Su1928 Chemerin Is Associated With the Risk of Colorectal Adenoma and Promotes the Proliferation of Colorectal Cancer Cell

Survival in BMI>25 versus normal BMI: a meta-analysis Su1926 Long-Term Treatment With a Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin, Suppresses Intestinal Tumors in Models of Diabetes and Obesity Kaori Fujiwara, Naoki Yorifuji, Sadaharu Nouda, Kazuki Kakimoto, Toshihiko Okada, Ken Kawakami, Toshihisa Takeuchi, Takuya Inoue, Kazuhide Higuchi Survival in overweight versus normal weight: a meta-analysis Background: The association between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. It is also known that a high fat diet (HFD) promotes insulin resistance which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used clinically in diabetes therapy to prolong the effects of glucagon-like peptide-1 (GLP-1). Since the intestinotrophic hormone GLP-2 and chemokines such as CXCL5 and CXCL12/stromal cell-derived factor-1 (SDF-1) (which are related to tumor progression) are also substrates of DPP-4, DPP-4 inhibitors may enhance intestinal tumorigenesis. However, the influence of long term administration of DPP-4 inhibitors on intestinal neoplasia in patients with type-2 diabetes is unknown. Material and Methods: As we previously reported, the mucosal DPP-4 mRNA expression and DPP activity is quite different between the small and the large intestine. Therefore we used two different kinds of models, one was APCMin/+ mouse, used as a model of small intestinal tumors, and the other was leptin-deficient (ob/ob) C57BL/6J mouse, which received 1,2-dimethlhydrazine (DMH) and dextran sulfate sodium (DSS), as a model of large intestinal tumors. DMH was administered at a dose of 20mg/kg body weight subcutaneously three times within a week, and then chronic colitis was induced by the administration of two cycles of DSS (each cycle: 3% DSS for 7 days followed by distilled water for 14 days). Ob/ob mice were sacrificed 28 days after the completion of both cycles of DSS. APCMin/+ mice were fed a HFD (60 kcal fat) for nine weeks. To evaluate the effect of long-term administration of a DPP-4 inhibitor, sitagliptin (STG; 3mg/day) was given to both mice models by oral gavage during the entire experimental period. Results: The administration of STG suppressed the number of intestinal tumors although not significantly in APCMin/+ mice. In APCMin/+ mice, the administration of STG suppressed the level of plasma CXCL5 and SDF-1 which were significantly elevated in mice fed a HFD, suggesting that STG administration improved the metabolic status. The mucosal concentration of total GLP-2 was significantly increased in mice fed a HFD, and was decreased by the administration of STG. In ob/ob mice, the mucosal concentration of GLPs and plasma levels of SDF-1 were not affected by the administration of STG. However, the number of tumors were significantly suppressed by the administration of STG. Real-time PCR analysis revealed that colonic mucosal IL-6 mRNA expression, which was up-regulated in the ob/ ob mice, was significantly suppressed by the long-term administration of STG. Conclusion: The long-term administration of a DPP-4 inhibitor suppressed intestinal tumors regardless of whether the metabolic status was altered or not. DPP-4 inhibitors may suppress intestinal tumorigenesis independent of DPPs substrates.

Su1928 Chemerin Is Associated With the Risk of Colorectal Adenoma and Promotes the Proliferation of Colorectal Cancer Cell Makoto Yagi, Yu Sasaki, Yasuhiko Abe, Takeshi Sato, Daisuke Iwano, Kazuya Yoshizawa, Kazuhiro Sakuta, Shotaro Akiba, Shoichi Nishise, Yoshiyuki Ueno Metabolic syndrome has been recognized as a risk factor for colorectal adenoma and cancer. We have previously shown that insulin resistance, an increased visceral fat, hypoadiponectinemia, and low-grade systemic inflammation as assessed by serum IL-6 levels are associated with the risk of colorectal adenoma. Furthermore, we reported that serum concentrations of chemerin, a novel adipokine, are increased in patients with colorectal adenoma and are correlated with the number of adenomas. However, the role of chemerin in human colorectal adenoma and cancer is remains unclear. We hypothesize that chemerin affects the development of colorectal adenoma and cancer. Methods: We conducted a prospective study of 80 male subjects without any adenoma lesions in the entire colorectum, which was confirmed by total colonoscopy as a part of health check-ups at Tohoku Central Hospital between 2008 and 2009. They were prospectively followed by total colonoscopy at least once more until December 2014. Based on median levels of serum chemerin (4.2 ng/ml) at base line, they were divided into two groups. The incidence of colorectal adenoma was evaluated using the Kaplan-Meier method and log-rank tests. Hazard ratios (HRs) were calculated for the occurrence of adenoma by the Cox proportional Hazard model. In vitro, colon cancer cell line (HT-29) was treated with chemerin and cell proliferation was assessed by WST-1 assay. Results: In the high-chemerin group, the mean levels of weight, waist circumference, serum levels of insulin, values of homeostasis model assessment of insulin resistance (HOMAIR), and proportion of metabolic syndrome tended to be higher than those in the lowchemerin group. The mean observational period of this prospective study was 48 months. Colorectal adenoma was newly detected in 18 subjects in the high-chemerin group and in 6 patients in the low-chemerin group ( p < 0.01). High chemerin levels had significant effects on the risk for colorectal adenoma (HRs 2.93; 95% CI, 1.11-7.68) after adjustment for age, waist circumstance, HOMA-IR, and status of being a current smoker. In addition, HT-29 cell proliferation was promoted by chemerin exposure ( p < 0.01). In conclusion, our present study suggested that chemerin could play an important promotional role in the development of colorectal adenoma and cancer. These findings may offer new insight into understanding the relationship between chemerin and colorectal carcinogenesis.

Su1927 The Influence of Overweight and Obesity on Survival in Gastric Cancer: A Systematic Review and Meta-Analysis Sashidhar Manthravadi, Raj Shah, Sravan Jeepalyam, Madhusudhana Sheshadri

Su1929

Background: Overweight and obesity have been described to be risk factors for gastric cancer in epidemiologic studies. Body mass index (BMI) is a known prognostic indicator in several other malignancies. It also affects outcomes in the immediate post-operative setting in patients with gastric cancer but studies describing the impact of overweight and obesity on longterm outcomes have had varying results. Methods: A systematic search of PubMed and Embase was performed to identify studies which described outcomes in gastric cancer patients who had elevated BMI in comparison with those who were of normal weight. Pooled hazard ratio (HR) with 95% confidence intervals for overall survival (OS) was estimated using the random effects model. Outcomes in gastric cancer were ascertained for three different groups namely high BMI (BMI>25), overweight (BMI 25-30) and obesity (BMI>30). Results: After reviewing 987 abstracts, 15 studies which met inclusion criteria were selected. A total of 16,461 patients with gastric cancer were followed in these studies of whom 4063 patients had a BMI greater than 25. 14 studies reported hazard ratios for outcomes in patients with BMI >25 but further stratification on the basis of overweight and obesity was only performed in 3 and 4 studies respectively. Meta-analysis of 14 studies which included 16,336 patients showed that high BMI (>25) was associated with improved outcomes in comparison with controls (HR 0.88; 95% CI 0.78-0.99). Substantial heterogeneity was noted

Sarcopenia Is an Independent Risk Factor for Advanced Colorectal Adenoma Youn Su Park, Ji Won Kim, Byeong Gwan Kim, Kook Lae Lee, Seong-Joon Koh Background/Aims Although sarcopenia is associated with the increased risk of mortality after curative resection of colorectal cancer, its influence on the development of advanced colonic neoplasia including colorectal cancer remains unclear. We investigated the effect of sarcopenia on the development of advanced colorectal neoplasia in the general population. Methods This is a cohort study of 1278 subjects aged between 40 and 79 years undergoing first time screening colonoscopies at Boramae Health Care Center from January 2010 to February 2015. Skeletal muscle index (SMI) was measured by Inbody 720 (direct segmental multi-frequency bioelectrical impedance analysis method, DSM-BIA), a body composition analyzer. Multiple logistic regression analysis was performed to determine whether sarcopenia is an independent risk factor for advanced adenoma. Results Of 1278 subjects, 69 had advanced colorectal adenoma (5.3%). According to the SMI, 249 subjects (19.4%) had sarcopenia. In the univariate analysis, advanced adenoma group is older ( P<0.001) and the prevalence of male gender ( P=0.014), hypertension (P=0.031), and sarcopenia (P<0.001) were higher than in those without advanced adenoma. According to the multiple logistic

S-591

X : 10052$CH01 03-28-16 00:57:27 PDFd : 10052B : o

Page 591

AGA Abstracts

AGA Abstracts

in this meta-analysis (I2= 64%, P= 0.0005). These findings remained unchanged even after meta-analysis was restricted to studies which included patients with resected gastric cancer (11 studies, HR 0.85, 95% CI 0.73- 0.99). When obesity and overweight were reviewed separately, the survival benefit of excessive body weight was restricted to patients who were overweight (HR 0.75; 95% CI 0.59- 0.95, I2= 20%). Obesity was not a prognostic indicator as seen in a meta-analysis of 4 studies (HR 0.97; 95%CI 0.76- 1.24, I2= 0%). Conclusions: In contrast to several other malignancies, high BMI is associated with improved survival in patients with gastric cancer. However, this benefit appears to be restricted to patients who are overweight and does not extend to those who are obese. We hypothesize that the high heterogeneity in the meta-analysis for BMI> 25 versus controls may be secondary to variation in the proportion of overweight and obese patients across the included studies. Further studies are required to evaluate treatment-related factors and variation in tumor biology in overweight and obese patients that may explain these findings.

sites currently participating in an ongoing phase 3 mesalamine study in children and adolescents with UC (NCT02093663). Questions addressed: 1) the number and proportion of pediatric UC patients (pts) treated with 5-ASA at each site, and the disease status for pts 5 to <12 y and 12 to <18 y of age; 2) familiarity with placebo-controlled randomized withdrawal studies; 3) acceptability of placebo-controlled randomized withdrawal studies for pediatric UC pts; and 4) willingness to participate in such studies and reasons for declining. RESULTS: A total of 27 responses were received: 17 completed the survey (CS) and 10 declined to complete the full survey (DS) considering placebo-controlled randomized withdrawal studies to be unethical in pediatric UC pts. Sixteen of 17 (94%) CS respondents stated that they were familiar with placebo-controlled randomized withdrawal studies. Of 27 total CS and DS respondents, 21 (78%) found such studies to be unethical. Other reasons mentioned for not wanting to participate in pediatric placebo-controlled randomized withdrawal studies included: challenges obtaining parental assent/pt consent (52%); significant regulatory agency and/or Ethics Committee/Institutional Review Board issues (43%); availability of other efficacious drugs (29%); and reasons not listed (10%). Placebo-controlled randomized withdrawal studies with 5-ASA in pediatric UC pts was deemed acceptable in 5 respondents, and 1 additional respondent felt that these studies were only appropriate in children 12 to <18 y of age. The median (range) number of pts with UC treated at each site in the 5 to <12 y and 12 to <18 y age groups was 20 (2-125) and 40 (14-200), respectively, and the proportion of these pts treated with mesalamine was 70% and 77%, respectively. Out of all mesalaminetreated pts, 86% and 85% were in remission, respectively. CONCLUSION: A large majority of surveyed physicians considered placebo-controlled randomized withdrawal studies of 5ASA for pediatric UC either unethical and/or unacceptable. Consequently, the enrollment of pediatric pts with UC into such studies will be difficult and possibly not feasible.