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.

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).

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.

Symptoms of gastroesophageal reflux disease in severely mentally retarded people: a systematic review.

BACKGROUND: Gastroesophageal reflux disease (GERD) occurs when stomach acid frequently backs up (or refluxes) into the gullet (or esophagus), and it has serious consequences for the quality of life. Usually this is felt as heartburn. Because severely mentally retarded people usually do not utter complaints of heartburn, it requires a high index of suspicion to discover possible GERD. Therefore it is relevant for care professionals such as nurses to have knowledge of those with a higher risk of GERD and of the possible manifestations of GERD. METHODS: Using a predefined search method, electronic databases were searched for studies relating the presence of symptoms to the presence of GERD. Relevant data were extracted and the methodological quality of the studies assessed. The results of the included studies were synthesized and conclusions about the level of evidence were drawn. RESULTS: Nineteen studies were found relating symptoms to the presence of GERD. Only four were of good methodological quality. The studies were very diverse concerning the studied population, the study method, and the kind of symptoms examined. This makes it difficult to synthesize the results of the studies. There is evidence that patients with cerebral palsy, patients using anticonvulsive drugs, and those with an IQ lower than 35 more frequently have GERD. There is also evidence that vomiting, rumination and hematemesis are associated with a higher risk of the presence of GERD, whereas there is no clear scientific evidence that particular behavior symptoms are indicative for GERD. CONCLUSION: The possible manifestations of GERD are many and varied. A guideline will be made for care professionals to aid systematic observation of possible manifestations of GERD.

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.

The incidence of adenocarcinoma in Barrett's esophagus in an institutionalized population.

OBJECTIVE: To ascertain the incidence rate of adenocarcinoma in Barrett's esophagus (ACE) in a stable population of 28,000 institutionalized intellectually disabled individuals (IDI) in whom the prevalence rate of Barrett's esophagus (BE) was previously estimated in a representative sample by 24 h pH monitoring and endoscopy, and in which all cases of ACE were ascertained over a 6-year period. These IDI do not smoke or drink alcohol and are known to have exceptionally high prevalence rates of gastro-esophageal reflux disease, and consequently of BE. METHODS: A population comprising 52,038 person-years was observed and all cases of ACE were ascertained. On the basis of the representative sample, the percentage of this population with BE was estimated to be 10.8%. ACE incidence rates could then be estimated and compared with those found in a free-living BE cohort after correction for age and gender differences. RESULTS: In IDI an incidence rate of ACE of 2.5/1000 person-years was found against 6.3/1000 person-years in the free-living BE cohort. However, the age distributions of the IDI and of the free-living BE cohort were very different, and after correction for this factor there was no significantly lower incidence rate of ACE in the IDI (relative risk, 0.79; P = 0.61). CONCLUSIONS: This is the first reported incidence study of ACE in a stable, well-defined population. In contrast to squamous cell carcinoma, our findings suggest only a minor role for smoking and alcohol in the etiology of ACE.