Ori Segol

Standard forward-viewing colonoscopy versus full-spectrum endoscopy: an international, multicentre, randomised, tandem colonoscopy trial

BACKGROUND Although colonoscopy is the accepted standard for detection of colorectal adenomas and cancers, many adenomas and some cancers are missed. To avoid interval colorectal cancer, the adenoma miss rate of colonoscopy needs to be reduced by improvement of colonoscopy technique and imaging capability. We aimed to compare the adenoma miss rates of full-spectrum endoscopy colonoscopy with those of standard forward-viewing colonoscopy. METHODS We did an international, multicentre, randomised trial at three sites in Israel, one site in the Netherlands, and two sites in the USA between Feb 1, 2012, and March 31, 2013. Patients aged 18-70 years referred for colorectal cancer screening, polyp surveillance, or diagnostic assessment underwent same-day, back-to-back tandem colonoscopy with standard forward-viewing colonoscope and the full-spectrum endoscopy colonoscope. The patients were randomly assigned (1:1), via computer-generated randomisation with block size of 20, to which procedure was done first. The endoscopist was masked to group allocation until immediately before the start of colonoscopy examinations; patients were not masked. The primary endpoint was adenoma miss rates. We did per-protocol analyses. This trial is registered with ClinicalTrials.gov, number NCT01549535. FINDINGS 197 participants were enrolled. 185 participants were included in the per-protocol analyses: 88 (48%) were randomly assigned to receive standard forward-viewing colonoscopy first, and 97 (52%) to receive full-spectrum endoscopy colonoscopy first. By per-lesion analysis, the adenoma miss rate was significantly lower in patients in the full-spectrum endoscopy group than in those in the standard forward-viewing procedure group: five (7%) of 67 vs 20 (41%) of 49 adenomas were missed (p<0·0001). Standard forward-viewing colonoscopy missed 20 adenomas in 15 patients; of those, three (15%) were advanced adenomas. Full-spectrum endoscopy missed five adenomas in five patients in whom an adenoma had already been detected with first-pass standard forward-viewing colonoscopy; none of these missed adenomas were advanced. One patient was admitted to hospital for colitis detected at colonoscopy, whereas five minor adverse events were reported including vomiting, diarrhoea, cystitis, gastroenteritis, and bleeding. INTERPRETATION Full-spectrum endoscopy represents a technology advancement for colonoscopy and could improve the efficacy of colorectal cancer screening and surveillance. FUNDING EndoChoice.

Treatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins.

OBJECTIVES:Hepatitis B virus (HBV) is a noncytopathic virus, and hepatocellular injury is mediated by a defective host antiviral immune response. We have previously shown that antiviral immunity can be modulated through oral feeding of viral proteins. The aims of this study were to determine the safety and efficacy of treatment of patients with chronic HBV by means of p.o. administration of HBV envelope proteins.METHODS:A total of 42 chronic HBV patients were treated p.o. with HBV envelope proteins (HBsAg+preS1+preS2), three times/wk for 20–30 wk, and followed for an additional 20 wk. Patients were monitored for HBV-DNA levels, liver enzymes, and liver histology. HBV-directed T cell immune modulation was assessed in vitro by HBV specific T cell-proliferation, cytotoxicity, IFNγ, and IL10 ELISPOT assays, and reverse transcription–polymerase chain reaction cytokines assay.RESULTS:Favorable response in one of the primary endpoints was achieved in 28/42 patients (66.6%) by means of p.o. immune regulation. A significant decrease in viral load was observed in 15 patients (35.7%). HBsAg/HBcAg biopsy scores improved in 41% and 57.1% of patients, respectively. Histological improvement in liver necroinflammatory score was noted in 12/40 patients (30%). In all, 80% showed biochemical response. Five of 19 HBeAg positive patients (26.3%) became negative for HBeAg. A favorable augmentation in anti-HBV specific T cell response, with increased HbsAg specific T cell proliferation (78%), cytotoxicity (75%), and IFNγ positive T cell clones (62.9%) was noted. In addition, a decrease in the IL10 γ positive T cell clones was achieved (48.1%). Natural killer T (NKT) lymphocytes increased significantly in all treated patients.CONCLUSIONS:Immune regulation of the anti-HBV immune response via p.o. administration of HBV envelope proteins alleviated the immune-mediated liver injury while augmenting the effective antiviral immunity.

Multicenter, randomized, tandem evaluation of EndoRings colonoscopy--results of the CLEVER study.

BACKGROUND AND STUDY AIMS Adenoma miss rate during colonoscopy has become a widely acknowledged proxy measure for post-colonoscopy colorectal cancer. Among other reasons, this can happen because of inadequate visualization of the proximal aspects of colonic folds and flexures. EndoRings (EndoAid Ltd., Caesarea, Israel) is a silicone-rubber device that is fitted onto the distal end of the colonoscope. Its flexible circular rings engage and mechanically stretch colonic folds during withdrawal. The primary aim of this study was to compare adenoma miss rates between standard colonoscopy and colonoscopy using EndoRings. METHODS In this multicenter, randomized, tandem colonoscopy study, we performed same-day, back-to-back colonoscopies with EndoRings followed by standard colonoscopy, or vice versa. RESULTS After exclusion of 10 patients for protocol violations, 116 patients (38.8% female; mean age 58.7) remained for analysis. The adenoma miss rate of EndoRings colonoscopy (7/67; 10.4%) was significantly lower (P<0.001) compared with standard colonoscopy (28/58; 48.3%). Similar results were found for polyp miss rates: EndoRings (9.1%) and standard colonoscopy (52.8%; P<0.001). Mean cecal intubation times (9.3 vs. 8.4 minutes; P=0.142) and withdrawal times (7.4 vs. 7.2 minutes; P=0.286), respectively, were not significantly different between EndoRings and standard colonoscopy. Mean total procedure time was longer with EndoRings than with standard colonoscopy (21.6 vs. 18.5 minutes, P=0.001) as more polyps were removed. CONCLUSIONS This study demonstrates that colonoscopy with EndoRings has lower adenoma and polyp miss rates than standard colonoscopy, which may improve the efficacy particularly of screening and surveillance colonoscopies. ClinicalTrials.gov NCT01955122.

Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial

Therapy for Crohns disease (CD) with thiopurines is limited by systemic side effects. A novel formulation of fixed‐dose, delayed‐release 6‐mercaptopurine (DR‐6MP) was developed, with local effect on the gut immune system and minimal absorption. The aim of this study was to evaluate the safety and efficacy of DR‐6MP in patients with moderately severe CD compared to systemically delivered 6‐mercaptopurine (Purinethol). Seventy CD patients were enrolled into a 12‐week, double‐blind controlled trial. The primary end‐point was the percentage of subjects with clinical remission [Crohns Disease Activity Index (CDAI) < 150] or clinical response (100‐point CDAI reduction). Twenty‐six (56·5%) and 13 (54·2%) subjects from the DR‐6MP and Purinethol cohorts, respectively, completed the study. DR‐6MP had similar efficacy to Purinethol following 12 weeks of treatment. However, the time to maximal clinical response was 8 weeks for DR‐6MP versus 12 weeks for Purinethol. A higher proportion of patients on DR‐6MP showed clinical remission at week 8. A greater improvement in Inflammatory Bowel Disease Questionnaire (IBDQ) score was noted in the DR‐6MP group. DR‐6MP led to a decrease of CD62+ expression on T cells, implying a reduction of lymphocyte adhesion to site of inflammation. DR‐6MP was safer than Purinethol, with significantly fewer adverse events (AEs). There was no evidence of drug‐induced leucopenia in the DR‐6MP group; the proportion of subjects who developed hepatotoxicity was lower for the DR‐6MP. Non‐absorbable DR‐6MP is safe and biologically active in the gut. It is clinically effective, exerting a systemic immune response with low systemic bioavailability and a low incidence of side effects.

Mo1211 Oral Administration of Non-Absorbable Delayed Release 6-Mercaptopurine is Locally Active in the Gut, Exerts a Systemic Immune Effect and Alleviates Crohn's Disease With Low Rate of Side Effects: Results of Double Blind Phase II Clinical Trial

Objective: Low FODMAP (Fermentable Oligo-, Di-, Monosaccharides and Polyols) diet (LFD) has been shown to be efficient in irritable bowel syndrome (IBS). The objective of this study was to investigate the impact of a LFD on IBS-like symptoms, disease activity and quality of life in inflammatory bowel disease (IBD) (SIBDQ). Design: Randomised, non-blinded controlled six weeks trial of IBD patients in remission or mild to moderate disease activity and IBS-like symptoms (Rome III criteria) were allocated to either LFD or normal diet. Patients had to fill out the IBS symptom severity scale (IBS-SSS) and quality of life (IBS-QOL) at week 0 and 6 on a web-based program and IBD activity symptom scores: SCCAI for ulcerative colitis (UC), HBI for Crohns disease (CD) and quality of life (SIBDQ) on paper. Results: A total of 89 patients: 61(69%) UC and 28 (21%) CD, 67 (75%) females, median age 40 years (20-70) were randomized: 44 to LFD and 45 as controls. Significant reduction in IBS-SSS at week 6 in LFD compared to controls (114 vs. 68), p= 0.02 was observed. In UC a significant reduction of SCCAI (0.7 vs. 0.1), p=0.02 but not in CD was observed. SIBDQ improved significantly in LFD (9.1-0.9), p<0.001. Conclusion: LFD is effective in IBD patients in remission or mild-to moderate activity, predominantly improving IBS-like symptoms in patients and further reduce disease activity for UC and improve SIBDQ.

Original contributionTreatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins

Treatment of chronic hepatitis B virus infection via oral immune regulation toward hepatitis B virus proteins