Long-standing Ulcerative Colitis Research Articles

Serrated Epithelial Change Is Associated With High Rates of Neoplasia in Ulcerative Colitis Patients: A Case-controlled Study and Systematic Review With Meta-analysis.

Patients with long-standing ulcerative colitis (UC) are at an increased risk of colorectal cancer. Risk stratification is important to identify patients who require more frequent endoscopic surveillance. Serrated epithelial change (SEC) found in patients with long-standing colitis may be associated with neoplasia and serve as a marker to stratify patients at higher risk of colorectal cancer (CRC). A case-control study was performed to compare the rates of neoplasia between UC patients with SEC and UC patients without SEC who were matched for age, disease duration, and disease extent. Paired tests, conditional logistic regression, and Kaplan-Meier analyses were used to compare groups. A systematic review with meta-analysis was performed, combining our local data with previously published data. This study included 196 UC patients without prior neoplasia, 98 with SEC and 98 without SEC. Ulcerative colitis patients with SEC had a significantly higher rate of synchronous or metachronous neoplasia than UC patients without SEC (26.5% vs 3.1%; P < 0.001). Synchronous or metachronous high-grade dysplasia and CRC were found more frequently in UC patients with SEC than UC patients without SEC (11.2% vs 2.0%; P = 0.02). A meta-analysis was consistent with these findings, showing a higher rate of neoplasia in patients with SEC compared with those without SEC (16.4% vs 3.9%; P < 0.001). Serrated epithelial change is associated with a significantly increased risk of synchronous and metachronous neoplasia including high-grade dysplasia and CRC in patients with UC. Histopathological findings of SEC should warrant closer endoscopic surveillance for CRC.

Some Morphology Frontiers of Dysplasia in the Tubular Gastrointestinal Tract: The Rodger C. Haggitt Memorial Lecture.

This review, based on the content of the 2020 US Gastrointestinal Pathology Society's Rodger Haggitt Lecture, concerns an array of tubular gastrointestinal tract dysplastic or possible "predysplastic lesions" with an almost purely morphologic focus based on our collaborative efforts over the past few years. These processes include esophageal epidermoid metaplasia, Barrett esophagus-associated dysplasia, polypoid gastric dysplastic lesions, small intestinal dysplasia, and the ability of metastases to mimic it, the controversial "serrated epithelial change" encountered in the setting of long-standing ulcerative and Crohn colitis, and recently described anal columnar human papilloma virus-associated neoplasms.

Long-Standing Ulcerative Colitis and Sulphasalazine Treatment Complicated by Adult Celiac Disease

The risk of celiac disease may be increased in patients with inflammatory bowel disease (IBD), however, the precise pathogenetic mechanisms involved remain controversial. In this report, an elderly man with long-standing and extensive ulcerative colitis was treated with daily salazopyrine for over 30 years. His medication was eventually discontinued although endoscopic surveillance studies showed healed colitis with minimal inflammatory change and no dysplasia. He subsequently volunteered as an IBD control in a celiac disease research study. Endomysial and tissue transglutaminase antibodies were unexpectedly positive and a small bowel biopsy showed changes of celiac disease that later responded to a gluten-free diet. Earlier historical duodenal and ileal biopsies had been normal suggesting that changes were new, developing after cessation of the salazopyrine. This unusual presentation “unmasking” celiac disease after cessation of long-standing salazopyrine for colitis raises the potential that the drug may have acted to suppress the inflammatory process in celiac disease and may offer another alternate and inexpensive therapeutic approach.

Adherence to Recommendations and Quality of Endoscopic Colorectal Cancer Surveillance in Long-Standing Ulcerative Colitis

Background: Long-standing ulcerative colitis has been associated with an increased risk of colorectal cancer (CRC). Current guidelines recommend endoscopic CRC screening after 8 years of disease duration. The objectives of our study were to assess the adherence to recommendations and the quality of endoscopic procedure in long-standing ulcerative colitis. Methods: This is a retrospective cohort study. We selected patients included in the Swiss IBD cohort with a disease duration of ≥8 years and an extension above the rectosigmoid junction. The complementary medical chart review focused on endoscopy and associated histological reports in 8 Swiss centers. Descriptive analyses focused on patients and their colonoscopies. Results: 309 colonoscopies were conducted among 116 patients with the following characteristics: women 47%, mean age at diagnosis 31 years, and pancolitis disease extent in 65.5% of cases; 38.8% of patients had a first screening colonoscopy <8 years, 13.8% between 8 and 10 years, and 47.4% >10 years. Cecal intubation was performed in 94.5% of cases, and bowel preparation was good to excellent in 61.5% of endoscopies. Chromoendoscopy was used in 7.4% of cases, and the mean withdrawal time was 16.4 min. Dysplasia was found in 6.2% of cases. Conclusion: Despite current international recommendations, a significant number of patients did not receive a proper endoscopic surveillance. An increased use of chromoendoscopy, monitoring of withdrawal time, and appropriate bowel preparation would increase the quality of CRC screening. The adherence to screening guidelines and endoscopic quality should be promoted and standardized.

Chromoendoscopy with targeted biopsies is superior towhite-light endoscopy for the long-term follow-up detection of dysplasia in ulcerative colitis patients: amulticenter randomized-controlled trial.

BackgroundData from single-center experience or small sample-sized studies have shown that chromoendoscopy (CE) might be superior to white-light endoscopy (WLE) for dysplasia surveillance in ulcerative colitis (UC) patients. We performed a prospective randomized trial with a long-term follow-up to compare the detection rate of dysplasia among WLE with targeted biopsies (WLT), WLE with random biopsies (WLR), and dye-based CE with targeted biopsies (CET) in UC patients.MethodsPatients with long-standing UC were enrolled from 11 medical centers from March 2012 to December 2013 and randomized into three arms (WLT, WLR, and CET). Only high-definition endoscopy was used in all three groups. The patients were followed up by annual endoscopy with biopsies through December 2017.ResultsWith a median follow-up time of 55 months, a total of 122 patients with 447 colonoscopies were finally analysed in the per-protocol set: WLT (n = 43), WLR (n = 40), and CET (n = 39). A total of 34 dysplastic lesions were found in 29 colonoscopies of 21 patients. WLR and CET could identify more colonoscopies that diagnosed dysplasia than WLT (8.1% and 9.7% vs 1.9%; P = 0.014 and 0.004, respectively). WLR obtained more biopsied samples than WLT and CET (16.4 ± 5.1 vs 4.3 ± 1.4 and 4.3 ± 1.4; both P < 0.001). During the second half of the follow-up (37 − 69 months), CET could identify more colonoscopies that diagnosed dysplasia than WLT (13.3% vs 1.6%, P = 0.015) and showed a trend for increasing the detection rate compared with WLR (13.3% vs 4.9%, P = 0.107).ConclusionsFor a better outcome of cancer/dysplasia surveillance in patients with long-standing UC, CET appeared to be more effective than WLT and less tedious than WLR. CET was found to be particularly useful when a long-term (>3 years) follow-up was conducted for dysplasia surveillance. The trial was registered on www.chictr.org.cn (ChiCTR1900023689).

Crohn’s disease: half and half

A 63-year-old man with longstanding ulcerative colitis (UC), total proctocolectomy, and ileal J-pouch reconstruction with ileoanal anastomosis presented with abdominal pain, diarrhea, and elevated fecal lactoferrin. The patient underwent colonoscopy, which showed severe inflammation affecting precisely half of the luminal area of the J-pouch with a clear line of demarcation between the affected and the unaffected areas (A). Nearly 20% of the affected area showed typical Crohn’s disease (CD) deep and large (0.5 to 2 cm) ulcerations—a picture corresponding to a simple endoscopic score for CD (SES-CD) of 5.

Endoscopic visualization of cancer and dysplasia in patients with ulcerative colitis following sensitization with oral 5-aminolevulinic acid.

ObjectiveEarly diagnosis of colitis‐associated cancer and dysplasia through surveillance endoscopy is vital for patients with ulcerative colitis (UC). This study aimed to evaluate the efficacy of autofluorescence endoscopy (AFE) using 5‐aminolevulinic acid (ALA) and to investigate the fluorescence signal localization pattern following 5‐ALA administration in tumorous lesions diagnosed as colitis‐associated cancer and dysplasia. The sensitivity and specificity of tumorous lesions detected by white light endoscopy (WLE) with and without AFE were evaluated.MethodsOverall, 13 endoscopic procedures were performed in 11 patients with UC using WLE and AFE following the oral administration of 5‐ALA. The biopsied lesions detected via endoscopy and resected specimens from cases underwent colectomy were assessed histopathologically. The sensitivity and specificity of detecting tumorous lesions by WLE with and without AFE were evaluated.ResultsOf the 68 lesions detected and biopsied, 63 were detected via WLE, and five were detected via AFE alone. The sensitivity of detecting colitis‐associated cancer and dysplasia via WLE combined with AFE was 36.4%, and the specificity, positive predictive value and negative predictive value were 94.2%, 57.1%, and 87.5%, respectively. Tumorous lesions displayed three types of fluorescence patterns on AFE.ConclusionsAFE using 5‐ALA can detect colitis‐associated cancer and dysplasia in patients with long‐standing UC and lesions that could not be detected via WLE. The distinctive fluorescence patterns in lesions may permit qualitative diagnoses of colitis‐associated cancer and dysplasia.

Abstract 5875: Analysis of clonal expansion in epithelium affected by ulcerative colitis reveals frequent mutations affecting IL-17 signaling pathway and novel cancer vulnerability

Abstract Chronic inflammation is a major cause of morbidity and mortality in the human population and is associated with a substantial cancer risk. It has recently been demonstrated that extensive tissue remodeling can take place even in apparently normal tissues in an age-dependent manner and is mediated by expansion of numerous clones carrying common cancer-related mutations. Given the inflammation-associated cancer risks, clonal expansion may also play a role in inflammation-associated tissue remodeling. However, it is largely unknown whether this actually happens, with what mutations it occurs if ever, and how it modifies cancer development. To address these issues, we studied ulcerative colitis (UC) which is a chronic inflammatory bowel disease. Long-standing UC is associated with an increased risk (15-20%) of colitis-associated colorectal cancer (CAC). We performed whole exome sequencing (WES) of single crypts (n=441) and bulk crypts (n=569) from patients with UC and control individuals, as well as CAC samples (n=99). WES of single crypts from control individuals revealed UC crypts showed a more than 3 times higher mutation rate than non-UC crypts. We analyzed history of crypt expansion in clusters of single crypts. From mutations detected in each crypt, we reconstructed phylogenetic trees of clusters of crypts. Non-UC trees showed many early branches before 20 years of age, whereas, UC trees were characterized by a prominently long trunk with many short branches, suggesting crypts rapidly expanded from a common ancestral crypt during the past few years. Bulk-crypt analysis from surgically resected UC rectums showed many expanded clones, among which the maximum clone was as large as 19 cm2 in size. While no driver gene was detected in control individuals, the dN/dS analysis on 399 non-dysplasia UC samples revealed 14 driver genes, within which NFKBIZ were most frequently mutated, followed by PIGR and ZC3H12A. These drivers displayed a surprising overlap to signaling pathways converging on NFKBIZ. Among these pathways most prominent was IL-17 signaling, in which IL-17 receptors (IL17RA/IL17RC) and its adaptor, TRAF3IP2 were significantly mutated in UC epithelium. A driver role of NFKBIZ mutations was confirmed by growth advantage of Nfkbiz-KO cells compared with control cells under IL-17A stimulation in vitro or in a DSS-induced colitis model. Despite a substantial overlap of driver genes between CAC and UC epithelium, their frequencies significantly differed between both tissues. NFKBIZ mutations, which is most prevalent in UC non-dysplasia, were never found in 99 CAC samples. We confirmed a negative role of NFKBIZ mutations by compromised cell-competition of NFKBIZ-disrupted colorectal cancer cells and significantly attenuated colitis-induced tumor formation in Nfkbiz-deficient mice. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which unexpectedly reveal cancer vulnerability potentially utilized for therapeutics of colorectal cancer. Citation Format: Nobuyuki Kakiuchi, Kenichi Yoshida, Motoi Uchino, Takako Kihara, Akaki Kotaro, Yoshikage Inoue, Kenji Kawada, Satoshi Nagayama, Akira Yokoyama, Tomonori Hirano, Yasuhide Takeuchi, Hiroyuki Miyoshi, Yoshiharu Sakai, Hironori Haga, Seiichi Hirota, Hiroki Ikeuchi, Osamu Takeuchi, Satoru Miyano, Hiroshi Seno, Seishi Ogawa. Analysis of clonal expansion in epithelium affected by ulcerative colitis reveals frequent mutations affecting IL-17 signaling pathway and novel cancer vulnerability [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5875.

Heading in the Right Dissection: Toward an Endoscopic Cancer Cure in a Patient with Long-Standing Ulcerative Colitis

Heading in the Right Dissection: Toward an Endoscopic Cancer Cure in a Patient with Long-Standing Ulcerative Colitis

Efficacy of various endoscopic modalities in detecting dysplasia in ulcerative colitis: A systematic review and network meta-analysis

BACKGROUNDLongstanding ulcerative colitis (UC) is associated with an increased risk of colonic neoplasia. Various endoscopic modalities, such as chromoendoscopy (CE), narrow band imaging (NBI) and random biopsy have been introduced for surveillance, however, there exists a paucity of direct comparisons between them. We aimed to conduct a network meta-analysis of randomized controlled trials (RCTs) performed for surveillance of neoplasia in UC.AIMTo provide a comparative evaluation of the efficacy of the above-mentioned various modalities.METHODSWe searched MEDLINE/PubMed, Web of Science, Embase, Google Scholar and Cochrane Central Registry through May 2016 for RCTs evaluating the efficacy of endoscopic modalities for surveillance of neoplasia in UC. The primary outcomes of interest were dysplasia (low- or high-grade) detection rates per biopsy and per patient, and dysplasia numbers per patient. Studies were simultaneously analyzed using a random-effects network meta-analysis under the Bayesian framework to identify the modality with the highest dysplasia detection rate. The best ranking probability for the dysplasia detection rate was analyzed by surface under the cumulative ranking (SUCRA) technique.RESULTSSix prospective RCTs of a total 1038 patients were identified. We identified 4 different modalities; white light (WL) high definition (HD) or standard definition (SD), CE HD, and NBI HD. For dysplasia per biopsy, direct meta-analysis showed superiority of NBI HD over WL HD and CE HD over WL SD. Network meta-analysis demonstrated the rank order of best modality as NBI HD, CE HD, WL HD and WL SD with close SUCRA scores of the first two. For dysplasia per patient, direct meta-analyses showed equivocal results between each modality. Network meta-analysis demonstrated the rank order of best modality as WL HD, NBI HD, CE HD and WL SD with small differences of the SUCRA score among the first two. For dysplasia numbers per patient, direct meta-analysis showed superiority of CE HD over WL SD. Network meta-analysis demonstrated the rank order of best modality as WL HD, NBI HD, CE HD, and WL SD with small differences of the SUCRA score among the first three.CONCLUSIONWe demonstrated that there were small differences among WL HD, NBI HD, and CE HD, while WL SD was inferior, in detecting dysplasia in UC.

Expression of CA2 and CA9 carbonic anhydrases in ulcerative colitis and ulcerative colitis-associated colorectal cancer.

Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic mucosa and submucosa with repeating relapse and remission, but the pathogenesis is unknown. Patients with long-standing UC are at high risk of neoplasm development. The aim of the present study was to identify molecules whose expression is associated with UC and UC-associated colorectal cancer (UCCA). Biopsy specimens from UC and normal colonic mucosae were analyzed using a proteomics approach, in which carbonic anhydrase 2 (CA2) was identified as a molecule downregulated in UC mucosae. Immunohistochemically, CA2 expression was detected in normal and diverticulitis mucosal epithelia, and its expression decreased as UC activity increased. CA2 expression was almost undetectable in UCCA. We also analyzed the expression of another carbonic anhydrase, CA9, and its upstream molecule, hypoxia-inducible factor-1α (HIF-1α), both of which are induced under hypoxic conditions. It was revealed that CA9 expression was relatively low in normal, diverticulitis and UC mucosae, and was upregulated in UCCA. HIF-1α expression was consistently low in all tissue types examined. In conclusion, these results suggest that CA2 and CA9 may be possible indicators of UC activity and UCCA development, respectively.

Leiomyosarcoma and ulcerative colitis: Case report

Ulcerative colitis (UC) and Crohn’s disease (CD) patients present an increased risk of colorectal cancer (CRC) due to chronic inflammation, genetic susceptibility and environmental risk factors. In contrast, non-epithelial neoplasms are uncommon.&#x0D; We discuss the case of an 83-year-old male with a long-standing UC, presenting with a polypoid lesion. Once resected, the lesion was identified as a high-grade leiomyosarcoma. A review of the literature revealed that only three previous cases of leiomyosarcoma among patients with UC have been published. Thus, this one would represent the fourth case where this rare non-epithelial neoplasm was detected in a patient with UC. The direct association of UC and leiomyosarcoma has not been well established; however, immunosuppression is suggested to be a risk factor for leiomyosarcoma in the literature.

ENDOSCOPIC DIAGNOSIS OF DYSPLASIA IN PATIENTS WITH LONGSTANDING ULCERATIVE COLITIS

AIM: to evaluate high-definition colonoscopy (HD-WLE) using chromoendoscopy for dysplasia in the longstanding ulcerative colitis (UC).PATIENTS AND METHODS: a cohort prospective study included 140 patients (aged 29-79 years old) with a long course of UC (6-44 years) in time of endoscopic remission with good quality of bowel cleansing. A white-light endoscopy was performed using high-definition colonoscopies (HD-WLE). Chromoendoscopy (0.4% solution of indigo carmine), targeted biopsy, and histological analysis were performed.RESULTS: HD-WLE revealed 34 lesions with endoscopic signs of dysplasia in 27 (19.3%) patients: in 20 patients – 1 (74.1%) lesion, in 7 patients 2 (25.9%). In 22 patients (64.7%) lesions were more than 1 cm.Chromoendoscopy confirmed the signs of dysplasia in 100.0% of cases (88.2% – low grade dysplasia).Histologically, low-grade dysplasia was detected in 58.8% of cases, undetected dysplasia – in 20.6%, sporadic adenomas – in 20.6%.The effectiveness of endoscopic diagnosis for detecting dysplasia was 74%. A comparative analysis of the endoscopic signs of dysplasia and sporadic adenomas showed the absence of significant differences.CONCLUSION: the additional chromoendoscopy during HD-WLE colonoscopy with targeted biopsy does not lead to increase of colorectal epithelial dysplasia detection in UC.The experience of endoscopist should be considered when making decision which type of endoscopy for dysplasia detection in UC is needed.

MiR-370-3p Alleviates Ulcerative Colitis-Related Colorectal Cancer in Mice Through Inhibiting the Inflammatory Response and Epithelial-Mesenchymal Transition.

IntroductionUlcerative colitis (UC) is a chronic and inflammatory bowel disease. UC-associated colorectal cancer (UC-CRC) is one of the most severe complications of long-standing UC. In the present study, we explored the effects of miR-370-3p on UC-CRC in vivo and investigated its underlying mechanisms in vivo and in vitro.MethodsAzoxymethane (AOM) and dextran sodium sulfate (DSS) were used to induce UC-CRC in C57BL/6 mice. AOM/DSS-induced mice were treated with 5×108 pfu miR-370-3p overexpressing-adenovirus via tail-vein injection every two weeks.ResultsWe found that miR-370-3p significantly improved the body weights and survival rates and inhibited the tumorigenesis of UC-CRC in AOM/DSS mice. Mechanically, miR-370-3p inhibited AOM/DSS-induced inflammatory response by decreasing tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) through targeting toll-like receptor 4 (TLR4), as demonstrated by down-regulation of TLR4, cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), and phosphorylated epidermal growth factor receptor (pEGFR). miR-370-3p decreased the expression of tumor-associated proteins, including p53, β-catenin, and ki67 in AOM/DSS-treated mice. Additionally, miR-370-3p remarkably inhibited epithelial-mesenchymal transition (EMT) via increasing E-cadherin expression and reducing N-cadherin and Vimentin expression in vivo. Further studies showed that miR-370-3p repressed proliferation and EMT of colon cancer cells in vitro. Moreover, we proved that miR-370-3p decreased the expression of tumor-associated proteins and reversed EMT by regulating β-catenin in colon cancer cells.ConclusionTaken together, miR-370-3p alleviated UC-CRC by inhibiting the inflammatory response and EMT in mice, which suggested miR-370-3p as a novel potential target for UC-CRC therapy.

Adenosquamous carcinoma of the right colon with diffuse signet-ring mucinous component

Colorectal carcinoma is one of the most frequent human malignant neoplasms. Besides the most common histological types, colorectal adenosquamous carcinoma is very rare, being microscopically constituted by tumoural glandular and squamous components. The diagnosis of primary colon adenosquamous carcinoma requires the exclusion of a metastatic squamous cell carcinoma and the extension of a primary squamous cell carcinoma from the anal-rectum junction. We report a case of primary adenosquamous carcinoma of the ascending colon in a 62-year-old Caucasian man affected by long-standing ulcerative colitis. Peritumoural lymph nodes and distant metastasis were present. We reported also a diffuse signet-ring mucinous component, which has not been previously observed. Moreover, we investigated microsatellite and all-RAS/B-RAF status, p16 and p53 protein expression, and the molecular presence of human papillomavirus DNA in all the morphologically distinct components, in order to suggest pathogenetic factors influencing the aggressive prognosis of colon adenosquamous carcinoma.

Double-tunneling butterfly method for endoscopic submucosal dissection of extensive rectal neoplasms.

Background and aimsEndoscopic submucosal dissection (ESD) is the preferred technique for en bloc resection of superficial colorectal neoplasms. Resection of extensive lesions with ESD can be challenging, owing to loss of orientation in the submucosal space. In this case series, we describe the double-tunneling (DoT) butterfly method for ESD of extensive rectal neoplasms.MethodsThe key feature of the DoT butterfly method is the creation of 2 tunnels that are transformed into bilateral flaps, leaving a submucosal septum between them.ResultsFour rectal neoplasms measuring (maximum diameter) 7 cm, 8 cm, 9 cm, and 18 cm, respectively, were resected in 4 patients by use of the DoT butterfly method. The lesions included recurrent adenoma (n = 1) and dysplasia (n = 1) in longstanding ulcerative colitis. Curative R0 resection was confirmed in all 4 cases. Histologic examination showed tubular adenomas with low-grade dysplasia in 1 of 4 patients and focal high-grade dysplasia in 3 of 4 patients. One patient experienced postprocedural bleeding that required endoscopic reintervention.ConclusionThe DoT butterfly method appears to be useful for the resection of extensive rectal neoplasms. A prospective study is required to assess whether these results can be reproduced in a large cohort of patients.

P596 Risk of colorectal cancer and other malignancies in association with the use of thiopurines, tumour necrosis factor antagonists or mesalazine

Abstract Background Mesalazine, thiopurines and TNF antagonists play an important role in management of inflammatory bowel disease (IBD). It is generally accepted that longstanding ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). In addition to colorectal cancer, there are data that suggest that IBD is also associated with an increased risk of extra-intestinal malignancies but the results are inconclusive. The evidence concerning the effects of mesalazine on the risk of CRC in IBD patients remains conflicting. Methods In this review, cancer-reported outcomes with IBD drugs reported to FAERS (USA) were extracted for adalimumab, infliximab, thiopurines and mesalazine and compared with all other 25’382 drugs in the database. The data were used to calculate reporting odds ratio (ROR) and 95% CI for CRC, lymphoma, Hodgkin’s disease and all cancers outcomes. A sub-analysis was conducted to include patients exposed to mesalazine alone without IBD co-medications. Results The databases contained approximately 17 million reports for all drugs of which 401’084 were for adalimumab, 121 562 for infliximab, 11’985 for mesalazine, and 25’286 for thiopurines. Of these, a total of 259 757 concerned cancer-related AEs associated with the drugs under consideration. All IBD drugs were associated with a positive ROR for CRC with infliximab presenting the highest point estimate 8.01 (CI 95% 7.48–8.59) and adalimumab the lowest 2.52 (CI 95% 2.35–2.69). Considering patients exposed to only mesalazine, this association remained positive at 2.39 (CI 95% 1.58–3.59). For lymphoma, all IBD drugs also showed a positive ROR where thiopurines were associated with the highest 7.25 (CI 95% 6.69–7.84) and mesalazine with the lowest 1.46 (CI 95% 1.14 -2.73) point estimate. With regards to patients only exposed to mesalazine, the association showed protective effect, 0.24 (CI 95% 0.13–0.47). For Hodgkin’s disease again all IBD drugs showed a positive ROR where thiopurines were associated with the highest 34.65 (CI 95% 28.88–41.59) and adalimumab with the lowest 4.98 (CI 95% 4.39 -5.65) point estimate. In patients only exposed to mesalazine, no association 0.66 (CI 95% 0.09–4.66) was observed. Considering all cancers only positive ROR were observed where infliximab was associated with the highest 7.31 (CI 95% 7.17–7.45) and mesalazine with the lowest 1.33 (CI 95% 1.17–1.51) point estimate. In patients only exposed to mesalazine, a protective effect 0.73 (CI 95% 0.61–0.88) was observed. Conclusion FAERS data showed an association between reported occurrence of cancer and the drugs under consideration. Considering patients only exposed to mesalazine the odds ratio was positive only for colorectal cancer but lower than all other IBD drugs.

P254 Virtual chromoendoscopy with Narrow Band Imaging (NBI) for the classification of polypoid and non-polypoid lesions in ulcerative colitis: A prospective study using different endoscopic classifications

Abstract Background In ulcerative colitis (UC), the diagnostic accuracy of virtual chromoendoscopy with non-magnified Narrow Band Imaging (NBI) was disappointing in the detection and differential diagnosis of neoplastic lesions in most trials performed according to unclear diagnostic criteria. The Kudo and NICE criteria are validated in the general population, but controversial in UC. Recently, a modified Kudo classification specific for the inflammatory setting of UC has been developed using virtual chromoendoscopy with Fuji Intelligence Color Enhancement (FICE). The performance of NBI according to these three classifications for optical diagnosis of neoplastic and non-neoplastic lesions in UC has never been analysed. Methods All visible, polypoid and non-polypoid, lesions found during consecutive surveillance colonoscopies with non-magnified NBI (Exera II CV180) for long-standing UC (&amp;gt;8 years from disease onset) were included in a prospective, single-centre study, and classified as suspected or not suspected for neoplasia according to the NICE, Kudo and Kudo-modified criteria. The primary endpoint was to compare the sensitivity (SE), specificity (SP), negative (-LR) and positive (+LR) likelihood ratios of the three classifications, using histology as the reference standard. Results 394 lesions (mean size 6 mm, range 2–40 mm; type 0-Is 83%) from 84 patients (males 62%; mean age 57 y, range 30–79 y; mean disease duration 20 y) were found: 21 (5%) were neoplastic, 49 (12%) hyperplastic and 324 (82%) inflammatory lesions. The diagnostic accuracy of the NICE, Kudo and modified-Kudo classifications were, respectively: SE 76% vs. 71% vs. 86% (p = not significant); SP 55% vs. 69% vs. 79% (p &amp;lt; 0.05 Kudo-mod vs. both Kudo and NICE); +LR 1.69 vs. 2.34 vs. 4.15 (p &amp;lt; 0.05 Kudo-mod vs. both Kudo and NICE); -LR 0.43 vs. 0.41 vs. 0.18 (p = not significant). Conclusion The diagnostic accuracy of NBI for the differentiation of neoplastic and non-neoplastic lesions in UC is low if used with the conventional classifications validated in the general population, but it is significantly better with the modified Kudo classification specific for UC. The role of NBI in UC surveillance for neoplasia should be re-evaluated according to more accurate diagnostic criteria.

Malignant perforation of sigmoid colon in long-standing ulcerative colitis

Chronic ulcerative colitis (UC) is a risk factor for malignancy in long-term disease process. Obstruction, perforation, and hemorrhage are the possible emergency situations in colorectal malignancy. A 68-year-old male with chronic UC for 18 years with steroid-dependent disease (on 10 mg prednisolone daily) presented with acute pain abdomen with distention not passing stool or flatus for 2 days. The patient was diagnosed to have perforation of colon secondary to rectosigmoid malignancy. Following the adjuvant therapy, the patient denied any definitive surgery and opted to stay on a colorectal cancer surveillance program. At present, the patient's positron emission tomography/computed tomography shows pelvic, liver surface, and small bowel deposits, suggestive of recurrence or metastasis. This case report is discussed to emphasize the importance of aggressive surgical treatment in long-term steroid-dependent disease and poor prognosis of perforated malignancy irrespective of pathological staging.

Hypermethylation of Corticotropin Releasing Hormone Receptor-2 Gene in Ulcerative Colitis Associated Colorectal Cancer.

The difficulty of early diagnosis of colitis associated colorectal cancer (CACRC) due to colonic mucosal changes in long-standing ulcerative colitis (UC) patients is often experienced in daily clinical practice. Noninvasive objective monitoring for cancer development is advantageous for optimizing treatment strategies in UC patients. We aimed to examine the epigenetic alterations occurring in CACRC, focusing on DNA hypermethylation of CpG islands. The level of DNA methylation in CpG cites was compared between CACRC and the counterpart non-tumorous mucosa using Infinium HumanMethylation 450K BeadChip. Our subjects included 3 males and 3 females (median age, 49.5 years). The 450K CpG site DNA methylation microarray revealed that the difference in β value (level of hypermethylation) was the highest for corcicotropin releasing hormone receptor 2 (CRHR2) between CACRC and counterpart non-tumorous mucosa. Detection of hypermethylation of CRHR2 may be promising for cancer screening in UC patients.