Marjolein Sikkema

Risk of esophageal adenocarcinoma and mortality in patients with Barrett's esophagus: a systematic review and meta-analysis.

BACKGROUND & AIMS As the risk of esophageal adenocarcinoma (EAC) and mortality in patients with Barretts esophagus (BE) are important determinants of the potential yield and cost-effectiveness of BE surveillance, clarification of these factors is essential. We therefore performed a systematic review and meta-analysis to determine the incidence of EAC and mortality due to EAC in BE under surveillance. METHODS Databases were searched for relevant cohort studies in English language that reported EAC risk and mortality due to EAC in BE. Studies had to include patients with histologically proven BE, documented follow-up, and histologically proven EAC on surveillance. A random effects model was used with assessment of heterogeneity by the I(2)-statistic and of publication bias by Beggs and Eggers tests. RESULTS Fifty-one studies were included in the main analysis. The overall mean age of BE patients was 61 years; the mean overall proportion of males was 64%. The pooled estimate for EAC incidence was 6.3/1000 person-years of follow-up (95% confidence interval, 4.7-8.4) with considerable heterogeneity (P < .001; I(2) = 79%). Nineteen studies reported data on mortality due to EAC. The pooled incidence of fatal EAC was 3.0/1000 person-years of follow-up (95% confidence interval, 2.2-3.9) with no evidence for heterogeneity (P = .4; I(2) = 7%). No evidence of publication bias was found. CONCLUSIONS Patients with BE are at low risk of malignant progression and predominantly die due to causes other than EAC. This undermines the cost-effectiveness of BE surveillance and supports the search for valid risk stratification tools to identify the minority of patients that are likely to benefit from surveillance.

Predictors for neoplastic progression in patients with Barrett's Esophagus: a prospective cohort study

OBJECTIVES:Patients with Barretts esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EAC). As the absolute risk remains low, there is a need for predictors of neoplastic progression to tailor more individualized surveillance programs. The aim of this study was to identify such predictors of progression to high-grade dysplasia (HGD) and EAC in patients with BE after 4 years of surveillance and to develop a prediction model based on these factors.METHODS:We included 713 patients with BE (≥2 cm) with no dysplasia (ND) or low-grade dysplasia (LGD) in a multicenter, prospective cohort study. Data on age, gender, body mass index (BMI), reflux symptoms, tobacco and alcohol use, medication use, upper gastrointestinal (GI) endoscopy findings, and histology were prospectively collected. As part of this study, patients with ND underwent surveillance every 2 years, whereas those with LGD were followed on a yearly basis. Log linear regression analysis was performed to identify risk factors associated with the development of HGD or EAC during surveillance.RESULTS:After 4 years of follow-up, 26/713 (3.4%) patients developed HGD or EAC, with the remaining 687 patients remaining stable with ND or LGD. Multivariable analysis showed that a known duration of BE of ≥10 years (risk ratio (RR) 3.2; 95% confidence interval (CI) 1.3–7.8), length of BE (RR 1.11 per cm increase in length; 95% CI 1.01–1.2), esophagitis (RR 3.5; 95% CI 1.3–9.5), and LGD (RR 9.7; 95% CI 4.4–21.5) were significant predictors of progression to HGD or EAC. In a prediction model, we found that the annual risk of developing HGD or EAC in BE varied between 0.3% and up to 40%. Patients with ND and no other risk factors had the lowest risk of developing HGD or EAC (<1%), whereas those with LGD and at least one other risk factor had the highest risk of neoplastic progression (18–40%).CONCLUSIONS:In patients with BE, the risk of developing HGD or EAC is predominantly determined by the presence of LGD, a known duration of BE of ≥10 years, longer length of BE, and presence of esophagitis. One or combinations of these risk factors are able to identify patients with a low or high risk of neoplastic progression and could therefore be used to individualize surveillance intervals in BE.

Aneuploidy and overexpression of Ki67 and p53 as markers for neoplastic progression in Barrett's esophagus: A case-control study

OBJECTIVES:Surveillance of patients with Barretts esophagus (BE) aims at early detection and treatment of neoplastic changes, particularly esophageal adenocarcinoma (EAC). The histological evaluation of biopsy samples has its limitations, and biomarkers may improve early identification of BE patients at risk for progression to EAC. The aim of this study was to determine the predictive value of p53, Ki67, and aneuploidy as markers of neoplastic progression in BE.METHODS:A total of 27 BE patients with histologically proven progression to high-grade dysplasia (HGD) or EAC (cases) and 27 BE patients without progression (controls) were selected and matched for age, gender, and duration of follow-up. Dysplasia grade was determined in 212 biopsy samples obtained during surveillance endoscopies from cases and in 231 biopsy samples collected from controls. DNA ploidy status was determined by flow cytometry, whereas Ki67 and p53 expression was determined by immunohistochemistry. Hazard ratios (HRs) were calculated by Cox regression adjusted for potentially confounding variables.RESULTS:A univariate analysis showed that low-grade dysplasia (LGD) increased the risk of developing HGD/EAC compared with no dysplasia (HR 3.6; 95% confidence interval (CI): 1.6 – 8.1). Aneuploidy (HR 3.5; 95% CI: 1.3–9.4), strong Ki67 overexpression (HR 5.2; 95% CI: 1.5–17.6), and moderate p53 overexpression (HR 6.5; 95% CI: 2.5–17.1) were also associated with an increased risk of developing HGD/EAC, independent of the histological result. A multivariable analysis showed that in the presence of LGD, p53 overexpression, and to a lesser extent, Ki67 overexpression remained important risk factors for neoplastic progression, whereas aneuploidy was no longer predictive.CONCLUSIONS:p53 overexpression and, to a lesser extent, Ki67 overexpression could predict neoplastic progression in BE irrespective of the histological result. These markers may be useful for identifying patients at an increased risk of developing EAC, either alone or used as a panel.

Biomarker-based prediction of inflammatory bowel disease-related colorectal cancer: a case-control study.

BackgroundRegular colonoscopic surveillance for detection of dysplasia is recommended in longstanding inflammatory bowel disease (IBD), however, its sensitivity is disputed. Screening accuracy may increase by using a biomarker-based surveillance strategy.MethodsA case-control study was performed to determine the prognostic value of DNA ploidy and p53 in IBD-related neoplasia. Cases with IBD-related colorectal cancer (CRC), detected in our surveillance program between 1985-2008, were selected and matched with two controls, for age, gender, disease characteristics, interval of follow-up, PSC, and previous surgery. Biopsies were assessed for DNA ploidy, p53, grade of inflammation and neoplasia. Progression to neoplasia was analyzed with Cox regression analysis, adjusting for potentially confounding variables.ResultsAdjusting for age, we found statistically significant Hazard ratios (HR) between development of CRC, and low grade dysplasia (HR5.5; 95%CI 2.6-11.5), abnormal DNA ploidy (DNA index (DI) 1.06-1.34, HR4.7; 95%CI 2.9-7.8 and DI>1.34, HR6.6; 95%CI 3.7-11.7) and p53 immunopositivity (HR3.0; 95%CI 1.9-4.7) over time. When adjusting for all confounders, abnormal DNA ploidy (DI 1.06-1.34, HR4.7; 95%CI 2.7-7.9 and DI>1.34, HR5.0; 95%CI 2.5-10.0) and p53 immunopositivity (HR1.7; 95%CI 1.0-3.1) remained statistically significant predictive of neoplasia. ConclusionIn longstanding IBD, abnormal DNA ploidy and p53 immunopositivity are important risk factors of developing CRC. The yield of surveillance may potentially increase by adding these biomarkers to the routine assessment of biopsies.