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Summary The ReBus cohort is a matched nested case–control cohort of patients with nondysplastic (ND) Barrett’s esophagus (BE) at baseline who progressed (progressors) or did not progress (nonprogressors) to high-grade dysplasia (HGD) or cancer. This cohort is constructed using the most stringent inclusion criteria to optimize explorative studies on biomarkers predicting malignant progression in NDBE. These explorative studies may benefit from expanding the number of cases and by incorporating samples that allow assessment of the biomarker over space (spatial variability) and over time (temporal variability). To (i) update the ReBus cohort by identifying new progressors and (ii) identify progressors and nonprogressors within the updated ReBus cohort containing spatial and temporal information. The ReBus cohort was updated by identifying Barrett’s patients referred for endoscopic work-up of neoplasia at 4 tertiary referral centers. Progressors and nonprogressors with a multilevel (spatial) endoscopy and additional prior (temporal) endoscopies were identified to evaluate biomarkers over space and over time. The original ReBus cohort consisted of 165 progressors and 723 nonprogressors. We identified 65 new progressors meeting the same strict selection criteria, resulting in a total number of 230 progressors and 723 matched nonprogressors in the updated ReBus cohort. Within the updated cohort, 61 progressors and 107 nonprogressors (mean age 61 ± 10 years) with a spatial endoscopy (median level 3 [2–4]) were identified. 33/61 progressors and 50/107 nonprogressors had a median of 3 (2–4) additional temporal endoscopies. Our updated ReBus cohort consists of 230 progressors and 723 matched nonprogressors using the most strict selection criteria. In a subgroup of 168 Barrett’s patients (the SpaTemp cohort), multiple levels have been sampled at baseline and during follow-up providing a unique platform to study spatial and temporal distribution of biomarkers in BE.

Background and aimsColonoscopy is the current reference standard for the detection of colorectal neoplasia, but nevertheless adenomas remain undetected. The Endocuff, an endoscopic cap with plastic projections, may improve colonic visualisation and adenoma detection. The aim of this study was to compare the mean number of adenomas per patient (MAP) and the adenoma detection rate (ADR) between Endocuff-assisted colonoscopy (EAC) and conventional colonoscopy (CC).MethodsWe performed a multicentre, randomised controlled trial in five hospitals and included fecal immonochemical test (FIT)-positive screening participants as well as symptomatic patients (>45 years). Consenting patients were randomised 1:1 to EAC or CC. All colonoscopies were performed by experienced colonoscopists (≥500 colonoscopies) who were trained in EAC. All colonoscopy quality indicators were prospectively recorded.FindingsOf the 1063 included patients (52% male, median age 65 years), 530 were allocated to EAC and 533 to CC. More adenomas were detected with EAC, 722 vs 621, but the gain in MAP was not significant: on average 1.36 per patient in the EAC group versus 1.17 in the CC group (p=0.08). In a per-protocol analysis, the gain was 1.44 vs 1.19 (p=0.02), respectively. In the EAC group, 275 patients (52%) had one or more adenomas detected versus 278 in the CC group (52%; p=0.92). For advanced adenomas these numbers were 109 (21%) vs 117 (22%). The adjusted caecal intubation rate was lower with EAC (94% vs 99%; pInterpretationThough more adenomas are detected with EAC, the routine use of Endocuff does not translate in a higher number of patients with one or more adenomas detected. Whether increased detection ultimately results in a lower rate of interval carcinomas is not yet known.Trial registration numberhttp://www.trialregister.nlDutch Trial Register: NTR3962.

Background and study aims: The Prague C&M classification for Barrett’s esophagus has found widespread acceptance but has only been validated by Barrett’s experts scoring video sequences. To date, validation has been lacking for its application in routine practice during real-time endoscopy. The aim of this study was to evaluate agreement between Barrett’s experts and community hospital endoscopists when using this classification to describe Barrett’s esophagus and hiatal hernia length during real-time endoscopy. Patients and methods: Patients underwent two consecutive endoscopies performed by different endoscopists. The study was performed in two cohorts: one cohort was seen by Barrett’s experts and the other cohort by community hospital endoscopists. Landmarks were recorded according to the Prague classification. Outcomes were interobserver agreement (assessed with intraclass correlation coefficient [ICC]), absolute agreement, and relative agreement. Results: A total of 187 patients were included, with median extent of C3M5 (IQR C1 – 7 M4 – 9) for Barrett’s esophagus and 3 cm (IQR 2 – 5) for hiatal hernia length. ICC was 0.91 (95 % confidence interval [CI] 0.88 – 0.93) for maximum length, 0.92 (95 %CI 0.90 – 0.94) for circumferential extent, and 0.59 (95 %CI 0.49 – 0.68) for hiatal hernia length. Absolute agreement within ≤ 1 cm was 74 % (95 %CI 68 – 80) for circumference, 68 % (95 %CI 62 – 75) for length, and 63 % (95 %CI 56 – 70) for hiatal hernia length. Relative agreement was 91 % for Barrett’s esophagus and 80 % for hiatal hernia length. Barrett’s experts and community hospital endoscopists showed no differences in agreement. Shorter Barrett’s segments (≤ 5 cm) had lower agreement compared with longer segments (> 5 cm). Conclusions: Agreement was good for Barrett’s esophagus and reasonable for hiatal hernia length. These findings strengthen the value of the Prague C&M classification to describe Barrett’s esophagus and hiatal hernia length. Although absolute agreement during real-time endoscopy was high, one should anticipate that Barrett’s values may vary by 1 – 2 cm between two endoscopies.

BACKGROUND & AIMS: Radiofrequency ablation (RFA), with or without endoscopic resection effectively eradicates Barrett's esophagus (BE) containing high-grade intraepithelial neoplasia and/or early-stage cancer. We followed patients who received RFA for BE containing high-grade intraepithelial neoplasia and/or early-stage cancer for 5 years to determine the durability of treatment response.METHODS: We followed 54 patients with BE (2-12 cm), previously enrolled in 4 consecutive cohort studies in which they underwent focal endoscopic resection in case of visible lesions (n = 40 [72%]), followed by serial RFA every 3 months. Patients underwent high-resolution endoscopy with narrow-band imaging at 6 and 12 months after treatment and then annually for 5 years (median, 61 months; interquartile range, 53-65 months); random biopsy samples were collected from neosquamous epithelium and gastric cardia. After 5 years, endoscopic ultrasound and endoscopic resection of neosquamous epithelium were performed. Outcomes included sustained complete remission of neoplasia or intestinal metaplasia (IM), IM in gastric cardia, or buried glands in neosquamous epithelium.RESULTS: After 5 years, Kaplan-Meier analysis showed sustained complete remission of neoplasia and intestinal metaplasia in 90% of patients; neoplasia recurred in 3 patients and was managed endoscopically. Focal IM in the cardia was found in 19 of 54 patients (35%), in 53 of 1143 gastric cardia biopsies (4.6%). The incidence of IM of the cardia did not increase over time; and IM was diagnosed based on only a single biopsy in 89% of patients. Buried glands were detected in 3 of 3543 neosquamous epithelium biopsies (0.08%, from 3 patients). No endoscopic resection samples had buried glands.CONCLUSIONS: Among patients who have undergone RFA with or without endoscopic resection for neoplastic BE, 90% remain in remission at 5-year follow-up, with all recurrences managed endoscopically. This treatment approach is therefore an effective and durable alternative to esophagectomy; www.trialregister.nl number, NTR2938.

BACKGROUND & AIMS: Real-time differentiation of diminutive polyps (1-5 mm) during endoscopy could replace histopathology analysis. According to guidelines, implementation of optical diagnosis into routine practice would require it to identify rectosigmoid neoplastic lesions with a negative predictive value (NPV) of more than 90%, using histologic findings as a reference, and agreement with histology-based surveillance intervals for more than 90% of cases.METHODS: We performed a prospective study with 39 endoscopists accredited to perform colonoscopies on participants with positive results from fecal immunochemical tests in the Bowel Cancer Screening Program at 13 centers in the Netherlands. Endoscopists were trained in optical diagnosis using a validated module (Workgroup serrAted polypS and Polyposis). After meeting predefined performance thresholds in the training program, the endoscopists started a 1-year program (continuation phase) in which they performed narrow band imaging analyses during colonoscopies of participants in the screening program and predicted histological findings with confidence levels. The endoscopists were randomly assigned to groups that received feedback or no feedback on the accuracy of their predictions. Primary outcome measures were endoscopists' abilities to identify rectosigmoid neoplastic lesions (using histology as a reference) with NPVs of 90% or more, and selecting surveillance intervals that agreed with those determined by histology for at least 90% of cases.RESULTS: Of 39 endoscopists initially trained, 27 (69%) completed the training program. During the continuation phase, these 27 endoscopists performed 3144 colonoscopies in which 4504 diminutive polyps were removed. The endoscopists identified neoplastic lesions with a pooled NPV of 90.8% (95% confidence interval 88.6-92.6); their proposed surveillance intervals agreed with those determined by histologic analysis for 95.4% of cases (95% confidence interval 94.0-96.6). Findings did not differ between the group that did vs did not receive feedback. Sixteen endoscopists (59%) identified rectosigmoid neoplastic lesions with NPVs greater than 90% and selected surveillance intervals in agreement with those determined from histology for more than 90% of patients.CONCLUSIONS: In a prospective study following a validated training module, we found that a selected group of endoscopists identified rectosigmoid neoplastic lesions with pooled NPVs greater than 90% and accurately selected surveillance intervals for more than 90% of patients over the course of 1 year. Providing regular interim feedback on the accuracy of neoplastic lesion prediction and surveillance interval selection did not lead to differences in those endpoints. Monitoring is suggested, as individual performance varied. ClinicalTrials.gov no: NCT02516748; Netherland Trial Register: NTR4635.

Background and study aims We have recently proposed a classification of mucosal morphology in Barrett's esophagus based on three criteria: regularity of mucosal pattern, regularity of vascular pattern, and presence of abnormal blood vessels. We aimed to evaluate the interobserver agreement with the proposed mucosal morphology classification and to assess the additional value of narrow band imaging (NBI) over high resolution white light endoscopy (HR-WLE). Patients and methods Five international experts in the field of Barrett's imaging and seven community endoscopists with no expertise in this field independently evaluated magnified still images from 50 areas, obtained with HR-WLE and NBI, in Barrett's esophagus patients. Visual analogue scales (VAS) were used for scoring imaging quality. Interobserver agreement for mucosal morphology and yield for identifying early neoplasia were assessed. Results Imaging qualities of NBI were rated more highly than HR-WLE, when evaluated separately as well as in a side-by-side comparison. The interobserver agreement ranged from 0.40 to 0.56 and did not significantly differ between expert and non-expert endoscopists. The overall yield for correctly identifying images of early neoplasia was 81 % for HR-WLE, 72 % for NBI and 83 % for HR-WLE + NBI, with no significant difference between experts and non-experts. Conclusion Interobserver agreement for the classification of mucosal morphology was moderate. Although NBI was rated more highly than HR-WLE for imaging quality, this did not result in improved interobserver agreement or increased yield for identifying early neoplasia in Barrett's esophagus. This applied to non-expert as well as expert endoscopists.

Objective Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett9s oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett9s Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD. Design We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC. Results 293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16–72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively. Conclusions Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.

Background: Endoscopic trimodal imaging (ETMI) may improve detection of early neoplasia in Barrett's esophagus (BE). Studies with ETMI so far have been performed in tertiary referral settings only. Objective: To compare ETMI with standard video endoscopy (SVE) for the detection of neoplasia in BE patients with an intermediate-risk profile. Design: Multicenter, randomized, crossover study. Setting: Community practice. Patients and Methods: BE patients with confirmed low-grade intraepithelial neoplasia (LGIN) underwent both ETMI and SVE in random order (interval 6-16 weeks). During ETMI BE was inspected with high-resolution endoscopy followed by autofluorescence imaging (AFI). All visible lesions were then inspected with narrow-band imaging. During ETMI and SVE, visible lesions were sampled followed by 4-quadrant random biopsies every 2 cm. Main Outcome Measurements: Overall histological yield of ETMI and SVE and targeted histological yield of ETMI and SVE. Results: A total of 99 patients (79 men, 63 10 years) underwent both procedures. ETMI had a significantly higher targeted histological yield because of additional detection of 22 lesions with LGIN/high-grade intraepithelial neoplasia (EIGIN)/carcinoma (Ca) by AFT. There was no significant difference in the overall histological yield (targeted + random) between ETMI and SVE. HGIN/Ca was diagnosed only by random biopsies in 6 of 24 patients and 7 of 24 patients, with ETMI and SVE, respectively. Limitations: Inspection, with high-resolution endoscopy and AFT, was performed sequentially. Conclusion: ETMI performed in a community-based setting did not improve the overall detection of dysplasia compared with SVE. The diagnosis of dysplasia is still being made in a significant number of patients by random biopsies. Patients with a confirmed diagnosis of LGIN have a significant risk of HGIN/Ca. (Clinical trial registration number: ISRCTN91816824; NTR867.) (Gastrointest Endosc 2011;73:195-203.)

OBJECTIVES: Published data on the natural history of low-grade dysplasia (LGD) in Barrett's esophagus (BE) are inconsistent and difficult to interpret. We investigated the natural history of LGD in a large community-based cohort of BE patients after reviewing the original histological diagnosis by an expert panel of pathologists. METHODS: Histopathology reports of all patients diagnosed with LGD between 2000 and 2006 in six non-university hospitals were reviewed by two expert pathologists. This panel diagnosis was subsequently compared with the histological outcome during prospective endoscopic follow-up. RESULTS: A diagnosis of LGD was made in 147 patients. After pathology review, 85% of the patients were downstaged to non-dysplastic BE (NDBE) or to indefinite for dysplasia. In only 15% of the patients was the initial diagnosis LGD. Endoscopic follow-up was carried out in 83.6% of patients, with a mean follow-up of 51.1 months. For patients with a consensus diagnosis of LGD, the cumulative risk of progressing to high-grade dysplasia or carcinoma (HGD or Ca) was 85.0% in 109.1 months compared with 4.6% in 107.4 months for patients downstaged to NDBE (P

OBJECTIVES: Endoscopic tri-modal imaging incorporates high-resolution white-light endoscopy (HR-WLE), narrow-band imaging (NBI), and autofluorescence imaging (AFI). Combining these advanced techniques may improve endoscopic differentiation between adenomas and non-neoplastic polyps. In this study, we aimed to assess the interobserver variability and accuracy of HR-WLE, NBI, and AFI for polyp differentiation and to evaluate the combined use of AFI and NBI. METHODS: First, still images of 50 polyps (22 adenomas; median 3 mm) were randomly displayed to three experienced and four non-experienced endoscopists. All HR-WLE and NBI images were scored for Kudo classification and AFI images for color. Second, the combined AFI and NBI images were assessed using a newly developed algorithm by six additional non-experienced endoscopists. RESULTS: The outcomes measured were interobserver agreement and diagnostic accuracy using histopathology as reference standard. Experienced endoscopists had better interobserver agreement for NBI (kappa=0.77) than for AFI (kappa=0.33), whereas non-experienced endoscopists had better agreement for AFI (kappa=0.58) than for NBI (kappa=0.33). The accuracies of HR-WLE, NBI, and AFI among experienced endoscopists were 65, 70, and 74, respectively. Figures among non-experienced endoscopists were 57, 63, and 77. The algorithm was associated with a significantly higher accuracy of 85% among all observers (P

Background Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications. The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. Methods/design Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment. Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures. Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group. Discussion The TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas. Trial registration number (trialregister.nl) NTR1422

Background The effectiveness of colorectal cancer screening programs based on the fecal immunochemical test (FIT) is influenced by program adherence during consecutive screening rounds. We aimed to evaluate the participation rate, yield, and interval cancers in a third round of biennial CRC screening using FIT and to compare those with the first and the second screening round. Methods A total of 3566 average-risk individuals aged 50–75 years were invited to participate in a third round of biennial FIT-based CRC screening. All FIT positives were recommended to undergo colonoscopy. We merged our data with the national cancer registry in the Netherlands to identify all non-screen-detected cancers in our cohort. Results Of the invitees, 2142 (60%) returned the FIT in this third screening round, compared to 56% in the second round and 57% in the first round. Overall, 153 of the third-round participants (7.1%) had a positive FIT result, versus 7.9% in the second round and 8.1% in the first round ( P =0.05). Of all FIT positives, 123 (80%) underwent colonoscopy. Within this group, 33 persons had advanced neoplasia. The predictive value of FIT positivity for advanced neoplasia was 27% (33/123), compared to 42% in the second round and 54% in the first round – a significant decline ( P Conclusion In an FIT-based screening program, participation rates remained stable over consecutive biennial screening rounds, while the FIT positivity rate and positive predictive value for advanced neoplasia gradually declined. Cancers in non-participants are significantly more advanced in staging than cancers in participants in the first round of screening.