Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus.

BACKGROUND & AIMS: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. METHODS: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. RESULTS: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). CONCLUSIONS: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and meta-analysis.

BACKGROUND & AIMS: Central adiposity has been implicated as a risk factor for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), possibly promoting the progression from inflammation to metaplasia and neoplasia. We performed a systematic review and meta-analysis of studies to evaluate the association between central adiposity and erosive esophagitis (EE), BE, and EAC, specifically exploring body mass index (BMI)-independent and gastroesophageal reflux (GERD)-independent effects of central adiposity on the risk of these outcomes. METHODS: We performed a systematic search of multiple databases through March 2013. Studies were included if they reported effect of central adiposity (visceral adipose tissue area, waist-hip ratio, and/or waist circumference) on the risk of EE, BE, and EAC. Summary adjusted odds ratio (aOR) estimates with 95% confidence intervals (CIs), comparing highest category of adiposity with the lowest category of adiposity, were calculated by using random-effects model. RESULTS: Forty relevant articles were identified. Compared with patients with normal body habitus, patients with central adiposity had a higher risk of EE (19 studies; aOR, 1.87; 95% CI, 1.51-2.31) and BE (17 studies; aOR, 1.98; 95% CI, 1.52-2.57). The association between central adiposity and BE persisted after adjusting for BMI (5 studies; aOR, 1.88; 95% CI, 1.20-2.95). Reflux-independent association of central adiposity and BE was observed in studies that used GERD patients as controls or adjusted for GERD symptoms (11 studies; aOR, 2.04; 95% CI, 1.44-2.90). In 6 studies, central adiposity was associated with higher risk of EAC (aOR, 2.51; 95% CI, 1.54-4.06), compared with normal body habitus. CONCLUSIONS: On the basis of a meta-analysis, central adiposity, independent of BMI, is associated with esophageal inflammation (EE), metaplasia (BE), and neoplasia (EAC). Its effects are mediated by reflux-dependent and reflux-independent mechanisms.

Progress in Screening for Barrett's Esophagus: Beyond Standard Upper Endoscopy.

The rapid increase in the incidence of esophageal adenocarcinoma in Western populations over the past 4 decades and its associated poor prognosis, unless detected early has generated great interest in screening for the precursor lesion Barrett's esophagus (BE). Recently, there have been significant developments in imaging-based modalities and esophageal cell-sampling devices coupled with biomarker assays. In this review, the authors discuss the rationale for screening for BE and the factors to consider for targeting the at-risk population. They also explore future avenues for research in this area.

Influence of reflux and central obesity on intercellular space diameter of esophageal squamous epithelium.

BACKGROUND: While central obesity increases gastroesophageal reflux (GER) by mechanically disrupting the anti-reflux barrier, limited data exist on pathways by which central obesity may potentiate esophageal injury by non-mechanical means. Obesity has been associated with an impaired epithelial intestinal barrier. OBJECTIVE: We aimed to assess the influence of central obesity and reflux on the squamous esophageal epithelial intercellular space diameter (ICSD). METHODS: The ICSD was measured using electron microscopy in esophageal biopsies from individuals who underwent ambulatory pH monitoring and endoscopy. Anthropometric measurements were obtained on all participants. Participants were classified into four groups: with and without central obesity and reflux. RESULTS: Sixteen individuals were studied with four in each study group. The mean ICSD was almost three-fold greater (p < 0.001) in the group with central obesity without reflux, compared to controls without central obesity and reflux. It was also comparable to the ICSD in groups with acid reflux only and those with both reflux and central obesity. CONCLUSIONS: There is evidence of esophageal squamous ICSD increase in individuals with central obesity who do not have evidence of acid and nonacid reflux on ambulatory pH monitoring. This may reflect a mechanism by which central obesity potentiates reflux-induced esophageal injury and inflammation.