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Item does not contain fulltext BACKGROUND: Despite its effectiveness in treating Crohn's disease, adalimumab is associated with an increased risk of infections and high health-care costs. We aimed to assess clinical outcomes of increased adalimumab dose intervals versus conventional dosing in patients with Crohn's disease in stable remission. METHODS: The LADI study was a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial, done in six academic hospitals and 14 general hospitals in the Netherlands. Adults (aged ≥18 years) diagnosed with luminal Crohn's disease (with or without concomitant perianal disease) were eligible when in steroid-free clinical and biochemical remission (defined as Harvey-Bradshaw Index [HBI] score

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.

Reported epidemiology and phenotype distributions vary widely and disease burden of inflammatory bowel disease (IBD) is poorly described. Our aim was to establish these features in a population-based cohort covering 319 976 inhabitants. Furthermore, differences between tertiary referral and peripheral hospital patients were quantified. IBD patients in the adherence area of three peripheral hospitals (2004-2012) were included. Medical and surgical treatment data were obtained. Quality of life and disease activity were evaluated. An outpatient cohort from a tertiary referral centre was accrued. A total of 1461 patients were included: 761 (52.1%) with ulcerative colitis (UC), 579 (39.5%) with Crohn's disease (CD) and 121 (8.3%) with IBD-unspecified. Point prevalence of IBD was 432.1 per 100 000 inhabitants in 2010, which increased significantly over time, P-value of less than 0.0001. The mean annual incidence was 17.2 for UC, 10.5 for CD and 2.2 for IBD-unspecified. Tertiary referral Crohn's patients used thiopurines and biological therapy and underwent surgery significantly more often than patients in peripheral hospitals (P

Massive haemorrhage in ulcerative colitis mainly occurs as a result of exacerbated disease, usually acute or even fulminant colitis. Emergency proctocolectomy is currently advocated as the only reliable treatment of this patient group. However, this type of surgical intervention has a high rate of morbidity and mortality. Recently, several promising studies have been published that describe transcatheter embolization for the treatment of massive lower gastrointestinal bleeding in cases of bleeding colonic diverticular disease and angiodysplasia. Success rates of 48-88% have been reported. To avoid the high risk associated with emergency colectomy, this modern procedure was performed in an ulcerative colitis patient with intractable lower gastrointestinal bleeding. To our knowledge, this is the first patient with ulcerative colitis presenting with massive lower gastrointestinal blood loss to be successfully treated by highly selective transcatheter embolization. This interventional procedure is suggested as an alternative therapeutic approach to haematochezia in selected ulcerative colitis patients.

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.

Item does not contain fulltext BACKGROUND: Colonoscopy is a frequently performed procedure worldwide with a negative perception, leading to reluctance to undergo the procedure. Perceptions could differ depending on the specific indication for the colonoscopy. AIMS: To compare patient satisfaction with the colonoscopy procedure between five different patient groups: inflammatory bowel disease (IBD), familial predisposition for cancer, adenoma/carcinoma surveillance, symptoms suggestive of cancer, and irritable bowel syndrome (IBS). METHODS: A prospective questionnaire study was carried out in two regional hospitals and two tertiary teaching hospitals in the Netherlands. A total of 797 consecutive patients scheduled for colonoscopy between October 2009 and June 2010, 146 (18%) IBD, 153 (19%) adenoma or carcinoma surveillance, 104 (13%) familial predisposition, 280 (35%) symptoms suggestive of cancer, and 114 (14%) IBS-like symptoms, were included. Two questionnaires were administered: one on the day of the procedure and another 6 weeks after the procedure. The main outcome measurements were embarrassment, pain, burden, most burdensome aspect, and overall level of satisfaction. RESULTS: Patients with IBD and IBS reported significantly more embarrassment and burden from the bowel preparation phase (P=0.040 and 0.018, respectively) and more pain during the colonoscopy procedure (P=0.018). This difference in pain was also observed when adjusting for volume of sedation administered, familiarity with the endoscopist, duration of the colonoscopy, or whether or not an intervention was performed. All patient groups were less satisfied with the procedure at 6 weeks than directly after the colonoscopy; they recalled more embarrassment and burden, but less pain. CONCLUSION: Patient groups, defined by indication for colonoscopy, experience the colonoscopy procedure differently.

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 and aims. Both genetic and microbial factors seem to play a pivotal role in the aetiopathogenesis of Crohn's disease. The CARD15 frameshift mutation might link host genetic factors and the indigenous microbial flora, since CARD15 expression is stimulated by peptidoglycan, thereby activating NF-kappaB. It is hypothesised that CARD15 mutation carriers have defective anti-microbial reactions, resulting in more penetrating lesions and antibody responses, which are now being used as highly specific markers for Crohn's disease. The serological marker anti-Saccharomyces cerevisiae antibody directed against cell wall oligomannosidic epitopes has high specificity for Crohn's disease. Perinuclear anti-neutrophil cytoplasmic antibodies have been found in a subgroup of Crohn's disease patients, mostly with colonic involvement. Methods. We investigated the incidence of two CARD15 mutations (3020insC and 2722G > C), anti-S. cerevisiae antibody, and perinuclear anti-neutrophil cytoplasmic antibody in 108 (73F/35M) patients with Crohn's disease with a mean duration of disease since diagnosis of 16 (1-41) years in relation to their phenotype, according to the Vienna classification. Results. The prevalence of CARD15 frameshift mutation was 21%. Of all patients, 62% were anti-S. cerevisiae antibody positive, and 9% had perinuclear anti-neutrophil cytoplasmic antibodies. The prevalence of both anti-S. cerevisiae antibodies and perinuclear anti-neutrophil cytoplasmic antibodies was higher in the mutation carriers compared to non-carriers. Remarkably, all patients with a CARD15 mutation and positive anti-S. cerevisiae antibody had ileal disease. Carriership of the mutation was significantly associated with penetrating behaviour of the disease and weakly associated with stricturing behaviour. Furthermore, anti-S. cerevisiae antibody was associated with ileal disease involvement. Finally, most perinuclear anti-neutrophil cytoplasmic antibody positive patients showed ulcerative-like behaviour of disease (by means of colonic localisation). Conclusions. Genetic and serologic markers might be useful in defining patient subgroups. This may result in a more accurate prediction of disease behaviour, prognosis and therapeutic approach. (C) 2003 Editrice Gastroenterologica Italiana S.H. Published by Elsevier Ltd. All rights reserved.

Accurate diagnosis of inflammatory bowel disease, in particular the differentiation between ulcerative colitis and Crohn's disease, is important for treatment and prognosis. Several serological markers have been used as non-invasive diagnostic tools in inflammatory bowel disease patients both to differentiate ulcerative colitis from Crohn's disease and to define patient subgroups.To evaluate the diagnostic accuracy of three serological tests in differentiating ulcerative colitis from Crohn's disease by single or combined use.Sera from 51 patients with clinically well-defined ulcerative colitis and 50 patients with clinically well-defined Crohn's disease were analysed. Detection assays for the presence of perinuclear anti-neutrophil cytoplasmatic antibodies (pANCA), antibodies against (ASCA) and serum agglutinating antibodies to anaerobic coccoid rods were studied. Sensitivity, specificity, predictive values and likelihood ratios of each of these serological tests were determined.In supporting the diagnosis of ulcerative colitis, the sensitivity and specificity of the pANCA test were 63% and 86%, respectively. The ASCA test (immunoglobulin A or immunoglobulin G positive) for diagnosing Crohn's disease had a sensitivity of 72% and a specificity of 82%. The sensitivity of antibodies to anaerobic coccoid rods in diagnosing Crohn's disease was 52%, whereas specificity was 90%. A combination of pANCA-positive and ASCA-negative results in the case of ulcerative colitis showed a sensitivity and specificity of 51% and 94%, respectively. However, for ASCA-positive and pANCA-negative results in the case of Crohn's disease, sensitivity was 64% and specificity was 94%. The combination of all three tests increased positive predictive value and specificity to 100% for both ulcerative colitis and Crohn's disease. In Crohn's disease patients, positive pANCA was correlated with colonic involvement. No correlation was found between the presence of any of these antibodies and disease activity, duration and behaviour or medical treatment.The value of these serological tests in differentiating ulcerative colitis from Crohn's disease is limited when used separately but, by combining two or more tests, the positive predictive value and specificity can be improved substantially. These tests might be of help in studying disease heterogeneity, and may contribute to defining various subgroups of patients with different pathogeneses.

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 (

Radiofrequency Ablation /Endoscopic Resection for Barrett’s Esophagus With High-Grade Dysplasia and/or Early Cancer: Durability of the Post-Treatment Neosquamous Epithelium At 5-Year Follow-Up Kai Yi N. Phoa, Roos E. Pouw, Frederike G. Van Vilsteren, Carine Sondermeijer, Lorenza Alvarez Herrero, Fiebo J. Ten Kate, Mike Visser, Mark I. Van Berge Henegouwen, Bas L. Weusten, Rosalie C. Mallant-Hent, Jacques J. Bergman Gastroenterology, Academic Medical Center, Amsterdam, Netherlands; Gastroenterology, St Antonius hospital, Nieuwegein, Netherlands; Pathology, Academic Medical Center, Amsterdam, Netherlands; Surgery, Academic Medical Center, Amsterdam, Netherlands; Gastroenterology, Flevoziekenhuis, Almere, Netherlands Background: Radiofrequency ablation (RFA) is safe and effective for complete eradication of Barrett’s esophagus (BE) with high-grade dysplasia (HGD) and/or early cancer (EC), and may be safely preceded by focal endoscopic resection (ER) to remove visible lesions. Less is known regarding the long-term (5-year) durability of the neosquamous epithelium (NSE) that repopulates the esophagus after RFA. Aim: In a prospective cohort of BE patients with HGD/EC, all of whom achieved complete epithelial reversion after RFA /focal ER at 1-year follow-up, we assessed the 5-year durability of the treatment response. Methods: At study entry, patients had BE 10cm with HGD or EC( T1sm1) confirmed by an expert pathologist. We removed visible lesions with focal ER, followed by repeat biopsy to establish the post-ER diagnosis. We performed RFA at 2-month intervals until all Barrett’s mucosa was visibly eradicated. Annually thereafter we performed high-resolution endoscopy with NBI, taking biopsies (4Q/2cm) from the NSE above the top of the gastric folds. Additionally, biopsies were obtained distal to the neosquamocolumnar junction (gastric cardia, analyzed separately). During and after treatment patients received high-dose PPI maintenance medication. Primary outcomes: 1) complete histological remission of HGD/EC (CR-neo), 2) complete histological remission of intestinal metaplasia (CR-IM) in esophageal biopsies. Secondary outcome: presence of IM in biopsies from the gastric cardia. Results: Twenty-three patients were analyzed (17 men, mean age 63.4, median BE C4M7). Entry ER was performed in 13 patients for lesions showing: EC (n 4), HGD (n 6) or LGD (n 3). Worst grade post-ER (pre-RFA): HGD(n 20), LGD(n 3). All patients achieved CR-neo/CR-IM at 1-year (2 required focal escape ER). Three patients exited the study at 16, 28 and 44 mo due to unrelated comorbidity. All were CR-neo/CR-IM at last follow-up. Median follow-up (n 23) since study entry was 52 mo (IQR 44-55). Follow-up endoscopy with biopsies was performed a median of 5 (IQR 4-5) times per patient (mean 77 38 biopsies per pt (61 NSE, 17 cardia)). All patients (n 23, 100%) demonstrated sustained CR-neo and CR-IM at every biopsy session during follow-up. None of the 1780 NSE biopsies demonstrated subsquamous IM. In 37 of the 379 gastric cardia biopsies (9 pts) focal non-dysplastic IM was detected (not treated). Conclusion: We have previously reported that RFA /focal ER for BE with HGD and/or EC is safe and effective, resulting in 100% CR-neo and CRIM at 1-year. The results of the present long-term follow-up of this cohort suggest that the histologically normal NSE achieved after treatment at 1-year is further durable at 5-year follow-up. No patient in this cohort developed invasive cancer or sustained BE-related morbidity. The clinical relevance of focal IM in a normal appearing cardia remains unknown.