Hidenori Ohkubo

Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

BackgroundColorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients.Methods/DesignThis study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation.DiscussionThis is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps.Trial registrationThis trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254

Assessment of Small Bowel Motility in Patients With Chronic Intestinal Pseudo-Obstruction Using Cine-MRI

OBJECTIVES:Chronic intestinal pseudo-obstruction (CIPO) is a rare, serious motility disorder, with life-threatening complications over time. However, lack of an established, non-invasive diagnostic method has caused delays in the diagnosis of this intractable disease. Cine-magnetic resonance imaging (MRI) is an emerging technique, with a potential to evaluate the motility of the entire bowel. We compared small bowel motility in healthy volunteers, patients with irritable bowel syndrome (IBS), and those with CIPO, using cine-MRI, and evaluated the usefulness of cine-MRI as a novel diagnostic method for CIPO.METHODS:Twelve healthy volunteers, IBS patients, and CIPO patients prospectively underwent cine-MRI at 1.5 T. Luminal diameter, contraction ratio, and contraction cycle were measured and compared between the groups.RESULTS:Cine-MRI provided sufficient dynamic images to assess the motility of the entire small bowel. Luminal diameter (mean±s.d.) in CIPO patients was significantly higher than that in healthy volunteers and IBS patients (43.4±14.1, 11.1±1.5, and 10.9±1.9 mm, respectively), and contraction ratio was significantly lower in CIPO patients than that in healthy volunteers and IBS patients (17.1±11.0%, 73.0±9.3%, and 74.6±9.4%, respectively). No significant differences were observed in the contraction cycle.CONCLUSIONS:This study is the first to assess the clinical utility of cine-MRI in CIPO patients. Cine-MRI clearly detected contractility impairments in CIPO patients. Cine-MRI is noninvasive, radiation-free, and can directly evaluate the entire small bowel peristalsis, and can detect the affected loops at a glance; therefore, it might be extremely useful for the diagnosis and follow-up of CIPO patients in clinical practice.

Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry

BACKGROUND To develop appropriate management strategies for patients who take low-dose aspirin, it is important to identify the risk factors for GI injury. However, few studies have described the risk factors for small-bowel injury in these patients. OBJECTIVE To investigate factors influencing the risk of small-bowel mucosal breaks in individuals taking continuous low-dose aspirin. DESIGN Capsule endoscopy data were collected prospectively from 5 institutions. SETTING Yokohama City University Hospital and 4 other hospitals. PATIENTS A total of 205 patients receiving treatment with low-dose aspirin for over 3 months. INTERVENTIONS Colonoscopic and upper GI endoscopy had been performed in all of the patients before the capsule endoscope evaluation. MAIN OUTCOME MEASUREMENTS Risk factors for small-bowel mucosal breaks. RESULTS Of the 198 patients (141 male; mean age 71.9 years) included in the final analysis, 114 (57.6%) had at least 1 mucosal break. Multivariate analysis identified protein pump inhibitor (PPI) use (OR 2.04; 95% confidence interval [CI], 1.05-3.97) and use of enteric-coated aspirin (OR 4.05; 95% CI, 1.49-11.0) as independent risk factors for the presence of mucosal breaks. LIMITATIONS Cross-sectional study. CONCLUSION PPI use appears to increase the risk of small-bowel injury in patients who take continuous low-dose aspirin. Clinicians should be aware of this effect of PPIs; new strategies are needed to treat aspirin-induced gastroenteropathy.

Differences in the severity of small bowel mucosal injury based on the type of aspirin as evaluated by capsule endoscopy

BACKGROUND The differences in the small intestinal toxicity of low-dose aspirin based on the type of aspirin used remains unclear. The purpose of this study was to evaluate the differences in the small bowel mucosal injury between buffered and enteric-coated aspirin users by capsule endoscopy. METHODS We retrospectively reviewed the findings in chronic low-dose aspirin users (>3 months) who underwent capsule endoscopy for the investigation of obscure gastrointestinal bleeding. The patients were classified into two groups based on the type of low-dose aspirin that they had been prescribed (enteric-coated aspirin group or buffered aspirin group), and evaluated the numbers of small bowel lesions and the Lewis score. RESULTS Capsule-endoscopic findings of a total of 70 patients taking low-dose aspirin were reviewed. Significant differences in the number of erosions and ulcers were observed between the buffered and enteric-coated aspirin groups (P=0.017 and P=0.037, respectively). The median Lewis score for the small bowel mucosal inflammatory change was significantly higher in the enteric-coated aspirin group than in the buffered aspirin group (P=0.035). CONCLUSIONS The results of this study suggested that enteric-coated aspirin might be more injurious to the small bowel mucosa than buffered aspirin.

Factors predicting the presence of small bowel lesions in patients with obscure gastrointestinal bleeding

To identify the predictive factors for the presence of small bowel lesions in patients with obscure gastrointestinal bleeding (OGIB).

An Epidemiologic Survey of Chronic Intestinal Pseudo-Obstruction and Evaluation of the Newly Proposed Diagnostic Criteria

Background and Aims: Chronic intestinal pseudo-obstruction (CIPO) is an intractable disease in which clinical symptoms of intestinal obstruction appear without mechanical cause. No clear diagnostic criteria have been established; therefore, we proposed diagnostic criteria to facilitate the diagnosis of this rare disease and aim to evaluate their usefulness and validity. Materials andMethods: A questionnaire was sent to 378 institutions belonging to the Japanese Society of Gastroenterology between December 2009 and February 2010. We summarized the returned data and performed a statistical analysis. Results: A total of 160 cases were included, and 141 cases (88.1%) fulfilled the criterion of disease duration of >6 months, 157 cases (98.1%) the criterion of the clinical symptoms of abdominal pain and/or bloating and 154 cases (96.2%) fulfilled the criterion of imaging findings. Eventually, 138 cases (86.3%) fulfilled all criteria. Conclusions: The proposed diagnostic criteria were useful, with a high sensitivity of 86.3% for Japanese patients. Improved recognition of CIPO and practical use of the criteria are desired. The criteria should be appropriately modified by additional researchers to make them more practical and internationally applicable.

Capsule endoscopy with flexible spectral imaging color enhancement reduces the bile pigment effect and improves the detectability of small bowel lesions

BackgroundCapsule endoscopy with flexible spectral imaging color enhancement (CE-FICE) has been reported to improve the visualization and detection of small-bowel lesions, however, its clinical usefulness is still not established. Therefore, we conducted a study to evaluate whether CE-FICE contributes to improve the detectability of small-bowel lesions by CE trainees.MethodsFour gastroenterology trainees without prior CE experience were asked to read and interpret 12 CE videos. Each of the videos was read by conventional visualization method and under three different FICE settings. To evaluate whether the lesion recognition ability of the CE trainees could be improved by the FICE technology, the lesion detection rate under each of the three FICE settings was compared with that by conventional CE. CE trainees tend to miss small-bowel lesions in bile-pigment-positive condition, therefore we evaluated whether CE-FICE contributes to reducing the bile-pigment effect. The bile-pigment condition was determined by the color values around the small-bowel lesions according to the results of the receiver-operating-characteristic analysis. Moreover, we also evaluated whether poor bowel preparion might affect the accuracy of lesion recognition by CE-FICE.ResultsOf a total of 60 angioectasias, CE trainees identified 26 by conventional CE, 40 under FICE setting 1, 38 under FICE setting 2, and 31 under FICE setting 3. Of a total of 82 erosions/ulcerations, CE trainees identified 38 by conventional CE, 62 under FICE setting 1, 60 under FICE setting 2, and 20 under FICE setting 3. Compared with conventional CE, FICE settings 1 and 2 significantly improved the detectability of angioectasia (P = 0.0017 and P = 0.014, respectively) and erosions/ulcerations (P = 0.0012 and P = 0.0094, respectively). Although the detectability of small-bowel lesions by conventional CE (P = 0.020) and under FICE setting 2 (P = 0.0023) was reduced by the presence of bile-pigments, that under FICE setting 1 was not affected (P = 0.59). Our results also revealed that in poor bowel visibility conditions, CE-FICE yielded a high rate of false-positive findings.ConclusionsCE-FICE may reduce the bile-pigment effect and improve the detectability of small-bowel lesions by CE trainees; the reliability of CE-FICE may be improved by good bowel preparation.

Epidemiology and Clinical Experience of Chronic Intestinal Pseudo-Obstruction in Japan : A Nationwide Epidemiologic Survey

Background We estimated the prevalence and incidence of chronic intestinal pseudo-obstruction (CIPO) in Japan, investigated the patterns of hospital visits among those with CIPO, and examined present knowledge of CIPO among medical professionals. Methods A self-administered questionnaire survey was distributed to targeted hospitals throughout Japan, which were selected using stratified random sampling. The questionnaire asked about the number of patients receiving treatment for CIPO, the frequency of their hospital visits, and overall clinical knowledge of CIPO among medical professionals. Results CIPO prevalence was estimated to be 1.00 and 0.80 cases per 100 000 males and females, respectively. Incidence was 0.21 and 0.24 cases per 100 000 males and females, respectively. Prevalence and incidence did not significantly differ males and females. Mean age of patients was 63.1 years for males and 59.2 for females. Accurate diagnosis of CIPO sometimes required more than 3 months after initial presentation. Most medical professionals were unaware of or poorly understood CIPO. Conclusions We estimated the prevalence and incidence of CIPO in Japan, using data from a nationwide survey. The findings suggest that knowledge of CIPO should be further disseminated so that the disease is not overlooked and is diagnosed without delay.

Visceral obesity as a risk factor for left-sided diverticulitis in Japan: a multicenter retrospective study.

Background/Aims Left-sided diverticulitis is increasing in Japan, and many studies report that left-sided diverticulitis is more likely to be severe. Therefore, it is important to identify the features and risk factors for left-sided diverticulitis. We hypothesized that left-sided diverticulitis in Japan is related to obesity and conducted a study of the features and risk factors for this disorder in Japan. Methods Right-sided diverticulitis and left-sided diverticulitis patients (total of 215) were compared with respect to background, particularly obesity-related factors to identify risk factors for diverticulitis. Results There were 166 (77.2%) right-sided diverticulitis patients and 49 (22.8%) left-sided diverticulitis patients. The proportions of obese patients (body mass index ≥25 kg/m2, p=0.0349), viscerally obese patients (visceral fat area ≥100 cm2, p=0.0019), patients of mean age (p=0.0003), and elderly patients (age ≥65 years, p=0.0177) were significantly higher in the left-sided-diverticulitis group than in the right-sided-diverticulitis group. The proportion of viscerally obese patients was significantly higher in the left-sided-diverticulitis group than in the left-sided-diverticulosis group (p=0.0390). Conclusions This study showed that obesity, particularly visceral obesity, was a risk factor for left-sided diverticulitis in Japan.

Small bowel injury in low-dose aspirin users.

The use of low-dose aspirin (LDA) is well known to be associated with an increased risk of serious upper gastrointestinal complications, such as peptic ulceration and bleeding. Until recently, attention was mainly focused on aspirin-induced damage of the stomach and duodenum. However, recently, there has been growing interest among gastroenterologists on the adverse effects of aspirin on the small bowel, especially as new endoscopic techniques, such as capsule endoscopy (CE) and balloon-assisted endoscopy, have become available for the evaluation of small bowel lesions. Preliminary CE studies conducted in healthy subjects have shown that short-term administration of LDA can induce mild mucosal inflammation of the small bowel. Furthermore, chronic use of LDA results in a variety of lesions in the small bowel, including multiple petechiae, loss of villi, erosions, and round, irregular, or punched-out ulcers. Some patients develop circumferential ulcers with stricture. In addition, to reduce the incidence of gastrointestinal lesions in LDA users, it is important for clinicians to confirm the differences in the gastrointestinal toxicity between different types of aspirin formulations in clinical use. Some studies suggest that enteric-coated aspirin may be more injurious to the small bowel mucosa than buffered aspirin. The ideal treatment for small bowel injury in patients taking LDA would be withdrawal of aspirin, however, LDA is used as an antiplatelet agent in the majority of patients, and its withdrawal could increase the risk of cardiovascular/cerebrovascular morbidity and mortality. Thus, novel means for the treatment of aspirin-induced enteropathy are urgently needed.