Long-standing Ulcerative Colitis Research Articles

Covering the Cover

Covering the Cover

Pit pattern analysis with high-definition chromoendoscopy and narrow-band imaging for optical diagnosis of dysplasia in patients with ulcerative colitis

Patients with longstanding ulcerative colitis (UC) are at increased risk of developing colorectal neoplasia. Chromoendoscopy (CE) increases detection of lesions, and Kudo pit pattern classification I and II have been suggested to be predictive of benign polyps in UC. Little is known on the use of this classification in nonmagnified high-definition (HD) (virtual) CE and narrow-band Imaging (NBI) or on the interobserver agreement. The aim of this pilot study was to assess the diagnostic accuracy and the interobserver agreement of the Kudo pit pattern classification in UC patients undergoing surveillance with methylene blue CE or NBI in a multicenter study. Fifty images of lesions identified in 27 UC patients (13 neoplastic) either with classical CE (methylene blue .1%; n= 24) or NBI (n= 26) were selected by an independent investigator. Images were selected from a randomized controlled trial to compare CE and NBI. All nonmagnified images were obtained with a processor and mounted in a PowerPoint file in a standardized way (same size; black background). Ten endoscopists with extensive experience in NBI/CE were asked to assess the lesions for the predominant Kudo pit pattern (I, II, IIIL, IIIS, IV, and V) to indicate if they believed the lesion was neoplastic and how confident they were about the diagnosis. Histology was used as the criterion standard. Median sensitivity, specificity, negative predictive value, and positive predictive value for diagnosing neoplasia based on the presence of pit pattern other than I or II was 77%, 68%, 88%, and 46%, respectively. Diagnostic accuracy was significantly higher when a diagnosis was made with a high level of confidence (77% vs 21%, P< .001). The overall interobserver agreement for any pit pattern was only fair (κ= .282), with CE being significantly better than NBI (.322 vs .224, P< .001). From a clinical viewpoint the difference between neoplastic and non-neoplastic lesions is important. The agreement for differentiation between non-neoplastic patterns (I, II) and neoplastic patterns (IIIL, IIIS, IV, or V) was moderate (κ= .587) and even significantly better for NBI in comparison with CE (κ= .653 vs .495, P< .001). Differentiation between non-neoplastic and neoplastic pit patterns in UC lesions shows a moderate to substantial agreement among expert endoscopists. The agreement for differentiating neoplastic from non-neoplastic lesions is significantly better for NBI in comparison with HD CE. The assessment of pit pattern I or II with nonmagnified HD CE or NBI has a high negative predictive value to rule out neoplasia. (Clinical trial registration number: NCT01882205.).

Increased cholestatic enzymes in two patients with long-term history of ulcerative colitis: consider primary biliary cholangitis not always primary sclerosing cholangitis

Several hepatobiliary disorders have been reported in ulcerative colitis (UC) patients with primary sclerosing cholangitis (PSC) being the most specific. Primary biliary cholangitis (PBC), previously known as primary biliary cirrhosis,...

Strategies for detecting colon cancer in patients with inflammatory bowel disease.

Patients with longstanding ulcerative colitis and colonic Crohn's disease have an increased risk of colorectal cancer (CRC) compared with the general population. This review assessed the evidence that endoscopic surveillance may prolong life by allowing earlier detection of CRC or its pre-cursor lesion, dysplasia, in patients with inflammatory bowel disease (IBD). To assess the effectiveness of cancer surveillance programs for diagnosis of IBD-associated colorectal cancer and in reducing the mortality rate from colorectal cancer in patients with IBD. We searched MEDLINE, EMBASE, CENTRAL and clinical clinicaltrials.gov from inception to 19 September 2016. We also searched conference abstracts and reference lists to identify additional studies. Potentially relevant articles were reviewed independently and unblinded by two authors to determine eligibility. Randomised controlled trials (RCTs) or observational studies (cohort or case control) assessing any form of endoscopic surveillance aimed at early detection of CRC were considered for inclusion. Studies had to have a no surveillance comparison group to be eligible for inclusion. Eligible studies were reviewed in duplicate and the results of the primary research trials were independently extracted by two authors. The primary outcome was detection of CRC. Secondary outcomes included death from CRC, time to cancer detection, time to death and adverse events. Deaths from CRC were derived from life tables, survival curves or where possible, by calculating life tables from the data provided. The presence of significant heterogeneity among studies was tested by the chi-square test. Because this is a relatively insensitive test, a P value of less than 0.1 was considered statistically significant. Provided statistical heterogeneity was not present, the fixed effects model was used for the pooling of data. The 2x2 tables were combined into a summary test statistic using the pooled odds ratio (OR) and 95% confidence intervals as described by Cochrane and Mantel and Haenszel. The methodological quality of the included studies was assessed using the Newcastle-Ottawa scale for non-randomised studies The overall quality of the evidence supporting the primary and selected secondary outcomes was assessed using the GRADE criteria. No RCTs were identified. Five observational studies (N = 7199) met the inclusion criteria. The studies scored well on the Newcastle-Ottawa scale, but due to the nature of observational studies, a high risk of bias was assigned to all the studies. Three studies were pooled to assess the rate of cancer detected in the surveillance group compared to the non-surveillance group. The studies found a significantly higher rate of cancer detection in the non surveillance group compared to the surveillance group. CRC was detected in 1.83% (53/2895) of patients in the surveillance group compared to 3.17% (135/4256) of patients in the non-surveillance group (OR 0.58, 95% CI 0.42 to 0.80; P = 0.0009). Four studies were pooled to assess the death rate associated with CRC in patients who underwent surveillance compared to patients who did not undergo surveillance. There was a significantly lower death rate associated with CRC in the surveillance group compared to the non-surveillance group. Eight per cent (15/176) of patients in the surveillance group died from CRC compared to 22% (79/354) of patients in the non-surveillance group (OR 0.36, 95% CI 0.19 to 0.69, P=0.002). Data were pooled from two studies to examine the rate of early stage versus late stage colorectal cancer (Duke stages A & B compared to Duke stages C & D) in patients who underwent surveillance compared to patients who do not undergo surveillance. A significantly higher rate of early stage CRC (Duke A & B) was detected in the surveillance group compared to the non-surveillance group. Sixteen per cent (17/110) of patients in the surveillance group had early stage CRC compared to 8% (9/117) of patients in the non-surveillance group (OR 5.40, 95% CI 1.51 to 19.30; P = 0.009). A higher rate of late stage CRC (Duke C & D) was observed in the non-surveillance group compared to the surveillance group. Nine per cent (10/110) of patients in the surveillance group had late stage CRC compared to 16% (19/117) of patients in the non-surveillance group (OR 0.46, 95% CI 0.08 to 2.51; P = 0.37). A GRADE analysis indicated that the quality of the data was very low for all of these outcomes. The included studies did not report on the other pre-specified outcomes including time to cancer detection, time to death and adverse events. The current data suggest that colonoscopic surveillance in IBD may reduce the development of both CRC and the rate of CRC-associated death through early detection, although the quality of the evidence is very low. The detection of earlier stage CRC in the surveillance group may explain some of the survival benefit observed. RCTs assessing the efficacy of endoscopic surveillance in people with IBD are unlikely to be undertaken due to ethical considerations.

Short-term treatment with eicosapentaenoic acid improves inflammation and affects colonic differentiation markers and microbiota in patients with ulcerative colitis

Patients with long-standing ulcerative colitis (UC) have an increased colorectal cancer (CRC) risk. In this pilot study we evaluated the effect of Eicosapentaenoic acid as free fatty acid (EPA-FFA) supplementation on mucosal disease activity, colonic differentiation markers and microbiota composition in UC patients. Twenty long-standing UC patients in stable clinical remission and with fecal calprotectin (FC) > 150 µg/g were enrolled (T0) and supplemented with EPA-FFA 2 g/daily for 90 days (T3). Endoscopic and histologic disease activities were measured by Mayo and Geboes scores, respectively. HES1, KLF4, STAT3, IL-10 and SOCS3 levels were determined using western blotting and qRT-PCR, while phospho-STAT3 levels were assessed by western blotting. Goblet cells were stained by Alcian blue. Microbiota analyses were performed on both fecal and colonic samples. Nineteen patients completed the study; seventeen (89.5%) were compliant. EPA-FFA treatment reduced FC levels at T3. Patients with FC > 150 µg/g at T3 (n = 2) were assumed as non-responders. EPA-FFA improved endoscopic and histological inflammation and induced IL-10, SOCS3, HES1 and KLF4 in compliant and responder patients. Importantly, long-term UC-driven microbiota composition was partially redressed by EPA-FFA. In conclusion, EPA-FFA supplementation reduced mucosal inflammation, promoted goblet cells differentiation and modulated intestinal microbiota composition in long-standing UC patients.

Aggressive large-cell neuroendocrine carcinoma of the sigmoid colon in a patient with ulcerative colitis

Colonic inflammation seen in inflammatory bowel disease (IBD) predisposes to the development of colorectal adenocarcinoma. In contrast, colorectal neuroendocrine carcinomas (NECs) have rarely been reported in the setting of IBD,...

MiR-4728-3p Functions as a Tumor Suppressor in Ulcerative Colitis-associated Colorectal Neoplasia Through Regulation of Focal Adhesion Signaling.

As mechanisms of neoplasia in patients with ulcerative colitis (UC) remain poorly understood, we sought to identify pathways of carcinogenesis in this high-risk population. MicroRNA (miRNA) and mRNA expression was examined in nondysplastic rectosigmoid mucosa from UC patients with (n = 19) or without remote colon neoplasia (n = 23). We developed a method to identify miRNA-regulated pathways based on differentially expressed miRNAs and their putative mRNAs targets in the same samples. One key pathway identified in the analysis, miR-4728-3p regulation of focal adhesion signaling was further evaluated in vitro and through examination of expression in UC-cancers. There were 101 significantly up-regulated and 98 down-regulated miRNAs (adjusted P < 0.05) in the rectal mucosa of UC patients harboring proximal neoplasia. Bioinformatic analysis identified miR-4728-3p as a regulator of 3 proteins involved in focal adhesion signaling, CAV1, THBS2, and COL1A2. Real-time PCR validated down-regulation of miR-4728-3p in nondysplastic tissue remote from UC-neoplasia and in UC-associated colon cancers. miR-4728-3p transfection into colon cancer cells down-regulated expression levels and decreased luciferase activities in cells expressing a wild type 3' untranslated region compared with a mutant 3' untranslated region for all 3 genes. Exogenous transfected miR-4728-3p also delayed wound healing and decreased formation of focal adhesion complexes. Patients with long-standing UC who harbor neoplasia can be identified based on miRNA and mRNA profiles in nondysplastic tissue. Using a method to analyze miRNA and mRNA expression from the same tissues, we identified that miR-4728-3p is likely an important tumor suppressor in UC-associated colon carcinogenesis.

Stereomicroscopic features of colitis-associated tumors in mice: Evaluation of pit pattern.

Patients with longstanding ulcerative colitis have an increased risk of colorectal cancer. Mouse models for colitis-associated tumors are indispensable for the development of novel strategies for prevention and intervention, as well as an improved understanding of the mechanisms underlying tumor formation. The present study examined whether stereomicroscopic observations with dye-application were able to detect and discriminate tumors in a colitis-associated tumor model in mice. Colonic tumors were induced in C57BL/6 mice by 15 cycles of treatment with dextran sulfate sodium (DSS) in drinking water. The mice were then divided into 4 groups: normal mice fed a control diet, normal mice fed an iron-supplemented diet, 0.7% DSS mice fed an iron diet and 1.5% DSS mice fed an iron diet. The entire colons were characterized with respect to both morphology and histology. The pit pattern architecture was analyzed using stereomicroscopy with dye agents (0.2% indigo carmine or 0.06% crystal violet). The tumor histology was graded as negative, indefinite or positive for dysplasia. The positive category was divided into two subcategories: low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The tumor incidences and multiplicity were significantly higher in mice fed an iron diet and 1.5% DSS compared with in mice fed an iron diet and 0.7% DSS. Compared with LGD, HGD was predominantly located in the distal colon, was larger in size and had a higher incidence of elevated lesions (Is and IIa) and a lower incidence of flat lesions (IIb). In regards to the pit pattern, HGD had a high incidence of VI pits and a low incidence of IV, IIIL and II pits. In conclusion, evaluation of the pit pattern using stereomicroscopy with dye-application is useful for detecting and discriminating neoplastic changes in DSS mice and may further our understanding of the mechanisms that induce tumor formation in patients with ulcerative colitis and the characterization of pharmaceutical responses.

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Detection of colonic dysplasia in patients with ulcerative colitis using a targeted fluorescent peptide and confocal laser endomicroscopy: A pilot study.

AimTargeted molecular probes have been used to detect sporadic colonic dysplasia during confocal laser endomicroscopy (CLE) with promising results. This is a feasibility pilot study aiming to assess the potential role of CLE combined with a fluorescent-labeled peptide to stain and detect dysplasia associated with Ulcerative Colitis.MethodA phage-derived heptapeptide with predicted high binding affinity for dysplastic tissue, was synthesized and labeled with fluorescein. Eleven lesions with suspected dysplasia at endoscopy were excised from nine patients with long-standing ulcerative colitis. Specimens were sprayed with the peptide and examined by CLE. The CLE images were then compared to the corresponding histological sections.ResultsAt definitive histology, 4 lesions were diagnosed as inflammatory polyps, 6 as dysplastic lesions and one as invasive cancer. In inflammatory polyps, the fluorescence signal came from peri-cryptal spaces and crypt lumen due to passive accumulation of the peptide in these areas. Dysplasia was associated with active binding of the peptide to dysplastic colonocytes.ConclusionEx vivo staining of ulcerative colitis-associated dysplasia using a fluorescent labeled molecular probe and CLE is feasible. In vivo studies on larger populations are required to evaluate the safety and the effective contribution of molecular probes in cancer surveillance of ulcerative colitis.

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

Background:Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma.Methods:Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma.Results:Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects.Conclusions:Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.

Microcarcinoid arising in patients with long-standing ulcerative colitis: histological analysis

Some case reports of neuroendocrine tumors and neuroendocrine carcinoma associated with ulcerative colitis (UC) have been published. Most neuroendocrine tumor cases are small lesions corresponding to microcarcinoids (MCs). However, published case reports have presented findings of MCs as single-case reports. Thus, the frequency of MCs is still unclear. In this study, we described the clinical and morphological features of 14 cases of UC-associated MCs and estimated the frequency of MCs. Consecutive patients with UC who underwent complete removal of the large intestine were assessed, and 135 patients were selected. Of the 135 cases, 14 cases (10.4%) in which MC lesions were observed histologically were classified as the MC group, and the remaining 121 cases were classified as the control group. Seven cases in the MC group (50%) exhibited colitic cancer. No cases in either group had distinct carcinoid tumors. All MC lesions were located in the rectum, and the sizes ranged from 0.1 to 5.5 mm. Eight cases (57%) had multiple MC lesions. The frequency of MCs in UC was estimated to be 10.4%. Most cases of MC were quite unlikely to develop into clinically distinct carcinoid tumors. Thus, when MC lesions remain microscopic, they may not represent true neoplasms, which require immediate surgical resection. Because MC often arose in cases with UC complicated by dysplasia or cancer, patients with UC whose rectal biopsies reveal MC may be at high risk of colitic cancer.

Mo2046 - Eicosapentaenoic Acid-Free Fatty Reduces Fecal Calprotectin Levels and Affects Colitis-Associated Colorectal Cancer Pathways in Patients with Long-Standing Ulcerative Colitis

Mo2046 - Eicosapentaenoic Acid-Free Fatty Reduces Fecal Calprotectin Levels and Affects Colitis-Associated Colorectal Cancer Pathways in Patients with Long-Standing Ulcerative Colitis

Tu1969 - Increases in Mucosal miR-215 Precede Neoplastic Development in Patients with Long-Standing Ulcerative Colitis

Tu1969 - Increases in Mucosal miR-215 Precede Neoplastic Development in Patients with Long-Standing Ulcerative Colitis

Patients with longstanding ulcerative colitis in remission do not have more irritable bowel syndrome-like symptoms than controls.

BackgroundIrritable bowel syndrome (IBS) is more common in patients with ulcerative colitis (UC) than expected. The prevalence of IBS in patients with UC with longstanding disease is not known. We investigated the prevalence of IBS-like symptoms in patients with UC in remission and longstanding disease in comparison to control subjects.MethodsSixty-eight patients with UC and 33 patients with hereditary familiar colon cancer and who underwent colonoscopy surveillance were included. Faecal calprotectin (FC), Gastrointestinal Symptoms Rating Scale-Irritable Bowel Syndrome (GSRS-IBS) and Hospital Anxiety and Depression scale were fulfilled prior to endoscopy. UC in remission was define by steroid-free clinical remission, a Mayo Score ≤ 1 on endoscopy, a FC ≤ 200 μg/g and no significant active inflammation on colon biopsies.ResultsFifty-five UC patients met the criteria for being in remission. The median disease duration was 17 years. The patients with UC in remission tended to have lower scores on total GSRS-IBS score (6 vs 10.5; p = 0.062) and lower or equal scores on all specific IBS symptoms in comparison to controls. There was a moderate but significant correlation between diarrhoea scores and FC levels (in the span ≤ 200 μg/g) (rs 0.38; p = 0.004) in the UC in remission group.ConclusionPatients with UC with longstanding disease and in remission do not have more IBS symptoms than controls. In UC patients in remission the FC level in the lower span showed a moderate correlation to symptoms of diarrhoea.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-016-0553-x) contains supplementary material, which is available to authorized users.

A low-cost method for chromoendoscopy for surveillance in ulcerative colitis.

The risk of colorectal cancer in Indian patients with long-standing ulcerative colitis is high and similar to that in the West. Surveillance for dysplasia in these patients is therefore important. Recent studies and guidelines suggest an increasing role for chromoendoscopy-guided biopsy in surveillance for dysplasia. We report our experience with the technique of chromoendoscopy and an economical method of performing it. Reconstituting indigo carmine from a powder form rather than the dyes available commercially is a better economical alternative and should help make chromoendoscopy the standard of care for dysplasia surveillance across the country.

Covering the Cover

Covering the Cover

34P - Co-expression of HGFR and CD133 cancer stem cell marker in subepithelial cells of chronically active ulcerative colitis

Chronic, longstandig inflammation is known to be a hallmark of cancer. Colorectal cancer risk is elevated in longstanding ulcerative colitis (UC). Previously, we found that in active, newly diagnosed UC HGFR+ circulating and subepithelial cells display an expression profile characteristics for mesenchymal-epitehlial transition. The aim of this study was to characterize the regeneration-associated stem cell-related phenotype of hepatocyte-derived growth factor receptor (HGFR)-expressing cells in longstanding, chronically active UC. Forty matched peripheral blood and colonic biopsy samples from 20 patients with chronically active UC and 20 healthy controls were collected. After preparing tissue microarrays and blood smears HGFR, CDX2, CD133 and Musashi-1 conventional and double fluorescent immunolabelings were performed, then the samples were digitalized. For semiquantitative counting of immunopositive lamina propria (LP) and blood cells were counted, then mean ± SD were determined. Using laser microdissection subepithelial cells from the lamina propria were collected. Gene expression analysis of HGFR, CD133, CDX2, Lgr5, Musashi-1 and CK20 were performed in all samples by using real-time RT-PCR. Higher number of HGFR (blood: 7.4 ± 1.3 vs 28.4 ± 2.23; LP: 2.4 ± 0.7 vs 8.15 ± 0.59; P < 0.05), CDX2 (blood: 0 vs 0.9 ± 0.68; LP: 0.7 ± 0.44 vs 2.02 ± 0.76; P < 0.05), CD133 (blood: 2.3 ± 0.98 vs 9.72 ± 1.57; LP: 12.1 ± 0.55 vs 31.14 ± 2.15; P < 0.05) and Musashi-1 (blood and LP: 0 vs scattered) positive cells were detected in blood and LP of UC samples as compared to controls. HGFR/CDX2 (blood: 0 vs scattered; LP: 0.8 ± 0.2 vs 0.98 ± 0.38, n.s.) and Musashi-1/CDX2 (blood and LP: 0 vs scattered) co-expressions were found rarely in blood and LP of UC samples. HGFR/CD133 (2.3 ± 0.46) and CD133/CDX2 (scattered) co-expressions appeared only in UC LP samples. In chronically active UC, the portion of circulating and subeithelial HGFR-expressing cells decreased, indicating a lower activity of mucosal regeneration by mesenchymal-epithelial transition. However, the higher number of HGFR/CD133 double positive cells may indicate the involvement of CD133 expression in colitis-associated carcinogenesis.

722 Comparison Between Newly-Developed Narrow Band Imaging and Panchromoendoscopy for Surveillance Colonoscopy in Patients With Longstanding Ulcerative Colitis: A Prospective Multicenter Randomized Controlled Trial, Navigator Study

722 Comparison Between Newly-Developed Narrow Band Imaging and Panchromoendoscopy for Surveillance Colonoscopy in Patients With Longstanding Ulcerative Colitis: A Prospective Multicenter Randomized Controlled Trial, Navigator Study

P287. Differentiating neoplasic and non-neoplasic raised lesions (polyps and pseudopolyps) in long-standing ulcerative colitis: results from a prospective systematic study using virtual chromoendoscopy with i-SCAN and the Kudo classification

P287. Differentiating neoplasic and non-neoplasic raised lesions (polyps and pseudopolyps) in long-standing ulcerative colitis: results from a prospective systematic study using virtual chromoendoscopy with i-SCAN and the Kudo classification