Anamay N. Sharma

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 Barretts 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.

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 Barretts 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.

Strategy for prevention of cancers of the esophagus

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the animal reflux–inflammation models for Barretts esophagus and esophageal adenocarcinoma; genomic/epigenomic analyses; eflornithine‐based combinations; the molecular derangements that promote neoplastic transformation; the role of COX‐2 inhibitors, proton pump inhibitors, and phase II trials in Barretts adenocarcinoma; statins in chemoprevention and treatment of esophageal cancer; and biomarkers as potential targets in Barretts adenocarcinoma.

Translational research on Barrett's esophagus

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on translational research on Barretts esophagus that address evidence for genetic instability in esophageal cancer; the role of microsatellite instability; the use of histologic and serum Doublecortin‐like kinase 1 expression for progression of Barretts esophagus to adenocarcinoma; the oxidative stress in Barretts tumorigenesis; the genomic alterations in esophageal cancer; in vivo modeling in Barretts esophagus; epigenetic and transcriptional regulation in Barretts esophagus and esophageal adenocarcinoma; and normal and disordered regeneration in Barretts esophagus.

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.

Inflammation, Obesity, Barrett’s Esophagus, and Esophageal Adenocarcinoma

Esophageal adenocarcinoma arising in metaplastic Barrett’s esophagus is one of the most rapidly increasing cancers in Western countries. Accumulating epidemiological evidence provides support that both chronic reflux injury and being overweight are strongly associated with the risk of esophageal adenocarcinoma. It is proposed that being overweight could contribute to increased predisposition to reflux by mechanically disrupting the physiological mechanisms that prevent reflux injury to the esophagus. Furthermore, mechanistic investigations also provide a link between being overweight to the risk of esophageal adenocarcinoma through increased loco-systemic injury response and metabolic syndrome. Together these observations provide the basis for the hypothesis that being overweight could be a key early trigger for the initiation and an ongoing stimulus for the progression of esophageal adenocarcinoma. In this chapter we will summarize the existing data that supports this hypothesis and discuss ongoing and future investigations to address this hypothesis that links obesity to risk of esophageal adenocarcinoma.

Sa1965 Garcinol Interferes With Oncogenic IL1b-STAT3 and Facilitates Tumor Suppressive KLF11-Sin3A to Down-Regulate AKT1 Expression and Cell Growth in Barrett's Epithelium

ESR2 physical interactions. Surprisingly, our preliminary results showed an upregulation in EGFR signals in ERB041 treated ESR2 transfectants. Summary: In AA with adenomas, reductions in ESR2 expression might contribute to higher colon cancer incidence and worse prognosis. The in vitro studies confirmed that ESR2 suppresses colon cancer cell proliferation. We postulate that the antiproliferative effects of ESR2 involve miR-145 dependent, EGFRindependent pathways. Our study suggests that ESR2 down-regulation might play an important role in colon cancer risk and contribute to racial differences in cancer progression.

Tu1218 Prostaglandin E2 Levels Are Not Elevated in Mucinous Pancreatic Cysts

branch duct (n = 20), main duct (n = 4), mixed type (n = 8). LGD was present in 5 patients, MD in 17 patients, HGD in 9 patients, and invasive cancer in 1 patient. HMGA2 protein was detected in the cyst fluid of 30/32 (94%) specimens. Mean HMGA2 concentration (ng/ ml): LGD 0.52 ± 0.40, MD 2.56 ± 2.52, HGD 10.5 ±15.22 (p , 0.05). No HMGA2 was detected in the one sample from IPMNwith invasive cancer. Themean HMGA2 concentration was significantly higher in the HGD group (10.5 ± 15.22 ng/ml) compared to the concentration in the low-risk IPMN group (2.1 ± 2.38 ng/ml, p = 0.03). The ROC for HMGA2 had an area under the curve of 0.74. Conclusions: HMGA2 protein is present in the cyst fluid of IPMN. Significantly higher concentrations of cyst fluid HMGA2 proteins are found in IPMN with HGD as compared to lesions with LGD or MD. Cyst fluid concentration of HMGA2 may thus serve as a biomarker to differentiate patients with high-risk IPMN lesions from patients with low-risk IPMN lesions. Such a biomarker could help guide clinical decision making regarding which patients may benefit from surgical resection of their IPMN. Further investigation of this cyst fluid biomarker on prospectively obtained samples from EUS-FNA is warranted.

388 IL-1β-STAT3 Mediated Up-Regulation of AKT1 Expression in Barrett's Esophagus: A Potential Link Between Inflammation and Carcinogenesis

BACKGROUND AND AIM: We have recently shown that, in addition to AKT1 activation through its phosphorylation, overall increased expression of AKT1 that is observed during neoplastic progression in patients with Barretts also plays a direct role in this injury-induced oncogenesis. Since pro-inflammatory cytokine IL-1β promotes esophageal adenocarcinoma and its downstream effector STAT3 could bind to the core promoter region of AKT1, it is plausible that IL-1β-STAT3-AKT1 could link inflammation to carcinogenesis in Barretts esophagus. The aims of this study were to examine IL-1 β-STAT3 mediated regulation of AKT1 expression and explore the underlying mechanisms in Barretts epithelium. METHODS and RESULTS: Using Barretts epithelial cells, we noted that both IL-1 β and constitutively active STAT3c induced AKT1 promoter activity. Moreover, in a dose and time dependent manner IL-1β increased AKT1 mRNA expression. Similarly, constitutively active STAT3c also increased AKT1 mRNA expression. We also noted that IL-1 β increased cellular p300 levels, a histone acetyl transferase that STAT3 recruits on target promoter chromatin to activate them by acetylating histone H3. We found that while constitutively active STAT3c increased AKT1 promoter activity/expression, there was an increased acetylation of AKT1 promoter (ChIP using anti H3 K18 and 27 antibody) during neoplastic progression in Barretts epithelium. Additionally, both IL-1β and STAT3c partially interfered with repression of AKT1 promoter by anti-inflammatory transcription factor KLF11, a known recruiter of Sin3-HDAC that deacetylates and represses AKT1 promoter. Together, these findings raise a possibility that pro-inflammatory IL-1β, by simultaneously increasing p300 and STAT3 activation could direct p300 onto the AKT1 promoter to hyper acetylate and activate AKT1 promoter. Alternatively, pro-inflammatory IL-1β-pSTAT3 through antagonizing the antiinflammatory KLF11-Sin3-histone deacetylase pathway preserve AKT1 promoter acetylation to activate AKT1 promoter/expression. CONCLUSION: Our observations expose an antagonism between pro-inflammatory IL-1β-STAT3-p300 and anti-inflammatory KLF11-Sin3HDAC pathways in regulating oncogenic AKT1 during neoplastic transformation in Barretts esophagus, providing a potential link between inflammation and carcinogenesis.