Adrenomedullin for biologic-resistant Crohn's disease: A randomized, double-blind, placebo-controlled phase 2a clinical trial.

BACKGROUND AND AIM: Adrenomedullin is a bioactive peptide with many pleiotropic effects, including mucosal healing and immunomodulation. Adrenomedullin has shown beneficial effects in rodent models of inflammatory bowel disease and, more importantly, in clinical trials including patients with ulcerative colitis. We performed a successive clinical trial to investigate the efficacy and safety of adrenomedullin in patients with Crohn's disease (CD). METHODS: This was a multicenter, double-blind, placebo-controlled phase 2a trial that evaluated 24 patients with biologic-resistant CD in Japan. Patients were randomly assigned to three groups and were given an infusion of 10 or 15 ng/kg/min of adrenomedullin or placebo for 8 h per day for 7 days. The primary endpoint was the change in the CD activity index (CDAI) at 8 weeks. The main secondary endpoints included changes in CDAI from week 4 to week 24. RESULTS: No differences in the primary or secondary endpoints were observed between the three groups by the 8th week. Changes in CDAI in the placebo group gradually decreased and disappeared at 24 weeks, but those in the adrenomedullin-treated groups (10 or 15 ng/kg/min group) remained at steady levels for 24 weeks. Therefore, a significant difference was observed between the placebo and adrenomedullin-treated groups at 24 weeks (P = 0.043) in the mixed-effects model. We noted mild adverse events caused by the vasodilatory effect of adrenomedullin. CONCLUSION: In this trial, we observed a long-lasting (24 weeks) decrease in CDAI in the adrenomedullin-treated groups. Adrenomedullin might be beneficial for biologic-resistant CD, but further research is needed.

Diffuse large B-cell lymphoma originating from the rectum and diagnosed after rectal perforation during the treatment of ulcerative colitis: a case report.

BACKGROUND: Gastrointestinal lymphomas like diffuse large B-cell lymphoma (DLBCL) are rare complications of ulcerative colitis (UC), and only a few studies have reported intestinal ulcers caused by DLBCL, which got perforated during the treatment of UC. CASE PRESENTATION: A 43-year-old man with severe lower abdominal pain and an 8-year history of UC was admitted in our hospital. He was diagnosed UC since 8 years and received a maintenance oral dose of 5-aminosalicylic acid, and no other immunosuppressive drugs. A deep rectal ulcer was endoscopically diagnosed 10 months before admission, no malignancy or cytomegalovirus infection was detected on biopsy. After 7 months a further endoscopy with biopsies confirmed the finding and the absence of malignancy. Three months later the patient developed sudden abdominal pain and was admitted in our hospital. Rectal perforation was suspected on X-ray and computed tomography imaging, and an emergency surgery was performed. Surgical exploration revealed a perforation on the anterior wall of the rectum. A subtotal colectomy with temporary ileostomy was performed. Pathology examinations showed lymphocyte infiltration of all of the layers of the perforated site and an immunohistochemical evaluation revealed DLBCL. Clinical staging was stage IV, and the patient received a 6-months regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Positron emission tomography restaging revealed disappearance of distant uptake and a slight uptake in the residual rectum, and completion proctectomy with ileal pouch-anal anastomosis was performed. No residual tumor in the specimen was found, and the patient was disease-free at 2 years follow-up. CONCLUSIONS: DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. This case study emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies during the treatment of UC.

Colonoscopy screening and surveillance guidelines.

The Colonoscopy Screening and Surveillance Guidelines were developed by the Japan Gastroenterological Endoscopy Society as basic guidelines based on the scientific methods. The importance of endoscopic screening and surveillance for both detection and post-treatment follow-up of colorectal cancer has been recognized as essential to reduce disease mortality. There is limited high-level evidence in this field; therefore, we had to focus on the consensus of experts. These clinical practice guidelines consist of 20 clinical questions and eight background knowledge topics that have been determined as the current guiding principles.

Effect of a concomitant elemental diet with maintenance anti-tumor necrosis factor-α antibody therapy in patients with Crohn's disease: A multicenter, prospective cohort study.

BACKGROUND AND AIM: The aim of this study was to clarify the additional effect of a concomitant elemental diet (ED) for patients with Crohn's disease on maintenance anti-tumor necrosis factor-α antibody (anti-TNF). METHODS: Crohn's disease patients who received anti-TNF induction therapy were enrolled. Patients who achieved clinical response (defined as delta Crohn's disease activity index [CDAI] > 70 and CDAI < 200) at 10-14 weeks after the start of infliximab or adalimumab were included. Eligible patients took a tolerability test of ED (900 kcal/day) for 3 days. Then, patients who preferred concomitant ED and whose ED tolerance was confirmed were allocated to the ED group and given Elental 900 kcal/day or more. Other patients were allocated to the non-ED group. The primary endpoint was the cumulative remission rate at 2 years after baseline. Clinical relapse was defined as CDAI > 200 and/or need for additional treatment. Adherence to the ED was confirmed at each visit. RESULTS: Seventy-two patients were included. Thirty-seven were allocated to the ED group, and 35 were allocated to the non-ED group. The cumulative remission rate at 2 years was not significantly different between the two groups (60.9% vs 56.7%, P = 0.98). Adherence to the ED in the ED group was relatively low, and only 11 patients were maintained on an ED of 900 kcal/day. CONCLUSIONS: The addition of ED for Crohn's disease patients who responded to initial anti-TNF induction therapy was not found to improve outcomes. The efficacy of concomitant ED in other clinical settings, such as loss of response, needs to be clarified in the future (UMIN000009789).

Guidelines for standardizing cleansing and disinfection of gastrointestinal endoscopes.

As part of the activities toward standardizing endoscopy procedures, the Japan Gastroenterological Endoscopy Society has prepared guidelines for cleansing and disinfection of gastrointestinal endoscopes. The environment of gastrointestinal endoscopy differs between Japan and advanced Western countries. In advanced Western countries, gastrointestinal endoscopy is performed almost exclusively at specialized facilities, where strict provisions are observed for cleansing and disinfecting endoscopes. In Japan, however, gastrointestinal endoscopy is performed even in small clinics, and the annual number of gastrointestinal endoscopy cases is enormous. In addition, the method for cleansing and disinfecting endoscopes differs among hospitals. Although there is a distinct lack of evidence for how gastrointestinal endoscopes are cleaned and disinfected, it is necessary to standardize the method for doing so to advance the field of endoscopic medicine.

Adverse events during CT colonography for screening, diagnosis and preoperative staging of colorectal cancer: a Japanese national survey.

OBJECTIVES: To retrospectively evaluate the frequencies and magnitudes of adverse events associated with computed tomographic colonography (CTC) for screening, diagnosis and preoperative staging of colorectal cancer. METHODS: A Japanese national survey on CTC was administered by use of an online survey tool in the form of a questionnaire. The questions covered mortality, colorectal perforation, vasovagal reaction, total number of examinations, and examination procedures. The survey data was collated and raw frequencies were determined. Fisher's exact test was used to determine differences in event rates between groups. RESULTS: At 431 institutions, 147,439 CTC examinations were performed. No deaths were reported. Colorectal perforations occurred in 0.014% (21/147,439): 0.003% (1/29,823) in screening, 0.014% (13/91,007) in diagnosis and 0.028% (7/25,330) in preoperative staging. The perforation risk was significantly lower in screening than in preoperative staging CTC procedures (p = 0.028). Eighty-one per cent of perforation cases (17/21) did not require emergency surgery. Vasovagal reaction occurred in 0.081% (120/147,439): 0.111% (33/29,823) in screening, 0.088% (80/91,007) in diagnosis and 0.028% (7/25,330) in preoperative staging. CONCLUSIONS: The risk of colorectal perforation and vasovagal reaction in CTC is low. The frequency of colorectal perforation associated with CTC is least in the screening group and greatest in the preoperative-staging group. KEY POINTS: • The colorectal perforation rate during preoperative-staging CTC was 0.028 %. • The perforation rates for screening and diagnosis were 0.003 % and 0.014 %, respectively. • The perforation risk is significantly lower in screening than in preoperative staging. • Eighty-one per cent of perforation cases did not require emergency surgery. • Use of an automatic colon insufflator can reduce the risk of bowel perforation.

Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn's disease in adults.

BACKGROUND: One of the problems associated with infliximab (IFX) treatment for Crohn's disease (CD) is loss of response during maintenance therapy. AIMS: The aim of this multicenter, retrospective, cohort study was to determine whether enteral nutrition (EN) added to the IFX therapy regimen is effective for maintaining remission in adult CD patients. METHODS: Patients with CD who had started IFX therapy between April 2003 and March 2008 at any one of the seven participating medical centers and who met the following inclusion criteria were enrolled in the study: remission after triple infusions of IFX followed by IFX maintenance therapy every 8 weeks, and follow-up data available for ≥ 1 year. Remission was defined as a C-reactive protein (CRP) level of <0.3 mg/dL, and recurrence was defined as an increase in CRP to ≥ 1.5 mg/dL or shortening of the IFX interval. Patients were classified by EN dosage into two groups (EN group and non-EN group). The cumulative remission period and related factors were analyzed. RESULTS: Of the 102 adult CD patients who met the inclusion criteria, 45 were in the EN group and 57 were in the non-EN group. The cumulative remission rate was significantly higher in the EN group than in the non-EN group (P = 0.009). Multivariate analysis revealed that EN was the only suppressive factor for disease recurrence (P = 0.01). CONCLUSIONS: The results demonstrate that among this CD patient cohort, EN combined with IFX maintenance treatment was clinically useful for maintaining remission.

Recent trends in the prevalence and distribution of colonic diverticula in Japan evaluated using computed tomography colonography.

BACKGROUND: Computed tomography colonography (CTC) may be superior to colonoscopy and barium enema for detecting diverticula. However, few studies have used CTC to diagnose diverticula. AIM: To evaluate the current prevalence and distribution of colonic diverticula in Japan using CTC. METHODS: This study was conducted as part of the Japanese National Computed Tomographic Colonography Trial, which included 1181 participants from 14 hospitals in Japan. We analyzed the prevalence and distribution of colonic diverticula and their relationships with age and sex. The relationship between the diverticula and the length of the large intestine was also analyzed. RESULTS: Diverticulosis was present in 48.1% of the participants. The prevalence of diverticulosis was higher in the older participants (P < 0.001 for trend). The diverticula seen in younger participants were predominantly located in the right-sided colon. Older participants had a higher frequency of bilateral type (located in the right- and left-sided colon) diverticulosis (P < 0.001 for trend). The length of the large intestine with multiple diverticula in the sigmoid colon was significantly shorter in those without diverticula (P < 0.001). CONCLUSION: The prevalence of colonic diverticulosis in Japan is higher than that previously reported. The prevalence was higher, and the distribution tended to be bilateral in older participants.

Evidence-based clinical practice guidelines for management of colorectal polyps.

BACKGROUND: The Japanese Society of Gastroenterology (JSGE) published ''Daicho Polyp Shinryo Guideline 2014'' in Japanese and a part of this guideline was published in English as "Evidence-based clinical practice guidelines for management of colorectal polyps" in the Journal of Gastroenterology in 2015. A revised version of the Japanese-language guideline was published in 2020, and here we introduce a part of the contents of revised version. METHODS: The guideline committee discussed and drew up a series of clinical questions (CQs). Recommendation statements for the CQs were limited to items with multiple therapeutic options. Items with established conclusions that had 100% agreement with previous guidelines (background questions) and items with no (or old) evidence that are topics for future research (future research questions: FRQs) were given descriptions only. To address the CQs and FRQs, PubMed, ICHUSHI, and other sources were searched for relevant articles published in English from 1983 to October 2018 and articles published in Japanese from 1983 to November 2018. The Japan Medical Library Association was also commissioned to search for relevant materials. Manual searches were performed for questions with insufficient online references. RESULTS: The professional committee created 18 CQs and statements concerning the current concept and diagnosis/treatment of various colorectal polyps, including their epidemiology, screening, pathophysiology, definition and classification, diagnosis, management, practical treatment, complications, and surveillance after treatment, and other colorectal lesions (submucosal tumors, nonneoplastic polyps, polyposis, hereditary tumors, ulcerative colitis-associated tumors/carcinomas). CONCLUSIONS: After evaluation by the moderators, evidence-based clinical practice guidelines for management of colorectal polyps were proposed for 2020. This report addresses the therapeutic related CQs introduced when formulating these guidelines.

Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial.

BACKGROUND: Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC. METHODS: This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0. RESULTS: No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (- 9.3 ± 1.2 vs. - 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM. CONCLUSIONS: In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM. CLINICAL TRIAL REGISTRY: JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp .

Relation between obesity and adenomatous polyps of the large bowel.

BACKGROUND: We compared the prevalence of colorectal adenoma (polyps) in men and women and examined the role of body mass index (BMI) on polyp risk according to patient age and gender. METHODS: The risk of developing colorectal polyps was studied in 15 380 subjects (7155 men and 8225 women) who underwent colonoscopy for the first time from April 1998 to March 2006 at our 'Human Dry Dock', which is the check-up service provided in Japan. Eligible subjects were 20-86 years old (mean age +/- SD, 47.3 +/- 8.5) and were free of invasive cancer, hyperplastic polyps and familial polyposis. Polyps were found in 1590 subjects (1062 men and 528 women). The odds ratio (OR) of detection of polyps in relation to obesity was determined in all cases by multivariate logistic regression analysis after making an adjustment for gender and age. RESULTS: The OR of polyp detection in obese subjects (BMI >or= 25) versus non-obese subjects (BMI < 25, OR = 1) was 1.34 (P < 0.001) in men and 1.13 (P = 0.26) in women. As the BMI increased in increments of one, the OR in men increased significantly to 1.01 (P < 0.001), whereas the OR in women was unchanged at 1.00 (P = 0.23), which was without significance. CONCLUSIONS: We conclude that obesity in men is a risk factor for the development of polyps. These results must be confirmed by additional epidemiological studies.