Feasibility of deep sedation with a combination of propofol and dexmedetomidine hydrochloride for esophageal endoscopic submucosal dissection.

BACKGROUND AND AIM: The aim of the present study was to evaluate the efficacy and safety of sedation with a combination of propofol (PF) and dexmedetomidine (DEX) compared with sedation with benzodiazepines in esophageal endoscopic submucosal dissection (ESD). METHODS: We retrospectively reviewed clinical data for 40 consecutive patients who had undergone esophageal ESD at the Yokohama City University Hospital between July 2012 and August 2014. Of these patients, 20 were sedated with benzodiazepines (conventional group) and another 20 patients were sedated with a combination of PF and DEX (combination group). Parameters for efficacy and safety of sedation were evaluated by comparisons between the two groups. RESULTS: Median procedural times in the combination group were shorter than those in the conventional group (61 min vs. 89 min, P = 0.03), and the percentage of patients who showed restlessness in the combination group was significantly lower than that in the conventional group (25% vs. 65%, P = 0.025). Incidences of hypotension and bradycardia in the combination group were higher than those in the conventional group (60% vs. 15%, P = 0.008, and 60% vs. 15%, P = 0.008, respectively). CONCLUSION: This retrospective study suggests that a combination of PF and DEX may provide stable deep sedation with less body movement than benzodiazepines during esophageal ESD.

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

BACKGROUND AND AIM: To evaluate the clinical value of capsule endoscopy (CE) in patients with intestinal Behçet's disease (BD). METHODS: The present study was a case-control pilot study conducted in intestinal BD patients and healthy volunteers. A total of 19 patients with intestinal BD (intestinal BD group) and 19 healthy volunteers (control group) matched for age and sex were enrolled. Frequency, number of small bowel lesions per subject, and Lewis score were comparatively evaluated between the two groups. RESULTS: Of the 19 patients with intestinal BD, 18 (94.7%) had reddened lesions, 15 (78.9%) had erosions, and nine (47.4%) had ulcers. There were significant differences in the frequency of reddened lesions (P < 0.0001), erosions (P < 0.0001) and ulcers (P = 0.0011) between the two groups. The difference in the number of small bowel lesions between the two groups was also statistically significant. The median Lewis score in the intestinal BD group was significantly higher than that in the control group (intestinal BD group 237 (0-768) vs. control group 8 (0-135); P < 0.0001). Analysis according to the location in the small bowel revealed that the frequency of ulcers tended to increase towards the distal intestine. CONCLUSION: This is the first CE study conducted to examine small bowel involvement in intestinal BD patients. Our results suggest that CE evaluation is necessary, in addition to colonoscopy, in all intestinal BD patients.

Early effects of oral administration of esomeprazole and omeprazole on the intragastric pH.

BACKGROUND/AIMS: The aim of our study was to investigate the inhibitory effects on gastric acid secretion of a single oral dose of a proton pump inhibitor, esomeprazole 20 mg and omeprazole 20 mg. METHODOLOGY: A total of 14 Helicobacter pylori-negative male subjects participated in this study. Intragastric pH was monitored continuously for 6 hours after a single oral dose of omeprazole 20 mg and a single oral dose of esomeprazole 20 mg. Each administration was separated by a 7-day washout period. RESULTS: During the 6-hour study period, the average pH after administration of esomeprazole was higher than that after the administration of omeprazole. Also during the 6-hour study period, each of pH > 2, 3, 3.5, 4, and 5 was maintained for a longer duration after administration of esomeprazole 20 mg than after administration of omeprazole 20 mg (median: 75.4% vs. 53.8%, p = 0.0138; 52.1% vs. 33.4%, p = 0.0188; 45.8% vs. 28.2%, p = 0.0262; 42.5% vs. 20.7%, p = 0.0414; 35.8% vs. 11.6%, p = 0.0262; respectively). CONCLUSIONS: In Helicobacter pylori-negative healthy male subjects, single oral administration of esomeprazole 20 mg increased the intragastric pH more rapidly than single oral administration of omeprazole 20 mg.

Conditional knockout of the leptin receptor in the colonic epithelium revealed the local effects of leptin receptor signaling in the progression of colonic tumors in mice.

Leptin, secreted by the adipose tissue and known to be related to obesity, is considered to be involved in the onset and progression of colorectal cancer. However, the exact role of leptin in colorectal carcinogenesis is still unclear, as several controversial reports have been published on the various systemic effects of leptin. The aim of this study was to clarify the local and precise roles of leptin receptor (LEPR)-mediated signaling in colonic carcinogenesis using intestinal epithelium-specific LEPRb conditional knockout (cKO) mice. We produced and used colonic epithelium-specific LEPRb cKO mice to investigate the carcinogen-induced formation of aberrant crypt foci (ACF) and tumors in the colon, using their littermates as control. There were no differences in the body weight or systemic condition between the control and cKO mice. The tumor sizes and number of large-sized tumors were significantly lower in the cKO mice as compared with those in the control mice. On the other hand, there was no significant difference in the proliferative activity of the normal colonic epithelial cells or ACF formation between the control and cKO mice. In the control mice, marked increase of the LEPRb expression level was observed in the colonic tumors as compared with that in the normal epithelium; furthermore, signal transducer and activator of transcription (STAT3) was activated in the tumor cells. These findings suggest that STAT3 is one of the important molecules downstream of LEPRb, and LEPRb/STAT3 signaling controls tumor cell proliferation. We demonstrated the importance of local/regional LEPR-mediated signaling in colorectal carcinogenesis.

Methylation epigenotypes and genetic features in colorectal laterally spreading tumors.

Aberrant DNA methylation plays an important role in genesis of colorectal cancer (CRC). Previously, we identified Group 1 and Group 2 methylation markers through genome-wide DNA methylation analysis, and classified CRC and protruded adenoma into three distinct clusters: high-, intermediate- and low-methylation epigenotypes. High-methylation epigenotype strongly correlated with BRAF mutations and these aberrations were involved in the serrated pathway, whereas intermediate-methylation epigenotype strongly correlated with KRAS mutations. Here, we investigated laterally spreading tumors (LSTs), which are flat, early CRC lesions, through quantitative methylation analysis of six Group 1 and 14 Group 2 methylation markers using pyrosequencing. Gene mutations in BRAF, KRAS and PIK3CA, and immunostaining of TP53 and CTNNB1 as well as other clinicopathological factors were also evaluated. By hierarchical clustering using methylation information, LSTs were classified into two subtypes; intermediate-methylation epigenotype correlating with KRAS mutations (p = 9 × 10(-4)) and a granular morphology (LST-G) (p = 1 × 10(-7)), and low-methylation epigenotype correlating with CTNNB1 activation (p = 0.002) and a nongranular morphology (LST-NG) (p = 1 × 10(-7)). Group 1 marker methylation and BRAF mutations were barely detected, suggesting that high-methylation epigenotype was unlikely to be involved in LST development. TP53 mutations correlated significantly with malignant transformation, regardless of epigenotype or morphology type. Together, this may suggest that two molecular pathways, intermediate methylation associated with KRAS mutations and LST-G morphology, and low methylation associated with CTNNB1 activation and LST-NG morphology, might be involved in LST development, and that involvement of TP53 mutations could be important in both subtypes in the development from adenoma to cancer.

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.

Metabolic factors accelerate colorectal adenoma recurrence.

BACKGROUND: Metabolic factors have been reported to increase the prevalence of colorectal adenomas, however, whether metabolic factors might also accelerate the recurrence after removal of adenomas has not yet been discussed. In this retrospective multicenter study, we clarified the risk factors for adenoma recurrence focusing on metabolic factors. METHODS: We analyzed the medical records of 43,195 patients who had undergone colonoscopy between January 2005 and December 2011 at 5 hospitals in Japan. Of these, the data of 1111 patients who had undergone removal of adenomas at the first screening colonoscopy, and then been followed up by colonoscopy 1 year and 2 years later were analyzed. RESULTS: The following 8 factors were demonstrated with a multivariate analysis as being associated with colorectal adenomas recurrence: for adenoma-related factors, 5 factors (villous features, grade of dysplasia, location and size of the largest removed adenoma, and number of the removed adenomas) were identified; for metabolic factors and other factors, 3 factors (age, body mass index (BMI), and fasting blood glucose (FBG)) were identified. A risk score (0-10 points) was developed based on these 8 factors. The risk of adenoma recurrence increased as the risk score increased. When the risk score was ≥3 (3-10) points, the odds ratio relative to <3 (0-2) points was 7.07 (95% CIs 5.30-9.43). CONCLUSIONS: In addition to adenoma-related factors (villous features, grade of dysplasia, location, size and number), 3 factors (age, BMI and FBG) were demonstrated to influence the recurrence rate of colorectal adenoma. When the risk score was ≥3, the risk of recurrence was significantly elevated.

Frequency and risk factors for rebleeding events in patients with small bowel angioectasia.

BACKGROUND: Small bowel angioectasia is reported as the most common cause of bleeding in patients with obscure gastrointestinal bleeding. Although the safety and efficacy of endoscopic treatment have been demonstrated, rebleeding rates are relatively high. To establish therapeutic and follow-up guidelines, we investigated the long-term outcomes and clinical predictors of rebleeding in patients with small bowel angioectasia. METHODS: A total of 68 patients were retrospectively included in this study. All the patients had undergone CE examination, and subsequent control of bleeding, where needed, was accomplished by endoscopic argon plasma coagulation. Based on the follow-up data, the rebleeding rate was compared between patients who had/had not undergone endoscopic treatment. Multivariate analysis was performed using Cox proportional hazard regression model to identify the predictors of rebleeding. We defined the OGIB as controlled if there was no further overt bleeding within 6 months and the hemoglobin level had not fallen below 10 g/dl by the time of the final examination. RESULTS: The overall rebleeding rate over a median follow-up duration of 30.5 months (interquartile range 16.5-47.0) was 33.8% (23/68 cases). The cumulative risk of rebleeding tended to be lower in the patients who had undergone endoscopic treatment than in those who had not undergone endoscopic treatment, however, the difference did not reach statistical significance (P = 0.14). In the majority of patients with rebleeding (18/23, 78.3%), the bleeding was controlled by the end of the follow-up period. Multiple regression analysis identified presence of multiple lesions (≥3) (OR 3.82; 95% CI 1.30-11.3, P = 0.02) as the only significant independent predictor of rebleeding. CONCLUSION: In most cases, bleeding can be controlled by repeated endoscopic treatment. Careful follow-up is needed for patients with multiple lesions, presence of which is considered as a significant risk factor for rebleeding.

Effects of ramosetron oral disintegrating tablets on gastric emptying: crossover study using the 13C-acetic acid breath test.

BACKGROUND/AIMS: Ramosetron is a new selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist that reportedly has more potent antiemetic effects than other 5-HT3 receptor antagonists. The aim of this study was to determine the effect of ramosetron pretreatment on gastric emptying using the 13C-acetic acid breath test. METHODOLOGY: Ten healthy male and female volunteers participated in this randomized, twoway crossover study. After they had fasted overnight, the subjects were randomly assigned to receive 0.1 mg ramosetron 1 hour before ingestion of a test meal (200 kcal per 200 mL, containing 100 mg 13C acetate) or to receive the test meal alone. Under both conditions, breath samples were collected for 150 min following ingestion of the meal. Statistical comparison of the parameters between the two test conditions was performed. RESULTS: No significant differences in the calculated parameters, including T 1/2, T lag, GEC or ß and κ, were observed between the two test conditions. CONCLUSIONS: The present study revealed that 0.1 mg ramosetron had no significant effect on the rate of gastric emptying. Thus, our results suggest that ramosetron can be administered safely, without gastrointestinal adverse effects, even to terminal cancer patients with delayed or accelerated gastric emptying abnormality.

Protective effect of lactoferrin on acute acid reflux-induced esophageal mucosal damage.

BACKGROUND/AIMS: The natural immunomodulator lactoferrin is known to possess anti-inflammatory effects. However, there have been no studies examining the mode of action of lactoferrin in protecting the esophageal mucosa against damage. We investigated the effect of lactoferrin on gastric acid secretion and in protecting against acute acid reflux-induced esophagitis in rats. METHODOLOGY: Male Wistar rats aged 8 weeks, weighing 210-240 g, were used for all the experiments. A gastric perfusion system was installed using the method of Ghosh et al. Lactoferrin was administered once via the caudate vein, starting 24 hours before an acute acid reflux (treatment mode), or saline (control). Statistical comparison of the parameters between the two test conditions was performed. RESULTS: No significant differences in basal or stimulated gastric acid secretion, or in the serum gastrin level were observed between the two test conditions. Esophageal damage was attenuated by lactoferrin in a dose-dependent manner, as reflected by the improvement in the esophageal tissue weight and macroscopic scores. Significant reductions in the histological scores, myeloperoxidase activity and the levels of proinflammatory cytokines, tumor necrosis factor-α and interleukin-1ß were also observed following lactoferrin administration. CONCLUSIONS: We concluded that lactoferrin exerts a protective effect against acute acid reflux-induced esophageal damage in rats.

Correlation between gastric transit time measured by video capsule endoscopy and gastric emptying determined by the continuous real-time 13C breath test (BreathID system).

BACKGROUND/AIMS: The aim of this study was to determine the possible existence of a correlation between the gastric transit time (GTT) measured by video capsule endoscopy (VCE) and the parameters of gastric emptying determined using 13C breath test (BreathID system). METHODS: Eight healthy male volunteers participated in this randomized, two-way crossover study. The subjects were randomly assigned to undergo VCE using the PillCam SB capsule endoscopy system or the 13C breath test for 4 hours after a test meal (400 kcal per 400 mL) containing 100 mg of 13C acetic acid administered after overnight fasting. The VCE images were analyzed and the GTT was determined using the proprietary RAPID software. The parameters, namely T lag, T 1/2 and GEC were calculated using the Oridion Research Software (ß version). The GTT measured by VCE and the parameters of gastric emptying were compared statistically. RESULTS: No significant correlation was observed between the GTT and T lag (p = 0.5263), T 1/2 (p = 0.4100) or GEC (p = 0.2410), as determined by calculation of the Spearman's rank correlation coefficient. CONCLUSIONS: GTT measured by VCE cannot serve as asubstitute for the gastric emptying time measured bythe 13C breath test.

Anatomically-Inspired Robotic Finger with SMA Tendon Actuation for Enhanced Biomimetic Functionality.

This research introduces an advanced robotic finger designed for future generalist robots, closely mimicking the natural structure of the human finger. The incorporation of rarely discussed anatomical structures, including tendon sheath, ligaments, and palmar plates, combined with the usage of anatomically proven 3D models of the finger, give rise to the highly accurate replication of human-like soft mechanical fingers. Benefiting from the accurate anatomy of muscle insertions with the utilization of Shape Memory Alloy (SMA) wires' muscle-like actuation properties, the bonding in-between the flexor tendons and extensor tendons allows for the realization of the central and lateral band of the finger anatomy. Evaluated using the computer vision method, the proposed robotic finger demonstrates a range of motion (ROM) equivalent to 113%, 87% and 88% of the human dynamic ROM for the DIP, PIP and MCP joints, respectively. The proposed finger possesses a soft nature when relaxed and becomes firm when activated, pioneering a new approach in biomimetic robot design and offering a unique contribution to the future of generalist humanoid robots.

Influence of ensitrelvir or nirmatrelvir/ritonavir on tacrolimus clearance in kidney transplant recipients: a single-center case series.

BACKGROUND: Among the oral antivirals used for treating patients with mild-to-moderate novel coronavirus disease 2019 (COVID-19), nirmatrelvir/ritonavir (NMV/RTV) and ensitrelvir (ESV) are inhibitors of cytochrome P450 (CYP) 3A, and therefore, can cause drug-drug interactions with concomitant medications. Tacrolimus (TAC), a substrate of CYP3A4/5, is administered for a long period to prevent rejection after kidney transplantation. TAC should be discontinued while using NMV/RTV because blood TAC levels significantly increase when these drugs are concomitantly administered. However, the influence of ESV on blood TAC levels has not yet been reported, and the management of TAC doses during the use of ESV remains unclear. CASE PRESENTATION: We experienced three kidney transplant recipients with COVID-19, whose blood trough levels of TAC increased by the concomitant use of NMV/RTV or ESV. In two patients administering NMV/RTV, blood trough levels of TAC increased more than tenfold after combination therapy, whereas in one patient administering ESV, TAC level increased approximately threefold. CONCLUSIONS: These cases suggest that TAC administration should be discontinued during NMV/RTV treatment to maintain blood TAC levels within the therapeutic range, and a reduced TAC dose is sufficient during ESV treatment.

Colon epithelial proliferation and carcinogenesis in diet-induced obesity.

Colorectal cancer is the third leading cause of cancer death in Japan and the United States and is strongly associated with obesity, especially visceral obesity. Several metabolic mediators, such as adiponectin, have been suspected to play a role in obesity-related carcinogenesis. In a previous human study, the existence of a significant correlation between the number of human dysplastic aberrant crypt foci (ACF) and the visceral fat area was demonstrated, and also that of a significant inverse correlation between the number of dysplastic ACF and the plasma adiponectin level. Other studies have investigated the effect of adiponectin under the normal and high-fat diet conditions in a mouse model of azoxymethane-induced colon cancer. Enhanced formation of both ACF and tumors was observed in the adiponectin-deficient mice, as compared with that in the wild-type, under the high-fat diet condition but not under the normal diet condition. Furthermore, that the 5'-AMP-activated kinase/mammalian target of rapamycin pathway is involved in the promotion of colorectal carcinogenesis in adiponectin-deficient mice under the high-fat diet condition was shown. Therefore, that the 5'-AMP-activated kinase/mammalian target of rapamycin signaling pathway may play an important role in colorectal carcinogenesis was speculated. Metformin, a biguanide derivative widely used in the treatment of diabetes mellitus, has been shown to exert a suppressive effect on ACF formation in both mouse models and humans. Therefore, metformin might be a promising candidate as a safe drug for chemoprevention of colorectal carcinogenesis. Further studies with high evidence levels, such as randomized, controlled studies, are needed to clarify these relationships.

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

AIM: To identify the predictive factors for the presence of small bowel lesions in patients with obscure gastrointestinal bleeding (OGIB). METHODS: A total of 242 patients with OGIB (overt 149: occult 93) were retrospectively included in the present study. Capsule endoscopy (CE) was carried out to investigate the small bowel, and detected lesions were classified according to the P0-P2 system. Only P2 lesions were defined as significant lesions. Univariate and multivariate logistic regression analyses were carried out to define the predictive factors for the presence of small bowel lesions. RESULTS: In patients with overt OGIB, chronic kidney disease (CKD) ≥stage 4 (odds ratio [OR] 4.03; 95% confidence interval [CI] 1.45-11.1, P = 0.007) was identified as an independent predictor of the presence of vascular lesions, and a history of non-steroidalanti-inflammatory drug (NSAID) use as that of erosive/ulcerated lesions (OR 4.73; 95% CI 1.47-15.2, P = 0.009). However, in patients with occult OGIB, no significant predictors of the presence of vascular lesions were identified, whereas a history of low-dose aspirin (LDA) (OR 3.57; 95% CI 1.21-10.5, P = 0.02) and proton pump inhibitor (PPI) use (OR 3.18; 95% CI 1.02-9.92, P = 0.05) were identified as independent predictors of the presence of erosive/ulcerated lesions. CONCLUSIONS: Our results indicated that bleeding pattern and clinical characteristics could contribute to predicting the origin of OGIB.

Identification of preneoplastic lesions as mucin-depleted foci in patients with sporadic colorectal cancer.

In experimental models, mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucin production have been recognized to be correlated with colorectal carcinogenesis and to serve as preneoplastic lesions of colorectal cancer (CRC). In humans, there is only one report of identification of MDF in patients with familial adenomatous polyposis and CRC; however, the histological characteristics of human MDF are not discussed extensively in the report. In the present study, colonic samples from 53 patients with sporadic CRC were stained with Alcian blue and examined for the presence of MDF. Subsequently, the samples were examined for the presence of aberrant crypt foci (ACF) by methylene blue staining. We classified MDF into two categories: flat-MDF and protruded-MDF (having the characteristics of both ACF and MDF). We found a total of 354, 41 and 19 colonic mucosal lesions with a mean multiplicity of 44, 38.9 and 66.9 crypts (ACF, flat-MDF and protruded-MDF, respectively). The density of MDF was 0.0082 lesions/cm(2) . The ACF identified in sporadic CRC patients corresponded to hyperplastic or non-dysplasic lesions. However, MDF identified in these patients corresponded to low-grade dysplasia. In addition, we found that Paneth cell metaplasia and inflammatory cell infiltration were specific histological features of MDF. These histological characteristics are reported to be associated with the development of CRC. Therefore, our results indicate that MDF might represent preneoplastic lesions in human colorectal carcinogenesis.

Eicosapentaenoic acid (EPA) efficacy for colorectal aberrant crypt foci (ACF): a double-blind randomized controlled trial.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly occurring neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Eicosapentaenoic acid (EPA), the omega-3 polyunsaturated fatty acid that is widely used in the treatment of hyperlipidemia and prevention of cardiovascular disease, has recently been suggested to have a suppressive effect on tumorigenesis and cancer cell growth. In CRC chemoprevention trials, in general, the incidence of polyps or of the cancer itself is set as the study endpoint. Although the incidence rate of CRC would be the most reliable endpoint, use of this endpoint would be unsuitable for chemoprevention trials, because of the relatively low occurrence rate of CRC in the general population and the long-term observation period that it would necessitate. Moreover, there is an ethical problem in conducting long-term trials to determine whether a test drug might be effective or harmful. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are considered as a reliable surrogate biomarker of CRC. Thus, we devised a prospective randomized controlled trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of EPA against colorectal ACF formation and the safety of this drug, in patients scheduled for polypectomy. METHODS: This study is a multicenter, double-blind, placebo-controlled, randomized controlled trial to be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients shall be recruited for the study and the number of ACF in the rectum counted at the baseline colonoscopy. Then, the participants shall be allocated randomly to either one of two groups, the EPA group and the placebo group. Patients in the EPA group shall receive oral 900-mg EPA capsules thrice daily (total daily dose, 2.7 g per day), and those in the placebo group shall receive oral placebo capsules thrice daily. After one month's treatment with EPA/placebo, colonoscopic examination and polypectomy will be performed to evaluate the formation of ACF, and the cell-proliferative activity and cell-apoptotic activity in normal colorectal mucosa and colorectal polyps. DISCUSSION: This is the first study proposed to explore the effect of EPA against colorectal ACF formation in humans.This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000008172.

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

BACKGROUND: Colorectal 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/DESIGN: This 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. DISCUSSION: This 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 REGISTRATION: This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254.

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

BACKGROUND: Capsule 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. METHODS: Four 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. RESULTS: Of 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. CONCLUSIONS: CE-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.

Early effect of oral administration of omeprazole with mosapride as compared with those of omeprazole alone on the intragastric pH.

BACKGROUND: The ideal medication for acid-related diseases should have a rapid onset of action to promote hemostasis and cause efficient resolution of symptoms. The aim of our study was to comparatively investigate the inhibitory effect on gastric acid secretion of a single oral administration of omeprazole plus mosapride with that of omeprazole alone. METHODS: Ten Helicobacter pylori-negative male subjects participated in this randomized, two-way crossover study. Intragastric pH was monitored continuously for 6 hours after a single oral administration of omeprazole 20 mg or that of omeprazole 20 mg plus mosapride 5 mg (the omeprazole being administered one hour after the mosapride). Each administration was separated by a 7-days washout period. RESULTS: The average pH during the 6-hour period after administration of omeprazole 20 mg plus mosapride 5 mg was higher than that after administration of omeprazole 20 mg alone (median: 3.22 versus 4.21, respectively; p = 0.0247). CONCLUSIONS: In H. pylori -negative healthy male subjects, an oral dose of omeprazole 20 mg plus mosapride 5 mg increased the intragastric pH more rapidly than omeprazole 20 mg alone.