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Large Scale Genomic Instability in Patients With Colorectal Cancer in Inflammatory Bowel Disease. Association With Clinicohistological Factors and Survival
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patients with IBD and to assess the adequacy of surveillance colonoscopy every 1-2 years for these patients. Data and Methods: All patients in the Surveillance, Epidemiology and End Results Medicare (SEER-Medicare) linked database who were 67 years or older at the time of their first colonoscopy between 01/01/1998 and 12/31/2002 and subsequently diagnosed with colorectal cancer within 36 months (through 12/31/2005) were identified. We excluded Medicare HMO enrollees or those without Part B coverage in the 24 months prior to colonoscopy. Patients with pre-existing IBD were identified using the ICD-9 diagnosis codes 555 (Crohn's disease) and 556 (ulcerative colitis). Similar to previous studies, colorectal cancers diagnosed within 6 months of colonoscopy were categorized as detected cancers and those diagnosed 6 to 36 months after colonoscopy were categorized as interval cancers. The chi-square test and multivariate logistic regression were used in statistical analysis comparing interval and detected colorectal cancers. Results: Of the 31,045 patients included in the study, 562 (1.8%) had pre-existing IBD (208 Crohn's disease, 346 ulcerative colitis, and 8 indeterminate). The rates of interval colorectal cancer were 17.3% (97/562) among IBD patients and 6.9% (2,106/30,483) among non-IBD patients (p<0.001). Of the 2,203 patients with interval colorectal cancer, there was no difference between IBD and non-IBD patients in cancer location or grade, but interval cancers among IBD patients were more likely TNM stage I (36.1% vs. 26.1%, p<0.05). There was no significant difference between patients with Crohn's disease and those with ulcerative colitis. The rate of interval colorectal cancer remained higher among IBD patients in sensitivity analyses with interval cancers defined as those diagnosed (i) 6 to 24 months after colonoscopy (IBD 11.3% vs. non-IBD 4.3%, p<0.001), or (ii) 6 to 12 months after colonoscopy (IBD 4.3% vs. non-IBD 1.6%, p<0.001). Multivariate logistic regressions confirmed the robustness of these findings (all p<0.05). Conclusions: Older patients with IBD were more than twice as likely to develop interval colorectal cancer after colonoscopy compared to those without IBD. These findings provide further evidence to support intensive surveillance colonoscopy as recommended by current guidelines.
patterns of colonic mucosa with pancolitis (with or without dysplastic changes) are distinct from the patterns of colonic mucosa from patients with left sided colitis only. Specifically the overexpression of receptors for insulin and epidermal growth factors was confirmed in pancolitis mucosa (with or without dysplastic changes), and this observation suggests that the convergence of distinct signaling pathways might be of importance for colorectal cancer development in ulcerative colitis. Sa1933 Helicobacter pylori Induces Interleukin-32 Production by Human Gastric Epithelial Cell Kosuke Sakitani, Yoshihiro Hirata, Wachiko Nakata, Hiroto Kinoshita, Ryota Takahashi, Yoku Hayakawa, Kei Sakamoto, Hayato Nakagawa, Shin Maeda, Kazuhiko Koike Introduction: Interleukin (IL)-32 is a recently described inflammatory cytokine, and reported to be an inducer of several cytokines, such as TNF-α, IL-1. Previous report showed that IL-32 expression is increased in various inflammatory diseases such as rheumatoid arthritis and Crohn's disease, and is involved in the pathogenesis. IL-32 expression is reportedly observed in several malignancies, such as lung, pancreatic and gastric cancer. However, the mechanisms of IL-32 expression in gastric tissue as well as the roles of IL-32 in the development of gastric tumor are not clarified. In this study, we examined whether stimulation of H. pylori can induce IL-32 expression by human gastric epithelial cell. Materials and Methods: IL-32 expression in human gastric mucosa was examined by the immunoblot analysis of tissue lysates and immunohistochemistry of gastric tissue specimen. Human gastric epithelial cell lines, AGS, MKN45, TMK1 cells, were co-cultured with H. pylori strain (TN2). Intracellular and extracellular IL-32 expression was determined by immunoblot analysis. IL-32 mRNA was investigated by real time RT-PCR. Immunofluorescence staining was used to examine the expression of IL-32 in AGS after stimulation with H. pylori. IL-32 expression by stimulation of isogenic mutant of cag PAI was also investigated. The intracellular signaling pathways leading to the expression of IL-32 were evaluated with the use of siRNAs to IKKβ and JNK, as well as with the use of chemical inhibitors of IKKβ, JNK, p38, and ERK. Result: Analysis of human gastric tissues by immunoblot analysis showed that IL-32 expression was higher in H. pylori-infected gastric mucosa and gastric cancer tissue than H. pylori-uninfected gastric tissue. Immunohistochemistry of gastric tissue specimen revealed that IL-32 showed cytoplasimic expressions in gastric cancer cells. Co-culture of wild type of H. pylori with AGS, MKN45, and TMK-1 cells induced IL-32 production in immunoblot analysis. IL-32 mRNA in AGS cells increased after stimulation of H. pylori for 3 hours by RT-PCR. By means of immunofluorescence staining, IL-32 was observed in cytoplasm of H. pylori-stimulated AGS cells. IL-32 expression by stimulation of isogenic mutant of cag PAI decreased in immunoblot analysis and immunofluorescence staining. H. pylori-induced IL32 was reduced by inhibition of IKKβ using SC-514, or using IKKβ siRNA transfection. Conclusion: IL-32 expression was observed in gastritis and gastric cancer tissue. H. pylori induced IL-32 expression in gastric cancer cell lines via virulence factor and NF-κB signaling pathway. These results suggest IL-32 plays a role in gastric inflammation and carcinogenesis mediated by H. pylori.
Sa1931 Clostridium difficile Associated Diarrhea is a Predictor of Mortality in Nationwide Hospitalized Bone Marrow Transplant Patients Shahryar Ahmad, Muhammad Ali, Achuta K. Guddati, Nilay Kumar, Gagan Kumar Background Since the recognition of Clostridium difficile as the causative agent of pseudomembranous colitis in 1978, it has emerged as an important nosocomial pathogen. Recipients of bone marrow transplant are considered to be at high risk for developing infections secondary to chemotherapy & immunosuppression. Disruption of colonic mucosal integrity in patients with BMT who develop graft versus host disease puts them at high risk of this toxin-mediated disease. We identified the frequency and mortality associated with Clostridium difficile Associated Diarrhea (CDAD) in Bone Marrow Transplant (BMT) patients. Methods Using the Nationwide Inpatient Sample from year 2000 - 2008, patients older than 18 years, discharged with any diagnosis of BMT & CDAD were identified using appropriate international classification of diseases (ICD-9-CM) codes. A subgroup analysis was also performed in BMT patients developing graft versus host disease. Outcome variables included frequency, all cause in-hospital mortality and length of stay (LOS) of BMT patients with or without CDAD. Using the Stata software multivariate logistic regression was performed to adjust for age, sex, race and Elixhauser co-morbidity index. Appropriate survey commands allowed weighting of the stratified data to give a national estimate. Results There were 148,755 estimated adult discharges with BMT in 2008. The frequency of CDAD was 4.6% in BMT patients. The odds of CDAD were 6.5 times higher (95%CI 5.57-7.48) in BMT related hospitalizations than hospitalizations due to other causes. The frequency of CDAD was even higher if BMT patients developed Graft versus Host disease (OR 10.1 95%CI 7.213.3) In-hospital mortality of BMT patients having CDAD was significantly higher as compared to patients without CDAD (16% vs. 9%, p<0.001). The adjusted odds ratio for mortality from CDAD in BMT patients was 1.78 times higher than patients without CDAD (95% CI 1.5-2.1). Also the median LOS in BMT patients with CDAD was significantly higher than patients without CDAD 18 vs. 5 day (p<0.001). Conclusion Using nationally representative database, this observational data reveals that CDAD significantly increases mortality in BMT patients. CDAD also significantly prolongs the hospital stay in these patients.
Sa1934 SOCS3 Promoter Hypermethylation Status in Ulcerative Colitis Related Colorectal Cancer Yi Li, Colin de Haar, Ernst J. Kuipers, Christien J. van der Woude Background and aims: Ulcerative colitis (UC) is associated with an increased risk of developing colorectal cancer (CRC). We have previously shown that increased expression of IL-6 and p-STAT3 in epithelial cells from UC-CRC patients coincided with decreased levels or the absence of the negative regulator suppressor of cytokine signaling 3 (SOCS3). Since hypermethylation of the SOCS3 promoter regions has been implicated in tumorigenesis in various cancers, we assessed whether methylation of the SOCS3 promoter was involved in the lack of SOCS3 expression in UC-CRC. Materials and methods: Methylation of the SOCS3 promoter region was examined on DNA isolated from the macro-dissected epithelial layer of colon biopsies from patients with inactive UC, active UC, and UC-CRC patients and from various colon cancer-derived epithelial cell lines. DNA was bisulfate-treated and analyzed using methylation-specific PCR and pyrosequencing. Methylation in cell lines was confirmed by studying the IL-6/p-STAT3 induced expression of SOCS3 after demethylation using 5-aza2'-deoxycytidine (DAC). Results: Various regions of the SOCS3 promoter, with binding elements for different transcription factors, were methylated in DNA from UC-CRC biospies. No signs of SOCS3 promoter methylation was dected in inactive-UC patients, whereas limited methylation was detected in some of the active UC patients. In all the CRC cell lines, the SOCS3 methylation status correlated with the disability to upregulate SOCS3 upon IL-6 stimulation. Treatment with DAC restored IL-6 induced SOCS3 expression in the cells. Conclusion: Hypermethylation of the SOCS3 promoter region was detected in UC-CRC and in some of the CRC cell lines, explaining the lack of SOCS3 expression. Methylation of the SOCS3 enables uncontrolled IL-6/p-STAT3 signaling leading to enhanced proliferation and survival associated with carcinogenesis. As such, the restoration of SOCS3 may provide therapeutic target for UC-CRC.
Sa1932 Overexpression of Receptors for Insulin and Epidermal Growth Factor in Dysplastic Inflamed Colonic Mucosa Correlates With Increased Cancer Risk in Patients With Ulcerative Colitis Jørgen Olsen, Jacob T. Bjerrum, Morten Hansen, Jesper T. Troelsen, Valérie Pittet, Christoph Mueller, Gerhard Rogler, Ole H. Nielsen Background and Aims Patients with long term ulcerative colitis hold an increased risk for colorectal cancer development. The extension of the disease is positively correlated with the risk of cancer development. The purpose of the present work was to test the hypothesis that the inflammation associated with widespread disease (pancolitis) is molecular distinct from the inflammation in less extensive disease (e.g. left sided colitis only). Methods Mucosal pinch biopsies were obtained at colonoscopy from the descending colon displaying active inflammation (i.e. a Mayo score >2). Forty seven patients with active mucosal inflammation were enrolled (8 with dysplastic mucosa, 18 with pancolitis and 21 with left sided colitis only). Genome-wide gene expression analysis was conducted. Biostatistics analyses involved principal component analysis, Hotelling T-square test, and overrepresentation analysis for Gene Ontology terms. Results Distinct clustering of the three groups of patients were revealed (dysplasia, pancolitis, and left sided colitis only). Hotelling T-square test confirmed significant differences in gene expression signatures (dysplasia versus pancolitis P<0.05; pancolitis versus left sided colitis only P< 10-11). Annotation analysis suggested differences in the expression of genes involved in peptide hormone and insulin signaling as being important for defining the dysplastic and pancolitis expression patterns. Comparison between groups (dysplasia versus left sided colitis) let to the identification of 102 differentially expressed genes (all with more than a two-fold up-regulation; false discovery rate < 0.001). Several receptors for growth factors and cytokines were found to be up-regulated including epidermal growth factor receptor and the insulin receptor. Conclusions The gene expression
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Sa1935 Large Scale Genomic Instability in Patients With Colorectal Cancer in Inflammatory Bowel Disease. Association With Clinicohistological Factors and Survival Stephan Brackmann, Maria E. Pretorius, Solveig N. Andersen, Frøydis Langmark, Ole P. F. Clausen, Morten H. Vatn, Havard E. Danielsen Background: The risk of colorectal cancer (CRC) in inflammatory bowel diseases (IBD) is increased compared to the background population (sporadic CRC). Risk factors for CRCIBD include clinicohistological factors. DNA content (ploidy status) is an independent risk factor for survival in patients with sporadic CRC in whom large scale genomic instability
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in several cancer cell lines originating from tissues other then colon. In colorectal cancer cells, 5-ASA did not affect any of the pathways known to control the tuberous sclerosis complex (TSC), a major regulator of mTOR activity, including the AMPK, PKB/Akt and MAPK pathways. Indeed the 5-ASA effect was independent of TSC-integrity as assessed by knockdown of TSC-component TSC2. Using inhibitors and knockdown experiments, we were able to show that in colorectal cancer cells both proliferation and mTOR activity depended on PLD, an enzyme that generates phosphatidic acid (PA). 5-ASA treatment inhibited both PLD-activity and proliferation, and these effects could be rescued with exogenous PA. We conclude that 5-ASA interferes with proliferation of colorectal cancer cells via inhibition of PLD-dependent generation of PA and consequent loss of mTOR signaling. Sa1938 Different Risk Factors for Colitis Associated Colorectal Cancer in Ulcerative Colitis and Crohn's Disease Maurice W. Lutgens, Peter D. Siersema, Frank P. Vleggaar, Mark Broekman, Martijn G. van Oijen, Adriaan A. van Bodegraven, Gerard Dijkstra, Daniel W. Hommes, Dirk J. De Jong, Cyriel Ponsioen, Christien J. van der Woude, Bas Oldenburg Background: Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). However, the risk might not the same for every patient. It is not exactly known which factors increase CRC risk in subgroups of IBD, i.e., ulcerative colitis (UC) and Crohn's disease (CD). This information could help in further refining surveillance strategies to prevent advanced neoplasia in high risk patients. Aim: To identify risk factors for IBD-associated CRC in UC and CD. Methods: We designed a retrospective case-control study. All IBD-associated CRC cases diagnosed between 1990 and 2006 in 7 tertiary referral centers in the Netherlands were selected via the nationwide pathology database (PALGA). This tool was also used to identify controls matched to our referral population in a 1:2 ratio. Follow-up started Jan. 1, 1990 for all cases and controls. We chose this fixed date to adjust for varying incidence IBD diagnosis dates. All patient variables at that time point were collected from patient charts. Disease duration until Jan. 1, 1990 was used as a variable in the multivariate analysis. Disease extent was measured as more or less than 50% colonic inflammation for both UC and CD. Hazard ratios (HR) were calculated for patient variables by multivariate Cox regression. The endpoints were CRC and end of follow-up (proctocolectomy, end of study or lost to follow-up). Results: In total, 118 IBDassociated CRCs were diagnosed since Jan. 1, 1990. We identified 206 controls. Mean follow up after January 1st 1990 was 4059 days. The risk of CRC in CD was only half of the risk in UC (HR 0.5; 95%CI 0.3-0.7). Risk factors for CRC in UC were disease extent (>50% of the colon) (HR 3.0; 95%CI 1.4-6.5), presence of pseudopolyps (HR 2.5; 95%CI 1.2-5.2) and colonic stenosis (HR 5.2; 95%CI 2.6-10.3), whereas 5-ASA use >3 months was protecting (HR 0.4; 95%CI 0.2-0.8). A risk factor for CRC in CD was disease extent >50% of the colon (HR 4.7; 95%CI 1.6-14.1), whereas 5-ASA use >3 months was protecting (HR 0.4; 95%CI 0.2-0.9). The co-presence of primary sclerosing cholangitis was also associated with an increased hazard ratio but this was not statistically significant (UC: HR 1.7; 95%CI 0.6-4.3, CD: HR 1.8; 95%CI 0.2-14.8). Conclusion: Disease extent is an important risk factor for in both UC and CD for developing CRC, whereas 5-ASA medication is protective in both disorders. Pseudopolyps and colonic stenosis are only associated with CRC development in patients with UC.
Sa1936 VEGFR2 Signaling in Intestinal Epithelial Cells Drives Development of Colitis-Associated Colon Cancer Maximilian J. Waldner, Stefan J. Wirtz, Andre Jefremow, Clemens Neufert, Raja Atreya, Christoph Becker, Benno Weigmann, Michael Vieth, Stefan Rose-John, Markus F. Neurath Vascular endothelial growth factor (VEGF) has been regarded as a critical regulator of tumorangiogenesis in colorectal cancer (CRC) and the importance of VEGF-signaling is supported by the success of anti-VEGF therapeutics in affected patients. Whereas these data refer to sporadic tumor development, CRC can also evolve as a consequence of chronic intestinal inflammation as seen in patients with inflammatory bowel disease (IBD). Since the contribution of VEGF to this so-called colitis-associated cancer (CAC) has not been evaluated so far, the aim of this study was to determine the role of VEGF-signaling in the AOM+DSS mouse model of CAC. Wildtype and various transgenic mice were exposed to the AOM+DSS model and analyzed for tumor development with Narrow Band Imaging (NBI) endoscopy. The expression of VEGF and its receptors VEGFR1 and VEGFR2 was characterized by realtime PCR, immunohistochemistry, ELISA, Western blot analysis, and In Vivo luminescence imaging. The functional relevance of VEGF-signaling was analyzed with soluble decoy receptors for VEGF and conditional knock-out mice for VEGFR2. Intestinal inflammation induced by the AOM+DSS model resulted in an increased expression of VEGF and VEGFR2. Thereby, VEGFR2 expression was not only detected on vascular endothelial cells but also on intestinal epithelial cells (IECs). Mice treated with anti-VEGF soluble decoy receptors showed reduced tumor growth as a consequence of an inhibition of both, angiogenesis and VEGF-mediated tumor cell proliferation. Further In Vivo and In Vitro studies showed that VEGF was able to directly increase tumor cell proliferation in an autocrine fashion. This VEGF-dependent proliferation was mediated by the activation of VEGFR2 expressed by tumor cells and subsequent intracellular STAT3-phosphorylation. Interestingly, the expression of VEGFR2 was upregulated through the pro-inflammatory cytokine IL-6 and could not only be detected in tumor cells, but also in intestinal epithelial cells of the inflamed colon of AOM+DSS treated mice and patients with IBD. Thus, we conclude that the activation of VEGFR2 on intestinal epithelial cells supports the development of CAC and represents a new link between chronic intestinal inflammation and tumor development. The inhibition of VEGF through molecular therapeutics, which are frequently used in sporadic CRC, might also provide an important option for patients with CAC.
Sa1939 Primary Sclerosing Cholangitis is Equally Associated With Increased Risk for Colorectal Neoplasia in Ulcerative Colitis and Crohn's Disease Peter Rosenberg, Jan A. Björk, Anette Storlåhls, Ragnar Befrits BACKGROUND: Previous studies has shown that primary sclerosing cholangitis (PSC) increases the risk for patients with ulcerative colitis to develop colorectal neoplasia. Aim of this study was to evaluate if this also applies to patients with PSC and Crohn's disease. METHODS: Patients were identified using the IBD-registry at Karolinska University Hospital that includes 2149 patients (1015 women), treated at this hospital between years 1998 and 2010. Clinical data were acquired from the registry and from the medical charts. RESULTS: Eighty-nine patients (4.14%, 31 women), had PSC of which 67 had UC, 21 CD and one IC. 2059 patients (1097 women) did not have PSC of which 1149 had UC, 857 CD and 53 IC. Of those with PSC eight (9%, p=0.001, 6 UC, 2 CD) had developed colorectal cancer (CRC) compared to 21 (1%, 9 UC, 12 CD) of those without PSC. Ten patients (11.2%, p= 0.0033, 8 UC, 2 CD) with PSC had dysplasia as compared to 80 (3.9%, 27 UC, 53 CD) of those without PSC. 23 PSC patients (26%, p=0.0049, 20 UC, 3 CD) had underwent surgery with ileorectal anastomosis, ileostomy och pelvic pouch compared to 288 (14%, 111 UC, 173 CD) of those without PSC. CONCLUSION: In this cohort of IBD-patients, those with PSC had a higher occurrence of colorectal dysplasia and cancer and an increased frequency of colectomy. Within the PSC group as well as non-PSC group, there was no difference in occurrence of colorectal neoplasia between UC and CD. This indicates that PSC is associated with increased risk for colorectal neoplasia regardless of the underlying IBD-diagnosis.
Sa1937 5-ASA Inhibits Phospolipase D-Dependent Mammalian Target of Rapamycin Signaling in Colorectal Cancer Bart Baan, Ashwin A. Dihal, Eva Hoff, Philip W. Voorneveld, Pim J. Koelink, Hein W. Verspaget, Dick J. Richel, James C. Hardwick, Daniel W. Hommes, Maikel P. Peppelenbosch, Gijs R. van den Brink Mesalamine or 5-aminosalicylic acid (5-ASA) is a cornerstone in the induction and maintenance of remission of patients with ulcerative colitis. In addition to its anti-inflammatory activity it may also protect against the development of inflammation-associated colorectal cancer. The molecular mechanism of the anti-inflammatory and anti-cancer actions of 5ASA remain to be fully determined. Here we focus on mammalian Target of Rapamycin (mTOR), an important regulator of cell cycle progression, and examine the anti-proliferative effects of 5-ASA on colorectal cancer In Vitro and In Vivo and aim to dissect the signal transduction events that lead to 5-ASA mediated inhibition of proliferation in colorectal cancer cells. We examined the effect of 5-ASA on mTOR signaling in a panel of cancer cell lines originating from different tissues. Effects of 5-ASA on the pathways that control mTOR activity were studied in detail in two different colorectal cancer cell lines, using western blot, siRNA, a phospholipase D (PLD) activity assay and proliferation assays. The phosphorylation status of mTOR and its downstream target, ribosomal protein S6, was studied in colorectal cancer biopsies taken from patients before and after topical 5-ASA treatment. We found that treatment of colorectal cancer with 5-ASA inhibited mTOR signaling In Vitro and In Vivo. This effect seemed to be generic, as 5-ASA treatment also reduced mTOR signaling
Sa1940 Risk Factors for Advanced Neoplasia of the Rectal Stump in IBD Patients Maurice W. Lutgens, Peter D. Siersema, Frank P. Vleggaar, Mark Broekman, Martijn G. van Oijen, Adriaan A. van Bodegraven, Gerard Dijkstra, Daniel W. Hommes, Dirk J. De Jong, Cyriel Ponsioen, Christien J. van der Woude, Bas Oldenburg Background: Inflammatory bowel disease (IBD) patients are at an increased risk of colorectal cancer (CRC). Therefore colonoscopic surveillance is performed with proctocolectomy in patients with advanced neoplasia. However, some IBD patients undergo subtotal colectomy for refractory disease or colonic dysplasia and retain a rectal stump. The risk of developing advanced neoplasia is largely unknown in these patients. Aim: To identify risk factors for developing high grade dysplasia or carcinoma of the rectal stump. Methods: IBD-associated
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(aneuploidy) is associated with poorer prognosis. The association of clinicohistological factors with ploidy status and the effect of ploidy status on survival in patients with CRC-IBD are not well defined. Aim: To evaluate the association between DNA content in colon adenocarcinoma cells and clinicohistological risk factors as well as survival in patients with CRC-IBD. Method: Ploidy status of colon adenocarcinoma cells in 50 patients with CRCIBD (44 CRC in ulcerative colitis, 6 CRC in Crohn`s colitis) selected by matching the Norwegian Cancer Registry with IBD cohorts of three university hospitals in Oslo was measured by high-resolution image cytometry. Clinicohistological factors as previously described in this cohort were included. The association of clinicohistological factors and ploidy status were analyzed by non-parametric tests (Mann-Whitney) and the effect of ploidy status on survival by an adjusted Cox regression model. Results: 18/50 (36 %) patients with CRC-IBD showed euploid (13 diploid, 5 tetraploid) and 32/50 (64%) patients aneuploid tumors. Fifteen patients died of CRC related causes, four patients of CRC unrelated causes, four of unknown cause and 27 patients were alive at the end of the study. Adjusted for age at diagnosis of CRC and stage of CRC (stage 1,2,3 versus stage 4), patients with aneuploid CRC showed poorer overall survival compared to patients with euploid CRC (OR=3.275, 95%CI: 1.07-10.04, p=0.038), and, as a tendency, poorer CRC-specific survival (OR=3.252, 95%CI: 0.86-12.27,p=0.082). Median age at diagnosis of IBD was higher in euploid compared to aneuploid CRC-IBD patients (30y and 24y, respectively, p=0.045). Duration and type of IBD, active colonic inflammation and extent of inflammation at diagnosis of CRC, medication (5ASA compounds), concomitant primary sclerosing cholangitis, localization of the tumor in the colon (right versus left), the extent of neoplasia in the colon (multifocal versus unifocal), type and differentiation grade of adenocarcinomas were not associated with ploidy status, nor did they influence the effect of the ploidy status on survival. Conclusion: DNA content in colon adenocarcinomas measured by image cytometry is an independent predictor of prognosis in patients with CRC-IBD in our cohort. Patients with aneuploid CRC-IBD showed poorer survival than patients with diploid CRC. We could not identify clinical or histological risk factors for aneuploid CRC in our material.
patients with IBD and to assess the adequacy of surveillance colonoscopy every 1-2 years for these patients. Data and Methods: All patients in the Surveillance, Epidemiology and End Results Medicare (SEER-Medicare) linked database who were 67 years or older at the time of their first colonoscopy between 01/01/1998 and 12/31/2002 and subsequently diagnosed with colorectal cancer within 36 months (through 12/31/2005) were identified. We excluded Medicare HMO enrollees or those without Part B coverage in the 24 months prior to colonoscopy. Patients with pre-existing IBD were identified using the ICD-9 diagnosis codes 555 (Crohn's disease) and 556 (ulcerative colitis). Similar to previous studies, colorectal cancers diagnosed within 6 months of colonoscopy were categorized as detected cancers and those diagnosed 6 to 36 months after colonoscopy were categorized as interval cancers. The chi-square test and multivariate logistic regression were used in statistical analysis comparing interval and detected colorectal cancers. Results: Of the 31,045 patients included in the study, 562 (1.8%) had pre-existing IBD (208 Crohn's disease, 346 ulcerative colitis, and 8 indeterminate). The rates of interval colorectal cancer were 17.3% (97/562) among IBD patients and 6.9% (2,106/30,483) among non-IBD patients (p<0.001). Of the 2,203 patients with interval colorectal cancer, there was no difference between IBD and non-IBD patients in cancer location or grade, but interval cancers among IBD patients were more likely TNM stage I (36.1% vs. 26.1%, p<0.05). There was no significant difference between patients with Crohn's disease and those with ulcerative colitis. The rate of interval colorectal cancer remained higher among IBD patients in sensitivity analyses with interval cancers defined as those diagnosed (i) 6 to 24 months after colonoscopy (IBD 11.3% vs. non-IBD 4.3%, p<0.001), or (ii) 6 to 12 months after colonoscopy (IBD 4.3% vs. non-IBD 1.6%, p<0.001). Multivariate logistic regressions confirmed the robustness of these findings (all p<0.05). Conclusions: Older patients with IBD were more than twice as likely to develop interval colorectal cancer after colonoscopy compared to those without IBD. These findings provide further evidence to support intensive surveillance colonoscopy as recommended by current guidelines.
patterns of colonic mucosa with pancolitis (with or without dysplastic changes) are distinct from the patterns of colonic mucosa from patients with left sided colitis only. Specifically the overexpression of receptors for insulin and epidermal growth factors was confirmed in pancolitis mucosa (with or without dysplastic changes), and this observation suggests that the convergence of distinct signaling pathways might be of importance for colorectal cancer development in ulcerative colitis. Sa1933 Helicobacter pylori Induces Interleukin-32 Production by Human Gastric Epithelial Cell Kosuke Sakitani, Yoshihiro Hirata, Wachiko Nakata, Hiroto Kinoshita, Ryota Takahashi, Yoku Hayakawa, Kei Sakamoto, Hayato Nakagawa, Shin Maeda, Kazuhiko Koike Introduction: Interleukin (IL)-32 is a recently described inflammatory cytokine, and reported to be an inducer of several cytokines, such as TNF-α, IL-1. Previous report showed that IL-32 expression is increased in various inflammatory diseases such as rheumatoid arthritis and Crohn's disease, and is involved in the pathogenesis. IL-32 expression is reportedly observed in several malignancies, such as lung, pancreatic and gastric cancer. However, the mechanisms of IL-32 expression in gastric tissue as well as the roles of IL-32 in the development of gastric tumor are not clarified. In this study, we examined whether stimulation of H. pylori can induce IL-32 expression by human gastric epithelial cell. Materials and Methods: IL-32 expression in human gastric mucosa was examined by the immunoblot analysis of tissue lysates and immunohistochemistry of gastric tissue specimen. Human gastric epithelial cell lines, AGS, MKN45, TMK1 cells, were co-cultured with H. pylori strain (TN2). Intracellular and extracellular IL-32 expression was determined by immunoblot analysis. IL-32 mRNA was investigated by real time RT-PCR. Immunofluorescence staining was used to examine the expression of IL-32 in AGS after stimulation with H. pylori. IL-32 expression by stimulation of isogenic mutant of cag PAI was also investigated. The intracellular signaling pathways leading to the expression of IL-32 were evaluated with the use of siRNAs to IKKβ and JNK, as well as with the use of chemical inhibitors of IKKβ, JNK, p38, and ERK. Result: Analysis of human gastric tissues by immunoblot analysis showed that IL-32 expression was higher in H. pylori-infected gastric mucosa and gastric cancer tissue than H. pylori-uninfected gastric tissue. Immunohistochemistry of gastric tissue specimen revealed that IL-32 showed cytoplasimic expressions in gastric cancer cells. Co-culture of wild type of H. pylori with AGS, MKN45, and TMK-1 cells induced IL-32 production in immunoblot analysis. IL-32 mRNA in AGS cells increased after stimulation of H. pylori for 3 hours by RT-PCR. By means of immunofluorescence staining, IL-32 was observed in cytoplasm of H. pylori-stimulated AGS cells. IL-32 expression by stimulation of isogenic mutant of cag PAI decreased in immunoblot analysis and immunofluorescence staining. H. pylori-induced IL32 was reduced by inhibition of IKKβ using SC-514, or using IKKβ siRNA transfection. Conclusion: IL-32 expression was observed in gastritis and gastric cancer tissue. H. pylori induced IL-32 expression in gastric cancer cell lines via virulence factor and NF-κB signaling pathway. These results suggest IL-32 plays a role in gastric inflammation and carcinogenesis mediated by H. pylori.
Sa1931 Clostridium difficile Associated Diarrhea is a Predictor of Mortality in Nationwide Hospitalized Bone Marrow Transplant Patients Shahryar Ahmad, Muhammad Ali, Achuta K. Guddati, Nilay Kumar, Gagan Kumar Background Since the recognition of Clostridium difficile as the causative agent of pseudomembranous colitis in 1978, it has emerged as an important nosocomial pathogen. Recipients of bone marrow transplant are considered to be at high risk for developing infections secondary to chemotherapy & immunosuppression. Disruption of colonic mucosal integrity in patients with BMT who develop graft versus host disease puts them at high risk of this toxin-mediated disease. We identified the frequency and mortality associated with Clostridium difficile Associated Diarrhea (CDAD) in Bone Marrow Transplant (BMT) patients. Methods Using the Nationwide Inpatient Sample from year 2000 - 2008, patients older than 18 years, discharged with any diagnosis of BMT & CDAD were identified using appropriate international classification of diseases (ICD-9-CM) codes. A subgroup analysis was also performed in BMT patients developing graft versus host disease. Outcome variables included frequency, all cause in-hospital mortality and length of stay (LOS) of BMT patients with or without CDAD. Using the Stata software multivariate logistic regression was performed to adjust for age, sex, race and Elixhauser co-morbidity index. Appropriate survey commands allowed weighting of the stratified data to give a national estimate. Results There were 148,755 estimated adult discharges with BMT in 2008. The frequency of CDAD was 4.6% in BMT patients. The odds of CDAD were 6.5 times higher (95%CI 5.57-7.48) in BMT related hospitalizations than hospitalizations due to other causes. The frequency of CDAD was even higher if BMT patients developed Graft versus Host disease (OR 10.1 95%CI 7.213.3) In-hospital mortality of BMT patients having CDAD was significantly higher as compared to patients without CDAD (16% vs. 9%, p<0.001). The adjusted odds ratio for mortality from CDAD in BMT patients was 1.78 times higher than patients without CDAD (95% CI 1.5-2.1). Also the median LOS in BMT patients with CDAD was significantly higher than patients without CDAD 18 vs. 5 day (p<0.001). Conclusion Using nationally representative database, this observational data reveals that CDAD significantly increases mortality in BMT patients. CDAD also significantly prolongs the hospital stay in these patients.
Sa1934 SOCS3 Promoter Hypermethylation Status in Ulcerative Colitis Related Colorectal Cancer Yi Li, Colin de Haar, Ernst J. Kuipers, Christien J. van der Woude Background and aims: Ulcerative colitis (UC) is associated with an increased risk of developing colorectal cancer (CRC). We have previously shown that increased expression of IL-6 and p-STAT3 in epithelial cells from UC-CRC patients coincided with decreased levels or the absence of the negative regulator suppressor of cytokine signaling 3 (SOCS3). Since hypermethylation of the SOCS3 promoter regions has been implicated in tumorigenesis in various cancers, we assessed whether methylation of the SOCS3 promoter was involved in the lack of SOCS3 expression in UC-CRC. Materials and methods: Methylation of the SOCS3 promoter region was examined on DNA isolated from the macro-dissected epithelial layer of colon biopsies from patients with inactive UC, active UC, and UC-CRC patients and from various colon cancer-derived epithelial cell lines. DNA was bisulfate-treated and analyzed using methylation-specific PCR and pyrosequencing. Methylation in cell lines was confirmed by studying the IL-6/p-STAT3 induced expression of SOCS3 after demethylation using 5-aza2'-deoxycytidine (DAC). Results: Various regions of the SOCS3 promoter, with binding elements for different transcription factors, were methylated in DNA from UC-CRC biospies. No signs of SOCS3 promoter methylation was dected in inactive-UC patients, whereas limited methylation was detected in some of the active UC patients. In all the CRC cell lines, the SOCS3 methylation status correlated with the disability to upregulate SOCS3 upon IL-6 stimulation. Treatment with DAC restored IL-6 induced SOCS3 expression in the cells. Conclusion: Hypermethylation of the SOCS3 promoter region was detected in UC-CRC and in some of the CRC cell lines, explaining the lack of SOCS3 expression. Methylation of the SOCS3 enables uncontrolled IL-6/p-STAT3 signaling leading to enhanced proliferation and survival associated with carcinogenesis. As such, the restoration of SOCS3 may provide therapeutic target for UC-CRC.
Sa1932 Overexpression of Receptors for Insulin and Epidermal Growth Factor in Dysplastic Inflamed Colonic Mucosa Correlates With Increased Cancer Risk in Patients With Ulcerative Colitis Jørgen Olsen, Jacob T. Bjerrum, Morten Hansen, Jesper T. Troelsen, Valérie Pittet, Christoph Mueller, Gerhard Rogler, Ole H. Nielsen Background and Aims Patients with long term ulcerative colitis hold an increased risk for colorectal cancer development. The extension of the disease is positively correlated with the risk of cancer development. The purpose of the present work was to test the hypothesis that the inflammation associated with widespread disease (pancolitis) is molecular distinct from the inflammation in less extensive disease (e.g. left sided colitis only). Methods Mucosal pinch biopsies were obtained at colonoscopy from the descending colon displaying active inflammation (i.e. a Mayo score >2). Forty seven patients with active mucosal inflammation were enrolled (8 with dysplastic mucosa, 18 with pancolitis and 21 with left sided colitis only). Genome-wide gene expression analysis was conducted. Biostatistics analyses involved principal component analysis, Hotelling T-square test, and overrepresentation analysis for Gene Ontology terms. Results Distinct clustering of the three groups of patients were revealed (dysplasia, pancolitis, and left sided colitis only). Hotelling T-square test confirmed significant differences in gene expression signatures (dysplasia versus pancolitis P<0.05; pancolitis versus left sided colitis only P< 10-11). Annotation analysis suggested differences in the expression of genes involved in peptide hormone and insulin signaling as being important for defining the dysplastic and pancolitis expression patterns. Comparison between groups (dysplasia versus left sided colitis) let to the identification of 102 differentially expressed genes (all with more than a two-fold up-regulation; false discovery rate < 0.001). Several receptors for growth factors and cytokines were found to be up-regulated including epidermal growth factor receptor and the insulin receptor. Conclusions The gene expression
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Sa1935 Large Scale Genomic Instability in Patients With Colorectal Cancer in Inflammatory Bowel Disease. Association With Clinicohistological Factors and Survival Stephan Brackmann, Maria E. Pretorius, Solveig N. Andersen, Frøydis Langmark, Ole P. F. Clausen, Morten H. Vatn, Havard E. Danielsen Background: The risk of colorectal cancer (CRC) in inflammatory bowel diseases (IBD) is increased compared to the background population (sporadic CRC). Risk factors for CRCIBD include clinicohistological factors. DNA content (ploidy status) is an independent risk factor for survival in patients with sporadic CRC in whom large scale genomic instability
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in several cancer cell lines originating from tissues other then colon. In colorectal cancer cells, 5-ASA did not affect any of the pathways known to control the tuberous sclerosis complex (TSC), a major regulator of mTOR activity, including the AMPK, PKB/Akt and MAPK pathways. Indeed the 5-ASA effect was independent of TSC-integrity as assessed by knockdown of TSC-component TSC2. Using inhibitors and knockdown experiments, we were able to show that in colorectal cancer cells both proliferation and mTOR activity depended on PLD, an enzyme that generates phosphatidic acid (PA). 5-ASA treatment inhibited both PLD-activity and proliferation, and these effects could be rescued with exogenous PA. We conclude that 5-ASA interferes with proliferation of colorectal cancer cells via inhibition of PLD-dependent generation of PA and consequent loss of mTOR signaling. Sa1938 Different Risk Factors for Colitis Associated Colorectal Cancer in Ulcerative Colitis and Crohn's Disease Maurice W. Lutgens, Peter D. Siersema, Frank P. Vleggaar, Mark Broekman, Martijn G. van Oijen, Adriaan A. van Bodegraven, Gerard Dijkstra, Daniel W. Hommes, Dirk J. De Jong, Cyriel Ponsioen, Christien J. van der Woude, Bas Oldenburg Background: Patients with inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC). However, the risk might not the same for every patient. It is not exactly known which factors increase CRC risk in subgroups of IBD, i.e., ulcerative colitis (UC) and Crohn's disease (CD). This information could help in further refining surveillance strategies to prevent advanced neoplasia in high risk patients. Aim: To identify risk factors for IBD-associated CRC in UC and CD. Methods: We designed a retrospective case-control study. All IBD-associated CRC cases diagnosed between 1990 and 2006 in 7 tertiary referral centers in the Netherlands were selected via the nationwide pathology database (PALGA). This tool was also used to identify controls matched to our referral population in a 1:2 ratio. Follow-up started Jan. 1, 1990 for all cases and controls. We chose this fixed date to adjust for varying incidence IBD diagnosis dates. All patient variables at that time point were collected from patient charts. Disease duration until Jan. 1, 1990 was used as a variable in the multivariate analysis. Disease extent was measured as more or less than 50% colonic inflammation for both UC and CD. Hazard ratios (HR) were calculated for patient variables by multivariate Cox regression. The endpoints were CRC and end of follow-up (proctocolectomy, end of study or lost to follow-up). Results: In total, 118 IBDassociated CRCs were diagnosed since Jan. 1, 1990. We identified 206 controls. Mean follow up after January 1st 1990 was 4059 days. The risk of CRC in CD was only half of the risk in UC (HR 0.5; 95%CI 0.3-0.7). Risk factors for CRC in UC were disease extent (>50% of the colon) (HR 3.0; 95%CI 1.4-6.5), presence of pseudopolyps (HR 2.5; 95%CI 1.2-5.2) and colonic stenosis (HR 5.2; 95%CI 2.6-10.3), whereas 5-ASA use >3 months was protecting (HR 0.4; 95%CI 0.2-0.8). A risk factor for CRC in CD was disease extent >50% of the colon (HR 4.7; 95%CI 1.6-14.1), whereas 5-ASA use >3 months was protecting (HR 0.4; 95%CI 0.2-0.9). The co-presence of primary sclerosing cholangitis was also associated with an increased hazard ratio but this was not statistically significant (UC: HR 1.7; 95%CI 0.6-4.3, CD: HR 1.8; 95%CI 0.2-14.8). Conclusion: Disease extent is an important risk factor for in both UC and CD for developing CRC, whereas 5-ASA medication is protective in both disorders. Pseudopolyps and colonic stenosis are only associated with CRC development in patients with UC.
Sa1936 VEGFR2 Signaling in Intestinal Epithelial Cells Drives Development of Colitis-Associated Colon Cancer Maximilian J. Waldner, Stefan J. Wirtz, Andre Jefremow, Clemens Neufert, Raja Atreya, Christoph Becker, Benno Weigmann, Michael Vieth, Stefan Rose-John, Markus F. Neurath Vascular endothelial growth factor (VEGF) has been regarded as a critical regulator of tumorangiogenesis in colorectal cancer (CRC) and the importance of VEGF-signaling is supported by the success of anti-VEGF therapeutics in affected patients. Whereas these data refer to sporadic tumor development, CRC can also evolve as a consequence of chronic intestinal inflammation as seen in patients with inflammatory bowel disease (IBD). Since the contribution of VEGF to this so-called colitis-associated cancer (CAC) has not been evaluated so far, the aim of this study was to determine the role of VEGF-signaling in the AOM+DSS mouse model of CAC. Wildtype and various transgenic mice were exposed to the AOM+DSS model and analyzed for tumor development with Narrow Band Imaging (NBI) endoscopy. The expression of VEGF and its receptors VEGFR1 and VEGFR2 was characterized by realtime PCR, immunohistochemistry, ELISA, Western blot analysis, and In Vivo luminescence imaging. The functional relevance of VEGF-signaling was analyzed with soluble decoy receptors for VEGF and conditional knock-out mice for VEGFR2. Intestinal inflammation induced by the AOM+DSS model resulted in an increased expression of VEGF and VEGFR2. Thereby, VEGFR2 expression was not only detected on vascular endothelial cells but also on intestinal epithelial cells (IECs). Mice treated with anti-VEGF soluble decoy receptors showed reduced tumor growth as a consequence of an inhibition of both, angiogenesis and VEGF-mediated tumor cell proliferation. Further In Vivo and In Vitro studies showed that VEGF was able to directly increase tumor cell proliferation in an autocrine fashion. This VEGF-dependent proliferation was mediated by the activation of VEGFR2 expressed by tumor cells and subsequent intracellular STAT3-phosphorylation. Interestingly, the expression of VEGFR2 was upregulated through the pro-inflammatory cytokine IL-6 and could not only be detected in tumor cells, but also in intestinal epithelial cells of the inflamed colon of AOM+DSS treated mice and patients with IBD. Thus, we conclude that the activation of VEGFR2 on intestinal epithelial cells supports the development of CAC and represents a new link between chronic intestinal inflammation and tumor development. The inhibition of VEGF through molecular therapeutics, which are frequently used in sporadic CRC, might also provide an important option for patients with CAC.
Sa1939 Primary Sclerosing Cholangitis is Equally Associated With Increased Risk for Colorectal Neoplasia in Ulcerative Colitis and Crohn's Disease Peter Rosenberg, Jan A. Björk, Anette Storlåhls, Ragnar Befrits BACKGROUND: Previous studies has shown that primary sclerosing cholangitis (PSC) increases the risk for patients with ulcerative colitis to develop colorectal neoplasia. Aim of this study was to evaluate if this also applies to patients with PSC and Crohn's disease. METHODS: Patients were identified using the IBD-registry at Karolinska University Hospital that includes 2149 patients (1015 women), treated at this hospital between years 1998 and 2010. Clinical data were acquired from the registry and from the medical charts. RESULTS: Eighty-nine patients (4.14%, 31 women), had PSC of which 67 had UC, 21 CD and one IC. 2059 patients (1097 women) did not have PSC of which 1149 had UC, 857 CD and 53 IC. Of those with PSC eight (9%, p=0.001, 6 UC, 2 CD) had developed colorectal cancer (CRC) compared to 21 (1%, 9 UC, 12 CD) of those without PSC. Ten patients (11.2%, p= 0.0033, 8 UC, 2 CD) with PSC had dysplasia as compared to 80 (3.9%, 27 UC, 53 CD) of those without PSC. 23 PSC patients (26%, p=0.0049, 20 UC, 3 CD) had underwent surgery with ileorectal anastomosis, ileostomy och pelvic pouch compared to 288 (14%, 111 UC, 173 CD) of those without PSC. CONCLUSION: In this cohort of IBD-patients, those with PSC had a higher occurrence of colorectal dysplasia and cancer and an increased frequency of colectomy. Within the PSC group as well as non-PSC group, there was no difference in occurrence of colorectal neoplasia between UC and CD. This indicates that PSC is associated with increased risk for colorectal neoplasia regardless of the underlying IBD-diagnosis.
Sa1937 5-ASA Inhibits Phospolipase D-Dependent Mammalian Target of Rapamycin Signaling in Colorectal Cancer Bart Baan, Ashwin A. Dihal, Eva Hoff, Philip W. Voorneveld, Pim J. Koelink, Hein W. Verspaget, Dick J. Richel, James C. Hardwick, Daniel W. Hommes, Maikel P. Peppelenbosch, Gijs R. van den Brink Mesalamine or 5-aminosalicylic acid (5-ASA) is a cornerstone in the induction and maintenance of remission of patients with ulcerative colitis. In addition to its anti-inflammatory activity it may also protect against the development of inflammation-associated colorectal cancer. The molecular mechanism of the anti-inflammatory and anti-cancer actions of 5ASA remain to be fully determined. Here we focus on mammalian Target of Rapamycin (mTOR), an important regulator of cell cycle progression, and examine the anti-proliferative effects of 5-ASA on colorectal cancer In Vitro and In Vivo and aim to dissect the signal transduction events that lead to 5-ASA mediated inhibition of proliferation in colorectal cancer cells. We examined the effect of 5-ASA on mTOR signaling in a panel of cancer cell lines originating from different tissues. Effects of 5-ASA on the pathways that control mTOR activity were studied in detail in two different colorectal cancer cell lines, using western blot, siRNA, a phospholipase D (PLD) activity assay and proliferation assays. The phosphorylation status of mTOR and its downstream target, ribosomal protein S6, was studied in colorectal cancer biopsies taken from patients before and after topical 5-ASA treatment. We found that treatment of colorectal cancer with 5-ASA inhibited mTOR signaling In Vitro and In Vivo. This effect seemed to be generic, as 5-ASA treatment also reduced mTOR signaling
Sa1940 Risk Factors for Advanced Neoplasia of the Rectal Stump in IBD Patients Maurice W. Lutgens, Peter D. Siersema, Frank P. Vleggaar, Mark Broekman, Martijn G. van Oijen, Adriaan A. van Bodegraven, Gerard Dijkstra, Daniel W. Hommes, Dirk J. De Jong, Cyriel Ponsioen, Christien J. van der Woude, Bas Oldenburg Background: Inflammatory bowel disease (IBD) patients are at an increased risk of colorectal cancer (CRC). Therefore colonoscopic surveillance is performed with proctocolectomy in patients with advanced neoplasia. However, some IBD patients undergo subtotal colectomy for refractory disease or colonic dysplasia and retain a rectal stump. The risk of developing advanced neoplasia is largely unknown in these patients. Aim: To identify risk factors for developing high grade dysplasia or carcinoma of the rectal stump. Methods: IBD-associated
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(aneuploidy) is associated with poorer prognosis. The association of clinicohistological factors with ploidy status and the effect of ploidy status on survival in patients with CRC-IBD are not well defined. Aim: To evaluate the association between DNA content in colon adenocarcinoma cells and clinicohistological risk factors as well as survival in patients with CRC-IBD. Method: Ploidy status of colon adenocarcinoma cells in 50 patients with CRCIBD (44 CRC in ulcerative colitis, 6 CRC in Crohn`s colitis) selected by matching the Norwegian Cancer Registry with IBD cohorts of three university hospitals in Oslo was measured by high-resolution image cytometry. Clinicohistological factors as previously described in this cohort were included. The association of clinicohistological factors and ploidy status were analyzed by non-parametric tests (Mann-Whitney) and the effect of ploidy status on survival by an adjusted Cox regression model. Results: 18/50 (36 %) patients with CRC-IBD showed euploid (13 diploid, 5 tetraploid) and 32/50 (64%) patients aneuploid tumors. Fifteen patients died of CRC related causes, four patients of CRC unrelated causes, four of unknown cause and 27 patients were alive at the end of the study. Adjusted for age at diagnosis of CRC and stage of CRC (stage 1,2,3 versus stage 4), patients with aneuploid CRC showed poorer overall survival compared to patients with euploid CRC (OR=3.275, 95%CI: 1.07-10.04, p=0.038), and, as a tendency, poorer CRC-specific survival (OR=3.252, 95%CI: 0.86-12.27,p=0.082). Median age at diagnosis of IBD was higher in euploid compared to aneuploid CRC-IBD patients (30y and 24y, respectively, p=0.045). Duration and type of IBD, active colonic inflammation and extent of inflammation at diagnosis of CRC, medication (5ASA compounds), concomitant primary sclerosing cholangitis, localization of the tumor in the colon (right versus left), the extent of neoplasia in the colon (multifocal versus unifocal), type and differentiation grade of adenocarcinomas were not associated with ploidy status, nor did they influence the effect of the ploidy status on survival. Conclusion: DNA content in colon adenocarcinomas measured by image cytometry is an independent predictor of prognosis in patients with CRC-IBD in our cohort. Patients with aneuploid CRC-IBD showed poorer survival than patients with diploid CRC. We could not identify clinical or histological risk factors for aneuploid CRC in our material.