M1588

Impact of Previous Diagnoses of Barrett's Esophagus and GERD and PriorEndoscopy On Outcome from Esophageal Adenocarcinoma: A Population-Based AnalysisGregory S. Cooper, Tzuyung D. Kou, Amitabh Chak

Background: Current practice guidelines recommend screening the at risk population withlongstanding GERD with upper endoscopy (EGD) for the presence of Barrett's esophagus (BE).Although some studies have suggested a survival advantage after esophageal adenocarcinoma(EAC) diagnosis with this strategy, the relative contributions of recognition of BE, medicalfollow up of GERD and EGD is not well understood. Methods: We identified a cohort of2,754 patients aged 68 and older with newly diagnosed EAC from 1994-2002 who wereincluded in the population-based SEER cancer registries. Linked Medicare claims includinginpatient, outpatient and physician files were searched from three years through six monthsprior to EAC diagnosis for the presence of BE or GERD diagnoses, or the receipt of EGD.Diagnosis of in situ or local stage EAC was considered early stage, and patients were followedfor at least 3 years or through 2005 for long-term survival. Multivariate analyses adjustedfor demographics, comorbidity and socioeconomic measures, and survival analyses alsoadjusted for stage and treatment received. Results: Among the EAC patients, previous EGDwas received in only 11.5% and only 8.1% had a prior diagnosis of BE. The frequency ofa previous GERD diagnosis was 22.4%. The univariate and multivariate results are shownin the Table. Although individually, all three measures were associated with improvedoutcomes, only a BE diagnosis was associated with improved long-term survival in multivari-ate models. Interaction terms for BE, GERD and EGD were tested but were not statisticallysignificant. Conclusions: In this population-based study of EAC, despite guidelines forscreening, only a minority of patients were assigned a diagnosis of BE or GERD or underwentprevious EGD. Of the three measures examined, only the BE diagnosis was independentlyassociated with favorable survival, suggesting that recognition of increased risk patients isa worthwhile strategy.

*p<0.001; **p<0.0001

M1589

Lack of Temporal Changes in Diagnosis of Barrett's Esophagus and PriorEndoscopy in Patients with Esophageal AdenocarcinomaGregory S. Cooper, Tzuyung D. Kou, Amitabh Chak

Background: Screening for and surveillance of Barrett's esophagus (BE) has been increasinglypromoted through professional society guidelines. It is unknown whether this disseminationhas led to actual changes in practice and measurable outcomes in early detection of esophagealneoplasia. Methods: Using the SEER tumor registries, we identified patients aged 68 and olderwith incident esophageal adenocarcinoma (EAC) or squamous carcinoma (ESC) diagnosedbetween 1994 and 2002. Linked inpatient, outpatient and physician Medicare claims weresearched from three years to six months prior to diagnosis to identify previous diagnosesof GERD or BE, and receipt of upper endoscopy (EGD), and these were compared acrossyear of diagnosis. We also compared the frequency of early stage (in situ or local stage)cancer according to year of diagnosis. Patients were followed for at least 3 years after diagnosisor through 2005, and survival time compared between years of diagnosis. All multivariableanalyses adjusted for demographics, comorbidity, and socioeconomic measures, and survivalanalyses also adjusted for stage and treatment received. Results: We identified 5,671 patients(51.3% ESC, 48.7% EAC). Among EAC, the overall frequency of previous EGD was 11.5%,22.4% had a previous GERD diagnosis, and 8.1% had a previous diagnosis of BE. For ESC,the frequencies were 9.6%, 13.6% and 1.3%, respectively. In EAC, the frequency of previousEGD did not change from 1994 to 2002 (12.2% to 11.9%, p=0.4 by chi-square for trend),and previous BE and GERD diagnoses increased modestly (BE 6.1% to 8.3%, p=0.01; GERD20.3% to 25.9%, p=0.002). For ESC, there was no change over time in prior BE diagnosis(1.4% to 1.3%) but the frequency of EGD and GERD diagnosis increased (EGD 6.5% to12.2%, p=0.04; GERD 10.0% to 17.7%, p=0.002). In multivariate analyses, for both EACand ESC, year of diagnosis was neither associated with early stage disease nor survival time.Conclusions: During the 9 year period from 1994-2002, despite increased awareness ofscreening, the proportion of EAC patients with BE diagnoses and previous EGD increasedonly modestly at best. Since the EAC incidence has risen, this suggests that any increase inEGD use has been matched by the rise in EAC. Moreover, there was no improvement overtime in early stage cancer diagnosis or survival. The findings suggest that if increased targetedscreening is desired, there may need to be changes in implementation strategy.

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M1590

Rabeprazole Impedes the Development of Reflux Induced Esophageal Cancerin a Surgical Rat ModelTomoharu Miyashita, Furhawn A. Shah, Jiaai Wang, Guy Marti, Mark D. Duncan,Elizabeth A. Montgomery, Manabu Murakami, John W. Harmon

Introduction We investigated the efficacy of rabeprazole, a proton pump inhibitor, to protectindividuals with Barrett's esophageal dysplasia from progressing to esophageal cancer. Weevaluated the effectiveness of rabeprazole as a chemoprevention agent in a surgical rat refluxmodel of esophageal cancer. Methods The rat reflux model was created by performing ajejuno-esophagostomy on Sprague Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. Rabeprazole sodium (Eisai, Tokyo, Japan) was dis-solved in 0.9% physiological saline to a desired concentration of 1.5% (W/V). Beginningfour weeks post surgery, all animals were administered either 0.2mL per 100g body weightinjections of rabeprazole or equivalent injections of saline 3 days per week into the subcutane-ous tissue of the back. All surviving animals were sacrificed 40 weeks after surgery andtheir esophagi were examined. Results Forty rats survived 40 weeks post-surgery and wereincluded in the study. Of these, 23 were included in the control group, while the remaining17 were subjected to rabeprazole. While 74% (17/23) of the controls developed esophagealcancer, animals administered rabeprazole had an incidence of cancer of 29% (5/17) (Chi-squared, p<0.05) (Table 1). Barrett's metaplasia was found on 100% (23/23) of the rats inthe placebo group, but there was a protective tendency in the rabeprazole group with 65%(11/17) of the rats displaying signs of Barrett's metaplasia. The rats in the rabeprazoleand placebo groups developed proliferative hyperplasia. Conclusions Rabeprazole protectedagainst the development of esophageal cancer in a clinically relevant surgical reflux model.Rabeprazole warrants further investigation for potential clinical use as a chemopreventionagent.Table 1. Histopathological findings

#Two animals developed both squamous cell carcinoma and adenocarcinoma.

M1591

Activation of HGF/c-MET Is the Key Mechanism for Acid-Induced Proliferationof Barrett's-Derived Esophageal Cancer Cells. Critical Roles of FunctionalEGFR and COX2 in C-MET Activation and Therapeutic ImplicationsThomas Thong H. Nguyen, Amrita Ahluwalia, Andrzej Tarnawski

Background: Barrett's esophagus develops in the setting of chronic gastroesophageal acidreflux. Clinical and experimental data indicate that luminal acid activates COX2 and theMAPK and anti-apoptotic pathways. The molecular mechanism(s) of how acid exposureactivates MAPK pathway and stimulates Barrett's-derived esophageal cell proliferation isunclear. We investigated the role of hepatocyte growth factor (HGF)/c-Met receptor activationby acid as a mechanism of inducing Barrett's-derived cell proliferation and assessed the roleof functional EGF receptor (EGF) and/or COX2 in acid-induced c-Met activation. Methods:Human Barrett's-derived adenocarcinoma cell line (BIC-1) or normal human esophageal cellline were treated with various concentrations of acid (pH 4.0-6.0) with or without EGFreceptor inhibitor (AG1478), COX2 inhibitor (NS398) or c-Met inhibitor, NK4. Studies: 1)Human phospho-receptor tyrosine kinase (PTK) array which detects phosphorylation of 42different RTKs; 2) Western blotting; 3) cell proliferation and 4) apoptosis. 5) Humanesophageal adenocarcinoma tissue array was used to evaluate c-Met expression. Results: PTKarray revealed that treatment of BIC-1 cells with acid caused acid concentration dependentincrease in phosphorylation and activation of c-Met, at pH 4.0 a 3.8- fold activation; p<0.001.c-Met activation was most prominent out of 42 RTKs and was present in BIC-1 cells butnot in other esophageal derived cell lines SEG-1, HCE-7 or HET1A cells. Acid induced c-Met phosphorylation was inhibited by AG1478 (EGFR inhibitor) indicating that a functionalEGFR is necessary for c-Met activation by acid. Acid exposure increased BIC-1 cell prolifera-tion by 1.8 fold (p<0.01) in a COX-2 dependent manner. NK4, a selective c-Met inhibitorat 3 mg/ml inhibited cell proliferation and induced BIC-1 cell apoptosis of over 85% ofcells (p<0.001 vs. control). Human esophageal adenocarcinoma tissue array showed c-metoverexpression in 85% (48/56) of samples. Conclusions: 1) Acid exposure activates HGFR/c-Met receptor, which in turn activates MAPK pathway and stimulates proliferation ofBarrett's-derived esophageal adenocarcinoma cells. 2) Acid-induced c-Met activation andcell proliferation are dependent on functional EGFR and COX2. 3) c-Met is highly upregulatedin human esophageal adenocarcinoma. 4) Inhibition of c-Met with NK4 induces apoptosisin esophageal cancer cells. These data provide a novel mechanism of acid-induced prolifera-tion of Barrett's-derived esophageal cells; suggest a role for acid suppression in Barrett'sprevention and the use of c-Met inhibitor NK4 as therapeutic modality for Barrett's-derivedesophageal cancer.

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