responsible for the reduction of IFN-γ production from PBMCs of HCV-related HCC patients.CONCLUSIONS:Along with serum TNF-α, IL-10, IL-18 and IFN-γ levels, CD4CD57αβ Tcell counts in PB are valuable predictors for tumor progression and prognosis of HCV-related HCC patients.

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Tissue Inhibitor of Metalloproteinases 3 (TIMP3) Regulation inCholangiocarcinoma By MicroRNA-21 and Promoter HypermethylationFlorin M. Selaru, Bogdan C. Paun, James P. Hamilton, Alexandru Olaru, Yulan Cheng,Takatsugu Kan, John M. Abraham, Rachana Agarwal, Jian Yang, Stefan David, YurikoMori, Zhe Jin, Gregory J. Gores, John H. Kwon, Stephen J. Meltzer

Background. Cholangiocarcinoma (CCA) is an aggressive epithelial cancer of the biliary treewith survival measured in months. The only potentially curative treatment for CCA is surgicalresection. Unfortunately, the vast majority of patients are diagnosed at late stages, whensurgery is not an option. MicroRNAs (miRs) are short single stranded RNA sequences,recently shown to have major regulatory functions in cancer. TIMP3 is one of 4 membersof the metalloproteinases family and its role was associated with cancer invasion and meta-stasis. We aimed at elucidating the regulatory mechanisms of TIMP3 in CCA. Methods.Fifteen histologically confirmed CCAs and 9 normal liver specimens were collected at surgeryat Johns Hopkins Hospital after informed consent was obtained from all patients. The NLswere obtained at the time of surgery for CCA from normal liver. Quantitative RT-PCR (qRT-PCR) for messenger RNA (mRNA) and miRs and quantitative Methylation Specific PCR(qMSP) were performed as previously described. Results. We measured the qRT-PCR levelof TIMP3 mRNA and found it to be underexpressed in CCA vs. NL specimens, suggestinga tumor-suppressive role for TIMP3 in the biliary tree. In contrast, our previous workrevealed that miR-21 is overexpressed in CCA vs. NL, suggesting a possible negative regulationof TIMP3 by miR-21. In silico searches suggested that TIMP3 is indeed a putative target ofmiR-21. The CCA cell lines CAK1, TFK1 and HuCCT1 were transfected with a miR-21inhibitor and TIMP3 protein levels were measured. TIMP3 was significantly elevated in all3 cell lines transfected with the inhibitor, strongly suggesting that miR-21 downregulatesTIMP3 protein levels. Interestingly, miR-21 does not directly bind to TIMP3 mRNA, asevinced by luciferase assays, suggesting the presence of an intermediary molecule or adifferent mechanism of miR-21 regulation of TIMP3. To investigate a potential co-regulationof TIMP3 in CCA by hypermethylation, we measured the promoter methylation in all 24specimens. TIMP3 promoter was found to be hypermethylated in only 1/15 CCA (6.6%),0/3 CCA cell lines and 0/9 NL specimens. Conclusions: TIMP3 mRNA is elevated in NLand decreased in CCA specimens implicating TIMP3 as a tumor suppressor gene in thebiliary tree. Our data also suggests that TIMP3 promoter hypermethylation does not appearto play a major role in its downregulation in human CCA specimens. In contrast, miR-21is a major regulator of TIMP3 in CCA. Furthermore, miR-21 may exert at least part of itsoncogenic, pro-invasive effects in CCA by inhibiting TIMP3.

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Complex Antithrombotic Therapy (CAT) and the Risk of UpperGastrointestinal Events (UGIE) Among Vulnerable EldersNeena S. Abraham, Aanand D. Naik, Peter Richardson, Christine M. Hartman

Background: Prescription of complex antithrombotic therapy (i.e., dual and triple-combina-tion anticoagulants and antiplatelets) is common for secondary cardioprophylaxis amongpatients with a history of heart attack, stroke and peripheral vascular disease. These agentsare independently associated with UGIE, and the risk associated with combination use isunknown. Our aim was to quantify national CAT-related UGIE risk among elderly veterans.Methods: Veterans≥ 65 prescribed anticoagulant-antiplatelet [i.e., ACAP]; ASA-antiplatelet[i.e., ASAP]; ASA-anticoagulant [i.e., ASAC] therapy or triple therapy [i.e., TRIP; anticoagu-lant-antiplatelet-ASA prescription) therapy from 01/01/03-09/30/06, were identified fromthe Department of Veterans Affairs national pharmacy database. Prescription fill data werelinked in a longitudinal fashion to VA inpatient, outpatient and death files. Each person-day of follow-up was assessed for exposure to the CAT strategy, and UGIE were definedusing our published, validated algorithm. Unadjusted incidence density ratios were calculatedfor the 365 days following exposure. Cox Proportional Hazard Models assessed risk, whileadjusting for demographics, UGIE risk factors, co-morbidity, prescription channeling (i.e.,propensity score), geographic location, H. pylori infection and multiple time-dependentpharmacological covariates, including steroids, NSAIDs, PPI, statins and selective serotoninreuptake inhibitors. Estimates of risk were compared with periods of observation when thepatient was not prescribed the CAT strategy (i.e., none). Results: Among 78,084 patients(98.6% male; 54.4% white; mean age, 72.3 [SD 7.7]), 30.4% were prescribed CAT strategies(ACAP 5.2%; ASAC 7.0%; ASAP 16.7%; TRIP 1.5%), with 1061 UGIE occurring. Theunadjusted incidence density ratio was greatest for TRIP (5.3 UGIE/1000 person-years [95%CI: 2.6 to 15.6]). When adjusted for prescription channeling and confounders, the greatestrisk was still associated with TRIP prescription (HR 4.3; 95% CI: 3.0-6.3); least harmfulwas ACAP (HR 1.7; 95% CI: 1.2-2.4). Those prescribed ASAP and ASAC were 2 to 2.5times more likely to suffer an UGIE (HR 2.1; 95% CI: 1.6-2.6; and HR 2.5; 95% CI: 1.9-3.3, respectively). Conclusions: Among elderly patients, CAT-related UGIE is a significantand clinically relevant risk. The observed magnitude of UGIE risk may suggest an unfavorablerisk-benefit ratio in this population. Future studies are required to quantify the absoluteincreased benefit associated with CAT secondary cardioprophylaxis, given the observedabsolute two- to four-fold increased UGIE risk.

A-29 AGA Abstracts

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The Effect of Direct to Consumer Advertisement and Physician Promotion ofTegaserod (Zelnorm) On Physician Visits, Diagnoses, and Prescriptions forIrritable Bowel Syndrome and ConstipationSpencer D. Dorn, Joel F. Farley, Richard A. Hansen, Nilay Shah, Robert S. Sandler

BACKGROUND: Direct to consumer advertisement (DTCA) and physician promotion ofprescription drugs may influence patient and physician behavior. From July, 2002 throughMarch, 2007 Tegaserod (Zelnorm) was heavily promoted to both patients and physicians.We sought to determine the relationship between this promotion and the number of officevisits for abdominal pain, constipation, and bloating, irritable bowel syndrome (IBS) dia-gnoses, and Tegaserod prescriptions. METHODS: We used IMS Health's Integrated Promo-tional Services data to estimate Tegaserod DTCA and professional promotion expenditures,The National Ambulatory/Hospital Medical Care Surveys (1997-2005) to estimate the numberof ambulatory care visits for abdominal pain, constipation, and bloating, as well as diagnosesof IBS, and IMS Health's National Prescription Audit Plus to estimate the volume of Tegaserodprescriptions. We estimated segmented regression models to evaluate the effect of Tegaserodpromotion on levels and trends of U.S. physician visits and IBS diagnoses. Additionally, weestimated multivariate regression models to quantify the effects of different types of Tegaserodpromotion on physician visits, IBS diagnoses, and Tegaserod prescriptions. RESULTS: Inthe three months immediately following the start of Tegaserod DTCA, there was a significant1 million visit [95% CI: (0.5 million, 1.6 million)] increase in physician visits and 397,025[95% CI: (3909, 790141)] additional IBS diagnoses. Subsequently, there was a reductionin the trend of visits and IBS diagnoses. In multivariate analyses that examined the overallrelationship of promotion with visits, diagnoses, and prescriptions, only the relationshipbetween physician promotion and Tegaserod prescribing was significant: every one milliondollars spent on physician promotion resulted in an additional 4,108 prescriptions [95%CI: (2526, 5691)]. CONCLUSIONS: The initial DTCA of Tegaserod was associated with asignificant, immediate increase in physician visits for abdominal pain, constipation, andbloating as well as IBS diagnoses. However, over time this trend reversed and in multivariatemodels neither DTCA nor physician promotion had any overall effect on visits or diagnoses.Physician promotion (though not DTCA) was a significant predictor of Tegaserod prescrip-tion volume.

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Early Fecal Occult Blood Test (FOBT) After a Normal Colonoscopy: TooMuch, Too Soon?Douglas J. Robertson, Heiko Pohl, Dawn Provenzale

Background: Because the colorectal cancer risk after a normal colonoscopy is so low, expertsrecommend a follow-up screening interval of 10 years. Nonetheless, many patients undergoearly re-testing. Aim: To determine the frequency, timing and indication for FOBT afternormal colonoscopy; and the diagnostic yield of colonoscopies done because of positiveFOBTs. Methods We used local VA administrative data and identified all Veterans with anormal colonoscopy (CPT 45378) over a 6 year period: 1997 - 2002 (n=1,766, mean age64 years, 95% male). Using clinical data files, we then identified all FOBT testing and resultsdone after initial normal colonoscopy through August 2008. To determine who ordered theearly FOBT and why (e.g. screening vs. gastrointestinal signs/symptoms), we reviewed thecharts of a random sample (n=100). For all colonoscopies done within 1 year of a positiveFOBT, we reviewed the endoscopic database to see if any advanced adenomas (size ≥ 1cm, villous histology, high grade dysplasia) or cancer were detected. Results: Thirty-sixpercent (n=627) of the cohort underwent FOBT testing during the follow up period. Themean time to FOBT after normal colonoscopy was 4.5 years (range 12 days-10.9 years):4% within 1 year, 55% within 2-5 years, and 41% greater than 5 years. Most (74%) of theFOBTs were ordered by the patient's primary care physician. Fifty-six percent of the FOBTswere ordered for screening, 28% for gastrointestinal signs or symptoms and 16% performed aspart of a physical examination (e.g. hospital admission or emergency department evaluation).Among the 627 patients who had early FOBT, 20% (n=123) had a positive result and 6%(n=38) underwent follow up colonoscopy within one year. Of the 38 patients undergoingcolonoscopy, 8 had one or more adenomas, but none had advanced adenomas or cancer(table). Conclusion: Early FOBT after a normal colonoscopy is done frequently and often forcancer screening. Most FOBTs were not followed up with colonoscopy; for those undergoingcolonoscopy the yield was low. Our result suggest that early interval FOBT should be discour-aged.FOBT After Normal Colonoscopy

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Colonoscopy Yields Fewer Polyps As the Day Progresses Despite Use of SocialInfluence to Reverse the TrendMichael Y. Chan, Hartley Cohen, Jennifer Talley, Brennan M. Spiegel

Backgrond: We previously reported that colonoscopy polyp yield falls hour-by-hour as theday progresses (Chan et al DDW 2008 AB211). The effect was independent of patient factors,prep quality, cecal intubation, withdrawal time, & endoscopist. This suggests that providersmight be most adept at detecting polyps earlier in the work shift - a phenomenon thatcould be modified with “social influence theory,” in which unwanted behavior is positivelyinfluenced through auditing & feedback. As a proof-of-concept pilot study, we measuredthe impact of a social influence informational poster on the relationship between colonoscopy

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