SM-EAC found on EMR, or the outcome of SM-EAC who did or did not have esophagectomy.Our study aimed to 1) investigate the association of SM invasion on EMR with LNM onesophagectomy specimens; and 2) the mortality of SM-EAC patients with and withoutesophagectomy. METHODS: We analyzed a retrospective cohort of 422 patients with dyspla-sia/cancer who had 1,057 EMR procedures in a tertiary Barrett's Esophagus Unit from1995 to 2010. We identified SM-EAC patients on EMR histology. Pathology reports foresophagectomy, chemoradiation and endoscopic treatment for those without esophagectomywere reviewed. The slides of the 8 cases without a precise report were reviewed by anexperienced gastrointestinal pathologist, and depth of invasion was recorded. Per patientanalysis was performed. RESULTS: A total of 68 patients had SM-EAC on EMR; mean agewas 66.5 ± 16.7 years at diagnosis; 85% were male; mean Charlson index was 4.2 ± 3.3;cumulative mortality was 23.5% after a followup of 48.0 ± 32.9 months; 35 had esophagec-tomy. Among those without esophagectomy (n=33), 9 (27.3%) had chemoradiation therapyand 23 (69.7%) continued endoscopic treatment. Among patients post esophagectomy (n=35), 10 (28.6%) had LNM .After a follow-up of 54.3 ± 38.5 months, the mortality was50.0% and 8.0% for those with and without LNM respectively (p=0.006). Multivariatelogistic regression demonstrated 1) the need of > 1 EMR sessions was associated withhigher risk of LNM (OR=7.5); 2) patients with LNM had higher mortality (OR=10.5). Coxproportional hazard (PH) model analysis showed LNM was associated with poor survival(hazard ratio=11.2). For those with and without esophagectomy, the cumulative mortalityrates after a followup of 54.3 and 41.4 months were 20.0% and 27.3% (p=0.47), respectively.Between these 2 groups, there was no statistical difference in gender, age, Charlson index,total EMR sessions, number of EMR in each EGD session, findings from the random biopsies,length of BE, presence of ulcers, nodules or diaphragmatic hernia, or survival. Esophagectomywas not associated with better survival by multivariate logistic regression (p=0.28) or Cox PHmodel analysis (p= 0.13). CONCLUSION: Among the patients with submucosal esophagealadenocarcinoma who underwent esophagectomy, about 1/3 had positive regional lymphnode metastasis. However, in our series, patients who underwent esophagectomy had similarmortality as those that did not indicating that these patients have similar outcomes.

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Contrary to Prevailing Wisdom, the Risk of Adenocarcinoma is InverselyProportional to the Number of Goblet Cells in Patients With Barrett'sEsophagusAmitabh Srivastava, Kevin Golden, Carissa A. Sanchez, Pui Yee Fong, Xiaohong Li, DavidCowan, Carlo C. Maley, Patricia L. Blount, Brian J. Reid, Robert D. Odze

Background: Most Barrett's esophagus (BE)-associated adenocarcinomas (BEA) develop incolumnar mucosa with goblet cells (GC). As a result, GC have traditionally served as abiomarker of cancer risk in this condition. However, 95% of BE patients never developBEA, and the relationship between GC density and cancer risk has never been evaluated.One recently proposed hypothesis states that GCs represent a potentially successful adaptiveresponse by producing a thick mucous barrier to acidic reflux which may protect againstcancer development, but this has never been tested. The aim of this study was to determinethe association of GC density with risk of progression to BEA, and DNA content abnormalities,the latter of which represents a major step in the BE carcinogenic pathway. Design: Baselinemucosal biopsies (N=3970) from 214 patients enrolled in a large prospective surveillancecohort of high risk BE patients (M/F ratio:170/44, mean age: 63 yrs, mean BE segmentlength: 5.7 cm) all of whom had a baseline endoscopy and at least one follow-up endoscopy(mean follow up: 90.4 months), were scored in a blinded fashion, for the total # of GCsand crypts, and the # of crypts with≥ 1 GC, in both dysplastic and non-dysplastic epithelium,to determine the mean # and % GC/crypt and the mean # and % crypts with ≥ 1 GC, ineach patient. The relationship between the GC parameters and flow cytometric abnormalities(aneuploidy, tetraploidy) was compared using Wilcoxon rank sum test, and a weighted Coxregression model was used to assess BEA risk, after adjustment for age, gender, and BEsegment length. Result: 32 patients progressed to cancer during follow up, whereas 182patients did not. Increased GCs in baseline biopsies were significantly associated withprotection from BEA when analyzed for total # of GCs, mean # GC/crypt, # crypts with ≥1 GC and % crypts with ≥ 1 GC (p<0.0001 for each comparison). GCs in non-dysplasticbiopsies specifically were similarly significant for a protective association in all comparisons(p=0.007, 0.016, 0.0070 and 0.016, respectively). High GC values in all types of crypts(dysplastic and non-dysplastic) showed a significantly lower association with aneuploidy(p=0.0016), ploidies (>2.7N; p=0.0061), and tetraploidy (elevated 4N6%; p=0.0015). Con-clusion: The results of this study show, for the first time, that GC have a protective effecton progression to BEA, and on the development of flow cytometric DNA content abnormalitiesin patients with BE. GC in BE participate in mucosal defense and represent a successfuladaptative response which offers protection against developing adenocarcinoma.

409

Relationship Between Barrett's Esophagus (BE) Length and the Risk of HighGrade Dysplasia (HGD) and Esophageal Adenocarcinoma (EAC) in PatientsWith Non Dysplastic Barrett's Esophagus Results From a Large MulticenterCohortSrinivas Gaddam, Patrick E. Young, Benjamin R. Alsop, Neil Gupta, Hemanth Gavini,April D. Higbee, Sachin B. Wani, Mandeep Singh, Amit Rastogi, Ajay Bansal, Brooks D.Cash, David A. Lieberman, Richard E. Sampliner, Gary W. Falk, Prateek Sharma

Background: There are conflicting reports regarding BE length as a risk factor for progressionto HGD and EAC with the majority of the studies not accounting for important confoundingvariables (age, race, smoking, baseline dysplasia grade, etc). Aim: In a large multicentercohort of BE patients, to quantify the risk of HGD and EAC in non-dysplastic BE (NDBE)patients based on the segment length Methods: This is a multicenter outcomes project (5tertiary referral centers) of a large cohort of BE patients. Diagnosis of BE required histologicallyconfirmed intestinal metaplasia on endoscopic biopsies of a columnar lined esophagus.Demographics, medication use, family history, BE length, and endoscopy results wererecorded. Neoplasia was graded as low-grade dysplasia (LGD), HGD and EAC. Duration offollow up was calculated from time of BE diagnosis to the most recent endoscopy with

S-81 AGA Abstracts

biopsy. Only patients with NDBE on index endoscopy with documented BE length and withat least 1 year of follow up were included in this analysis. Patients developing HGD andEAC within 1-year of BE diagnosis were considered to be prevalent cases and excluded.Annual risk of HGD/EAC in NDBE patients was plotted in 3 cm length increments. Amultivariate logistic regression model (LRM) was built using the following variables - age,race, gender and smoking history. Results: Of a total of 3599 BE patients, 1208 met theinclusion criteria [90.9% Caucasian, 88.9 % men, mean age 59.7 (SD 11.6) years, smokinghistory 46%, mean follow up 5.4 (SD 3.2) years (6639 patient-years) and mean BE length3.79 (SD 3.2) cm]. 16 patients developed EAC with an annual incidence rate of 0.24%/year, and the risk of progression to EAC was higher for patients with longer BE length(0.1% for BE length 1-3cm vs. 0.8% for BE length 7-9cm). (Table) 44 patients developedHGD/EAC with an annual incidence rate of 0.65%/year with the mean time to HGD/EACdevelopment of 4.3 years (SD 3.8). Compared to non-progressors, patients with HGD/EAChad significantly longer BE lengths (6.2 vs. 3.7 cm, p<0.01) and were more likely to besmokers (95.7% vs. 69%, p<0.01). After adjusting for age, race, gender and smoking historyon logistic regression analysis, there was a 21% increase in risk of HGD/EAC for every 1cmincrease in BE length (p=0.03) (Figure). Conclusion: Results of this analysis demonstratethat BE length is a significant predictor of progression to HGD/EAC in patients with NDBE.These findings have clinical implications when considering risk stratification models forsurveillance intervals and endoscopic treatment options for patients with BE. Specifically,the effectiveness of continued endoscopic surveillance or ablation for patients with NDBE≤3cm needs to be re-evaluated considering the low risk of progression to EAC.

Figure: Annual risk of HGD/ EAC (%/ year) in patients with NDBE (p-value for trend = 0.035)

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Suppressive Effects of Pioglitazone, a PPAR Gamma Ligand, on ColorectalCarcinogenesis Induced in Obese Kk-Ay Mice by AzoxymethaneToshiya Ueno, Michihiro Mutoh, Hitoshi Nakagama, Keiji Wakabayashi, Akinori Yanaka

Background and Aims: Obesity is one of the well-determined risk factors for colorectalcancer. Mechanisms of the development of obesity-associated cancer are considered to beinsulin resistance, chronic inflammation and dyslipidemia. We previously reported thatobese KK-Ay mice, carrying the Agouti gene (Ay), are highly susceptible to azoxymethane(AOM)-induced colorectal carcinogenesis, accompanying severe hypertriglyceridemia, hyper-insulinemia, and dysregulation of adipocytokine production. Pioglitazone (Pio) is a memberof peroxisome proliferator-activated receptor gamma (PPARγ) ligands, and used widely forthe correction of dyslipidemina and insulin resistant status. In addition, PPARγ ligandsinduce differentiation in adipocytes and induce growth arrest and/or apoptosis In Vitro inseveral cancer cells. In the present study, we examined the effects of Pio on the developmentof colorectal aberrant crypt foci (ACF) induced in obese KK-Ay mice by AOM, and tried toclarify the underlying mechanisms by which a PPARγ ligand inhibits ACF development.Methods: KK-Ay mice at 6 weeks of age were purchased and treated with AOM (200 μg/animal) once a week for 3 weeks, and fed a diet with Pio at doses of 400 and 800 ppm.All mice were sacrificed at the age of 13 weeks, colon ACFs were stained with methyleneblue, and the number of lesions were counted with a microscope. Serum adipocytokines,lipids and insulin were measured, and gene expressions of adipocytokine in adipose tissuewere also analyzed using real-time PCR. Cell proliferation of colorectal epithelial cells wasevaluated immunohistochemically by staining of proliferation cell nuclear antigen (PCNA),and cell cycle-related gene products, such as p21, p27 and p53. Results: Treatment withPio at a dose of 800 ppm significantly reduced the number of colorectal ACF per mouseby 30% compared to those of untreated mice. Serum triglyceride levels were halved bytreatment with 800 ppm Pio compared with the untreated mice, and serum insulin levelswere 4.4 and 39.5 μg/ml, respectively. In Pio-treated and untreated mice, mRNA levels ofadipocytokines, such as leptin, MCP-1 and Pai-1, were decreased in visceral adipose tissueby Pio treatment accompanying the improvement of hypertrophic changes in adipose tissue.Similar changes were observed in serum levels of adipocytokines. Immnohistochemistry forPCNA revealed that Pio treatment suppressed cell proliferation in colorectal epithelial cellswith elevation of cell-cycle related genes. Conclusion: The present study demonstrates thatPio prevents the development of ACF by AOM in obese KK-Ay mice, partly through thegeneral correction of dysregulated adipocytokine levels and also of high serum levels oftriglyceride and insulin. These data suggest Pio could be of great use as a chemopreventiveagent against obesity-associated colorectal cancer.

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