Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: a prospective cohort study.

OBJECTIVE: The risk of developing adenocarcinoma in non-dysplastic Barrett's 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 Barrett's 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 Barrett's 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 Barrett's 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, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

Validation of the Prague C&M classification of Barrett's esophagus in clinical practice.

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.

Endoscopic trimodal imaging detects colonic neoplasia as well as standard video endoscopy.

BACKGROUND & AIMS: Endoscopic trimodal imaging (ETMI) is a novel endoscopic technique that combines high-resolution endoscopy (HRE), autofluorescence imaging (AFI), and narrow-band imaging (NBI) that has only been studied in academic settings. We performed a randomized, controlled trial in a nonacademic setting to compare ETMI with standard video endoscopy (SVE) in the detection and differentiation of colorectal lesions. METHODS: The study included 234 patients scheduled to receive colonoscopy who were randomly assigned to undergo a colonoscopy in tandem with either ETMI or SVE. In the ETMI group (n=118), first examination was performed using HRE, followed by AFI. In the other group, both examinations were performed using SVE (n=116). In the ETMI group, detected lesions were differentiated using AFI and NBI. RESULTS: In the ETMI group, 87 adenomas were detected in the first examination (with HRE), and then 34 adenomas were detected during second inspection (with AFI). In the SVE group, 79 adenomas were detected during the first inspection, and then 33 adenomas were detected during the second inspection. Adenoma detection rates did not differ significantly between the 2 groups (ETMI: 1.03 vs SVE: 0.97, P=.360). The adenoma miss-rate was 29% for HRE and 28% for SVE. The sensitivity, specificity, and accuracy of NBI in differentiating adenomas from nonadenomatous lesions were 87%, 63%, and 75%, respectively; corresponding values for AFI were 90%, 37%, and 62%, respectively. CONCLUSIONS: In a nonacademic setting, ETMI did not improve the detection rate for adenomas compared with SVE. NBI and AFI each differentiated colonic lesions with high levels of sensitivity but low levels of specificity.

Barrett's esophagus surveillance in a prospective Dutch multi-center community-based cohort of 985 patients demonstrates low risk of neoplastic progression.

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).

Chromoendoscopy and narrow-band imaging compared with high-resolution magnification endoscopy in Barrett's esophagus.

BACKGROUND & AIMS: The aim of this study was to compare magnified still images obtained with high-resolution white light endoscopy, indigo carmine chromoendoscopy, acetic acid chromoendoscopy, and narrow-band imaging to determine the best technique for use in Barrett's esophagus. METHODS: We obtained magnified images from 22 areas with the 4 aforementioned techniques. Seven endoscopists with no specific expertise in Barrett's esophagus or advanced imaging techniques and 5 international experts in this field evaluated these 22 areas for overall image quality, mucosal image quality, and vascular image quality. In addition, the regularity of mucosal and vascular patterns and the presence of abnormal blood vessels were evaluated, and this was correlated with histology. RESULTS: The interobserver agreement for the 3 features of mucosal morphology with white light images ranged from kappa = 0.51 (95% confidence interval [CI]: 0.46-0.55) to kappa = 0.53 (95% CI: 0.50-0.57) for all observers, from kappa = 0.43 (95% CI: 0.33-0.54) to kappa = 0.53 (95% CI: 0.41-0.64) for experts, and from kappa = 0.51 (95% CI: 0.15-0.33) to kappa = 0.64 (95% CI: 0.58-0.70) for nonexperts. The interobserver agreement in these groups did not improve by adding one of the enhancement techniques. The yield for identifying early neoplasia with white light images was 86% for all observers, 90% for experts, and 84% for nonexperts. The addition of enhancement techniques did not improve the yield neoplasia. CONCLUSIONS: The addition of indigo carmine chromoendoscopy, acetic acid chromoendoscopy, or narrow-band imaging to white light images did not improve interobserver agreement or yield identifying early neoplasia in Barrett's esophagus.

Combining autofluorescence imaging and narrow-band imaging for the differentiation of adenomas from non-neoplastic colonic polyps among experienced and non-experienced endoscopists.

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<0.023). These figures were confirmed in the second evaluation study. CONCLUSIONS: Non-experienced endoscopists have better interobserver agreement and accuracy for AFI than for HR-WLE or NBI, indicating that AFI is easier to use for polyp differentiation in non-experienced setting. The newly developed algorithm, combining information of AFI and NBI together, had the highest accuracy and obtained equal results between experienced and non-experienced endoscopists.

Quality of Barrett's surveillance in The Netherlands: a standardized review of endoscopy and pathology reports.

OBJECTIVE: The quality of Barrett's surveillance relies on an adequate endoscopic inspection, obtaining a sufficient number of biopsy specimens, good communication of the endoscopic findings to the pathologist, and an accurate description of the histological findings by the pathologist. The aim of this study was to assess the quality of Barrett's surveillance in daily practice in The Netherlands. MATERIALS AND METHODS: A structured scoring list was developed to evaluate systematically the quality of endoscopy and pathology reports. From 15 hospitals, endoscopy reports and corresponding pathology reports were selected randomly and evaluated by two observers. In case of disagreement, the observers re-evaluated the reports in a consensus meeting. RESULTS: One hundred and fifty cases were evaluated. The adherence to current standard biopsy protocols (four quadrant biopsies every 2 cm) decreased with increasing Barrett's length: 0-5 cm: 79%; 5-10 cm: 50%; 10-15 cm: 30%. The indication for the endoscopy was mentioned in 28% of the pathology reports, in 4% the presence/absence of oesophagitis was communicated, and in 19% the location and/or aetiology of biopsies was described. The presence/absence of dysplasia was mentioned in 93% of pathology reports. CONCLUSION: Endoscopy reports and pathology reports in current practice do not include all relevant information for an adequate Barrett's surveillance. In short Barrett's oesophagus, the adherence to current standard biopsy protocols is acceptable, but in longer segments (with a higher risk for neoplastic progression) this is clearly insufficient. The communication between endoscopists and pathologist is suboptimal.

MR Enteroclysis of inflammatory small-bowel diseases.

OBJECTIVE: MR enteroclysis has been introduced in the workup of small-bowel diseases. The major advantage of this technique over others is the combined visualization of luminal, mural, and extramural abnormalities. In this article we propose an MR enteroclysis protocol, present a stepwise approach for evaluation of these examinations, and discuss the different inflammatory conditions that can be detected. CONCLUSION: MR enteroclysis can be considered the current first-line imaging technique for inflammatory small-bowel disorders.

Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus.

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 cm(2) (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.

[Hepatic encephalopathy following a Whipple operation]. / Hepatische encefalopathie na een whipple-operatie.

A 65-year-old woman was admitted to our hospital with progressive confusion and hypersomnia. During admission she became comatose which was found to be caused by hepatic encephalopathy. Fifteen years earlier she had undergone a Whipple's pancreaticoduodenectomy for an adenocarcinoma of the pancreatic head. She had developed secondary endo- and exocrine pancreas insufficiency and a fatty liver. Non-alcoholic fatty liver disease (NAFLD) is a little-known late complication of a pancreaticoduodenectomy, possibly caused by postoperative exocrine pancreas insufficiency. NAFLD may lead to non-alcoholic steatohepatitis (NASH) which can ultimately result in liver cirrhosis. There have been no previous reports in the literature of hepatic encephalopathy presenting as liver failure secondary to NASH following pancreaticoduodenectomy.