Nanda Venu

Gene Signature Distinguishes Patients with Chronic Ulcerative Colitis Harboring Remote Neoplastic Lesions

Background:Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer. The standard method of surveillance for neoplasia in UC by colonoscopy is invasive and can miss flat lesions. We sought to identify a gene expression signature in nondysplastic mucosa without active inflammation that could serve as a marker for remote neoplastic lesions. Methods:Gene expression was analyzed by complementary DNA microarray in 5 normal controls, 4 UC patients without dysplasia, and 11 UC patients harboring remote neoplasia. Common gene ontology pathways of significantly differentially expressed genes were identified. Expression of genes which were progressively and significantly upregulated from controls to UC without neoplasia, to UC with remote neoplasia were evaluated by real-time polymerase chain reaction. Several gene products were also examined by immunohistochemistry. Results:Four hundred and sixty-eight genes were significantly upregulated, and 541 genes were significantly downregulated in UC patients with neoplasia compared with UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly upregulated from controls to nondysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increased expression of S100A9 and REG1&agr; in UC-associated cancer and in nondysplastic tissue from UC patients harboring remote neoplasia compared with UC patients without neoplasia and controls. Conclusions:Gene expression changes occurring as a field effect in the distal colon of patients with chronic UC identify patients harboring remote neoplastic lesions. These markers may lead to a more accurate and less invasive method of detection of neoplasia in patients with inflammatory bowel disease.

Multiple Abdominal Vascular Anomalies in a Patient with Alagille Syndrome

Alagille syndrome affects multiple organ systems. The most common vascular manifestation of Alagille syndrome is peripheral pulmonary artery stenosis. A few cases of abdominal vasculature involvement have been reported, particularly in the pediatric age group. Herein, the authors describe an adult patient with Alagille syndrome who presented with multiple visceral vascular abnormalities, including a high-grade stenosis of the celiac artery, superior mesenteric artery (SMA), aneurysms of the distal common hepatic artery, and distal SMA detected with computed tomographic angiography.

Multiple progressive focal nodular hyperplasia lesions of liver in a patient with hemosiderosis

Focal nodular hyperplasia (FNH) is the second most common benign lesion of the liver. It is a solitary lesion and usually does not enlarge. We present the magnetic resonance imaging findings of multiple progressive FNH lesions in a patient with hemosiderosis using Gadolinium-EOB-DTPA (Eovist) as a hepatobiliary contrast agent. The possible mechanisms underlying the occurrence and progression of FNH lesions and the potential value of Eovist in characterizing the lesions were discussed.

S1698 MiR-143 and miR-145 are Differentially Expressed in the Right and Left Colon and Likely Regulate Differential Expression of K-RAS and Irs-1: Implications for Colon Cancer

G A A b st ra ct s at the enhancer in Pargyline-treated cells. These results suggest that H3K9Me or H3K9Me2specific demethylase activity of LSD1 at the secretin enhancer with acetylation of H3K9 is prerequisite for transcriptional activation by NeuroD. We conclude that LSD1 and CtBP, in the context of the secretin gene, engage specific chromatin-modifying activities to function as coactivator rather than a corepressor. Demethylation may represent one such activity that removes the repressive mark, H3K9Me2 to maintain expression of the secretin gene. Our observations illustrate the increasingly recognized importance of chromatin structure and the histone code in regulation of gene transcription.

839 Development of Irritable Bowel Syndrome Symptoms in Quiescent Inflammatory Bowel Disease: Significant Association With Presence of Psychiatric Illness and Early Onset IBD

genome-wide association study (GWAS) using Illumina OmniExpress, comparing patients with and without perianal disease (n=780). Serum was analyzed by ELISA for anti-Saccharomyces cerevisiae (ASCA), anti-outer membrane porin C (anti-OmpC), anti-Cbir1, and antiPseudomonas fluorescens (anti-I2). Data analysis was undertaken using univariate logistic regression for clinical and serologic data (statistical significance at p ,0.001). Multivariate regression was used for GWAS data, with principal components/disease location as covariates. We report single nucleotide polymorphisms (SNPs) that reached p=10E-6. Results: Perianal disease was documented in 35% (n=297). Perianal disease was associated with colonic and ileocolonic disease locations (p,0.0001), as well as with upper GI (p=0.0006) and rectal disease (p,0.0001). Anti-OmpC was significantly more prevalent among individuals with perianal disease (p, 0.0001). Two statistically significant SNPs were identified. One was a SNP at chromosome 8q24 (rs6470545, p=9x10E-6), which is 200 kilobases upstream from the proto-oncogene MYC, and near a colon cancer locus (rs6983267) known to control MYC expression. Three nearby SNPs (rs10091329, rs6470537, rs6470552) in close linkage disequilibrium (r2 .0.8) had p-values of 10E-5. Another SNP on chromosome 8 in a gene desert was also associated with perianal disease (rs10092418, p=8x10E-6). Conclusions: We report novel genetic and serologic associations with perianal disease in a large cohort of Crohns disease patients. The association between perianal disease and a locus near MYC, which encodes a transcription factor with broad activity in cell proliferation, apoptosis, and differentiation, suggests novelmechanisms in the development of perianal disease. Replication will be important to confirm findings and direct further investigation into this unique Crohns disease phenotype. *Dr. Weizman and Dr. Murdoch contributed equally to this study.

The Colectomy and Mortality Rates in Inflammatory Bowel Disease Patients with Clostridium Difficile Associated Disease: A Nationwide Analysis from 2000-2008.: P-43 YI

determine whether the earlier use of anti-TNF therapy was associated with better short-term outcomes in a biologic-naı̈ve cohort. METHODS: A retrospective cohort of patients with biopsy-proven UC or CD, naı̈ve to biologic therapy, who started therapy with infliximab (IFX), adalimumab (ADA) or certolizumab (CTZ) between 2000-2011, was selected. Subjects with a prior history of IBD-related surgery were excluded. Primary non-responders to biologic therapy, individuals who were on corticosteroids beyond the biologic induction period, and subjects with less than six months of continuous follow-up were also excluded. Subjects were followed for a maximum of three years or until lost to follow up. The primary outcome of interest was the occurrence of any IBD-related hospitalization, surgery or corticosteroid use (after biologic induction) during follow-up. Subjects were stratified according to whether they started a biologic early (within 1 year of IBD diagnosis) or late (>1 year since diagnosis). Multivariable logistic regression was performed with the composite outcome as the dependent variable of interest. A survival analysis was also performed comparing early versus late initiators and their time to the composite outcome with subjects censored at three years or when lost to follow up. RESULTS: Early initiators (N 1⁄4 34) were younger (mean age D 5.4 years) than late initiators (N 1⁄4 78) (P 1⁄4 0.02), and had a higher frequency of ADA/CTZ use than the late initiators (38.2% versus 15.4%, P 1⁄4 0.03). They were also more likely to be on corticosteroids at the time of biologic initiation (64.7% versus 42.3%, P 1⁄4 0.03) and less likely to be on aminosalicylates (8.8% versus 28.2%, P 1⁄4 0.02). The groups did not differ by sex distribution, mean body weight, immunomodulator use, presence of extra-intestinal disease, tobacco use or IBD subtype (including clinical phenotype among CD patients or extent of colitis among UC patients) (P>0.10). The mean follow-up time between groups did not differ (719 days [SE 57.9] in the early group versus 774 days [SE 41.1] in the late group, P 1⁄4 0.45). After multivariable adjustment, there was a higher likelihood of the composite outcome in late initiators of biologic therapy (adjusted OR 6.6, SE 5.5, P 1⁄4 0.02). When initiation was considered as a continuous function, it remained significantly associated with the composite outcome (adjusted OR 1.1 per year since diagnosis, SE 0.06, P 1⁄4 0.05). When modeled as a survival function, the adjusted hazard ratio for the composite outcome was 4.9 in the late initiators (SE 3.8, P 1⁄4 0.04). CONCLUSION(S): Early initiation of anti-TNF therapy in patients with IBD who already have indications for its use may be associated with better outcomes. These findings support a possible role for ‘top-down’ therapy in IBD treatment. This is in line with other emerging data that the early use of anti-TNF agents may alter the natural history of IBD.

Sa2064 Probiotics Associated With Higher Rates of Subsequent Clostridium difficile Infection in Inflammatory Bowel Disease Population

Introduction:There has been an increased rate of Clostridium difficile infection (CDI) with disproportionately higher impact on the inflammatory bowel disease (IBD) populationCrohns disease (CD) and Ulcerative Colitis (UC). Treatment protocol has traditionally consisted of vancomycin or metronidazole. The outcome of probiotic treatment in this unique population is not defined. We sought to evaluate the impact of probiotics on rates of subsequent CDI and disease course. Methods:This was a retrospective observational study of all IBD pts followed at a single IBD center with CDI confirmed by suggestive gastrointestinal symptoms and either positive toxin A/B ELISA stool test or nucleic acid amplification stool test (NAAT). Pt demographics and disease characteristics were collected. We evaluated the performance of probiotics used by assessing rate of subsequent CDI over the following year. Probiotic used was Florajen (reported to have 20 billion live, freeze dried, human source strains of lactobacillus acidophilus). IBD clinical course the year following CDI was evaluated using inflammatory markers, corticosteroid usage, and disease related complications including hospitalizations and surgeries. Results:There were 101 IBD (62 CD, 39 UC) pts who had CDI confirmed (35 inpts and 66 outpts). 31 IBD pts (20 CD, 11 UC) with CDI were in the probiotic group (P) and 70 IBD pts (42 CD and 28 UC) were in the control group (C). There was no difference in disease duration, IBD maintenance therapy, disease type/ behavior between these groups. Initial antibiotic therapy used for treatment of CDI was metronidazole (M) in 48 pts, vancomycin (V) in 38 pts and combination of metronidazole + vancomycin (M+V) in 15 pts. The rate of subsequent CDI (>1) over the following year was 39% (12/31pts) in P group and 16% (11/70pts) in the C group (p=0.01). Probiotic treatment rates were 15% (7/48) in the M group, 42% (16/38) in the V group, and 53% (8/15) in the M+V group. There was a higher rate of probiotic treatment in the V group compared with the M group (42% vs 15%; p=0.04) and in the M+V group compared with the M group (15% vs 53%; p=0.002). There was no difference in probiotic use between V andM+V groups (42% vs 53%; p=0.46). Recurrence rate was not affected by IBDmaintenance therapy (biologic/immunomodulator or both). Antibiotic used in initial CDI had no impact on rate of hospitalizations, IBD related surgeries or mean ESR and CRP values over the following year. Conclusions:In our cohort, use of lactobacillus acidophilus single strain probiotic during initial CDI was associated with higher rates of subsequent CDI. Probiotic usage was higher in the CDI treatment groups with vancomycin alone and in combination with metronidazole. Further studies are necessary to define appropriate roles for probiotic strains in combination with antibiotics for preventing CDI recurrence.