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Background and Aims Barrett's esophagus (BE) is accompanied by an increased risk of developing esophageal cancer. Accurate risk‐stratification is warranted to improve endoscopic surveillance. Most data available on risk factors is derived from tertiary care centers or from cohorts with limited surveillance time or surveillance quality. The aim of this study was to assess endoscopic and clinical risk factors for progression to high‐grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) in a large prospective cohort of BE patients from community hospitals supported by an overarching infrastructure to ensure optimal surveillance quality. Methods A well‐defined prospective multicenter cohort study was initiated in six community hospitals in the Amsterdam region in 2003. BE patients were identified by PALGA search and included in a prospective surveillance program with a single endoscopist performing all endoscopies at each hospital. Planning and data collection was performed by experienced research nurses who attended all endoscopies. Endpoint was progression to HGD/EAC. Results Nine hundred eighty‐five patients were included for analysis. During median follow‐up of 7.9 years (IQR 4.1–12.5) 67 patients were diagnosed with HGD (n = 28) or EAC (n = 39), progression rate 0.78% per patient‐year. As a clinical risk factor age at time of endoscopy was associated with neoplastic progression (HR 1.05; 95% CI 1.03–1.08). Maximum Barrett length and low‐grade dysplasia (LGD) at baseline were endoscopic predictors of progression (HR 1.15; 95% CI 1.09–1.21 and HR 2.36; 95% CI 1.29–4.33). Conclusion Risk of progression to HGD/EAC in a large, prospective, community‐based Barrett's cohort was low. Barrett's length, LGD and age were important risk factors for progression. (www.trialregister.nl NTR1789)

Background & Aims: We compared the diagnostic yields of colonoscopy, flexible sigmoidoscopy, and fecal immunochemical tests (FITs) in colorectal cancer (CRC) screening. Methods: A total of 30,007 asymptomatic persons, 50–74 years old, were invited for CRC screening in the Netherlands. Participants were assigned to groups that received 4 rounds of FIT (mailed to 15,046 participants), once-only flexible sigmoidoscopy (n = 8407), or once-only colonoscopy (n = 6600). Patients with positive results from the FIT (≥10 μg Hb/g feces) were referred for colonoscopy. Patients who underwent flexible sigmoidoscopy were referred for colonoscopy if they had a polyp of ≥10 mm; adenoma with ≥25% villous histology or high-grade dysplasia; sessile serrated adenoma; ≥3 adenomas; ≥20 hyperplastic polyps; or invasive CRC. The primary outcome was number of advanced neoplasia detected (diagnostic yield) by each test. Secondary outcomes were number of colonoscopies needed to detect advanced neoplasia and number of interval CRCs found during each primary screening test. Patients with interval CRCs were found through linkage with Netherlands Cancer Registry. Advanced neoplasia were defined as CRC, adenomas ≥ 10 mm, adenomas with high-grade dysplasia, or adenomas with a villous component of at least 25%. Results: The cumulative participation rate was significantly higher for FIT screening (73%) than for flexible sigmoidoscopy (31%; P < .001) or colonoscopy (24%; P < .001). The percentage of colonoscopies among invitees was higher for colonoscopy (24%) compared to FIT (13%; P < .001) or flexible sigmoidoscopy (3%; P < .001). In the intention to screen analysis, the cumulative diagnostic yield of advanced neoplasia was higher with FIT screening (4.5%; 95% CI 4.2–4.9) than with colonoscopy (2.2%; 95% CI, 1.8–2.6) or flexible sigmoidoscopy (2.3%; 95% CI, 2.0–2.7). In the as-screened analysis, the cumulative yield of advanced neoplasia was higher for endoscopic screening with colonoscopy (9.1%; 95% CI, 7.7–10.7) or flexible sigmoidoscopy (7.4%; 95% CI, 6.5–8.5) than with the FIT (6.1%; 95% CI, 5.7–6.6). All 3 screening strategies detected a similar proportion of patients with CRC. Follow-up times differed for each test (median 8.3 years for FIT and flexible sigmoidoscopy and 5.8 years for colonoscopy). Proportions of patients that developed interval CRC were 0.13% for persons with a negative result from FIT, 0.09% for persons with a negative result from flexible sigmoidoscopy, and 0.01% for persons with a negative result from colonoscopy. Conclusions: Mailed multiple-round FITs detect significantly more advanced neoplasia, on a population level, compared with once-only flexible sigmoidoscopy or colonoscopy screening. Significantly fewer colonoscopies are required by individuals screened by multiple FITs. Trialregister.nl numbers: first round, NTR1096; second round and additional invitees, NTR1512; fourth round, NTR5874; COCOS trial NTR1829.

SUMMARYPatient selection is suboptimal in most studies focused on identifying biological markers for neoplastic progression in Barrett's esophagus (BE). This study aims to describe a stringently selected community-based case-control cohort of non-dysplastic BE (NDBE) patients who progressed to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) and BE patients who never progressed to be used for future biomarker studies. We identified all patients referred for endoscopic work-up of BE neoplasia at three tertiary referral centers for treatment of BE neoplasia between 2000 and 2013. We performed a detailed registration of any endoscopic surveillance history before neoplastic progression. Controls were selected from a retrospective BE surveillance registration in 10 community hospitals. A total of 887 patients were referred for endoscopic work-up of BE neoplasia. Based on predefined selection criteria, we identified 165 progressor patients (82% men; mean age 55 years ± 10.4) with a baseline endoscopy demonstrating NDBE > 2 years before neoplastic progression. Using the same predefined selection criteria, 723 nonprogressor patients (67% men; mean age 57 years ± 11.3) with >2 years of endoscopic surveillance were identified. Median length of the BE segment was 5 cm (IQR 4–7) in progressors and 4 cm (IQR 2–6) in controls. Median duration of surveillance was 89 months (IQR 54–139) in progressors and 76 months (IQR 47–116) in nonprogressors. Paraffin embedded biopsies are available for biomarker research in all patients. Ethical approval was obtained and material transfer agreements were signed with all 58 contributing pathology labs. This is the largest community-based case-control cohort of BE patients with and without progression to early neoplasia. The stringent selection criteria and the availability of paraffin embedded biopsy specimens make this a unique cohort for biomarker studies.

Over the past 20 years evidence has accumulated confirming the immunomodulatory role of the appendix in ulcerative colitis (UC). This led to the idea that appendectomy might alter the clinical course of established UC. The objective of this body of research is to evaluate the short-term and medium-term efficacy of appendectomy to maintain remission in patients with UC, and to establish the acceptability and cost-effectiveness of the intervention compared to standard treatment.These paired phase III multicenter prospective randomised studies will include patients over 18 years of age with an established diagnosis of ulcerative colitis and a disease relapse within 12 months prior to randomisation. Patients need to have been medically treated until complete clinical (Mayo score3) and endoscopic (Mayo score 0 or 1) remission. Patients will then be randomised 1:1 to a control group (maintenance 5-ASA treatment, no appendectomy) or elective laparoscopic appendectomy plus maintenance treatment. The primary outcome measure is the one year cumulative UC relapse rate - defined both clinically and endoscopically as a total Mayo-score ≥5 with endoscopic subscore of 2 or 3. Secondary outcomes that will be assessed include the number of relapses per patient at 12 months, the time to first relapse, health related quality of life and treatment costs, and number of colectomies in each arm.The ACCURE and ACCURE-UK trials will provide evidence on the role and acceptability of appendectomy in the treatment of ulcerative colitis and the effects of appendectomy on the disease course.NTR2883 ; ISRCTN56523019.

Surveillance of Barrett's oesophagus allows us to study the evolutionary dynamics of a human neoplasm over time. Here we use multicolour fluorescence in situ hybridization on brush cytology specimens, from two time points with a median interval of 37 months in 195 non-dysplastic Barrett's patients, and a third time point in a subset of 90 patients at a median interval of 36 months, to study clonal evolution at single-cell resolution. Baseline genetic diversity predicts progression and remains in a stable dynamic equilibrium over time. Clonal expansions are rare, being detected once every 36.8 patient years, and growing at an average rate of 1.58 cm2 (95% CI: 0.09–4.06) per year, often involving the p16 locus. This suggests a lack of strong clonal selection in Barrett's and that the malignant potential of ‘benign' Barrett's lesions is predetermined, with important implications for surveillance programs., Barrett's oesophagus is thought to be a precursor lesion for oesophageal cancer, and predicting the benign lesions that progress to cancer is clinically important. Here, the authors use FISH to study the clonal evolution of Barrett's oesophagus and show that genetic diversity and somatic mutations are present early in the benign disease.

Objective The risk of developing adenocarcinoma in non-dysplastic Barrett9s oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barrett9s oesophagus, we evaluated six molecular markers: p16 , p53 , Her-2/neu , 20q , MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett9s length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an ‘Abnormal Marker Count’ that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett9s length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). Conclusions A prediction model based on age, Barrett9s length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett9s oesophagus.

Background: During colonoscopy, correct assessment of polyps is important. Recognition of early carcinomas is needed for tailor-made treatment and avoidance of unnecessary complications. Moreover, accurate diagnosis of diminutive lesions could result in a safe resect and discard strategy. We assessed the accuracy of polyp assessment by general endoscopists without specific training or experience in image-enhanced endoscopy during routine colonoscopies within a fecal immunochemical test (FIT)-based screening program. Methods: Data were collected in the third round of a FIT-based colorectal cancer screening pilot program. Patients diagnosed as FIT-positive (318) underwent colonoscopy using Olympus (160 and 180 series) endoscopes without magnification or routine use of (virtual) chromoendoscopy. Endoscopists received no special training. They made an on-site evaluation and classified detected polyps as hyperplastic, adenoma, carcinoma. Samples of resected lesions were sent for histopathology. Sensitivity and specificity were calculated. We differentiated for fellows and consultants. Results: In the 318 patients with a positive FIT-screening result, 683 lesions were detected; 564 lesions were included in the analyses. The pathologist classified these lesions as 141 hyperplastic polyps, 349 adenomas, 16 carcinomas, and 58 other. Sensitivity for diagnosis of adenomas was 88 % (95 %CI 84 – 91); specificity 49 % (95 %CI 42 – 55). Of the 16 colorectal carcinomas, endoscopists diagnosed four incorrectly (sensitivity 75 % [95 %CI 44 – 89]; specificity 99 % [95 %CI 98 – 100]), including three stage I cancers and one stage III cancer. There were no differences in accuracy of diagnosis that related to different sizes of lesions or the experience of the endoscopist. Conclusion: In a routine FIT-based screening setting and without specific training or routine use of (digital) chromoendoscopy, endoscopic prediction of the histopathology of colonic lesions is inaccurate when the procedure is performed by general endoscopists.

Background Colorectal cancer (CRC) is the most common cancer in Europe with a mortality rate of almost 50%. The prognosis of patients is largely determined by the clinical and pathological stage at the time of diagnosis. Population screening has been shown to reduce CRC-related mortality rate. Most screening programs worldwide rely on fecal immunochemical testing (FIT). The effectiveness of a FIT screening program is not only influenced by initial participation rate, but also by program adherence during consecutive screening rounds. We aim to evaluate the participation rate in and yield of a third CRC screening round using FIT. Methods and design Four years after the first screening round and two years after the second round, a total number of approximately 11,000 average risk individuals (50 to 75 years of age) will be invited to participate in a third round of FIT-based CRC screening. We will select individuals in the same target area as in the previous screening rounds, using the electronic database of the regional municipal administration registrations. We will invite all FIT-negatives and all non-participants in previous screening rounds, as well as eligible first time invitees who have moved into the area or have become 50 years of age. FITs will be analyzed in the special technique laboratory of the Academic Medical Center of the University of Amsterdam. All FIT-positives will be invited for a consultation at the outpatient clinic. In the absence of contra-indications, a colonoscopy will follow at the Academic Medical Center or at the Flevohospital. The primary outcome measures are the participation rate, defined as the proportion of invitees that return a FIT in this third round of FIT-screening, and the diagnostic yield of the program. Implications This study will provide precise data on the participation in later FIT screening rounds. This enables to estimate the effectiveness of CRC screening programs that rely on repeated FIT- screening, such as the one that will be implemented in the Netherlands in 2013.

The SURF-Trial Pre-Assessment Cohort: A Multivariable Model Accurately Predicts Neoplastic Progression in Barrett's Esophagus Patients With LowGrade Dysplasia Lucas C. Duits, Cary C. Cotton, Kai Yi N. Phoa, Fiebo T. Ten Kate, Cees A. Seldenrijk, Johan Offerhaus, Mike Visser, Sybren L. Meijer, Rosalie C. Mallant-Hent, Kausilia K. Krishnadath, Roos E. Pouw, Jan Tijssen, Nicholas J. Shaheen, Jacques J. Bergman

Background and aims: The epidemiology of inflammatory bowel disease (IBD) is changing. In Europe, recent incidence and prevalence rates are lacking. The primary objective of this study is to update incidence and prevalence figures in a large well-phenotyped populationbased IBD cohort.Methods: All IBD patients living in the adherence area of 2 non-academic hospitals between 20042010 were identified. Patients were searched in 3 independent hospital databases case finding sources. 1378 Possible IBD cases were scrutinized, IBD diagnosis was based on established clinical, endoscopic and pathologic criteria. Location and behaviour of IBD was reported according to the Montreal classification. Results: 768 IBD patients were included. 255 (33.2%) patients were diagnosed with Crohn's disease (CD), 432 (56.3%) with ulcerative colitis (UC) and 81 (10.5%) with IBD-Unspecified (IBDU). The male-female ratio of IBD was 1:1.3 (P

Background Most European colorectal cancer (CRC) screening programs rely on fecal occult blood testing (FOBT), of which fecal immunochemical tests (FIT) have the best accuracy and adherence rates. The effectiveness of these FOBT-based programs is not only influenced by the participation and yield of the initial screening round, but also by program adherence during consecutive rounds. FIT sensitivity is relatively low and is increased by repeated screening rounds. We aim to evaluate the participation rate, yield and progression of FIT screening for CRC over three rounds of CRC screening . Methods A total number of 10,050 average risk individuals were invited to participate in a third round of biennial FIT-based CRC screening, using OC-Sensor with a cut-off of 50 ng/ml buffer(or 10 ug/mg feces). Invitees were between 50 and 75 years of age. They received an invitation, including an information leaflet, a FIT-test, and a pre-paid return envelope. All FIT-positives were recommended to undergo a colonoscopy unless contraindicated. Colonoscopy findings were classified as CRC, advanced adenoma, advanced neoplasia (CRC plus advanced adenoma) or other. Participation rates, FIT positivity rate, FIT positive predictive value and mean level of FIT-result were calculated, and compared to the results of the first two screening rounds. Results Within this cohort, 5,671 invitees (56%) returned the FIT in this third screening round, compared to 52% in the second round and 56% in the first round (p ,0.001). Overall, 377 (6.8%) of the third round participants had a positive FIT result, versus 7.4% in the second round and 8.1% in the first round (p ,0.01). Of the FIT positives, 316 (84%) underwent colonoscopy. 59 could not undergo colonoscopy because of medical reasons or did not want to undergo colonoscopy. 88 participants had at least one advanced adenoma (28% of positives) and 17 had cancer (5%). The FIT positive predictive value for advanced neoplasia was 30%, compared to 44% in the second round and 55% in the first round; a significant decline (p,0.01) The average FIT result decreased in consecutive screening rounds from 430 ng/ml in the first round to 370 ng/ml in the second and 348 ng/ml in the third round. This decrease was not significant (round one versus round 2 p= 0.16; round one versus round three: 0.08). Conclusion In consecutive CRC screening rounds with FIT, the participation rate stays stable, but both FIT positivity rate for advanced neoplasia and its positive predictive value decline significantly. The average concentration of Hb in Feces decreased over several rounds of FIT based screening, though not significant.

G A A b st ra ct s 16), were 3.7 for CRCs (95%CI= 2.8 to 4.6, p ,.0001 vs. SNADs), 2.3 for CAs (95%CI= 1.7 to 3.0, p,.0001 vs. SNADs), 1.3 for LPGDs (95%CI= 0.8 to 1.8, p=.0001 vs. SNADs), and 0.3 for SNADs (95%CI= 0.2 to 0.5), respectively. Conclusion: Fecal DNA methylation strategy can robustly detect a variety of gastrointestinal tumors, including pancreatic cancers. Our improved fecal DNA methylation assay provides an effective and promising tool for the non-invasive screening of not only for CRC but also for LPGDs, highlighting its tremendous clinical utility in reducing the mortality and morbidity associated with these malignancies.

routine service, the establishment of more accessible screening infrastructure to screening participants, and educational initiatives on the details and safety of the screening tests are therefore needed. Since the screening participants who have the associated factors identified in this study were more likely to encounter psychological obstacles of CRC screening, they should receive more thorough explanation of the nature of screening tests.

examine the effect of acid on Wnt/β-catenin signaling activation and on regulating the expression of Dickkopf1 (DKK1), an inhibitor of the Wnt. Methods: Normal esophageal squamous cells lines (EPC1-hTERT, EPC2-hTERT), a non-dysplastic Barrett's esophageal cell line (CP-A) and an esophageal adenocarcinoma cell line (OE33) were exposed to acidic media (pH 4.0) in a pulsive manner. Human esophageal mucosal biopsies in triplicate from healthy (n=1), NERD (n=1), GERD (n=1) and Barrett's (n=1) patients were obtained and cultured in acidic (pH 4.0) or non acidic media. Localization and levels of β-catenin were determined by Immunofluorescence staining and Western blot. Wnt-activity was assessed by Luciferase assay following transfection with β-catenin-LEF/TCF-sensitive (TOP) or βcatenin-LEF/TCF insensitive (FOP) reporter vector. Immunofluorescence was used for βcatenin and E-Cadherin co-localization. DKK1 and β-catenin gene expression was resolved by qRT-PCR. DKK1 secretion in cells culture media and organ culture media was quantified by ELISA assay.Results: Acid destabilized E-cadherin/β-catenin complex in cell-cell junctions and resulted in β-catenin translocation to nucleus. Wnt-activity correlated with nuclear translocation of β-catenin. Cytosolic shuttling of β-catenin occurred in a rapid and transient manner after acid withdrawal. Chronic pulsed acid exposure increased DKK1 expression in normal squamous cells but not in metaplastic columnar cells. DKK1 overexpression correlated with a significant degradation of β-catenin. Mucosal biopsies from patients with NERD/ GERD secreted significantly higher levels of Dkk1 than healthy and metaplastic mucosa biopsies. Conclusions: These findings suggest that acid reflux induces the activation of Wnt-signaling pathway and that the overexpression of DKK1 is the long term response in the normal squamous esophageal tissue but not in the Barrett's esophagus. These findings also suggest a homeostatic role for DKK1 in GERD and its dysfunction to be a potential mechanism for progression to Barrett's metaplasia.

Background and aims: Colonoscopy is generally perceived as invasive and burdensome. Patients frequently express dissatisfaction with the level of sedation. We aimed to compare endoscopists' and patients' views on adequacy of sedation during colonoscopy. Methods: Data were collected in the IMPROVE-study, a multicenter clinical trial assessing patients' experience during colonoscopy. A total of 1,157 consecutive patients scheduled for colonoscopy in 2 academic and 2 non-academic centers were asked to complete a questionnaire directly after the procedure. Depth of sedation and memory about the procedure were also assessed. Procedural data were collected by a questionnaire offered to the endoscopist. Adequacy of sedation could be scored on a 3-point scale (too little adequate too much). Results: Data on adequacy of sedation from both endoscopists and patients were available for 677 persons (40% male, median age 54, range 17 to 94). Midazolam was given in 664 (98%) procedures (mean dose 4.86mg), fentanyl or alfentanil in 470 (69%) (mean dose 0.06mg for fentanyl and 0.54mg for alfentanil)). In 468 (69%) colonoscopies both midazolam and fentanyl were administered. Depth of sedation was scored as “awake and responding to all instructions” or “responding to the majority of instructions (>50%)” in 547 procedures (81%). In 18 (3%) procedures sedation depth was scored as “responding to hardly any instruction (