Long-standing Ulcerative Colitis Research Articles

TP53/p53 alterations and Aurora A expression in progressor and non-progressor colectomies from patients with longstanding ulcerative colitis.

Aneuploidy is a common feature in the colonic mucosa of patients suffering from the inflammatory bowel disease ulcerative colitis (UC) and often precedes the development of dysplasia and cancer. Aneuploidy is assumed to be caused by missegregation of chromosomes during mitosis, often due to a faulty spindle assembly checkpoint. p53 is a tumour suppressor protein known to regulate the spindle assembly checkpoint and is frequently mutated in aneuploid cells. Aurora A is a presumed oncoprotein, also involved in regulation of the spindle assembly checkpoint. In the present study, we examined the mutational frequency of TP53 and the protein levels of p53 in a set of 20 progressor and 10 non-progressor colectomies from patients suffering from longstanding UC. In addition, we re-examined previously published immunohistochemical data on Aurora A expression using the same material. Levels of Aurora A were re-examined with regard to DNA ploidy status and dysplasia within the progressors, as well as in relation to p53 accumulation and TP53 mutational status. We detected p53 accumulation only within the progressor colectomies, where it could be followed back 14 years prior to the colectomies, in pre-colectomy biopsies. TP53 mutations were detected in both progressors and non-progressors. Expression levels of Aurora A were similar in the progressors and non-progressors. Within the group of progressors however, low levels of Aurora A were associated with areas of DNA aneuploidy, as well as with increasing degrees of dysplasia. Our results indicate that alterations in p53 may be an early biomarker of a progressor colon, and that p53 is accumulated early in UC-related carcinogenesis. Furthermore, a decreased Aurora A expression is associated with the development of DNA aneuploidy, as well as with dysplasia in UC progressors.

Predictive value of rectal aberrant crypt foci for intraepithelial neoplasia in ulcerative colitis – a cross-sectional study

Background. Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer (CRC). Aberrant crypt foci (ACF) are important biomarkers of sporadic CRC risk. Their correlation with the risk of intraepithelial neoplasia (IN) in UC remains unclear. Aims. To assess whether ACF are a risk factor for IN in long-standing UC and to investigate any correlation between the clinico-epidemiological characteristics and prevalence/number of ACF in these patients. Methods. Seventy-six patients with long-standing UC were prospectively screened by colonoscopy with chromoendoscopy-guided endomicroscopy. ACF were sought in the lower rectum. Results. Eight INs were detected in seven (9.2%) patients. The ACF prevalence and mean number were 60.5% and 2.4 ± 2.8, respectively. The number of ACF was independently associated with the risk of having IN (odds ratio = 1.338; 95% confidence interval 1.030–1.738). ACF number revealed a good calibration (area under the receiver operating characteristic curve = 0.829) and discriminative ability (p = 0.205, Hosmer–Lemeshow test) for the prediction of synchronous IN. Patients with ≥3 ACF have a significantly higher prevalence of IN than patients with <3 ACF (22.6% vs. 0%, p = 0.001). Using this cut-off value, the performance of ACF in predicting the presence of IN was as follows: sensitivity = 100%, specificity = 65.2%, positive predictive value = 22.6%, and negative predictive value = 100%. Age >40 years, family history of CRC, and increased body mass index (BMI) were associated with a significantly higher number of ACF. Conclusion. Long-standing UC patients with ≥3 ACF have a significantly higher likelihood of having IN. Age >40 years, family history of CRC, and increased BMI have significant positive associations with the number of ACF.

PTU-064 Increased Mucosal Expression Of Insoluble Keratins 8, 18 And 19 In Long-standing Ulcerative Colitis In Comparison To Recent-onset Ulcerative Colitis: Validation Of Mass Spectrometry Data

IntroductionIntermediate filaments (IF) are one of the main components of the human cell cytoskeleton with keratins (K) being the largest component. K8, K18 and K19 constitute the main keratins in...

DNA methylation of microRNA-124a is a potential risk marker of colitis-associated cancer in patients with ulcerative colitis.

Colitis-associated cancer (CAC) is the serious complication of ulcerative colitis (UC), and molecular markers to evaluate the individual risk are required. MicroRNA-124a (miR - 124a) is known to have tumor-suppressive function and be methylation-silenced during exposure to chronic inflammation. We analyzed whether higher methylation levels of miR-124a genes correlated with the higher epidemiologic risk of CAC development in UC patients. Forty UC patients without CAC, four patients with CAC or dysplasia, eight sporadic colorectal cancer (S-CRC) patients, and 12 healthy volunteers (HV) were studied. Methylation status of miR-124a genes (miR-124a-1, -2, and -3) was analyzed by methylation-specific polymerase chain reaction (MSP), and methylation levels were quantified by real-time MSP. Expression of cyclin-dependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry. Three miR-124a genes were methylated in all neoplastic tissues (CAC, dysplasia, and S-CRC), and CDK6 was highly expressed in those tissues. Regarding disease extent, mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis were 2.0, 5.3, and 12.3%, respectively, and were significantly higher in pancolitis than in HV (p < 0.01). Regarding disease duration, mean methylation levels in short-term and long-standing UC patients were 2.5 and 13.2%, respectively. Long-standing UC patients had significantly higher methylation levels than HV (p < 0.01). Moreover, UC patients with both pancolitis and long-standing had 7.4-fold higher methylation levels than those without these risk factors. MiR-124a genes are methylated during carcinogenesis in UC patients. The methylation level of miR-124a-3 is a promising marker for estimating individual risk for CAC.

Reduced hTERT protein levels are associated with DNA aneuploidy in the colonic mucosa of patients suffering from longstanding ulcerative colitis

Longstanding ulcerative colitis (UC) is a disease of chronic inflammation of the colon. It is associated with the development of colorectal cancer through a multistep process including increasing degrees of dysplasia and DNA-ploidy changes. However, not all UC patients will develop these characteristics even during lifelong disease, and patients may therefore be divided into progressors who develop dysplasia or cancer, and non-progressors who do not exhibit such changes. In the present study, the amount of hTERT, the catalytic subunit of the enzyme telomerase, was estimated by using peroxidase immunohistochemistry (IHC) in a set of progressor and non-progressor UC colectomies. The protein levels in the colonic mucosa of the progressors and non-progressors were compared, and further comparisons between different categories of dysplastic development and to DNA-ploidy status within the progressors were made. Levels of hTERT were elevated in the colonic mucosa of the progressors and non-progressors when compared to non-UC control samples, but no difference was observed between the hTERT levels in the mucosa of progressors and non-progressors. The levels of hTERT associated with levels of Ki67 to a significant degree within the non-progressors. hTERT expression in lesions with DNA-aneuploidy were decreased as compared to diploid lesions, when stratified for different classes of colonic morphology. Our results indicate an association between hTERT protein expression and aneuploidy in UC-progressor colons, and also a possible protective mechanism in the association between hTERT and Ki67, against development of malignant features within the mucosa of a UC-colon.

P255 Computed virtual chromoendoscopy with FICE in the definition of raised dysplastic lesions and pseudopolyps in long-standing ulcerative colitis: a preliminary, prospective, study towards a new classification

Background: Crohn’s disease (CD) is associated with penetrating complications such as phlegmons and intra-abdominal abscesses. As the management of the patients influenced by the presence of such complications, a readily available tool for the diagnosis of extramural complications in CD is needed. Preliminary findings suggest that the assessment of vascularity within intra-abdominal masses may distinguish between phlegmons and abscesses. Aim of our study was to evaluate the use of contrast enhanced ultrasound (CEUS) to distinguish between phlegmons and intra-abdominal abscesses in CD patients as a point-of-care technique. Methods: From November 2011, consecutive patients with complicated CD were enrolled. Indications of patient assessments by CEUS were symptoms, signs and biochemical exams indicating penetrating behavior (abdominal pain, mass, fever, elevated CRP and leukocytosis). A total of 22 CD pts (14 M; median age 27 yrs, range 18 75; disease duration: median 54 mos, range 1 564; CD site: ileal in 13 pts, ileo-colonic in 9 pts; CD behavior: penetrating in 20 pts, stricturing in 2 pts; previous ileocolonic resection in 9 pts) were included. Clinical evaluation by an IBD expert and other cross sectional imaging techniques (MR and CT) were considered as the standard. Results: CEUS detected abscesses in 9 and phlegmons in 12 pts. One patient had an unspecified lesion that was diagnosed as metastasis by PET. Six out of 9 abscesses were confirmed by CT-Enteroclysis and these pts underwent surgery during the follow up. The remaining 3 pts with abscesses were treated with antibiotics and are still in follow up (17.5 mos). In the phlegmon group, 4 out of 12 patients were evaluated by CT or MRI that confirmed CEUS findings in 3 cases but in one patient a deep abscess was identified and surgery was scheduled. Eight out of 12 pts were clinically followed up (median: 16 mos). Two of these patients developed an abscess after one week from CEUS despite medical treatment. Overall CEUS correctly identified 19 out of 22 lesions (86%) on the basis of cross sectional imaging modalities and clinical follow up used as final diagnosis. Conclusions: CEUS is a non-invasive, radiation free and point-of-care technique able to differentiate phlegmons from abscesses driving a prompt clinical management in complicated CD patients. P255 Computed virtual chromoendoscopy with FICE in the definition of raised dysplastic lesions and pseudopolyps in long-standing ulcerative colitis: a preliminary, prospective, study towards a new classification A. Cassinotti1 *, F. Buffoli2, P. Fociani3, V. Villanacci4, T. Staiano2, M. Fichera1, R. Grassia2, G. Manes1, M. Salemme4, M. Lombardini1, P. Molteni1, G. Sampietro5, D. Foschi5, G. Maconi1, R. de Franchis1, S. Ardizzone1. 1Luigi Sacco University Hospital, Gastroenterology and IBD Unit, Milan, Italy, 2Istituti Ospitalieri Cremona, Endoscopy Unit, Cremona, Italy, 3Luigi Sacco University Hospital, Pathology Unit, Milan, Italy, 4Spedali Civili, Pathology Unit, Brescia, Italy, 5Luigi Sacco University Hospital, General Surgery, Milan, Italy

P075 Epithelial Toll-like receptor 3-dependent synthesis of complement factor B and local complement activation in inflammatory bowel disease

presence of myofibroblasts in all layers of the intestinal wall. Ulcerative colitis (UC) is classically considered to be a purely mucosal disease although rarely transmural complications such as strictures and stenosis develop. Fibrogenesis in UC has not been studied systematically yet and may be a neglected phenomenon. We therefore investigated whether there is a different fibrotic load in acute vs longstanding UC and whether the degree of fibrosis in UC correlates with the severity of inflammation. Methods: Colectomy specimens from all UC patients operated at the AMC between 2007 2012 were reviewed. Specimens from patients with recent onset refractory therapy UC (diagnosis 10 years) were selected. Patients operated for colon cancer without UC served as controls. On HE 29% vs 33% vs 54%, p = 0.009). Between acute and late UC there was no difference in collagen deposition, however between UC together and controls there was more collagen I expression in the mucosa, MM and muscularis externa (50% vs 10%, p = 0.02; 28% vs 10%, p = 0.048; 71% vs 20%, p = 0.003). In both early and long UC duration, we did not find a correlation between inflammation or collagen deposition or MM thickness. There was a negative correlation between inflammation and aSMA positivity in the submucosa (R = 0.51, p = 0.003) and MM (R = 0.37, p = 0.04). Conclusions: In our series of colectomy specimens, there is more collagen deposition in UC than in controls. No association between disease duration and increased collagen deposition could be found. Expression of aSMA however is lower in UC and correlates with inflammation. Fibrosis in UC does not appear to increase significantly over time.

P074 Expression of CCL20 and its corresponding receptor CCR6 is located to epithelium and infiltrating cells in the mucosa of IBD patients

presence of myofibroblasts in all layers of the intestinal wall. Ulcerative colitis (UC) is classically considered to be a purely mucosal disease although rarely transmural complications such as strictures and stenosis develop. Fibrogenesis in UC has not been studied systematically yet and may be a neglected phenomenon. We therefore investigated whether there is a different fibrotic load in acute vs longstanding UC and whether the degree of fibrosis in UC correlates with the severity of inflammation. Methods: Colectomy specimens from all UC patients operated at the AMC between 2007 2012 were reviewed. Specimens from patients with recent onset refractory therapy UC (diagnosis 10 years) were selected. Patients operated for colon cancer without UC served as controls. On HE 29% vs 33% vs 54%, p = 0.009). Between acute and late UC there was no difference in collagen deposition, however between UC together and controls there was more collagen I expression in the mucosa, MM and muscularis externa (50% vs 10%, p = 0.02; 28% vs 10%, p = 0.048; 71% vs 20%, p = 0.003). In both early and long UC duration, we did not find a correlation between inflammation or collagen deposition or MM thickness. There was a negative correlation between inflammation and aSMA positivity in the submucosa (R = 0.51, p = 0.003) and MM (R = 0.37, p = 0.04). Conclusions: In our series of colectomy specimens, there is more collagen deposition in UC than in controls. No association between disease duration and increased collagen deposition could be found. Expression of aSMA however is lower in UC and correlates with inflammation. Fibrosis in UC does not appear to increase significantly over time.

Influence of receptor activator of nuclear factor kappa B ligand, osteoprotegerin and interleukin-33 on bone metabolism in patients with long-standing ulcerative colitis

BackgroundUlcerative colitis (UC) is a chronic disease with periods of remission and recurrences. Dysfunction of the local immune response leads to chronic inflammation within the large intestine which triggers morphological changes in the intestinal wall as well as induces the synthesis of numerous factors that have an adverse impact on the bone metabolism.The aim of the study was to determine the expression of RANKL, OPG and IL-33 in mucosal biopsies of UC patients with long disease duration as well as serum level of these cytokines in the context of bone density and bone metabolism. Materials and methodsThe UC group consisted of 56 patients with average disease duration of 16y. The control group comprised 37 healthy individuals. Local expression of cytokines was assessed in the biopsies of colonic mucosa by the real-time PCR and immunohistochemistry (IHC), and their serum concentration was measured by ELISA. ResultsThe increased bone resorption observed in patients with UC was reflected by low bone density and high serum level of C-terminal telopeptide (CTX). Mucosal RANKL expression and serum concentration were similar in UC group and healthy subjects, however, UC patients had higher local expression of OPG and serum OPG concentration. Increased IL-33 gene expression was observed only in UC at the mRNA level. We propose that bone resorption in UC patients despite OPG up-regulation could be caused by IL-33-induced mucosal synthesis of a potent proinflammatory cytokine, such as TNF-α, known as a possible inducer of osteoclastogenesis in the way independent of RANKL.

Telomere shortening correlates to dysplasia but not to DNA aneuploidy in longstanding ulcerative colitis

BackgroundUlcerative colitis (UC) is a chronic, inflammatory bowel disease which may lead to dysplasia and adenocarcinoma in patients when long-lasting. Short telomeres have been reported in mucosal cells of UC patients. Telomeres are repetitive base sequences capping the ends of linear chromosomes, and protect them from erosion and subsequent wrongful recombination and end-to-end joining during cell division. Short telomeres are associated with the development of chromosomal instability and aneuploidy, the latter being risk factors for development of dysplasia and cancer. Specifically, the abrupt shortening of one or more telomeres to a critical length, rather than bulk shortening of telomeres, seems to be associated with chromosomal instability.MethodsWe investigated possible associations between dysplasia, aneuploidy and telomere status in a total of eight lesions from each of ten progressors and four nonprogressors suffering from longstanding UC. We have analyzed mean telomere length by qPCR, as well as the amount of ultra-short telomeres by the Universal STELA method.ResultsAn increased amount of ultra-short telomeres, as well as general shortening of mean telomere length are significantly associated with dysplasia in longstanding UC. Furthermore, levels of ultra-short telomeres are also significantly increased in progressors (colons harbouring cancer/dysplasia and/or aneuploidy) compared to nonprogressors (without cancer/dysplasia/aneuploidy), whereas general shortening of telomeres did not show such associations.ConclusionsOur data suggest that ultra-short telomeres may be more tightly linked to colorectal carcinogenesis through development of dysplasia in UC than general telomere shortening. Telomere status was not seen to associate with DNA aneuploidy.

Histological healing favors lower risk of colon carcinoma in extensive ulcerative colitis.

To search for the answer in extensive ulcerative colitis as to whether histological inflammation persisting despite endoscopic mucosal healing serves to increase the risk of colon cancer (CC) or high grade dysplasia (HGD). This is a single center (Lenox Hill Hospital) retrospective cohort and descriptive study of extensive ulcerative colitis (UC) for 20 years or more with a minimum of 3 surveillance colonoscopies and biopsies performed after the first 10 years of UC diagnosis. Data analyzed included: duration of UC, date of diagnosis of (CC) or (HGD), number of surveillance colonoscopies, and biopsies showing histological inflammation and its severity in each of 6 segments when endoscopic appearance is normal. Two subgroups of patients were compared: group 1 patients who developed CC/HGD and group 2 patients who did not develop CC/HGD. Of 115 patients with longstanding UC reviewed, 68 patients met the inclusion criteria. Twenty patients were in group 1 and 48 in group 2. We identified the number of times for each patient when the endoscopic appearance was normal but biopsies nevertheless showed inflammation. Overall, histological disease activity in the absence of gross/endoscopic disease was found in 31.2% (95%CI: 28%-35%) of colonoscopies performed on the entire cohort of 68 patients. Histological disease activity when the colonoscopy showed an absence of gross disease activity was more common in group 1 than group 2 patients, 88% (95%CI: 72%-97%) vs 59% (95%CI: 53%-64%). Only 3/20 (15%) of patients in group 1 ever had a colonoscopy completely without demonstrated disease activity (i.e., no endoscopic or histological activity) as compared to 37/48 (77%) of patients in group 2, and only 3.3% (95%CI: 0.09%-8.3%) of colonoscopies in group 1 had no histological inflammation compared to 23% (95%CI: 20%-27%) in group 2. Progression to HGD or CC in extensive ulcerative colitis of long standing was more frequently encountered among those patients who demonstrate persistent histological inflammation in the absence of gross mucosal disease. Our findings support including the elimination of histological inflammation in the definition of mucosal healing, and support this endpoint as an appropriate goal of therapy because of its risk of increasing dysplasia and colon cancer.

A Case of Small-cell Neuroendocrine Carcinoma in a Patient with Long-standing Ulcerative Colitis

A Case of Small-cell Neuroendocrine Carcinoma in a Patient with Long-standing Ulcerative Colitis

Identification of Patients With Developing Ulcerative Colitis–associated Neoplasia by Nitrative DNA Damage Marker 8-Nitroguanin Expression in Rectal Mucosa

To clarify whether the expression of nitrative and oxidative DNA damage markers in the rectal mucosa of patients with ulcerative colitis (UC) could be used to predict UC-associated neoplasia. A longer duration of UC can increase the risk of developing UC-associated cancer (UCAC). Effective diagnostic markers are being sought to provide more selective screening and treatment strategies for patients with long-standing UC. A total of 141 patients with UC who underwent a proctocolectomy were enrolled in this study. The expression of 8-nitroguanine (8-NG), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and inducible nitric oxide synthase (iNOS) in the rectal mucosa were evaluated using immunohistochemistry (IHC) and assessed relative to the pathogenesis of UC-associated neoplasia. Eighteen patients (12.8%) had UC-associated neoplasia including low-grade or high-grade dysplasia and UCAC. IHC scores of 8-NG in UC-associated neoplasia group was significantly higher than in non-neoplasia group (P<0.0001). In contrast, IHC score of 8-oxodG in non-neoplasia group was significantly decreased compared with UC-associated neoplasia group (P=0.0028). In logistic regression analysis, duration of disease >8 years, high IHC scores of 8-NG, and low 8-oxodG in the rectal mucosa were significantly associated with the development of UC-associated neoplasia (P<0.01). The expression of 8-NG was more frequently observed in patients with UCAC than in patients with sporadic colorectal cancer (P<0.01). These results suggest that evaluating the expression levels of 8-NG in the rectal mucosa may be a useful biomarker for detecting patients with UC-associated neoplasia.

Gallbladder FISH: An Unusual Case of Early Detection and Cure of Gallbladder Cancer

Introduction: This is a case report of early diagnosis of gallbladder malignancy using fluorescence in situ hybridization (FISH) that led to surgical resection and cure from a malignancy, which otherwise has a very poor prognosis. Case Description: A 66-year-old Caucasian man with a 12-year history of ulcerative colitis (UC) was evaluated because of abnormal liver function tests and suspected primary sclerosing cholangitis (PSC). He had an abdominal CT scan that showed mildly dilated intrahepatic ducts with no other biliary ductal or gallbladder abnormalities. His Ca 19.9 was elevated at 80 units/mL. He underwent an endoscopic retrograde cholangiography (ERC) that showed irregularity in the distal common bile duct (CBD) and stricturing in the right hepatic duct (RHD) consistent with PSC. Brushing for cytology and FISH were obtained from the CBD and the RHD. Cytology showed reactive cellular atypia and acute inflammation and FISH showed 5 cells with gains of two or more chromosomes, 3(D3Z1), 7(D7Z1), and 17(D17Z1), and greater than 10 cells with gains of a single chromosome, 7(D7Z1). These results were consistent with malignancy. An endoscopic ultrasound was performed showing asymmetric gallbladder wall thickening and no evidence of a mass. The distal CBD was also mildly thickened. He was planned to undergo colectomy for colonic dysplasia in the setting of longstanding UC so he underwent a concomitant cholecystectomy based on our recommendations. Pathology showed a well-differentiated 2.2 cm gallbladder carcinoma with perimuscular invasion but no extension beyond the serosa or into the liver and no malignant adenopathy (stage T2 N0 M0). The patient has been followed-up closely for 2 years with multiple MRIs and ERCs with cytology and FISH being performed. These have been consistently negative for malignancy. He has no other clinical findings suggestive of cholangiocarcinoma. Discussion: While the molecular pathogenesis of adenocarcinoma of the biliary tree remains poorly understood, evidence suggests that there is a field carcinogenic effect in patients with PSC putting them at an increased risk of both cholangiocarcinoma and gallbladder cancer. A positive FISH in our patient with no clear evidence of cholangiocarcinoma prompted a careful examination of the gallbladder with findings suspicious enough to lead to cholecystectomy. This thorough evaluation led to early detection and long-term cure from gallbladder cancer, which otherwise has a very poor prognosis unless detected incidentally on cholecystectomy done for a different etiology.

Endoscopic Findings in Ulcerative Colitis

Patients with long-standing ulcerative colitis are at an increased risk for the development of intraepithelial neoplasia and colitis-associated cancer, and guidelines recommend colonoscopy as an outcome parameter for biological therapies or to assess therapeutic efficacy. This video highlights the various endoscopic findings in different disease stages of ulcerative colitis. The technique of advanced dysplasia detection in ulcerative colitis will be highlighted in another video of this library. This article is part of an expert video encyclopedia.

Cancer Risk After Resection of Polypoid Dysplasia in Patients With Longstanding Ulcerative Colitis: A Meta-analysis

American and European guidelines propose complete endoscopic resection of polypoid dysplasia (adenomas or adenoma-like masses) in patients with longstanding colitis, with close endoscopic follow-up. The incidence of cancer after detection of flat low-grade dysplasia or dysplasia-associated lesion or mass is estimated at 14 cases/1000 years of patient follow-up. However, the risk for polypoid dysplasia has not been determined with precision. We investigated the risk of cancer after endoscopic resection of polypoid dysplasia in patients with ulcerative colitis. MEDLINE, EMBASE, PubMed, and the Cochrane library were searched for studies of patients with colitis and resected polypoid dysplasia, with reports of colonoscopic follow-up and data on cancers detected. Outcomes from included articles were pooled to provide a single combined estimate of outcomes by using Poisson regression. Of 425 articles retrieved, we analyzed data from 10 studies, comprising 376 patients with colitis and polypoid dysplasia with a combined 1704 years of follow-up. A mean of 2.8 colonoscopies were performed for each patient after the index procedure (range, 0-15 colonoscopies). The pooled incidence of cancer was 5.3 cases (95% confidence interval, 2.7-10.1 cases)/1000 years of patient follow-up. There was no evidence of heterogeneity or publication bias. The pooled rate of any dysplasia was 65 cases (95% confidence interval, 54-78 cases)/1000 patient years. Patients with colitis have a low risk of colorectal cancer after resection of polypoid dysplasia; these findings support the current strategy of resection and surveillance. However, these patients have a 10-fold greater risk of developing any dysplasia than colorectal cancer and should undergo close endoscopic follow-up.

Colorectal neoplasia in long‐standing ulcerative colitis – a prospective study from a low‐prevalence area

Despite increasing recognition of ulcerative colitis (UC) in Asia in recent decades, reports on the occurrence of colorectal neoplasia (CRN) in UC are scarce and surveillance for this complication is not routinely practised in this region. We aimed to assess the outcome of a newly initiated pilot screening programme for screening CRN among UC patients in India. In this prospective study from an academic hospital setting, patients with UC at high risk of CRN were offered screening by magnifying chromocolonoscopy and the frequency of neoplastic lesions was assessed. Twenty-nine (70.7%) of 41 eligible patients [a median age of 46 (interquartile range 36-54.5) years; 17 (58.6%) men] enrolled for surveillance; 41 colonoscopies were undertaken over 42 months. The median disease duration was 10 (interquartile range 7.5-14.5) years. Sixteen (55.1%) had extensive colitis. On initial screening, low-grade dysplasia (LGD) was seen in five (17.2%) and high-grade dysplasia (HGD) in three (10.3%). Of these three, one accepted proctocolectomy immediately, one underwent surgery for adenocarcinoma and one refused surgery. Twelve follow-up colonoscopies in nine patients revealed three new LGD. High-grade dysplasia and subsequent adenocarcinoma can be detected with careful follow-up in Indian patients with long-standing UC but acceptance of surveillance and subsequent therapy are suboptimal. We found evidence that screening and surveillance programmes are useful for detecting neoplasias in UC, and need to be customized for this region.

Gene-set analysis is severely biased when applied to genome-wide methylation data

DNA methylation is an epigenetic mark that can stably repress gene expression. Because of its biological and clinical significance, several methods have been developed to compare genome-wide patterns of methylation between groups of samples. The application of gene set analysis to identify relevant groups of genes that are enriched for differentially methylated genes is often a major component of the analysis of these data. This can be used, for example, to identify processes or pathways that are perturbed in disease development. We show that gene-set analysis, as it is typically applied to genome-wide methylation assays, is severely biased as a result of differences in the numbers of CpG sites associated with different classes of genes and gene promoters. We demonstrate this bias using published data from a study of differential CpG island methylation in lung cancer and a dataset we generated to study methylation changes in patients with long-standing ulcerative colitis. We show that several of the gene sets that seem enriched would also be identified with randomized data. We suggest two existing approaches that can be adapted to correct the bias. Accounting for the bias in the lung cancer and ulcerative colitis datasets provides novel biological insights into the role of methylation in cancer development and chronic inflammation, respectively. Our results have significant implications for many previous genome-wide methylation studies that have drawn conclusions on the basis of such strongly biased analysis. cathal.seoighe@nuigalway.ie Supplementary data are available at Bioinformatics online.

Procedure Time and the Determination of Polypoid Abnormalities with Experience

Procedure length and agreement in detection of abnormalities may limit implementation of chromoendoscopy (CE) for dysplasia surveillance in ulcerative colitis (UC). We investigated these factors among endoscopists inexperienced in this technique. Six investigators performed surveillance colonoscopy with white light endoscopy (WLE) followed by CE on 75 patients with long-standing UC. Interobserver agreement for WLE and CE images of polyps and nonpolypoid mucosa was determined. Withdrawal times from the cecum were compared based on number of colonoscopies performed. Dysplasia detection rate with WLE was compared with CE. The analysis of 586 images (266 WLE and 320 CE) from 57 patients included images of 160 polyps (64 flat) with 29 dysplastic lesions. All investigators identified 10/11 WLE images of dysplasia and 4 identified all 18 CE dysplasia images, 1 missed 1 and 1 missed 3. Four dysplastic lesions were not identified by 1 or more investigators and all measured <5 mm. Interobserver agreement for lesions was high with kappa scores of 0.91 and 0.86 for WLE and CE, respectively. Among the 75 patients enrolled, dysplasia was found in 9.3% with WLE compared with 21.3% with WLE and CE (P = 0.007). Median colonoscopy withdrawal time improved from 31 minutes for endoscopists performing fewer than 5 procedures to 18 minutes for 5 to 14 and 19 minutes for more than 15 procedures. Indigo carmine CE for UC surveillance resulted in high rates of interobserver agreement for polyp detection, acceptable withdrawal times, and enhanced dysplasia detection. These results are encouraging for the implementation of CE programs for chronic UC.

Tu1126 Histological Healing Is Associated With a Decreased Risk of Colon Cancer in Cases of Longstanding Universal Ulcerative Colitis

BACKGROUND: The risk of developing colon cancer in patients with ulcerative colitis (UC) is increased by the chronicity of inflammation and extent of disease. The elimination of gross inflammation endoscopically is referred to as However, histological inflammation of various degrees may persist despite this gross mucosal healing. We hypothesized that histological mucosal healing indicates decreased likelihood for progression to dysplasia and cancer in cases of longstanding Universal UC. METHODS: This is a single center retrospective case control study of all UC patients seen by Dr. Burton Korelitz at Lenox Hill Hospital. A search was performed of the IBD database of over 3000 patients. The inclusion criteria were universal disease, 20 yrs of UC and a minimum of 3 surveillance colonoscopies with segmental biopsies performed after the first 10 years of UC diagnosis. Data included: age, date of onset of UC, date of diagnosis of colon cancer or severe dysplasia, number of total colonoscopies, and histological inflammation per segment and its severity when endoscopic appearance is normal. Two groups of patients were formed: Group 1, index patients with high grade dysplasia and/or cancer; and Group 2, control patients with long-standing UC without dysplasia or cancer. RESULTS: Of 115 charts of patients with longstanding UC reviewed, 68 patients (M:36 F:32) met the inclusion criteria. In group 1, 20 patients had developed colon cancer and/or high grade dysplasia. These 20 had 120 surveillance colonoscopies; 87(73%) revealed active disease and 33 (27%) did not. 29(88%) of the endoscopic negative colonoscopies showed histological inflammation. In the 48 patients of group 2who did not develop cancer or high grade dysplasia, 550 surveillance colonoscopies