (N=59)

Prior to Entering OLE OLE

All patients received ozanimod 1 mg in OLE

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Improvement in Active Disease Measures From OLE Baseline Through Week 92

9

• At the Week 92 visit in the OLE, 91.0% had little or no active disease based on the physician global assessment (PGA 0 or 1), 97.0% had little or no blood in their stools (rectal bleeding subscore [RBS] 0 or 1), 86.0% had no blood in the stools (RBS 0).

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% of Patients

Physician Global Assessment (PGA) score 0 or 1

Rectal Bleeding Subscore (RBS) 0 or 1

No Blood in Stools (RBS = 0)

OLE Week

Safety population using observed cases.

OLE Population, n (%)Total

(N=170)

Subjects with ≥1 AE 85 (50.0)

Subjects with ≥1 SAE 20 (11.8)

ALT ≥3 × ULN 5 (2.9)

AST ≥3 × ULN 5 (2.9)

Overview of Adverse Events

10

• The safety profile at week 92 was similar to that reported in the placebo controlled portion of the study with the most common AE: UC flare, anaemia, upper respiratory tract infection, back pain

• The only SAEs in ≥2 patients were anaemia, and ulcerative colitis flare.

• Liver transaminase elevations were asymptomatic, <5 × ULN, transient, and resolving while receiving continued treatment.

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Author’s Conclusions

• Partial Mayo Score (pMS) substantially improved by OLE Week 8, with the greatest improvement reported in patients who had received placebo or ozanimod 0.5 mg in the main study

• At OLE Week 92, in patients who remained on ozanimod, there was little or no active disease based on PGA, RBS 0 or 1 (little or no blood in the stools), or RBS = 0 (no blood in the stools)

• Long‐term treatment with ozanimod continues to be safe and well tolerated with evidence of durable efficacy

• Collectively, results support the 1 mg dose for Phase 3

11

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Paradoxical Trends in Hospitalization Rates for the Inflammatory Bowel Diseases Between the Western World and Newly Industrialized Countries: A Study of the Organisation for

Economic Co‐operation and Development (OECD) James A. King, BA – University of Calgary; Fox E. Underwood, MSc – University of Calgary;

Nicola Panaccione – University of Calgary; Josh Quan – University of Calgary; Paulo Kotze, MD, PhD – University of Calgary; Siew C. Ng, MBBS, PhD – Chinese University of Hong Kong; Subrata Ghosh, MD – University of Calgary; Peter L. Lakatos, MD – Semmelweis University & McGill

University; Tine Jess, MD – Statens Serum Institut; Remo Panaccione, MD, FRCP – University of Calgary; Gilaad G. Kaplan, MD, MPH – University of Calgary

Background: Prevalence and Incidence of Inflammatory Bowel Disease (IBD)

Kaplan, G.G. and Ng, S.C., 2017. Understanding and preventing the global increase of inflammatory bowel disease. Gastroenterology, 152(2), pp.313‐321.

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Background: Organisation for Economic Co‐operation and Development (OECD)

• Established in 1961• International collaboration between governments

• Collect data on various country‐level indicators

35 Member Countries

Objective

To investigate and compare global patterns of hospitalizations for IBD in Westernized and newly industrialized countries

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Methods: Data Extraction

•Hospital discharge rates for Crohn’s disease and ulcerative colitis (IBD) retrieved from OECD database• 34 countries• Annual rates per 100,000 persons• Time period: 1990‐2015

•Hospital discharge rates standardized for 2010‐2014

Methods: Temporal Analysis (1990‐2015)

•32 countries eligible for temporal analyses

•Joinpoint regression models calculated:•Average annual percent change (AAPC) •Temporal inflection points

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Results: Hospitalizations for IBDHospitalization Rates for IBD (2010‐2014) AAPC for IBD Hospitalizations (1990‐2015)

Denmark

Hospitalization Rate

63.6/100,000

AAPC

Decreasing at 1.1% per year


United States


33.9/100,000

AAPC

Increasing at 2.3% per year

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AAPC

Increasing at 5.2% per year

Chile


8.4/100,000

Joinpoint: Canada

25

27

29

31

33

35

37

39

41

43

45

47

49

1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

HOSPITALIZATIONS FO

R IB

D (PER

100,000)

CHART TITLE

APC: ‐0.2 APC: ‐2.4*

*Statistically significant (p ≤ 0.05). Non‐significance denotes stable hospitalization rates.

Joinpoint: 1998

AAPC: ‐1.7*

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Limitations

• Crohn’s disease and ulcerative colitis could not be stratified•Medical admissions could not be differentiated from surgical

• Country data not available for every single year within 1990‐2015 time period

•Definitions, sources and methods used for “hospital discharges” varied by country

Conclusion: Hospitalizations for IBD

Westernized countries

• High discharge rates

• Rates stable/decreasing in some, but not all

Newly industrialized countries

• Low discharge rates

• Rates increasing in most

Temporal Patterns

• Trends in hospitalization rates significantly changed in 17 countries

Potential Explanations

• Epidemiology

• Healthcare resources

• Societal factors

• Methodological discrepancies

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Thank you!

Questions?

Appendix: Northern EuropeCountry Discharge Rate

(2010‐2014)Time Period AAPC (95% CI) Joinpoint AAPC (95% CI) by

Joinpoint Segments

Denmark 63.6 2001‐2015 ‐1.1* (‐2.1, ‐0.0) 2010(1) 0.9 (‐0.1, 2.0)(2) ‐4.6* (‐7.1, ‐2.0)

Finland 54.8 2001‐2014 ‐1.1* (‐1.8, ‐0.4) 2011(1) ‐0.5* (‐1.0, ‐0.1)(2) ‐2.9 (‐5.8, 0.2)

Iceland 35.6 2000‐2014 ‐4.9* (‐9.4, ‐0.2) 2007(1) 10.5* (2.4, 19.1)(2) ‐18.1* (‐24.7, ‐11.0)

Ireland 43.6 1995‐2014 0.7 (‐0.0, 1.3) 2002(1) 3.7* (2.0, 5.4)(2) ‐1.1* (‐1.7, ‐0.4)

Latvia^ 18.7 2013‐2015 ‐ ‐ ‐

Lithuania^± 26.3 2013‐2014 ‐ ‐ ‐

Norway 59.5 2000‐2014 ‐1.0 (‐2.2, 0.2) 2004(1) 4.1 (‐0.0, 8.5)

(2) ‐3.0* (‐3.9, ‐2.0)

Sweden 51.9 2000‐2014 ‐2.3* (‐4.0, ‐0.6) 2010(1) ‐1.2* (‐1.7, ‐0.7) (2) ‐4.9 (‐11.3, 1.9)

United Kingdom 40.0 2000‐2014 1.1* (0.8, 1.4) ‐ No inner segments.

* Statistically significant (p < 0.05). Note: Non‐significance denotes stable hospitalization rates.^ Less than 5 years of data were available, so an AAPC could not be calculated.± not an OECD member country.

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Appendix: Southern & Eastern EuropeCountry Discharge Rate


Joinpoint Segments

Italy 28.1 2001‐2014 ‐0.8* (‐1.2, ‐0.4) 2006(1) 1.2* (0.3, 2.2)(2) ‐2.0* (‐2.5, ‐1.6)

Portugal 16.7 1995‐2014 8.1* (6.4, 9.8) 2001(1) 22.6* (16.7, 28.7)

(2) 2.0* (1.0, 3.1)

Slovenia 35.3 1997‐2014 1.2* (0.5, 1.8) ‐ No inner segments.

Spain 23.7 1990‐2014 5.5* (4.7, 6.3) 2001(1) 12.0* (10.3, 13.8)

(2) 0.3 (‐0.4, 1.1)

Czech Republic 47.4 2000‐2014 2.7* (1.9, 3.5) 2004(1) 6.5* (3.5, 9.4)(2) 1.2* (0.6, 1.8)

Hungary 50.4 2004‐2014 ‐3.6* (‐5.0, ‐2.2) ‐ No inner segments.

Poland 37.3 2003‐2014 6.8* (5.9, 7.8) ‐ No inner segments.

Slovak Republic 23.7 2000‐2014 0.1 (‐1.4, 1.6) ‐ No inner segments.

* Statistically significant (p < 0.05). Note: Non‐significance denotes stable hospitalization rates.

Appendix: Western Europe

Country Discharge Rate (2010‐2014)

Time Period AAPC (95% CI) Joinpoint AAPC (95% CI) by Joinpoint Segments

Austria 73.0 1990‐2014 2.2* (1.7, 2.6) 1999(1) 4.3* (3.2, 5.4)(2) 0.9* (0.5, 1.4)

Belgium 32.6 2000‐2013 ‐0.6* (‐1.0, ‐0.2) ‐ No inner segments.

France 27.0 1997‐2014 ‐0.1 (‐0.3, 0.1) ‐ No inner segments.

Germany 57.9 2000‐2014 2.2* (1.7, 2.6) ‐ No inner segments.

Luxembourg 33.7 1998‐2014 ‐2.0* (‐3.3, ‐0.6) ‐ No inner segments.

Netherlands 32.0 1990‐2012 1.7* (1.2, 2.2) 2000(1) ‐0.1 (‐1.0, 0.8)

(2) 3.3* (2.7, 3.9)

Switzerland 21.3 2002‐2014 0.7 (‐0.1, 1.4) ‐ No inner segments.


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Appendix: Americas, Asia & OceaniaCountry Discharge Rate


Joinpoint Segments

Canada 30.9 1990‐2013 ‐1.7* (‐1.9, ‐1.4) 1998(1) ‐0.2 (‐0.7, 0.3)

(2) ‐2.4* (‐2.6, ‐2.2)

Chile 8.4 2001‐2013 5.2* (4.3, 6.2) 2010(1) 3.7* (2.9, 4.5)(2) 9.9* (6.2, 13.7)

Mexico 1.6 1995‐2014 3.7* (2.5, 5.0) 2008(1) 2.3* (1.1, 3.6)

(2) 6.8* (3.5, 10.1)

United States 33.9 1990‐2010 2.3* (1.9, 2.7) ‐ No inner segments.

Israel 27.0 2000‐2014 2.0 (‐0.2, 4.3) 2007(1) 5.2* (1.2, 9.2)

(2) ‐1.0 (‐4.2, 2.3)

Japan 26.8 1993‐2014 3.8* (2.3, 5.4) ‐ No inner segments.

Korea 14.7 1996‐2014 4.9* (4.4, 5.3) 2005(1) 2.6* (1.6, 3.6)

(2) 7.2* (6.6, 7.8)

Turkey 10.0 2007‐2014 9.2* (5.9, 12.5) ‐ No inner segments.

Australia 31.2 1993‐2013 1.2* (1.0, 1.4) ‐ No inner segments.

New Zealand 25.9 2000‐2013 1.6* (1.0, 2.3) ‐ No inner segments.


Joinpoint: United States

15

17

19

21

23

25

27

29

31

33

35

37

39

1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011

HOSPITALIZATIONS FO

R IB

D (PER

100,000)

CHART TITLE

AAPC: 2.3*

* AAPC is statistically significant (p < 0.05). Note: Non‐significance denotes stable hospitalization rates.

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Joinpoint: Iceland

20

30

40

50

60

70

80

90

100

110

120

130

1999 2001 2003 2005 2007 2009 2011 2013 2015

HOSPITALIZATIONS FO

R IB

D (PER

100,000)

CHART TITLE

APC: 10.5* APC: ‐18.1*

Joinpoint: 2007

From 2007 onwards, only hospitals with a 24 hour physician presence were included in the definition of “hospital discharge”

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Therapy Escalation In Patients With Inflammatory Bowel Disease Following Clostridium difficile

Infection Is Not Associated With Adverse Clinical Outcomes: An IBD ReMEdY Study

Dana J. Lukin, Garrett Lawlor, David P. Hudesman, Laura Durbin, Alexandra Feathers, Monica Passi, Kimberly Cavaliere, Jordan E. Axelrad, Elliot Coburn, Michelle Loftus, Henry Jen, Melissa H. Rosen, Lisa B. Malter, Arun Swaminath

Background

• Approximately 29,300 deaths are estimated from C. difficile infection (CDI) annually in the US

• Rates of CDI and morbidity are substantially higher in patients with IBD than in the general population, with increased susceptibility to hypervirulent strains

• While CDI is common in IBD patients, differentiation of CDI from active IBD as a source of clinical symptoms is often difficult

1. Martin JSH et al. Nat. Rev. Gastroenterol. 2016;13(4):206‐16 2. Lessa FC et al. N Engl J Med. 2015;372:825‐343. Berg, Kelly, and Farraye. Inflamm Bowel Dis. 2013;19(1):1‐12

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• A study on 155 inpatients with IBD and CDI found increased severe outcomes in patients receiving both antibiotics and immunosuppressive medication

OR 11.9 for single medication, 17.1 for ≥ 2 medications1

1. Ben‐Horin S et al. Clin Gastroenterol Hepatol. 2009;7:981‐9872. Surawicz et al. Am J Gastroenterol. 2013; 108: 478‐98

Background

• From the 2013 ACG Guideline on C. difficile:“Escalation of the corticosteroid dose or initiation of anti‐TNF therapy in patients with a positive CDI probably should be avoided for 72 hours after initiating therapy for CDI”2

Aims

• To determine the impact of therapy escalation on 90‐day clinical outcomes in IBD patients with Clostridium difficile infection

• Secondary variables of interest: CDI Recurrence

Re‐hospitalization

Worsening of IBD following CDI

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Methods

• Multicenter, retrospective cohort study performed at 4 New York City academic medical centers

• Patient demographic and clinical data were abstracted from databases at each site for adult patients with an established diagnosis of IBD concurrently diagnosed with CDI.

• Outcomes were assessed at 30 and 90 days after last

positive C. difficile test.

Definitions

• Therapy escalation:

Initiation or dose‐escalation of corticosteroids or biologic medication

• Severe outcomes:

Occurrence of death, sepsis, or colectomy

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Statistical Analyses• Continuous variables were compared between groups using the

Student’s t‐test

• Categorical variables were compared using the Pearson’s chi squared test or Fisher’s exact test if expected frequencies were not sufficiently large

• Bivariate associations were performed to compare clinical CDI outcomes between groups who received and who did not receive escalation of therapy

• Multivariable logistic regression was performed to determine the relationship between severe outcomes and escalation of immunosuppressive therapy after adjusting for covariates

Patient Demographics

1Past indicates >30 days prior to CDI diagnosis; 2Past indicates >90 days prior to CDI diagnosis

Demographic Total#

n=207%

Age,years,mean(SD) 42.8(19.8)Sex,Male 94 45.4Inpatient 158 76.3Ethnicity

Caucasian 94 47.7AfricanAmerican 47 23.9HispanicorLatino 32 16.2

AsianorPacificIslander 13 6.6Other 11 5.6

CDIInitialTreatmentPOMetronidazole 90 45.2

PO+IVMetronidazole 16 8.0POVancomycin 85 42.7

FMT 1 0.5CombinationorOther 7 3.5

MeanDurationofIBD,years(SD) 7.6 (9.6)IBDSubtype

Crohn’sDisease 91 44.2UlcerativeColitis 111 53.9

IndeterminateColitis 4 1.9PriorC.difficile infection 30 14.6PPIusepastmonth 39 18.8Antibioticusepast3months 68 34.0PriorIBDTherapy

Aminosalicylates(currentorpast) 156 76.1Corticosteroids(past1) 67 32.7

Immunomodulators(past2) 34 16.7Biologics(past2) 38 18.5

Presenceof1orMoreComorbidities 142 68.6EscalationofTherapywithin90Days 62 31.4

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90‐Day Outcomes According to Therapy Escalation

Severe outcomes were significantly more frequent patients not receiving escalation of IBD Therapy

Outcome Within No Escalation Escalation P‐Value

90 Days n=142 n=62

Death 7 (5.2) 0 (0.0) 0.10

Sepsis 15 (11.2) 1 (1.8) 0.04

Colectomy 9 (6.8) 1 (1.7) 0.29

Severe Ouctome* 21 (15.6) 1 (1.8) <0.01

*Severe outcomes were defined as death, sepsis, and/or colectomy

Therapy Escalation After CDI

Type of Therapy n %

Escalation of Therapy (within 30 days) 44 22.6

Corticosteroids 24 11.8

Total 18 8.8

Infliximab 10 4.8

Biologics Adalimumab 1 0.5

Vedoluzumab 6 2.9

Combination Therapy 2 1.0

Escalation of Therapy (within 90 days) 62 30.4

Corticosteroids 28 13.7

Total 30 14.7

Infliximab 13 6.3

Biologics Adalimumab 5 2.4

Vedoluzumab 10 4.8

Combination Therapy 4 2.0

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Median time to therapy escalation: 13 days Escalation within 7 days: 21 patients (33.9%)

0

10

20

30

40

50

60

70

0 20 40 60 80 100

Number o

f Patients

Time (Days)

Time to Therapy Escalation Following CDI

Variables With Significant Association With Severe Outcomes on Bivariate Analysis

Non‐SevereOutcome n=171 SevereOutcome n=22P‐value

% %Lactate >2.2 4 3.8 6 35.3 <0.01

Albumin<2.5 8 5 4 19.1 0.04ICU Admission 1 0.6 6 27.3 <0.01

Hypotension(MAP<65)

2 1.2 4 18.2 <0.01

Ileus/Abd Distension 13 7.7 5 22.7 0.04

MentalStatusChange 1 0.6 2 9.1 0.04Age, years, mean (SD) 40.1 18.4 58.1 24.3 <0.01

Inpatient 128 74.9 21 95.5 0.03

Presence of 1 or More Comorbidities

117 68.4 17 77.3 0.4

Cardiovascular Disease 29 17 11 50 <0.01

Chronic Kidney Disease 9 5.3 4 18.2 <0.05

Rheumatologic Disease 5 2.9 4 18.2 0.01

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Analysis of Secondary Endpoints According to Type of Therapy Escalation

Escalation to Escalation to

Corticosteroids Biologics P‐Value

n=28 n=34

CDI Recurrence 0 (0.0) 5 (15.2) 0.07

Rehospitalization 7 (31.8) 5 (15.2) 0.36

Worsening of IBD 13 (48.2) 13 (36.4) 0.19

Adjusted Logistic Regression Model for Severe Outcomes

Adjusted odds ratio (95% CI)

EscalatedTreatmentWithin90Days 0.12 0.02‐0.94Inpatient 5.29 0.66‐42.20Age*

35‐65 2.00 0.64‐6.26>65 4.55 1.37‐15.12

Patients undergoing IBD therapy escalation within 90 days of CDI were less likely to experience a severe outcome (aOR 0.12) when adjusting for other covariates in the model

Multivariable analysis limited by low event rate

*Age<35 used as reference group

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Study Strengths

Large, multicenter cohort of real‐world patients

A broad range of demographic, treatment, and outcome variables were assessed

Study Limitations

Retrospective study

The small event rate for variables of interest limited the ability to perform multivariable analysis

Conclusions Escalation of immunosuppressive therapy following infection with C.

difficile in patients with IBD was not associated with adverse events

Severe outcomes were more frequent in patients not undergoing therapy escalation

Age >65, inpatient status, albumin <2.5, and co‐morbidities were associated with severe outcomes

Prospective studies are required to determine the optimal timing of initiation of immunosuppressive therapy following CDI

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Montefiore Medical Center:Kimberly Cavaliere, MDDana Lukin, MD, PhD

New York Presbyterian Hospital‐Columbia University Medical Center:Jordan Axelrad, MD, MPHGarrett Lawlor, MD

New York Univeristy Medical Center: Northwell Health‐ Lenox Hill Hospital, Elliot Coburn, MD North Shore University Medical CenterDavid Hudesman, MD Laura Durbin, MPHLisa Malter, MD Alexandra Feathers, MPA, MPHMelissa Rosen, MD Michelle Loftus, DO

Monica Passi, MDHenry Jen, MDArun Swaminath, MD

Backup Slides

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Analysis of Secondary Endpoints According to Therapy Escalation

No Escalation#

n=142%

Escalation#

n=62%

Total#

n=204%

P‐value

CDI Recurrence 8 6.1 5 8.8 13 6.9 0.54Worsening of IBD 28 21.2 25 41.7 53 27.5 <0.01Rehospitalization 29 22.0 12 21.8 41 21.9 0.98

Surrogate Markers of Disease Severity Were Not Associated With Therapy Escalation Status

No Escalation#

n=142%

Escalation#

n=62%

Total#

n=204%

P‐value

DiseaseSeverityVariableLeukocytosis 30 21.7 11 18.3 41 20.7 0.59

Creatinine>1.5x 5 3.6 2 3.4 7 3.6 1.00ICUAdmission 7 5.1 1 1.6 8 4.0 0.44

Hypotension(MAP<65) 6 4.4 1 1.6 7 3.5 0.68Ileus/AbdDistension 15 10.7 3 4.9 18 9.0 0.19MentalStatusChange 2 1.4 1 1.6 3 1.5 1.00

BloodinStool 57 40.7 32 52.5 89 44.3 0.12AbdominalTenderness 104 74.3 45 73.8 149 74.1 0.94

Fever(>100.4°F) 31 22.3 13 21.7 44 22.1 0.92ElevatedCRP/ESR‡ 46 42.6 30 58.8 76 47.8 0.06

ElevatedFecalCalpro‡ 4 66.7 5 50.0 9 56.3 0.63Lactate>2.2‡ 8 8.3 2 6.1 10 7.7 1.00Albumin<2.5 6 4.6 5 8.8 11 5.8 0.31

‡ >10% of pa ents missing data for each of these variables

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Salman Nusrat, Mohammad F. Madhoun, Mahammad Hassan Bashir, William M. Tierney University Of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, OK

Use of Diphenhydramine as an Adjunctive Sedative for

Colonoscopy in Patients on Opioids

Background Patient tolerance is important for successful and safe

completion of colonoscopy. Sedation during colonoscopy results in increased

compliance and willingness to undergo repeat procedures.

Chronic opioid use results in increased tolerance to sedatives, making sedation challenging.

Pezealla EJ et al. J Pain Res. 2017 Hamita Sachar et al Elsevier 2017

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ObjectivesPrimary objective

Determine whether the addition of diphenhydramine to conventional sedatives would reduce the dose of fentanyl and midazolam used during colonoscopy in individuals on chronic opioids.

Secondary objectives Evaluate the effect of diphenhydramine use on procedure-

related times.

Assess the tolerability and safety of diphenhydramine use during procedural sedation.

Methods Single-center, prospective, randomized, double-

blinded, controlled trial.

Conducted at the Oklahoma City Veterans’ Affairs Medical Center (VAMC) between July 2014 and November 2016.

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Inclusion criteria18-75 years

old

Outpatient colonoscopy

Chronic opioid use

Chronic opioid use was defined as useof at least 5 mg of morphine or itsequivalent at least 3 days per week formore than 3 months.

Exclusion criteria

Inability to execute informed consent Allergy to diphenhydramine, fentanyl or midazolam Pregnancy History of colon resection Severe cardiopulmonary disease Another endoscopic procedure scheduled on the

same day

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Methods

Randomization Colonoscopy

Quality of sedation was assessed by

physician and nurse

Patient rated pain and amnesia

Day of Procedure Next day

Study Medication

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Results

Baseline Characteristics Diphenhydramine(n=61)

Placebo(n=58)

p Value

Age, Y 60.7±9.3 60.1±9.7 0.71

Male sex, n (%) 57 (93.4) 56 (96.6) 0.43

White race, n (%) 45 (73.8) 46 (77.6) 0.34

BMI, mean± SD 30.4±5.5 30.6±6.8 0.83Indication (surveillance), n (%) 24 (39.3) 21 (36.2) 0.45Smoking, n (%) 31 (50.8) 24 (41.4) 0.30Alcohol, n (%) 20 (32.8) 11 (18.9) 0.17Drug abuse, n (%) 11 (18) 5 (8.6) 0.26Anxiety, n (%) 15 (24.6) 17 (29.3) 0.56

Depression, n (%) 38 (62.3) 30 (51.7) 0.24Morphine equivalent, mean ±SD

37.9±48.5 42.0±40.1 0.62

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Sedation Dose

125.4126

120121122123124125126127128129130

Fentanyl (mcg)Diphenhydramine Placebo

4.9 5

3.5

4

4.5

5

5.5

6

Midazolam mgDiphenhydramine Placebo

p = 0.88p = 0.79

Quantitative Assessment of Sedation

6.25.65.3 5.1

0

1

2

3

4

5

6

7

Physician Score Nurse ScoreDiphenhydramine Placebo

p = 0.0002 p = 0.04

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Qualitative Assessment of Sedation

Qualitative analysis by physicians (p=0.29) and nurses (p=0.35)showed no significant difference between groups.

Patient Assessment of Quality of Sedation

2.05

3.09

0

0.5

1

1.5

2

2.5

3

3.5

Patient Pain ScoreDiphenhydramine Placebo

7.8

6.5

5.5

6

6.5

7

7.5

8

Patient Amnesia scoreDiphenhydramine Placebo

p = 0.047 p = 0.047

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Procedural Times

6.4

34.8 34.4

6.3

34.732.4

0

5

10

15

20

25

30

35

40

45

Induction Duration Recovery

Diphenhydramine Placebo

p = 0.86

p = 0.98 p = 0.16

Adverse events

There were no major complications in either group. Transient hypotension during the procedure was

more common in the placebo group (12 vs. 22, p = 0.027).

There were no sedation-related hypoxic events, and no patient required sedation reversal agents.

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Limitations

Majority of patients were older than 55 years and were Caucasian males.

Analysis was restricted to patients who were on chronic opioid and were undergoing outpatient colonoscopies.

Conclusions In patients on chronic opioids,

administration of diphenhydramine doesn’t allow for lower doses of procedural sedatives.

Diphenhydramine does improve sedation scores as assessed by the physician and nurse and does appear to improve patient comfort without increasing the number of adverse events.

Further studies to identify the optimal use of diphenhydramine as an adjunct to sedation are warranted.

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Thank you

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Is CO2 better than Air in reducing

post-procedural pain following

colonoscopy?

A meta-analysis of RCTs

Authors

Ajai Rajabalan, MD

Kamaldeep Singh, MD

Sunil Paudel, MD

Diwas Shahi, MD

Thara Vidyasagaran, MD

Milan Dodig, MD

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Inclusion Criteria

• Only published RCTs

• No language restrictions were applied

• Indications – No restrictions for indications for colonoscopy

• Patients older than 18 years

Exclusion Criteria

• Studies other than RCTs

• Ongoing trials

• Duplicates

• RCTs comparing water immersion and CO2 or CO2 used during withdrawal of the scope

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83 records identified from online databases and other

sources

3 duplicates removed

80 records screened

52 excluded with reasons

18 included in meta-analysis

28 studies isolated

10 excluded, did not measure pain

Study Selection

18 studies

Screening5

Screening & Surveillance

4

Elective for various reasons

8

H/o Polyps1

• Total patients in CO2 group – 1658 and Air – 1556• Mean Age CO2 – 56.8 ± 4.8 and Air 56.2 ± 4.7.

• Sedation – 13 studies and no routine sedation in 5

Baseline characteristics

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Outcomes Measured

Pain

Immediate to15 min post-procedural pain

30min to 2hours post-procedural pain

Statistical Analysis

• Revman 5.3

• Pooled OR 95% CI with Random Effects model.

• Heterogeneity I2 Statistic and the Chi squared test

• I2 > 50 substantial level of heterogeneity

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Post-procedural pain: Immediate to15 min

OR 0.49, 95%CI (0.34, 0.72), p<0.00001, I2 =79%

Post-procedural pain: 30min to 120min

OR 0.35, 95%CI (0.22, 0.57), p<0.00001, I2 =82%

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Discussion

• At 15 min and 2 hrs, significantly lesser pain with CO2 than in air group.

• Determinant focus – Patient comfort – better with CO2

• Better patient comfort – improves compliance and colon cancer detection and hence survival

Limitations of the study

Heterogeneity >50% in both outcomes

Pain – measured in studies using VAS (most of the studies) –highly subjective

Gas volume – not measured in all RCTs – might have an impact

Use of sedation – not uniform in studies

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What makes colonscopyuncomfortable and undesirable?

• Thought of having a colonoscopy – education and counselling

• Preparation – low volume preps

• Complications – improving skills of provider

• Post procedural pain and discomfort

Projected Number of Colonoscopies

Joseph DA, Meester RGS, Zauber AG, et al. Colorectal cancer screening: Estimated future colonoscopy need and current volume and capacity. Cancer 2016. DOI: 10.1002/cncr.30070.

https://www.cdc.gov/cancer/dcpc/research/articles/crc_screening_model.htm

3.3

15

64

0

10

20

30

40

50

60

70

Number in m

illions

Year

2010 2012 2030

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Other Effects Of CO2

Air vs CO2

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Measuring Colonoscopy Value Without Penalizing Polyp

Detection

Meredith Clary MD, Nikki Tavasoli MA, Lauren Dedecker BSc, William E. Karnes MD AGAF

University of California Irvine

Division of Gastroenterology

H.H. Chao Comprehensive Digestive Disease Center

Background

Value = Quality/Cost

• Medicare reimbursement will increasingly emphasize quality and cost over the next 3 years

• Quality is reported by providers• Cost is determined by claims• No validated method of measuring colonoscopists’ value

• Ideally, Gastroenterologists will have input into how colonoscopy value is measured

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Moran et al Value Formula• Quality

‐ Detection rates of adenomas (ADR) and sessile serrated adenomas (SDR) ‐ Cecal intubation rate (CIR)

• Cost‐ Total procedure time (TT) ‐ Polyp detection rate (PDR) (surrogate for pathology cost)

Quality (ADR + SDR) x CIR x 100• Value = =

Cost TT x PDR

Moran et al DDW 2017

Objective

• Devise an alternative value formula that:• Avoids penalty for polyp detection• Addresses the “one and done” strategy

• Compare the two value formulas among colonoscopists at UC Irvine

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Methods

• Retrospective analysis of prospectively collected data at point‐of‐care using Qualoscopy

• 6/2012‐5/2017• Single academic center• Faculty and Fellows with > 75 procedures performed• Colonoscopy indication: Screening and polyp surveillance

Qualoscopy

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UCI Quality Index

UCI Quality Index = (ADR + SDR) x (CIR) x (ADR+ + SDR+) x

(% WT > 6 min) x 10

• ADR+: fraction of adenoma‐positive patients with >1 adenoma*

• SDR+: fraction of sessile serrated adenoma‐positive patients with >1 SSA

• % WT > 6 min: percent of procedures with withdrawal time over 6 minutes

*Wang et al Multiplicity Detection Rate GIE 2013

UCI Cost IndexUCI Cost Index = Sedation x Room utilization x Pathology x

Disposables x % Inadequate Prep

• Sedation: (number of sedation vials opened per procedure) x (percent of procedures requiring recovery) x (percent of procedures requiring anesthesia)

• Room utilization: percent of cases > 30 minutes

• Pathology: number of polyp pathology bottles used per procedure

• Disposables: (number of clips/polyp) x (number of assistive devices/procedure (e.g. Endocuff, Amplifeye, cap))

• Inadequate prep: percent of procedures with any segment Boston Prep Score < 2 (necessitating early repeat colonoscopy)*

*Clark et al. Gastro 2016; 150:2* 1 was added to each component to allow analysis of rates of zero

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UCI Value Index

Quality Index (QI)

UCI Value Index =

Cost Index (CI)

(ADR + SDR) x CIR x (ADR+ + SDR+) x %WT > 6 min x 10

=

Sedation x Room utilization x Pathology x Disposables x % Inadequate prep

Results

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Baseline Characteristics

• 29 colonoscopists

• Total colonoscopies: 6756

• Screening colonoscopies: 3091

• Mean patient age: 59

• Patient gender: 53% Females

UCI Value Index vs Moran Value by Colonoscopist

r = ‐0.2137

ADR

Red < 20%

Yellow 20%‐25%

Green 26%‐30%

Blue > 30%

Value (Moran et al)

UCI Value Index

Low ADR

Detection penalty

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r = ‐0.2137

ADR+

Red < 20%

Yellow 20‐39%

Green 40‐59%

Blue > 60% UCI Value Index

Value (Moran et al)

Low ADR+

UCI Value Index vs Moran Value by Colonoscopist

Limitations

• Single academic center

• Cost index was measured by resource use, not dollar cost

• Appropriate colonoscopy start age and intervals not factored into QI or CI

• Adverse events not factored

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Conclusions

• The UCI Value Index is a step toward a measurement of colonoscopy value without a “detection penalty” and addresses the “one and done” strategy.

Acknowledgements

• Thank you to:• Mentor: William Karnes, MD, AGAF

• UC Irvine

• American College of Gastroenterology

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PDR

ADR

Correlation of ADR and PDR

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Dupilumab Efficacy and Safety in Adult Patients With Active Eosinophilic Esophagitis:

a Randomized Double-Blind Placebo-Controlled Phase 2 Trial

Ikuo Hirano, Evan S. Dellon, Jennifer D. Hamilton, Margaret H. Collins, Kathryn Peterson, Mirna Chehade, Alain M. Schoepfer,

Ekaterina Safroneeva, Marc E. Rothenberg, Gary W. Falk, Yehudith Assouline-Dayan, Zhizhi Qing,

Brian N. Swanson, Gianluca Pirozzi, Leda Mannent, Neil M.H. Graham, Bolanle Akinlade, Allen Radin

Background

• EoE is a chronic, type 2 immune-mediated disease characterized by esophageal dysfunction and eosinophil-predominant inflammation in the esophagus

• There are currently no US FDA-approved treatments for EoE

• Swallowed corticosteroids are being used off-label with limited studies on long-term efficacy and safety

• Previous studies of targeted biologic therapies have shown significant histological improvement but not symptom response in EoE

EoE, eosinophilic esophagitis; FDA, US Food and Drug Administration.

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Background

1. Gandhi N, et al. Expert Rev Clin Immunol. 2017. 2. Simpson E, et al. N Engl J Med. 2016. 3. Wenzel S, et al. Lancet. 2016. 4. Bachert C, et al. JAMA. 2016.

• Dupilumab, a fully human anti-interleukin (IL)-4 receptor α monoclonal antibody, inhibits signaling of IL-4 and IL-13, key drivers of type 2-mediated inflammation, and is approved in the USA and in the EU for the treatment of adults with moderate-to-severe atopic dermatitis

• Dupilumab has also shown efficacy and an acceptable safety profile in patients with other type 2 immune diseases including uncontrolled persistent asthma and severe chronic sinusitis with nasal polyps

Objective

• To assess the efficacy and safety of dupilumab in adults with active EoE

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Study Design: Dupilumab EoE Phase 2 Trial

• Phase 2, multicenter, double-blind, randomized, placebo-controlled study in patients with active EoE

PRO, patient-reported outcome; SC, subcutaneous. ClinicalTrials.gov Identifier: NCT02379052.

Randomization (1:1)

N = 47

Dupilumab SC 300 mg every week with 600 mg loading dose

n = 23

Placebo n = 24

Screening period

(1–35 days)

12-week treatment period

16-week follow-up period

• PRO endpoints changed from 12 to 10 weeks prior to unblinding due to data capture issues

Key Inclusion and Exclusion Criteria

Inclusion criteria

• Age 18−65 years with prior EoE diagnosis per consensus guidelines

• Active inflammation with ≥ 15 eos/hpf in at least 2 of 3 esophageal regions at screening

• Patient-reported history of ≥ 2 episodes of dysphagia per week in the 4 weeks prior to screening and ≥ 2 episodes of dysphagia per week between screening and baseline

• Straumann Dysphagia Instrument (SDI) PRO score ≥ 5 at screening and baseline

• Presence of a coexisting allergic condition, peripheral eosinophil count ≥ 0.25 GI/L, or serum IgE ≥100 kU/L

Exclusion criteria

• Esophageal stricture unable to be passed with a standard adult upper endoscope

• Dilation required at screening

• Use of systemic corticosteroids < 3 months or swallowed topical corticosteroids (TCS)< 6 weeks prior to screening

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Primary Endpoint

• Change in SDI PRO total score from baseline to Week 10

Straumann A, et al. Gastroenterology 2010.

Dysphagia frequency (0−4)

None = 0

Once per week = 1

Several times per week = 2

Once per day = 3

Several times per day = 4

Dysphagia severity (0−5)

Swallowing unhindered = 0

Slight sensation of resistance = 1

Slight retching with delayed passage = 2

Short period of obstruction necessitating intervention = 3

Longer-lasting period of obstruction, only removable by regurgitation = 4

Long-lasting complete obstruction, requiring endoscopic intervention = 5

Secondary Endpoints

• % change in weekly Eosinophilic Esophagitis symptom Activity Index (EEsAI) PRO score from baseline to Week 10

– Scale 0−100; higher scores = worse symptoms

• % change in overall peak esophageal eosinophil count (eos/hpf) at Week 12

• Change in EoE endoscopy EREFS score from baseline to Week 12– Scale 0−8; higher scores = more severe endoscopic findings

• Incidence of treatment-emergent adverse events

EREFS, edema, rings, exudates, furrows, strictures. 1. Schoepfer AM, et al. Gastroenterology 2014. 2. Hirano I, et al. Gastroenterol Clin North Am. 2014.

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Exploratory Endpoints

• Change in EoE-Histological Scoring System (HSS) from baseline to Week 12

– 7 findings assessed; scale 0−63; higher scores = more severe histologic findings

• Change in esophageal distensibility plateau from baseline to Week 12– Measured using the Functional Lumen Imaging Probe (FLIP)

FLIP simultaneously measures the diameter of the esophageal lumen and pressure (e.g. esophageal rigidity).Collins MH, et al. Dis Esophagus. 2017.

Baseline Demographics and Clinical Characteristics

aCalculated using peak count from each esophageal region (mid, proximal, and distal).

CharacteristicPlacebo(n = 24)

Dupilumab 300 mg every week

(n = 23)

Age, mean (SD), years 36.1 (12.8) 33.1 (8.7)

Male sex, n (%) 10 (41.7) 13 (56.5)

White race, n (%) 21 (87.5) 23 (100)

Prior dilation, n (%) 10 (41.7) 11 (47.8)

Number of prior esophageal dilations, mean (SD) 3.9 (3.3) 5.7 (8.0)

≥ 1 prior use of a corticosteroid for EoE, n (%) 9 (37.5) 7 (30.4)

> 1 comorbid atopic disease, n (%) 19 (79.2) 20 (87.0)

Blood eosinophil count, mean (SD), GI/L 0.4 (0.3) 0.3 (0.2)

Serum total IgE, mean (SD), IU/mL 486.2 (900.7) 217.8 (288.8)

SDI PRO score, mean (SD), scale 0−9 6.4 (1.0) 6.4 (1.0)

EREFS score, mean (SD), scale 0−8 4.3 (1.5) 3.9 (1.9)

Overall peak eosinophil count, mean (SD), eos/hpfa 101.1 (57.1) 102.1 (53.5)

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-4

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

LS

mea

n (

±S

E)

chan

ge

fro

m

bas

elin

e in

SD

I sco

re

Primary EndpointDupilumab significantly reduced SDI PRO score at Week 10

LS, least-squares.

Placebo (n/N = 14/24)Dupilumab 300 mg every week(n/N = 17/23)

P = 0.0304

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Secondary EndpointDupilumab numerically reduced weekly EEsAI PRO score at Week 10


LS

mea

n (

±S

E)

% c

han

ge

fro

m

bas

elin

e in

EE

sAIs

core

P = 0.0850

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Secondary EndpointDupilumab significantly reduced overall peak esophageal intraepithelial eosinophil count at Week 12

-120

-100

-80

-60

-40

-20

0

20

40


LS

mea

n (

±S

E)

% c

han

ge

fro

m b

ase

line

in p

eak

eosi

no

ph

il co

un

t

P < 0.0001

Secondary EndpointDupilumab significantly reduced overall peak esophageal intraepithelial eosinophil count at Week 12

qw, every week.

-120

-100

-80

-60

-40

-20

0

20

40

Proportion of patients with response at Week 12, n (%)

Peak eos(eos/hpf) at Week 12

PlaceboDupilumab 300 mg qw

P value vs placebo

≤ 6 0 (0) 15 (65.2) < 0.0001

< 15 0 (0) 19 (82.6) < 0.0001


LS

mea

n (

±S

E)

% c

han

ge

fro

m b

ase

line

in p

eak

eosi

no

ph

il co

un

t

P < 0.0001

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Secondary EndpointDupilumab significantly decreased EREFS score at Week 12

-2.5

-2

-1.5

-1

-0.5

0

0.5


LS

mea

n (

±S

E)

chan

ge

fro

m

bas

elin

e in

ER

EF

S s

core

P = 0.0006

Exploratory EndpointDupilumab significantly improved total EoE-HSS grade and stage scores at Week 12

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20Total grade Total stage

Placebo (n/N = 20/24)

Dupilumab 300 mg every week(n/N = 23/23)

Placebo (n/N = 20/24)

Dupilumab 300 mg every week(n/N = 21/23)

P < 0.0001P < 0.0001L

S m

ean

(±

SE

) %

ch

ang

e fr

om

b

asel

ine

in E

oE

-HS

S g

rad

e sc

ore

LS

mea

n (

±S

E)

% c

han

ge

fro

m

bas

elin

e in

Eo

E-H

SS

sta

ge

sco

re

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Exploratory EndpointDupilumab significantly improved esophageal distensibilityplateau at Week 12

-10

-5

0

5

10

15

20

LS

mea

n (

±S

E)

% c

han

ge

fro

m

bas

elin

e in

dis

ten

sib

ility

pla

teau


P < 0.0001

Dupilumab Was Generally Well Tolerated During the Study Period

aSerious adverse events were considered to not be related to the investigational medicinal product. There were no cases of conjunctivitis during the study period in dupilumab or placebo treated patients despite a prior history of conjunctivitis of 3 patients in each group. HLT, high level Term; PT, preferred term.

n (%)

12-week end of treatment period 28-week end of study period

Placebo(n = 24)

Dupilumab300 mg qw

(n = 23)

Placebo(n = 24)

Dupilumab300 mg qw

(n = 23)

≥ 1 treatment-emergent adverse events 15 (62.5) 18 (78.3) 16 (66.7) 21 (91.3)

≥ 1 serious adverse eventa 0 0 0 3 (13.0)

Adverse events leading to treatment discontinuation 0 1 (4.3) 0 1 (4.3)

Deaths 0 0 0 0

Malignancies 0 0 0 0

Terms with the difference of number of patients between two groups ≥ 3

Injection-site reactions (HLT) 7 (29.2) 13 (56.5) 7 (29.2) 13 (56.5)

Injection-site erythema (PT) 2 (8.3) 8 (34.8) 2 (8.3) 8 (34.8)

Injection-site inflammation (PT) 0 3 (13.0) 0 3 (13.0)

Injection-site rash (PT) 0 3 (13.0) 0 3 (13.0)

Upper respiratory tract infections (HLT) 3 (12.5) 7 (30.4) 6 (25.0) 9 (39.1)

Nasopharyngitis (PT) 1 (4.2) 4 (17.4) 2 (8.3) 5 (21.7)

Musculoskeletal, connective tissue pain and discomfort (HLT) 0 3 (13.0) 0 4 (17.4)

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Conclusions

• Dupilumab significantly improved dysphagia, esophageal eosinophil counts, endoscopic features, histology, and esophageal distensibility in adults with active EoE compared with placebo

• Dupilumab was generally well tolerated, although nonseriousinjection-site erythema and nasopharyngitis occurred more frequently in the dupilumab group versus placebo

• These results confirm the critical role of IL-4 and IL-13 in EoE and support further evaluation of dupilumab

Acknowledgments

• Study investigators– Alpan, Oral

– Hardi, Robert

– Leung, John

– Wo, John

– Barish, Charles

– Gordon, Glen

– Garber, John

– Mitlyng, Benjamin

– Whitlock, Tom

– Hendrix, Paul

• Regeneron Pharmaceuticals, Inc.– Williams, Linda

– Chaudhry, Usman

• Sanofi– Barry, Dianne

Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov identifier: NCT02379052. Medical writing/editorialassistance provided by Xiomara V. Thomas, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.

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BACK-UP

Author Affiliations

Ikuo Hirano1, Evan S. Dellon2, Jennifer D. Hamilton3, Margaret H. Collins4, Kathryn Peterson5, Mirna Chehade6,

Alain M. Schoepfer7, Ekaterina Safroneeva8, Marc E. Rothenberg9, Gary W. Falk10, Yehudith Assouline-Dayan11, Zhizhi Qing3,

Brian N. Swanson12, Gianluca Pirozzi12, Leda Mannent13, Neil M.H. Graham3, Bolanle Akinlade3, Allen Radin3

1Northwestern University Feinberg School of Medicine, Chicago, IL, USA 2University of North Carolina School of Medicine, Chapel Hill, NC, USA

3Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA 4Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, USA

5University of Utah School of Medicine, Salt Lake City, UT, USA 6Mount Sinai Center for Eosinophilic Disorders, Icahn School of Medicine at Mount Sinai, New York, NY, USA

7Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland 8Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

9Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA10University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

11University of Iowa Hospitals and Clinics, Iowa City, IA, USA 12Sanofi, Bridgewater, NJ, USA 13Sanofi, Chilly-Mazarin, France

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CONSORT80 individuals screened

33 not enrolled47 randomly assigned to

receive dupilumab/placebo

Placebo(n = 24)

4 withdrew by Week 1020 completed the


4 withdrew by Week 12 20 completed the 12-week treatment period

20 completed the treatment and

follow-up period

Dupilumab 300 mg every week

(n = 23)

1 withdrew by Week 1022 completed the


1 withdrew by Week 12 22 completed the 12-week treatment period

22 completed the treatment and

follow-up period

Detailed Inclusion Criteria

• Age 18−65 years with prior EoE diagnosis

• Active inflammation with ≥ 15 eos/hpf in at least 2 of 3 esophageal levels at screening

• Patient-reported history of on average ≥ 2 episodes of dysphagia (defined as trouble swallowing solid food, or having solid food stick, by patient report) per week in the 4 weeks prior to screening and on average ≥ 2 episodes of documented dysphagia per weeks between screening and baseline

• Stabilized diet (defined as no initiation of single or multiple elimination diets or reintroduction of previously eliminated food groups) for ≥ 6 weeks prior to screening and during the course of the study

• SDI PRO score ≥ 5 at screening and baseline

• Documented history of presence of ≥ 1 of any of the following: allergic disease (e.g. allergic asthma, allergic rhinitis, AD, or food allergies), peripheral eosinophil count ≥ 0.25 GI/L, serum IgE ≥ 100 kU/L

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Detailed Exclusion Criteria

• Prior participation in a dupilumab (anti-IL-4receptor α) clinical trial

• Other causes of esophageal eosinophilia or the following diseases: hypereosinophilicsyndromes, Churg-Strauss vasculitis, and eosinophilic gastroenteritis

• Any esophageal stricture unable to be passed with a standard, diagnostic, adult (9−10 mm outer diameter) upper endoscope or any critical esophageal stricture that requires dilation at screening

• Treatment with an investigational drug < 2 months or < 5 half-lives (if known), whichever is longer, prior to screening

• Use of systemic corticosteroids < 3 months or swallowed TCS < 6 weeks prior to screening

• Use of inhaled (pulmonary or nasal) TCS < 3 months prior to screening and during the study, except stable dose for ≥ 3 months prior to screening biopsy, which cannot be changed during the study

• Treatment with oral immunotherapy < 6 months prior to screening

• Allergen immunotherapy unless on stable dose for ≥ 1 year prior to screening

• Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study

SDI PRO Score (Scale 0−9) During the Past Week

• Dysphagia frequency (0−4)– None = 0

– Once per week = 1

– Several times per week = 2

– Once per day = 3

– Several times per day = 4

• Dysphagia severity (0−5)– Swallowing unhindered = 0

– Slight sensation of resistance = 1

– Slight retching with delayed passage = 2

– Short period of obstruction necessitating intervention = 3

– Longer-lasting period of obstruction only removable by regurgitation = 4

– Long-lasting complete obstruction, requiring endoscopic intervention = 5

Straumann A, et al. Gastroenterology 2010.

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EEsAI PRO Score (Scale 0−100)

• Data collected by eDiary in this study

• Consists of 5 parts– Frequency of trouble swallowing

– Duration of trouble swallowing

– Pain when swallowing

– Visual Dysphagia Question (VDQ)

– Avoidance, Modification, and Slow eating (AMS)

• Questions included in the assessment collect information about patients’ perception of:

– Frequency of dysphagia

– Intensity of dysphagia

– Collects information about food avoidance and diet modification behaviors

• Food particle size

• Food consistency

Schoepfer AM, et al. Gastroenterology 2014.

Modified EREFs Was Used as the Visual Endoscopy Evaluation of Treatment Effect in EoE

The Edema Rings Exudates Furrows and Strictures (EREFS) score measures the following:• Edema: loss of vascular markings of

the mucosa• Rings: concentric rings around

esophagus• Exudates: white plaques• Furrows: vertical lines down the

esophagus• Strictures: narrowing of the

esophagus

• Modified EREFS in this study; total score range 0−8

• Edema 0−1

• Rings 0−3

• Exudates 0−2

• Furrows 0−1

• Strictures 0−1

• Total possible 8 x 1 total = 8 max

• 1 score for total region evaluated

Hirano I, et al. Gastroenterol Clin North Am. 2014.

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Edema (loss vascular markings)Grade 0: Distinct vascularityGrade 1: Decreased or absent markings

Rings (trachealization)Grade 0: NoneGrade 1: Mild (ridges)Grade 2: Moderate (distinct rings)Grade 3: Severe (not pass scope)

Exudates (white plaques)Grade 0: NoneGrade 1: Mild (≤ 10% surface area)Grade 2: Severe (>10% surface area)

Furrows (vertical lines)Grade 0: NoneGrade 1: Present

StricturesGrade 0: AbsentGrade 1: Present

Grade 0

Endoscopic Reference Score (EREFS)

Hirano I, et al. Gut. 2013.

Grade 1 Grade 2 Grade 3

EoE-HSS (Scale 0−21)

• The EoE-HSS generates separate severity (grade) and extent (stage) of disease scores

• Score includes 8 parameters: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratoticepithelial cells, lamina propria fibrosis

– 0−3 scale used for each measure, both grade and stage (0 being least inflamed, normal)

– Scores change with treatment

– Reliably measured between 3 pathologists

• Total score range for each region 0−21 for this study (excluding lamina propria parameter)

– Excluded lamina propria assessment given that ~50% of pinch biopsies would not be deep enough for lamina propria assessment

• 2 scores generated per patient per time point: 1 for each grade (severity) and stage (extent)

• Total score per patient (0−21 score x 3 regions = proximal + mid + distal scores per time point)

Collins MH, et al. Dis Esophagus. 2017.

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SDI PRO Score at Baseline and Week 10

P value versus placebo.Straumann A, et al. Gastroenterology 2010.

Higher scores indicate worse symptoms

0

1

2

3

4

5

6

7

8

9

Baseline Week 10

(n = 17)(n = 14)(n = 23)

Placebo Dupilumab 300 mg qw

(n = 24)

Mea

n (

±S

D)

SD

I sc

ore

−1.3 (0.6) −3.0 (0.5)LS mean (SE) change from baseline

; P = 0.0304

SDI PRO Change From Baseline During the 12-Week Treatment Period

P value versus placebo.

−3.0

−1.3

LS mean difference (CI): Week 10 −1.7 (−3.22, −0.16), P = 0.0304Week 12 −0.8 (−2.48, 0.96), P = 0.3830

Baseline: 6.4

Baseline: 6.4

−2.2

−2.9

LS

mea

n c

han

ge

fro

m

bas

elin

e S

DI (

±S

E)

0 1 2 3 4 5 6 7 8 9 10 11 12−4

−3

−2

−1

0

1

Number of patients at each visitPlacebo (N = 24) 24/0 21/3 16/8 15/9 14/10 15/9 12/12 15/9 10/14 14/10 14/10 10/14 9/15300 mg qw (N = 23) 23/0 20/3 18/5 17/6 20/3 14/9 18/5 15/8 14/9 18/5 17/6 16/7 16/7

Week

Placebo (n = 24)300 mg every week (n = 23)

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0

20

40

60

80

100

Baseline Week 10

Mea

n (

±S

D)

EE

sAIs

core

EEsAI PRO Score at Baseline and Week 10

P value versus placebo.Schoepfer AM, et al. Gastroenterology. 2014.

(n = 22) (n = 23)

Higher scores indicate worse symptoms

(n = 14) (n = 17)


–11.3% (9.9) –34.6% (9.1)LS mean (SE) % change from baseline

; P = 0.0850

LS mean difference (CI): Week 10 −23.23 (−49.677, 3.212), P = 0.0850Week 12 −33.65 (−68.828, 1.536), P = 0.0608

LS

mea

n %

ch

ang

e E

EsA

I(±

SE

)

−11.33%

−3.34%

−34.56% −36.99% −50

−30

−20

−10

0

10

−40

EEsAI PRO % Change From Baseline During the 12-Week Treatment Period

P value versus placebo.

0 1 2 3 4 5 6 7 8 9 10 11 12

Placebo (n = 24)300 mg every week (n = 23)

Number of patients at each visitPlacebo (N = 24) 22/2 20/4 15/9 14/10 13/11 14/10 11/13 14/10 9/15 13/11 13/11 9/15 8/16300 mg qw (N = 23) 23/0 20/3 18/5 17/6 20/3 14/9 18/5 15/8 14/9 18/5 17/6 16/7 15/8

Week

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Overall Peak Esophageal Intraepithelial Eosinophil Count (eos/hpf) at Baseline and Week 12

P value versus placebo.Peak esophageal intraepithelial eosinophil count was calculated using peak count from each esophageal region (mid, proximal, and distal).

-50

0

50

100

150

200

Baseline Week 12

Mea

n (

±S

D)

pea

k eo

sin

op

hil

cou

nt,

eo

s/h

pf


Proportion of patients with response at Week 12, n (%)

Peak eos(eos/hpf) at Week 12

PlaceboDupilumab 300 mg qw

P value vs placebo

≤ 6 0 (0) 15 (65.2) < 0.0001

<15 0 (0) 19 (82.6) < 0.0001

(n = 24) (n = 23) (n = 22) (n = 23)

+14.2% (12.5) –92.9% (12.1); P < 0.0001LS mean (SE) percent change from baseline

Modified EREFS at Baseline and Week 12

P value versus placebo.Hirano I, Aceves SS. Gastroenterol Clin North Am. 2014.

0

1

2

3

4

5

6

7

8

Baseline Week 12

(n = 24) (n = 23)

Higher scores indicate greater impairment

(n = 22) (n = 23)


Mea

n (

±S

D)

ER

EF

S s

core −0.3 (0.3) −1.9 (0.3); P = 0.0006

LS mean (SE) change from baseline

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EoE-HSS Score at Baseline and Week 12

P value versus placebo.Lamina propria excluded given that ~50% of pinch biopsies were not deep enough for assessment. Collins MH, et al. Dis Esophagus. 2017.

0

10

20

30

40

50

60

Baseline Week 120

10

20

30

40

50

60

Baseline Week 12

Total grade Total stage

(n = 23) (n = 23) (n = 21) (n = 21) (n = 23) (n = 23) (n = 21) (n = 23)


Mea

n (

±S

D)

Eo

E-H

SS

gra

de

sco

re

Mea

n (

±S

D)

Eo

E-H

SS

sta

ge

sco

re+3.9 (6.6) −64.2 (6.4); P < 0.0001

LS mean (SE) % change from baseline

−3.5 (5.0) −58.1 (4.7); P < 0.0001

LS mean (SE) % change from baseline

Total, Distal, Mid, and Proximal EoE-HSS Score Change From Baseline at Week 12

-100

-80

-60

-40

-20

0

20

40

60

80

100

Total Distal Mid Proximal-100

-80

-60

-40

-20

0

20

40

60

80

100

Total Distal Mid Proximal

Excluding Lamina Propria Fibrosis.


Total grade Total stage

All P < 0.0001 vs placebo All P < 0.0001 vs placebo

LS

mea

n (

±S

E)

% c

han

ge

in

HS

S s

tag

e s

co

re

LS

mea

n (

±S

E)

% c

han

ge

in

HS

S g

rad

e s

co

re

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Esophageal Distensibility Plateau (mm) at Baseline and Week 12

P value versus placebo.Esophageal distensibility plateau was measured using FLIP, a probe using impedence planimetry.

0

5

10

15

20

25

30

Baseline Week 12

(n = 18) (n = 17) (n = 13) (n = 15)


Mea

n (

±S

D)

dis

ten

sib

ility

pla

teau

, mm

–6.2% (2.7) +11.8% (2.7); P < 0.0001LS mean (SE) % change from baseline

Serious Adverse Events That Were Considered to not be Related to the Investigational Medicinal Product

• Dupilumab 300 mg every week– Food allergy: female (30 years) with prior history of anaphylaxis to tree nuts and

moderate allergy to milk and eggs developed a sudden episode of throat swelling after ingestion of a vegan shake; episode successfully resolved with epinephrine injection

– Creatine phosphokinase (CPK) elevation: male (28 years) with sudden onset of CPK elevation 3 months after stopping dupilumab; this was considered secondary to strenuous exercise and use of mineral supplements

– Spontaneous abortion: female (44 years) with prior history of cervical excision due to cancer so was not on contraceptives had spontaneous abortion after 12 weeks of dupilumab

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21

Injection-Site Reactions in Nasal Polyposis and Asthma Dupilumab Studies, n (%)

q2w, every 2 weeks; q4w, every 4 weeks.

Patients with severe chronic sinusitis with nasal polyps – Phase 2

Placebo(N = 30)

Dupilumab 300 mg qw(N = 30)

2 (6.7) 10 (33.3)

Patients with uncontrolled persistent asthma – Phase 2b

Placebo(N = 158)

Dupilumab 200 mg q4w

(N = 150)


(N = 157)


(N = 148)


(N = 156)

21 (13.3) 19 (12.7) 21 (13.4) 29 (19.6) 41 (26.2)

Injection-Site Reactions in Atopic Dermatitis Dupilumab Studies, n (%)

Patients with moderate-to-severe atopic dermatitis (LIBERTY AD SOLO 1) – Phase 3

Placebo(N = 222)


(N = 229)


15 (6.8) 23 (10.0) 43 (19.7)

Patients with moderate-to-severe atopic dermatitis (LIBERTY AD SOLO 2) – Phase 3

Placebo(N = 234)


(N = 236)


18 (7.7) 34 (14.4) 33 (13.9)

Patients with moderate-to-severe atopic dermatitis (LIBERTY AD CHRONOS) – Phase 3

Placebo + TCS(N = 315)

Dupilumab300 mg q2w + TCS

(N = 110)

Dupilumab300 mg qw + TCS

(N = 315)

18 (5.7) 13 (11.8) 53 (16.8)

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22

Statistical Analysis: Model-Based Imputation

• MI (multiple imputation): MI does not attempt to estimate each missing value through generated values but rather to represent a random sample of the missing values

– Less bias for the estimates comparing with single-step imputation method

– When the data are missing at random, MI can lead to consistent, asymptotically efficient, and asymptotically normal estimates

Statistical Analysis: MI steps

1. The missing values are replaced multiple times (M) under regression technique – Instead of imputing a single value for each missing observation, a set of M (say M = 10) values for

each missing observation is generated from estimated distribution

2. Each imputed data set is then analyzed separately using existing methods, i.e. ANCOVA; creates a set of parameter estimates for each M datasets

3. Results are combined by Rubin’s rule– The MI estimate is the average of the estimates from the M datasets, and the variance of the

estimate is the average of the variance plus the between-sample variance of the estimates

10/27/2017

1

Minimally Invasive Surgery versus Endoscopy Randomized (MISER) Trial

for Necrotizing Pancreatitis

1. Center for Interventional Endoscopy, Florida Hospital, Orlando, USA

2. Department of Surgery, Florida Hospital, Orlando, USA

3. University of Alabama at Birmingham, Alabama, USA

4. Department of Radiology, Florida Hospital, Orlando, USA

Ji Young Bang1, Pablo Arnoletti2, Bronte Holt1, Udayakumar Navaneethan1, Muhammad Hasan1, Bryce Sutton1, Mel C. Wilcox3,

Nicholas Feranec4, Robert Hawes1, Shyam Varadarajulu1

Introduction

• Acute pancreatitis is the most common gastrointestinal disease requiring hospitalization in the US1

• Total annual cost of hospitalization US $2.2 billion2

• Acute necrotizing pancreatitis occurs in 5‐10%3

• Mortality rate of 8‐39%

1. Peery AF et al. Gastroenterology 2012; 143:1179‐87.2. Fagenholz PJ et al. Pancreas 2007; 35:302‐7.

3. Banks PA et al. Gut 2013; 62:102‐111

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Introduction

1. PANTER trial (2010)

• Open necrosectomy vs. step‐up approach

• Step‐up approach resulted in significantly lower rate of composite end point of major complications/death: 69% vs. 40%, p=0.006

2. PENGUIN trial (2012)

• Surgical (open/minimally invasive) necrosectomy vs. endoscopic drainage/necrosectomy

• Endoscopic treatment resulted in lower post‐procedural IL‐6 levels and lower rate of composite clinical end point of major complications/death: 80% vs. 20%, p=0.03

1. van Santvoort HC et al. NEJM 2010; 362:1491‐5022. Bakker OJ et al. JAMA 2012; 307:1053‐1061

Objective

Minimally Invasive Surgery vs. Endoscopy Randomized (MISER) trial for treatment

of patients with acute necrotizing pancreatitis

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3

Methods

Patient selection

• Age ≥ 18 years

• Symptomatic and/or infected necrotic collection

• Amenable for both endoscopic and minimally invasive surgical treatment

Exclusion criteria

• Age < 18 years

• Pregnancy

• Not amenable for both endoscopic and minimally invasive surgical treatment

• Treatment response within 72 hours of percutaneous drain insertion

Inclusion criteria

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4

Procedure details

Endoscopic drainage Laparoscopic drainage/internal debridement

Endoscopic necrosectomy VARD

Primary outcome measure

• Composite of major adverse events from index intervention to 3 months

• Death

• New onset multiple organ failure

• New onset multiple systemic dysfunction

• Pancreaticocutaneous fistula

• Enterocutaneous fistula

• Visceral perforation

• Intraabdominal bleeding

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5

Secondary outcome measures

• Other adverse events due to underlying disease/intervention

• Post‐procedure SIRS

• No. of interventions

• No. of readmissions

• Exocrine/endocrine function

• Length of hospital stay (LOS)

• Costs

• Quality of life

Sample size calculation

• Sample size n=30 per group

• Based on rate of major adverse events: 12.5% for endoscopy1‐7, 50% for surgery7‐9

• Two‐sided sample size calculation

• 90% power, α=0.05

1. Varadarajulu S et al. J GI Surg 2011; 15:2080‐82. Varadarajulu S et al. GIE 2011; 74:74‐803. Bang JY et al. Ann Surg 2016 Nov 15.4. Bang JY et al. Br J Surg 2014; 101:1729‐38

5. Bang JY et al. J Gastroenterol Hepatol 2013; 28:1725‐326. Gardner TB et al. GIE 2011; 73:718‐267. Bakker OJ et al. JAMA.2012; 307:1053‐61 8. van Santvoort HC et al. NEJM 2010; 362:1491‐5029. Raraty MG et al. Ann Surg 2010; 251:787‐93

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Follow‐up post‐discharge

Endoscopy

6 weeks post‐discharge:

CT, ERCP, Removal of transmural stents

SF‐36

3 months post‐discharge:

SF‐36

Adverse events, admissions, reinterventions


SF‐36


Surgery

6 weeks post‐discharge:

CT

SF‐36


SF‐36


6months post‐discharge:

SF‐36


Results

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7

CONSORT flow diagram

Baseline characteristics

Endoscopy Surgeryp‐value

(n=34) (n=32)

Age (years): Median (IQR) 59 (46‐66) 57.5 (45‐64.5) 0.456

Gender: n (%) Female 12 (35.3) 11 (34.4) 0.938

Male 22 (64.7) 21 (65.6)

Cause of pancreatitis: n (%) Gallstones 14 (41.2) 8 (25.0) 0.214

Alcohol 6 (17.6) 11 (34.4)

Other 14 (41.2) 13 (40.6)

Necrotic collection size (cm): Median (IQR) 11.0 (8.6‐14.1) 11.2 (9.1‐15.5) 0.873

Confirmed infected necrosis: n (%) 16 (47.1) 15 (46.9) 0.988

ASA class: n (%) II 2 (5.9) 1 (3.1) 0.659

III 26 (76.5) 23 (71.9)

IV 6 (17.6) 8 (25.0)

Disease severity: n (%) SIRS 16 (47.1) 16 (50.0) 0.811

ICU/high acuity care 24 (70.6) 21 (65.6) 0.665

Single‐organ failure 2 (5.9) 3 (9.4) 0.668

Multi‐organ failure 7 (20.6) 7 (21.9) 0.898

Acute physiology score: Median (IQR) 18 (10‐37) 20 (13.5‐37.5) 0.724

Percutaneous drain in situ prior to intervention: n (%) 14 (41.2) 9 (28.1) 0.309

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8

Primary composite end point

Endoscopy Surgery Risk ratiop‐value

(n=34) (n=32) (95% CI)

Primary composite end point: n (%) 4 (11.8) 12 (37.5) 0.31 (0.11‐0.87) 0.015

Endoscopy Surgery Risk ratio p‐

value(n=34) (n=32) (95% CI)

Death: n (%) 3 (8.8) 2 (6.3) 1.41 (0.25‐7.91) 0.999

New onset multiple organ failure: n (%) 2 (5.9) 3 (9.4) 0.63 (0.11‐3.51) 0.668

New onset multiple systemic dysfunction: n (%) 0 1 (3.1) 0 0.485

Pancreaticocutaneous fistula: n (%) 0 8 (25.0) 0 0.002

Enterocutaneous fistula: n (%) 0 4 (12.5) 0 0.050

Visceral perforation: n (%) 0 0 0 0.999

Intraabdominal bleeding: n (%) 0 2 (6.3) 0 0.499

Individual primary end points

Post‐procedure SIRS


(n=34) (n=32) (95% CI)

SIRS at 72 hours post‐index procedure: n (%) 7 (20.6) 21 (65.6) 0.31 (0.15‐0.64) <0.001

New onset SIRS at 48 hours post‐index procedure: n (%) 1 (5.6) 9 (56.3) 0.099 (0.014‐0.70) 0.002

Resolution of SIRS at 48 hours post‐index procedure: n (%) 11 (68.8) 3 (18.8) 3.67 (1.25‐10.7) 0.004

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Other adverse events


(n=34) (n=32) (95% CI)

Incisional hernia: n (%) 0 2 (6.3) 0 0.231

Surgical site infection: n (%) 0 2 (6.3) 0 0.231

Intra‐procedural adverse events: n (%) 2 (5.9) 3 (9.4) 0.63 (0.11‐3.51) 0.668

Disease/procedure‐related adverse events: n (%) 14 (41.2) 18 (56.3) 0.73 (0.44‐1.21) 0.221

No. of disease/procedure related AEs: Median (IQR) 0 (0‐1) 1 (0‐2) 0.029

Endocrine and exocrine function


(n=34) (n=32) (95% CI)

New onset diabetes: n (%) 6 (27.3) 9 (36.0) 0.76 (0.32‐1.79) 0.522

Pancreatic insufficiency: n (%) 29 (85.3) 28 (87.5) 0.97 (0.80‐1.18) 0.999

Fecal elastase level (μg/g): Median (IQR) 62 (30‐128) 56.5 (23‐96.5) 0.472

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Health care resource utilization


(n=34) (n=32) (95% CI)

Reintervention performed: n (%) 15 (44.1) 12 (37.5) 1.18 (0.65‐2.11) 0.585

Total no. of interventions per patient: Median (IQR) 1 (1‐2) 1 (1‐2) 0.475

Total no. of interventions per study group: 58 49

New percutaneous drain placed from index to discharge: n (%) 6 (17.6) 5 (15.6) 1.13 (0.38‐3.34) 0.826

LOS (days) from index to discharge: Median (IQR) 14 (6‐22) 18.5 (11.5‐29.5) 0.057

ICU stay (days) from index to discharge: Median (IQR) 0 (0‐0) 0 (0‐6.5) 0.044

Total no. of readmissions: Median (IQR) 0 (0‐1) 0.5 (0‐2) 0.006

Procedure duration (mins): Median (IQR) 47.5 (22‐80) 120 (90‐135) <0.001

Cost analysis

Cost Endoscopy (US$) Surgery (US$) p‐value

Hospital 21,407.32 36,383.03 0.014

Procedure 11,864.50 11,226.30 0.703

Pharmacy 14,495.19 29,829.17 0.031

Radiology 8,122.95 10,872.78 0.070

Anesthesia 2,028.31 1,983.84 0.865

Laboratory 6,945.30 12,404.73 0.010

Other 10,966.21 14,792.10 0.191

Total 75,829.79 117,491.90 0.039

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11

Quality of life

Endoscopy Surgeryp‐value

(n=34) (n=32)

Quality of life (QOL) at 3‐month follow‐up: Mental health: β (95% CI) ‐0.22 (‐9.18 ‐ 8.87) 0.962

Physical health: β (95% CI) 5.29 (0.27 ‐ 10.3) 0.039

Conclusions

Endoscopy‐based interventions, as compared to minimally invasive surgery, was associated with lower rate of composite end point of major

complications/death, better physical health and lower costs

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12

Thank you

10/27/2017

1

A Prospective RCT Comparing Proximal ADR using Combined Chromoendoscopy with Water Exchange (CWE) vs Water Exchange (WE) vs Air Insufflation (AI)

in Screening Colonoscopy

1,2J Leung, MD., MACG, 1A Yen, MD., FACG, 1J Atkins, LVN., 1C Opada, RN., 1A Melnik, BSc., 1C Feller, RDN, CCRP,

3M Wilson, PhD., 4F Leung, MD., FACG.1Gastroenterology, Sacramento VA Medical Center and

2UC Davis Medical Center, 3CTSC, UC Davis, 4Sepulveda ACC, VAGLAHS and David Geffen School of Medicine at UCLA

Background

• Low adenoma detection rate (ADR) increases risk of interval cancer which tend to cluster in the proximal colon.

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2

Hypothesis

• Compared with water exchange and air method, combined chromoendoscopy(Indigocarmine) with water exchange will further improve proximal colon ADR

Aim• RCT to compare three different methods for screening colonoscopy

• Indications include– Asymptomatic average risk patients (50‐75yrs) or

– Positive family history of CRC or

– Positive FIT test done for CRC screening

• (ClinicalTrial.gov NCT#01607255)

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3

Outcome Measure

• Primary outcome measure: proximal ADR

Sample Size Calculation

• To show a 19% difference in proximal ADR between the study and control groups, 160 patients were required in each group (a total of 480 Veterans)

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4

Study Design

Randomize

Air method (AI)N=160

Water Exchange (WE)N=160

Chromoendoscopy & Water Exchange (CWE)N=160

811 patients were screened for recruitment

Consent to be randomized: N = 480

Approx. 2000 eligible Veterans for sedated colonoscopy for CRC screening

331 were excluded

Method I

• Patients attended open access colonoscopy education class

• Those interested in participation were contacted by the research coordinator

• Patients reviewed study and were given the informed consent

• All patients received split dose bowel prep

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Method II• Patients were consented for the colonoscopy and study

• All patients received IV moderate sedation (Fentanyl, Midazolam, and Diphenhydramine)

• Randomization was done just prior to scope insertion to avoid bias

Method III• AI was performed with conventional method with minimal

air insufflation and regular scope shortening • WE was done with air button turned off, water was infused

and exchanged until cecal intubation. Air was used on scope withdrawal to facilitate removal of lesions

• CWE used dilute Indigo carmine (IC 0.008%) solution instead of plain water. The method was same as WE.

• Polyps were removed using biopsy forceps, cold or hot snare.

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6

ResultsTable 1: Patients Demographic and Procedure

Characteristicsp‐values for pairwise comparisons@

CWE

(N=160)

WE

(N=161)

AI

(N=159)

Overall

p‐values

CWE vs WE CWE vs AI WE vs AI

BMI (SD) 29.2 (4.3) 29.6 (4.1) 29.4 (4.3) .70 ns ns ns

Age (SD) years 61.1 (6.4) 60.5 (6.5) 60.8 (6.5) .63 ns ns ns

Abdominal

compression 16.6% 17.1% 41.5% <.001 .90 <.001 <.001

Position Change 16.6% 17.1% 41.5% <.001 .90 <.001 <.001

CWE: chromoendoscopy+water exchange, WE= water exchange, AI= conventional air method@Note: only pairwise comparisons for tests for which the omnibus test was significant are required. *Chi square test, ** Analysis of variance, p<0.05 is significant, ns=not significant

ResultsTable 1: Patients Demographic and Procedure Characteristics

p‐values for pairwise

comparisons@

CWE

(N=160)

WE

(N=161)

AI

(N=159)

Overall

p‐values

CWE vs

WE

CWE vs

AI

WE vs

AI

Cecal Intubation success rate 97.5% 100% 98.1% .15 ns ns ns

Cecal intubation time (SD) min. 13.3 (7.8) 12.0 (6.3) 12.2 (7.8) .22 ns ns ns

Withdrawal time (SD) min. 23.4 (8.1) 18.7 (8.7) 18.4 (9.6) <.001 <.001 <.001 .92

Scope length at cecum (SD) cm 83.3 (13.3)83.9

(11.9)

91.4

(17.4)<.001 .94 <.001 <.001

Volume water infused for procedure

(SD) ml

655.5

(513.6)

614.0

(478.9)

479.2

(457.5.004 .08 <.001 <.001

Volume water (ml) suctioned at

completion of colonoscopy (SD)

621.0

(474.8)

550.2

(392.0)

454.7

(352.8).002 .07 <.001 <.001

Mean volume of water retained (SD) ml‐38.1

(245.6)

‐63.8

(232.2)

‐24.2

(232.2).32 ns ns ns

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7

ResultsCWE

(N=160)

WE

(N=161)

AI

(N=159)

Overall

p‐values

CWE vs

WE

CWE vs

AI

WE vs

AI

Overall preparation in 2.45 (0.29) 2.49 (0.24) 2.48 (0.27) .41 ns ns ns

Overall preparation out 3.33 (0.39) 3.48 (0.34) 3.22 (0.36) <.001* <.001 .03 <.001

Change in Na (post – pre) ‐0.29 (2.1) ‐0.26 (1.8) ‐0.11 (1.9) .69 ns ns ns

Change in K (post – pre) 0.08 (0.71) 0.07 (0.46) 0.11 (0.47) .84 ns ns ns

Bowel preparation is usually assessed by segment, the overall preparation is a mean of all segments

Under Water Bowel Preparation Score (UWBPS) (1‐4): 1= poor (solid stool, murky water, incomplete exam), 2= fair (residual stool, cloudy water, difficult exam), 3= good (minimal residual stool in water, does not affect exam), 4= excellent (no residual stool, clear view of mucosa under water).Under Air Bowel Preparation Score* (UABPS) (1‐4): 1=poor (Solid residual stool obscuring the lumen, cannot be washed off resulting in failed examination of the mucosa), 2=fair (Considerable residual solid and liquid stool resulting in incomplete examination of the mucosa), 3=good (Minimal residual stool, easily washed off, does not affect examination of mucosa), 4=excellent (No residual stool, good inspection and examination of mucosa). #adapted from the Boston Bowel Preparation Scale (BPPS).

Results: Adenoma Detection

CWE=chromoendoscopy + water exchange; WE=water exchange; AI=air insufflationADR=adenoma detection rate, Overall= tubular adenoma+ tubulovillous adenoma and adenoma with HGD Advanced lesions= adenoma > 10 mm or tubulovillous or HGD, Proximal colon: splenic flexure to cecum *Chi square test and ** Wilcoxon rank sum test, p<0.05 is significant; ns=not significant

CWE (n=160)

WE (n=161)

AI (n=159)

Overall p‐value*

CWE vs WE

CWE vs AI

WE vs AI

Overall ADR (%) 62.5 61.5 61.6 .98 ns ns nsOverall advanced lesions .63 .62 .63 .99 ns ns nsProximal ADR (%) 55.6 53.4 52.2 .82 ns ns ns

Median Number of Adenomas (IQR$)

N=100 N=99 N=98p‐

value**Pair‐wise comparison p‐

values

Adenomas per colonoscopy 1 (3) 1 (2) 1 (2) .47 ns ns ns

Adenomas per positive

colonoscopy2 (2) 2 (2) 2 (3) .08 ns ns ns

10/27/2017

8

ADR for PI over Past 10 YearsAdenoma Detection Rate (ADR)

Study Scope # patients Water method Air method Reference

Overall Proximal Overall Proximal

Unsedated PCF160 125 36.5% 25.8% GIE2009;69:546‐550

Retro review PCF160/180 1178 34.9% 26.9% JIG2011;1:3‐7

Unsedated PCF180 182 38% 29.3% 30% 16.7% JIG2011;1:8‐13

On‐demand PCF180 100 40% 40% 36% 24% GIE2011;73:103‐10

Unsedated PCF180 100 54% 40% 48% 28% JIG2013;3:7‐11

Sedated PCF180 480 62% 53% 61% 52% Current study

There was significant improvement in overall and proximal ADR with AIcolonoscopy over the yearsIt may be possible that the ADR increase in study methods over the years (including learning and practice with CWE and WE) enables colonoscopist to recognize lesions (they are there if looked for carefully) not previously seen with control (AI) method in the published preliminary studies?

Discussion• Comparable demographic variables attest to satisfactory randomization.

• Comparable APC and APPC indicated equivalent withdrawal inspection techniques were used.

• Like CWE and WE, proximal ADR almost double recommended community quality standard (30%) was achieved with AI.

• Use of WE and CWE did not further improve ADR results.

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9

Conclusions• Recent reports suggested that WE significantly increased ADR in colonoscopists with ADR meeting [1] and not meeting [2] quality standard.

• Prior practice in pilot studies with CWE and WE leading to the current trial suggested that CWE and WE (or at least WE) may still be necessary to improve ADR in AI

• Lower requirement for abdominal compression with WE and CWE may reduce costly assistant hand injury [3]

Endoscopy 2017;49:456; GIE 2017;86:192AJG 2017;112:568GEN 2013;36:329

Acknowledgement

• The study was supported by a VA Merit Review Grant (2013‐2017) awarded to the PI

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