T1841 Genistein Deactivates Immortal Pancreatic Stellate Cells Ralf Jesnowski, Wolfgang Hagmann, Matthias Löhr Tissue fibrosis is one of the characteristics of chronic pancreatitis and pancreatic adenocarcinoma. In chronic pancreatitis this tissue fibrosis gradually replaces functional pancreatic tissue and eventually results in exo- and endocrine pancreatic insufficiency. Activated pancreatic stellate cells (PSC) play a central role in this process. Moreover, activated PSC increase proliferation, invasion and chemoresistance of pancreatic tumor cells. A variety of factors, which contribute to this activation process, have been identified so far. These include cytokines, growth factors, ethanol and acetaldehyde. Platelet-derived growth factor (PDGF) seems to be the most potent mitogen, whereas transforming growth factor β 1 (TGFβ1) predominantly induces matrix synthesis. However, only a few factors which might reverse the activated phenotype of PSC have been analysed so far, although such an antifibrosis therapy might be beneficial for patients with chronic pancreatitis and pancreatic adenocarcinoma. In this study we analyzed the effects of the soybean isoflavone genistein on the activation state of an immortalized PSC cell line (RLT-PSC). RLT-PSC cells were incubated with different concentrations of genistein and the effects of this treatment on gene expression and proliferation were analyzed. Genistein dose- and time dependently decreased the proliferation rate of the PSC cell line. It only had marginal effects on the basal expression level of the genes analyzed, only TIMP1 expression was downregulated by genistein. However, genistein diminished TGFβ1 induced MMP2 and COL1A1 upregulation in RLT-PSC cells. Moreover, it decreased the expression of CYCD1 induced by FCS treatment. Thus, genistein treatment resulted in a deactivated phenotype of RLT-PSC cells and may be useful in an antifibrosis therapy for patients with chronic pancreatitis and pancreatic adenocarcinoma. T1877 A Pilot Feasibility Study of Screening for Barrett's Esophagus with a Novel Non-Endoscopic Capsule Sponge Device in a Primary Care Setting Device in a Primary Care Setting Sudarshan R. Kadri, Irene Debiram, Pierre Lao-Sirieix, Maria O'Donovan, Jane M. Blazeby, Anthony Males, Helen Morris, Fiona Walter, Jon Emery, Rebecca C. Fitzgerald INTRODUCTION: Screening for Barrett's esophagus (BE) may be key to improving survival of esophageal adenocarcinoma. We have developed a non-endoscopic screening test whereby the esophagus is sampled using a sponge contained within a gelatin capsule and stained for immunohistochemical markers. AIMS & METHODS: The current study aims to extend our previous experience (Lao-Sirieix Gut 2007) to the primary care setting. The prescribing database of the GP's clinic where the study was conducted was searched to identify patients 50-70 years old who had received acid suppressant therapy (>3 months in the last 5 years) but who had not undergo recent endoscopy. The capsule sponge test was administered in primary care after which the samples were processed to a paraffin block and slides were stained for a panel of biomarkers: alcian blue and ProExC (TriPath, BD Biosciences). Patients' symptoms and demographics were assessed when they attended to swallow the sponge. Acceptability of the capsule sponge was measured using a 10 point visual analogue scale (0 - unpleasant and 10 - enjoyable) at days 0 and 7. Impact of screening on anxiety was also assessed using standard questionnaires (Short-Form Spielberger State-Trait Anxiety Inventory, modified cancer worry scale and an Impact of Events scale) at days 0, 7 and 90. The capsule sponge diagnosis was compared with gold standard endoscopy. RESULTS: 39/ 211 (18.5%) patients participated (54 accepted but 15 did not attend or were excluded) in the primary care study with a 1:1 male-female ratio and a mean age of 59.6 years. The mean BMI was 31.2 (range 20-48) with a waist to hip ratio of 0.92 (moderate risk) for males and 0.87 for females (high risk). 36/39 (92%) had ongoing reflux which in 21 (55%) occurred >1 per week. 18 (47%) had uncontrolled symptoms despite being on medication. There were no adverse events from swallowing the capsule sponge. The acceptability rating on day 0 was 5.1 (range 2-10) and 4.7 (range 2-8) on day 7. Patients general anxiety levels were not increased by screening but their anxiety related to a diagnosis of BE increased significantly at day 7 (p<0.0001) and reverted back to baseline at day 90. The prevalence of BE was 2/39 patients (5.1%). CONCLUSION: 20% of patients contacted participated in this screening study. The capsule sponge is safe and was well tolerated and did not induce unnecessary anxiety. These pilot data are encouraging for the ongoing study which aims to recruit 500 individuals. REFERENCE: Lao-Sirieix P et al., 2007, Gut 56:1033 T1842 ND-07 As Novel Rescuing Therapeutics from Acute and Chronic Fibrosing Pancreatitis Ki-Baik Hahm, Jin Hwan Lee Since we have reported that ND-07, an novel antioxidative, anti-inflammatory, and cytoprotective drug derived from salicylate basis, showed significant efficacy against cerulean-induced edematous pancreatitis, and L-arginine or CDE diet-induced necrotizing pancreatitis and ensuing mortality (Gastroenterology 2008; 134:A372), in the current study, we extended our investigation adopting another animal model to ascertain that ND-07 could be potential therapeutics for the treatment of gallstone pancreatitis or post-ERCP pancreatitis. Pancreatic duct (PD) ligation-induced pancreatitis was established in SD rats and sacrifices were done at 16hrs and 8weeks, respectively. 10, 25, and 50mg/kg of ND-07 was pretreated before PD ligation. In acute model of pancreatic duct ligation-induced pancreatitis, ND-07 showed significant prevention of pancreatitis reflected with significantly decreased serum amylase and lipase, serum and pancreatic TNF-alpha levels, MDA formation, 8-OHdG, and nitrotyrosine formation. On immunochemical staining with ZO-1 and occluding, their intensities of acinar cell membrane were significantly preserved in ND-07 pretreatment. Electron spin resonance measurement showed significant quenching effect of ND-07 of hydroxyl radicals (DMPOOH). All of these biochemical and biological changes were seen in dose-dependent manner of ND-7. Mean pathological indices of pancreatitis showed very significant protection of ND-07 against pancreatitis. In chronic model of PD ligation, ND-07 showed marked preventive efficacy against chronic fibrosing pancreatitis as assessed pathological scoring and biochemical measurement of alpha-SMA, fibronectin levels, and collagen IV levels. In conclusion, ND-07 could be novel therapeutics for treating pancreatitis and preventing the development of chronic pancreatitis, anticipating due clinical trials. T1878 Esophageal Hypomotility On High Resolution Manometry Is An Independent Predictor of Barrett's Esophagus Nitin Kumar, C. Prakash Gyawali BACKGROUND: Compared to conventional manometry, high-resolution manometry (HRM) has improved sensitivity in detecting segments of abnormal esophageal motility. Esophageal hypomotility has been reported in Barrett's esophagus (BE) using conventional manometry; long-segment BE (LSBE) is associated with lower distal esophageal peristaltic amplitudes and lower esophageal sphincter (LES) basal pressures compared to SSBE. AIMS: To assess the prevalence of SSBE (<3cm) and LSBE (≥3cm) in subjects with reflux disease demonstrating HRM findings of esophageal hypomotility, and to determine if esophageal body or LES hypomotility can independently predict BE. METHODS: Subjects with reflux disease evaluated with both HRM and upper endoscopy over a 5 year period were included. HRM findings of hypomotility (esophageal body hypomotility: ≥50% failed sequences and/or distal mean amplitude ≤30mmHg; LES hypomotility: end-expiratory LES pressure ≤5 mmHg) and normal motility were cross referenced with pathology proven SSBE and LSBE on endoscopy. Univariate and multivariate logistic regression determined prevalence and esophageal motor predictors of BE. RESULTS: 317 subjects with normal motility (mean age 47.7±0.80 yr, distal mean amplitude 82.4±1.6mmHg, 4.3±0.5% failed sequences, endexpiratory LES pressures 11.9±0.3mmHg) were compared to 306 subjects with hypomotility (mean age 51.7±0.85 yr), which included 246 subjects with LES hypomotility, 16 with esophageal body hypomotility and 44 with both (end-expiratory LES pressures <5 mmHg; distal mean amplitude 15.9±1.5mmHg or 76.8±2.7% failed sequences). Prevalence of BE was 10.1% with normal motility, and 20.3% in the hypomotility group (p<0.001). On univariate analysis, likelihood of BE was higher with both esophageal body and LES hypomotility compared to either alone (Table), with OR for LSBE much higher than that for SSBE. On multivariate logistic regression, age>50 (OR 1.44, 95% CI 1.01-2.30) and male gender (OR 2.14, CI 1.35-3.39) were independent predictors of BE as expected; hiatal hernia (OR 1.21, CI 0.75-1.95) was not. Controlling for age, gender and hiatus hernia, LES hypomotility T1876 Has the Incidence of Esophageal Adenocarcinoma (EAC) in Barrett's Esophagus (BE) Increased? A Time-Trend Analysis Sachin B. Wani, Michael B. Cook, Matthew Hall, Hari Sayana, Ajay Bansal, Amit Rastogi, Mandeep Singh, Vikas Singh, Prateek Sharma Background: BE is a premalignant condition for EAC, the most rapidly increasing cancer in the Western world. It is unclear if incidence of EAC in BE pts is increasing. Aim A systematic review and meta-analysis to study the time-trends in the incidence of EAC in BE pts. Methods MEDLINE search was performed for all studies describing natural history of BE pts and providing estimates of EAC risk. Inclusion criteria: histologically proven BE without dysplasia at cohort inception; pts not having undergone endoscopic/surgical therapy; no EAC at time of enrollment or within 6 mths; f/u reported in person-time. All studies were reviewed by 2 investigators. Random and fixed effects models were used to calculate pooled estimate of incidence rates (IR). Poisson regression model was used to study time trends in IR of EAC in BE [categorizing studies into decades (1980-1989, 1990-1999, 2000-present)and by using time as continuous variable]. Exact methods were used to calculate 95% CI. Heterogeneity A-591 AGA Abstracts AGA Abstracts (by I2 statistic and χ2 test)and publication bias was assessed. Meta-regression and stratified analyses were performed. Results 54 studies were included: 8586 pts with 49,925 personyrs f/u. Pooled estimate of cancer incidence in BE pts(random-effects model) was 5.9/1000person yrs (95% CI 4.8-7.3). IR (95% CI) of EAC in BE pts in the 3 decades, chronologically, were 8.8 (4.1-18.5), 8.4 (6.0-11.7) and 4.6 (3.5-6.0)/1000 person-yrs. Time-trend analysis showed a significant decrease in the reported incidence of EAC in BE patients both by decade-wise analysis(p for trend=0.014)and by using time as a continuous variable (p= 0.003). There was significant heterogeneity in IR (p<0.001, I2 55%) and publication bias was identified (funnel plot method, p=0.01). Bubble plot based on study size showed lower IR of cancer in larger studies. Meta-influence methods did not show a significant influence of individual studies on cancer IR; however, patient-yrs in follow-up (p=0.003) and year of publication (p=0.014) were the two most significant variables influencing IR. When studies with at least 75 pts were included; no significant change in the incidence of EAC was noted over time (p=0.34). Conclusions This meta-analysis shows a decrease in incidence of EAC in BE cohorts over time and may be attributed to study heterogeneity and small study bias. Although the overall incidence of EAC is increasing, this is not paralleled by an increasing incidence of EAC in BE pts of cohort studies. To have an impact on this rising incidence of EAC, perhaps more BE patients need to be screened and surveyed and factors besides BE contributing to the development of EAC should be explored. 28 days. Results: (1) Infiltration of monocytes in the interlobular interstitium was observed after 2 days and fibroblasts were detected among them. The lobular structure was destroyed after 4 days and proliferation of fibroblasts was found in the intralobular interstitium. Myofilbroblasts with positive α-SMA staining appeared in the intralobular interstitium around the peripheral branching pancreatic ducts, i.e., activation and transformation of fibroblasts to myofibroblasts was observed. Thereafter, fibrosis of the interstitium progressed and after 28 days, acinar cells disappeared and were replaced with collagen fiber. The content of TGF-β secreted from the monocytes and fibroblasts increased slightly after 2 days, then showed a marked increase, reached a peak after 4 days, and then decreased. (2) In the A group after 28 days, improvements in the form of regeneration of acinar cells and a decrease in collagen fiber in the interstitium. However, no improvement was found in the B group. Conclusions: It was suggested that long-term administration of oral PI from the initial stage of pancreatic fibrosis improves pancreatic fibrosis. In this initial stage, fibroblasts in the interstitium are not activated and the expression of TGF-β is low.