Jun Arimoto

Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial

BACKGROUND The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. METHODS This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. FINDINGS Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38·0%; 95% CI 26·7-49·3] of 71 patients, placebo group 35 [56·5%; 95% CI 44·1-68·8] of 62; p=0·034, risk ratio [RR] 0·67 [95% CI 0·47-0·97]; adenomas: metformin group 22 [30·6%; 95% CI 19·9-41·2] of 71 patients, placebo group 32 [51·6%; 95% CI 39·2-64·1] of 62; p=0·016, RR 0·60 [95% CI 0·39-0·92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0·041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. INTERPRETATION The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. FUNDING Ministry of Health, Labour and Welfare, Japan.

Clinical manifestations of Behçet’s disease depending on sex and age: results from Japanese nationwide registration

Objective This report aimed to scrutinize the prevalence of Behçets disease (BD)-related clinical manifestations based on age- and sex-specific subgroups using a Japanese nationwide registration database. Methods The database of newly registered BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met the International Criteria for Behçets Disease were selected and analysed. Results Among 6627 International Criteria for Behçets Disease cases, 2651 (40.0%) were men and 3976 (60.0%) were women with a median age of 39 years (interquartile range: 31-50 years). Ocular lesion was more common in male [odds ratio (male: female) 2.64 (95% CI: 2.35, 2.95, P < 0.001)] and genital ulceration was more common in female (odds ratio = 0.29, 95% CI: 0.25, 0.32, P < 0.001). Ocular lesion (P < 0.001), arthritis (P < 0.001) and vascular lesions (P < 0.001) were more frequently observed in elderly registered patients. Contrarily, genital ulceration (P < 0.001), epididymitis of males (P = 0.023) and oral ulceration (P = 0.003) were more common in younger patients. Simultaneous assessment of sex and age revealed that male predominance of ocular involvement was found in the young adult generation, but not in patients over 70 year of age. A female predominance of genital ulcer was prominently observed in patients 20-59 year of age; however, the sex difference was not found in patients over 60 years of age. Sensitivity analysis using International Study Group criteria replicated the results. Conclusion We showed that clinical phenotype in early phase of BD was different depending on onset age and sex.

Efficacy of percutaneous endoscopic gastro‐jejunostomy (PEG‐J) decompression therapy for patients with chronic intestinal pseudo‐obstruction (CIPO)

Chronic intestinal pseudo‐obstruction (CIPO) is an intractable rare digestive disease manifesting persistent small bowel distension without any mechanical cause. Intestinal decompression is a key treatment, but conventional method including a trans‐nasal small intestinal tube is invasive and painful. Therefore, a less invasive and tolerable new decompression method is urgently desired. We conducted a pilot study and assessed the efficacy and safety of percutaneous endoscopic gastro‐jejunostomy (PEG‐J) decompression therapy in CIPO patients.

Diagnostic test accuracy of glutamate dehydrogenase for Clostridium difficile: Systematic review and meta-analysis

We performed this systematic review and meta-analysis to assess the diagnostic accuracy of detecting glutamate dehydrogenase (GDH) for Clostridium difficile infection (CDI) based on the hierarchical model. Two investigators electrically searched four databases. Reference tests were stool cell cytotoxicity neutralization assay (CCNA) and stool toxigenic culture (TC). To assess the overall accuracy, we calculated the diagnostic odds ratio (DOR) using a DerSimonian-Laird random-model and area the under hierarchical summary receiver operating characteristics (AUC) using Holling’s proportional hazard models. The summary estimate of the sensitivity and the specificity were obtained using the bivariate model. According to 42 reports consisting of 3055 reference positive comparisons, and 26188 reference negative comparisons, the DOR was 115 (95%CI: 77–172, I2 = 12.0%) and the AUC was 0.970 (95%CI: 0.958–0.982). The summary estimate of sensitivity and specificity were 0.911 (95%CI: 0.871–0.940) and 0.912 (95%CI: 0.892–0.928). The positive and negative likelihood ratios were 10.4 (95%CI 8.4–12.7) and 0.098 (95%CI 0.066–0.142), respectively. Detecting GDH for the diagnosis of CDI had both high sensitivity and specificity. Considering its low cost and prevalence, it is appropriate for a screening test for CDI.

Continued Use of a Single Antiplatelet Agent Does Not Increase the Risk of Delayed Bleeding After Colorectal Endoscopic Submucosal Dissection

BackgroundWith the aging of the population and rising incidence of thromboembolic events, the usage of antiplatelet agents is also increasing. There are few reports yet on the management of antiplatelet agents for patients undergoing colorectal endoscopic submucosal dissection (ESD).AimsThe aim of this study is to evaluate whether continued administration of antiplatelet agents is associated with an increased rate of delayed bleeding after colorectal ESD.MethodsA total of 1022 colorectal neoplasms in 927 patients were dissected at Yokohama City University Hospital and its three affiliate hospitals between July 2012 and June 2017. We included the data of 919 lesions in the final analysis. The lesions were divided into three groups: the no-antiplatelet group (783 neoplasms), the withdrawal group (110 neoplasms), and the continuation group (26 neoplasms).ResultsAmong the 919 lesions, bleeding events occurred in a total of 31 (3.37%). The rate of bleeding after ESD was 3.3% (26/783), 4.5% (5/110), and 0% (0/26), respectively. There were no significant differences in the rate of bleeding after ESD among the three groups (the withdrawal group vs. the no-antiplatelet group, the continuation group vs. the no-antiplatelet group, and the withdrawal group vs. the continuation group).ConclusionsContinued administration of antiplatelet agents is not associated with any increase in the risk of delayed bleeding after colorectal ESD. Prospective, randomized studies are necessary to determine whether treatment with antiplatelet agents must be interrupted prior to colorectal ESD in patients who are at a high risk of thromboembolic events.

Contrast-enhanced CT for Colonic Diverticular Bleeding before Colonoscopy: A Prospective Multicenter Study

Purpose To demonstrate the usefulness of precolonoscopy intravenous contrast material-enhanced CT for colonic diverticular bleeding (CDB). Materials and Methods A prospective, multicenter, observational study was performed. Patients with acute-onset hematochezia who were admitted to hospital were included, and those without CDB were excluded. CT was performed before colonoscopy. A Mann-Whitney U test, χ2 test, and multivariable logistic regression analysis were performed to determine the accuracy of CT before colonoscopy. Results A total of 442 patients (mean age, 71.2 years; 302 male patients; 68.3% men) were included between January 2014 and December 2015, and 202 patients were diagnosed as having CDB. The positive extravasation rate during CT was 50 of 202 (24.7%) among all patients and five of nine (55.6%) among patients who underwent CT within 1 hour of the last hematochezia. At multivariable analysis, the interval from the last hematochezia until CT was a predictor of extravasation (beta coefficient, -.0038 ± 0.0014 [standard deviation]). Extravasation at CT had a sensitivity of 38 of 66 (57.6%; 95% confidence interval: 44.8%, 69.7%) and a specificity of 124 of 136 (91.2%; 95% confidence interval: 85.1%, 95.4%) for the prediction of stigmata of recent hemorrhage of diverticula during colonoscopy. The sensitivity was higher in patients who underwent CT examination within 4 hours of hematochezia, compared with those examined after 4 hours (64.7% [33 of 51] vs 33.3% [five of 15]; P < .01). Conclusion Extravasation findings for CT with intravenous contrast material had high specificity for the prediction of stigmata of recent hemorrhage of diverticula during colonoscopy, regardless of the timing of the CT examination. Although the sensitivity was relatively low, it was higher when the CT examination was performed within 4 hours after the last hematochezia. Therefore, urgent precolonoscopy CT may contribute to decision making regarding whether an urgent colonoscopy should be performed.

The ocular involvement did not accompany with the genital ulcer or the gastrointestinal symptoms at the early stage of Behçet’s disease

Abstract Objectives: This study aimed to identify patients with high-probability of ocular involvement of Behçet’s disease (BD). Methods: The Japanese Ministry of Health, Labour and Welfare provided dataset of ongoing nationwide BD registration project. A patient who had confirmed BD and who was suspected to have BD was registered. We mainly analyzed newly registered patients who had the data for all demographic and diagnostic parameters regardless of fulfilment of any diagnostic criteria. Results: Among 3213 patients with confirmed or possible BD, 1382 (43.0%) were men and 1831 (57.0%) were women with a median age of 38 years (interquartile range (IQR) 30–49 years). The median duration between onset and registration was 0 year (IQR 0–3). A binomial multivariable logistic regression analysis revealed that being female (odds ratio (OR) 0.63, 95% confidence interval (CI) 0.53–0.75, p < .001), duration since onset (OR 1.33 per 10 years, 95% CI 1.18–1.51, p < .001), genital ulceration (OR 0.28, 95% CI 0.23–0.34, p < .001), and gastrointestinal symptoms (OR 0.36, 95% CI 0.30–0.44, p < .001) were related to the ocular lesion. Analyses based on data of 2800 patients who satisfied International criteria of BD, age-, sex-, duration-based subgroup analyses, analyses targeting iridocyclitis and retino-uveitis, and analysis including patients with missing data confirmed that the four factors were associated with the probability of eye involvement. Conclusion: The ocular involvement did not accompany with genital ulcer or gastrointestinal symptoms at the early stage of BD.

Risk factors for post-colorectal endoscopic submucosal dissection (ESD) coagulation syndrome: a multicenter, prospective, observational study

Background and study aims  Colorectal cancer (CRC) is one of the most common neoplasms and endoscopic submucosal dissection (ESD) is an effective treatment for early-stage CRC. However, it has been observed that patients undergoing ESD often complain of pain, even if ESD has been successfully performed. Risk factors for such pain still remain unknown. The aim of this study was to explore the risk factors for post-colorectal ESD coagulation syndrome (PECS). Patients and methods  This was a prospective multicenter observational trial (UMIN000016781) conducted in 106 of 223 patients who underwent ESD between March 2015 and April 2016. We investigated age, sex, tumor location, ESD operation time, lesion size, duration of hospitalization, and frequency of PECS. We defined PECS as local abdominal pain (evaluated on a visual analogue scale) in the region corresponding to the site of the ESD that occurred within 4 days of the procedure. Results  PECS occurred in 15/106 (14.2 %), and 10 were women ( P  = 0.01, OR: 7.74 [1.6 – 36.4]), 7 had lesions in the cecum ( P  < 0.001, OR: 20.6 [3.7 – 115.2]), and 9 in whom ESD operation time was > 90 min ( P  = 0.002, OR: 10.3 [2.4 – 44.6]). Frequency of deviation from the prescribed clinical path was significantly higher (47 % [7/15] vs. 2 % [2/91], P  < 0.001, OR: 38.9 [6.9 – 219.6]), and hospital stay was significantly longer in the PECS group.  Conclusions  Female gender, location of lesion in the cecum, and ESD operation time > 90 minutes were significant risk factors independent of PECS. These findings are important to management of PECS. 

Clinical value of capsule endoscopy for detecting small bowel lesions in patients with intestinal Behçet's disease.

To evaluate the clinical value of capsule endoscopy (CE) in patients with intestinal Behçets disease (BD).

Complete Histopathological Disappearance of Rectal Malt Lymphoma after Eradication of Helicobacter pylori Confirmed by ESD

In a 77-year-old Japanese housewife who was undergoing regular colonoscopy for follow-up of a colon polyp, a total colonoscopy showed an elevated lesion in the rectum. Histological findings of a conventional biopsy from the lesion showed a mucosa-associated lymphoid tissue (MALT) lymphoma, and the patient was diagnosed as having clinical stage 1 disease. We elected to administer antibiotic therapy as the serological test for anti-Helicobacter pylori antibody was positive and Helicobacter pylori was detected in a culture of the biopsy specimens. The antibiotic therapy was successful, however, colonoscopy after the eradication therapy showed a residual lesion. Histologic examination can’t deny the possibility of the presence of a residual MALT lymphoma. Endoscopic ultrasonography revealed that the lesion was confined to the mucosa. We performed endoscopic submucosal dissection (ESD) and histological examination of the ESD specimen showed complete disappearance of the tumor. The patient remains in complete remission now, 1 year after the treatment.