Infliximab versus ciclosporin for steroid-resistant acute severe ulcerative colitis (CONSTRUCT): a mixed methods, open-label, pragmatic randomised trial.

BACKGROUND: Infliximab and ciclosporin are of similar efficacy in treating acute severe ulcerative colitis, but there has been no comparative evaluation of their relative clinical effectiveness and cost-effectiveness. METHODS: In this mixed methods, open-label, pragmatic randomised trial, we recruited consenting patients aged 18 years or older at 52 district general and teaching hospitals in England, Scotland, and Wales who had been admitted, unscheduled, with severe ulcerative colitis and failed to respond to intravenous hydrocortisone within about 5 days. Patients were randomly allocated (1:1) to receive either infliximab (5 mg/kg intravenous infusion given over 2 h at baseline, and again at 2 weeks and 6 weeks after the first infusion) or ciclosporin (2 mg/kg per day by continuous infusion for up to 7 days, followed by twice-daily tablets delivering 5·5 mg/kg per day for 12 weeks). Randomisation used a web-based password-protected site, with a dynamic algorithm to generate allocations on request, thus protecting against investigator preference or other subversion, while ensuring that each trial group was balanced by centre, which was the only stratification used. Local investigators and participants were aware of the treatment allocated, but the chief investigator and analysts were masked. Analysis was by treatment allocated. The primary outcome was quality-adjusted survival-ie, the area under the curve (AUC) of scores from the Crohn's and Ulcerative Colitis Questionnaire (CUCQ) completed by participants at baseline, 3 months, and 6 months, then every 6 months from 1 year to 3 years. This trial is registered with the ISRCTN Registry, number ISRCTN22663589. FINDINGS: Between June 17, 2010, and Feb 26, 2013, 270 patients were recruited. 135 patients were allocated to the infliximab group and 135 to the ciclosporin group. 121 (90%) patients in each group were included in the analysis of the primary outcome. There was no significant difference between groups in quality-adjusted survival (mean AUC 564·0 [SD 241·9] in the infliximab group vs 587·0 [226·2] in the ciclosporin group; mean adjusted difference 7·9 [95% CI -22·0 to 37·8]; p=0·603). Likewise, there were no significant differences between groups in the secondary outcomes of CUCQ scores, EQ-5D, or SF-6D scores; frequency of colectomy (55 [41%] of 135 patients in the infliximab group vs 65 [48%] of 135 patients in the ciclosporin group; p=0·223); or mean time to colectomy (811 [95% CI 707-912] days in the infliximab group vs 744 [638-850] days in the ciclosporin group; p=0·251). There were no differences in serious adverse reactions (16 reactions in 14 participants receiving infliximab vs ten in nine patients receiving ciclosporin); serious adverse events (21 in 16 patients vs 25 in 17 patients); or deaths (three in the infliximab group vs none in the ciclosporin group). INTERPRETATION: There was no significant difference between ciclosporin and infliximab in clinical effectiveness. FUNDING: NIHR Health Technology Assessment programme.

Comparison of high definition with standard white light endoscopy for detection of dysplastic lesions during surveillance colonoscopy in patients with colonic inflammatory bowel disease.

BACKGROUND: Dysplasia in colonic inflammatory bowel disease (IBD) is often multifocal and flat. High-definition (HD) colonoscopy improves adenoma detection rates by improving the ability to detect subtle mucosal changes. The utility of HD colonoscopy in dysplasia detection in patients with IBD has not been reported so far. We aimed to compare the yield of dysplastic lesions detected by standard definition (SD) white light endoscopy with HD endoscopy. METHODS: A retrospective cohort study of patients with long-standing (>7 years) colonic IBD undergoing surveillance colonoscopy at Nottingham University Hospital was studied between September 2008 and February 2010. Details of diagnosis, duration of disease, and outcomes of the colonoscopy were collected from the endoscopy database, electronic patient records, and patient notes. RESULTS: There were 160 colonoscopies (101 ulcerative colitis [UC] and 59 Crohn's disease [CD]) in the SD group and 209 colonoscopies (147 UC and 62 CD) in the HD group. The groups were well matched for all demographic variables. Thirty-two dysplastic lesions (27 on targeted biopsy) were detected in 24 patients in the HD group and 11 dysplastic lesions (six on targeted biopsy) were detected in eight patients the SD group. The adjusted prevalence ratio of detecting any dysplastic lesion and dysplastic lesion on targeted biopsy was 2.21 (95% confidence interval [CI] 1.09-4.45) and 2.99 (95% CI 1.16-7.79), respectively, for HD colonoscopy. CONCLUSIONS: HD colonoscopy improves targeted detection of dysplastic lesions during surveillance colonoscopy of patients with colonic IBD in routine clinical practice. Randomized controlled studies are required to confirm these findings.

Optical Microangiography: High-Definition Magnification Colonoscopy with Narrow Band Imaging (NBI) for Visualizing Mucosal Capillaries and Red Blood Cells in the Large Intestine.

BACKGROUND/AIMS: Recent advances in zoom endoscopy have enabled the subepithelial capillary network (SECN) in different organs of the gastrointestinal tract to be visualized. Ex vivo studies have suggested that the SECN demonstrates a honeycomb-like structure in the large intestine, but this has not yet been visualized in vivo. The high clarity and resolution of narrow-band imaging (NBI) may allow visualization at the single red-blood-cell (RBC) level and more accurate visualization of the SECN. We investigated whether high-definition magnification colonoscopy with NBI is useful for visualizing capillaries and RBCs in the large intestine. METHODS: Sixteen patients with bowel symptoms undergoing routine colonoscopy with normal findings in a tertiary referral academic gastroenterology and endoscopy unit were included in the study. Total colonoscopies were performed using a high-definition magnification colonoscope (CF-H260AZI, Olympus, Tokyo) and a prototype high-definition electronic endoscopy system capable of NBI. Each part of the large intestine (cecum, ascending, transverse, descending, and sigmoid colon, and rectum) was observed at the maximum magnification with white-light imaging (WLI) and NBI. The normal honeycomb-like SECN and RBC movement by high-definition magnification colonoscopy with either WLI or NBI was prospectively successfully visualized for each part of the large intestine. RESULTS: In all subjects, high-definition magnification colonoscopy with NBI allowed the visualization of a honeycomb-like SECN together with RBC movement in each segment of the large intestine except for the rectum. In contrast, with WLI alone, neither this SECN structure nor RBC movement could be detected. CONCLUSIONS: High-definition magnification colonoscopy with NBI could be a new optical method for facilitating noninvasive investigations of both the microvascular architecture and microcirculation without the need for contrast materials.

Fascin, an actin-bundling protein, modulates colonic epithelial cell invasiveness and differentiation in vitro.

In epithelial tissue, cell-matrix and cell-cell adhesive interactions have important roles in the normal organization and stabilization of the cell layer. The malignant conversion of epithelial cells involves alterations in the expression and function of these adhesion systems that enable a switch to a migratory phenotype in tumor invasion and metastasis. Fascin is an actin-crosslinking protein that is found in the core actin bundles of cell-surface spikes and projections that are implicated in cell motility. We demonstrate that fascin is not detectable in normal colonic epithelium, but is dramatically up-regulated in colorectal adenocarcinoma. To test the hypothesis that fascin could participate in tumor invasive behavior, we developed a cell culture model to examine the effect of fascin expression on the adhesive interactions, invasiveness, and differentiation of colonic epithelial cells. We report marked effects on the organization of cell-surface protrusions, actin cytoskeleton, and focal adhesions in the absence of alterations in the protein levels of the major components of these structures. These effects correlate with alterations in cell movements on two-dimensional matrix, and increased invasiveness in three-dimensional matrix. The cells also show increased proliferation and decreased capacity for normal glandular differentiation in collagen gels. We propose that up-regulation of fascin, by promoting the formation of protrusive, actin-based, cell-motility structures, could be a significant component in the acquisition of invasive phenotype in colonic carcinoma.