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The utility of endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) for gastric subepithelial lesions (SELs) has been reported. In this study, we examined the optimal number of needle punctures during EUS-FNB for gastric SELs without rapid on-site evaluation (ROSE). The factors that allowed for a single needle puncture to arrive at the correct diagnosis were also analyzed. We conducted a retrospective study of all patients who underwent EUS-FNB to evaluate gastric SELs between April 2015 and September 2020; 51 patients with 57 gastric SELs were enrolled. The optimal number of needle punctures was determined when additional needle passes did not increase diagnostic sensitivity by more than 10%. Factors allowing for only a single needle puncture to arrive at the correct diagnosis were identified by univariate and multivariate logistic regression analyses. EUS-FNB resulted in a definitive final diagnosis in 48 of 57 lesions (84%). Lesions in the gastric body (odds ratio [OR] 6.15, 95% confidence interval [CI] 1.75–21.6; P

Demands for higher-voltage MOSFET application are increasing, for which a Super-Junction MOSFET, sustaining the voltages in the range of 500V, has been developed based on the trench-type structure. Due to the huge bias applied, a new leakage-current type is induced during switching, which causes a switching-power-loss increase. Creating a compact model for circuit design, which includes this additional leakage current, is the purpose of the present development. The model describes the depletion-width variation, caused during the switching-on of the device, with the use of the internal node potential, determined accurately by iteration. It is verified, that the new compact model can accurately predict the device performances for different device structures. This capability can be used for device optimization to realize low-power circuitry.

Aspirin use is reportedly not to be associated with fecal immunochemical occult blood test (FIT) false-positive results for the detection of colorectal cancer. The need for additional small bowel exploration in FIT-positive, low-dose aspirin users with a negative colonoscopy is controversial. The aim of this study was to assess the ability of FIT to judge whether capsule endoscopy (CE) should be performed in low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy findings by comparing FIT results with CE findings. A total of 264 consecutive low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy who were scheduled to undergo CE at five hospitals in Japan were enrolled. Patients had been offered FIT prior to the CE. The association between the FIT results and the CE findings was then assessed. One hundred and fifty-seven patients were included in the final analysis. Eighty-four patients (53.5 %) had positive FIT results. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of positive FIT results for small bowel ulcers were 0.56, 0.47, 0.30, and 0.73, respectively. Furthermore, the NPV of positive FIT results for severe small bowel injury (Lewis score ≥790) was markedly high (0.90). When the analysis was performed only in low-dose aspirin users with anemia, the sensitivity of the positive FIT results was notably improved (0.72). Small bowel evaluation using CE is not recommended for FIT-negative, low-dose aspirin users. However, small bowel evaluation using CE should be considered in both FIT-positive and anemic low-dose aspirin users.

Summary 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.

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.

A 53-year-old man was admitted to our hospital with the complaint of neck pain and dyspnea. His blood examination revealed increased C-reactive protein and amylase levels. Enhanced computed tomography (CT) images demonstrated a retropharyngeal and a mediastinal low-density area extending to the portal area. He was diagnosed with pancreatic pseudocyst from the abdominal cavity to the cervical region accompanied by spontaneous rupture into the portal vein. Endoscopic ultrasound-guided cyst drainage (EUS-CD) of the most inferior cavity around the superior mesenteric artery was performed through the gastric wall. No adverse events were recorded during the procedure, and a near-complete resolution of his symptoms and the pseudocyst was achieved.

Aberrant crypt foci (ACF) are regarded as potential biomarkers for colorectal cancer (CRC), and have been used as such in recent early-phase chemoprevention trials. However, the associations between the presence of ACF and other factors associated with the development of CRC, such as lifestyle factors, medication use and comorbid medical conditions, remain unknown. Thus, the present retrospective, large, cross-sectional study was conducted to evaluate the potential usefulness of ACF as a surrogate biomarker of CRC. Total colonoscopy was performed and the number of rectal ACF was counted in a total of 902 subjects. A retrospective review of the medical records of the study subjects was performed, and the factors associated with the increased prevalence of ACF was investigated using univariate and multivariate logistic regression analyses. The analysis results identified older age [odds ratio (OR), 9.24; 95% confidence interval (CI), 4.80–17.8; P

Although chronic constipation is common, colonic functional evaluating tests are uncommon. This study examines whether chronic constipation and gastrointestinal symptoms are correlated with the lateral diameter of the colon measured from MRI images. We included chronic constipation patients in a prospective, cross-sectional study using MRI at three centers. We divided 3D MRI colorectal images into 6 segments using with specified sequences and selected the maximum luminal diameter from each segment. We used the GSRS questionnaire to evaluate gastrointestinal symptoms. We evaluated the correlation between luminal diameters and GSRS scores. We found the following positive correlations: descending colon and unsatisfactory defecation symptoms; sigmoid colon and diarrhea; and rectum and constipation. The sum and ratio of the ascending and sigmoid colon diameters correlated with nausea and diarrhea. The sum of the transvers to the sigmoid colon diameter also correlated with nausea and diarrhea. The sum of all segment diameters correlated with nausea and constipation. In conclusion, we showed cross-sectional study of colonic MRI correlate with gastrointestinal symptoms. MRI might be useful for colonic motility evaluations to determine appropriate constipation treatments (Clinical trial registry number UMIN 000021274).

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.

Background/Aims: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by diffuse mucosal inflammation, traditionally regarded as being limited to the colorectum. Although several gastroduodenal lesions have also been reported recently in cases of UC, in general, small-bowel lesions in UC are believed to be extremely rare. The aim of this study was to examine the small bowel by capsule endoscopy in patients with UC. Methods: The study was conducted in 23 well-documented UC patients and 23 control volunteers. The frequency of small-bowel lesions, the number of small-bowel lesions per patient and the capsule endoscopy score were comparatively evaluated between the two groups. Results: Of the 23 UC patients, 13 (57%) showed small-bowel lesions, and 8 (35%) had erosions. There were significant differences in the frequency of the small-bowel lesions (p < 0.001) and erosions (p = 0.009) between the two groups. The capsule endoscopy score was correlated with the UC disease activity index (r = 0.718, p < 0.001). Conclusions: This is the first capsule-endoscopic study conducted to examine the small-bowel involvement in UC patients as compared with the healthy volunteers. It was concluded that UC, a chronic inflammatory bowel disease, can also involve the small bowel.

A 61-year-old woman presented to our hospital with epigastric pain. She underwent abdominal contrast-enhanced computed tomography, which showed signal enhancement in the gallbladder fundus. As biliary obstruction was suspected, endoscopic nasobiliary drainage was performed, which revealed hemobilia. Based on this finding, gallbladder tumor was suspected, and open cholecystectomy was performed. Immunohistological staining of the resected tissue was positive for factor VIII that led to the diagnosis of gallbladder angiosarcoma. Hepatectomy and biliary reconstruction were performed for disease control; however, the patient died due to multiple liver metastases 4 months after the surgery.

AIM: To evaluate the effectiveness of barium impaction therapy for patients with colonic diverticular bleeding. METHODS: We reviewed the clinical charts of patients in whom therapeutic barium enema was performed for the control of diverticular bleeding between August 2010 and March 2012 at Yokohama Rosai Hospital. Twenty patients were included in the review, consisting of 14 men and 6 women. The median age of the patients was 73.5 years. The duration of the follow-up period ranged from 1 to 19 mo (median: 9.8 mo). Among the 20 patients were 11 patients who required the procedure for re-bleeding during hospitalization, 6 patients who required it for re-bleeding that developed after the patient left the hospital, and 3 patients who required the procedure for the prevention of re-bleeding. Barium (concentration: 150 w%/v%) was administered per the rectum, and the leading edge of the contrast medium was followed up to the cecum by fluoroscopy. After confirmation that the ascending colon and cecum were filled with barium, the enema tube was withdrawn, and the patient’s position was changed every 20 min for 3 h. RESULTS: Twelve patients remained free of re-bleeding during the follow-up period (range: 1-19 mo) after the therapeutic barium enema, including 9 men and 3 women with a median age of 72.0 years. Re-bleeding occurred in 8 patients including 5 men and 3 women with a median age of 68.5 years: 4 developed early re-bleeding, defined as re-bleeding that occurs within one week after the procedure, and the remaining 4 developed late re-bleeding. The DFI (disease-free interval) decreased 0.4 for 12 mo. Only one patient developed a complication from therapeutic barium enema (colonic perforation). CONCLUSION: Therapeutic barium enema is effective for the control of diverticular hemorrhage in cases where the active bleeding site cannot be identified by colonoscopy.

Background and Aims : The natural immunomodulator, lactoferrin, is widespread among various biological fluids and is known to exert an anti-inflammatory effect. However, there has been only one study that examined the mode of action of lactoferrin in reducing intestinal damage. We investigated the therapeutic role of lactoferrin and its effect on the levels of pro-inflammatory and anti-inflammatory cytokines, by using a rat model of dextran sulfate sodium (DSS) induced-colitis. Methods: Male Sprague–Dawley rats were given distilled drinking water containing 2.5% (wt/vol) synthetic DSS ad libitum. Bovine lactoferrin was given once daily through gavage, starting 3 days before beginning the DSS administration, until death. The whole colon was removed to be examined macroscopically and histologically. Myeloperoxidase activity, and pro-inflammatory and anti-inflammatory cytokines in the colonic tissue were also measured. Results: Dextran sulfate sodium-induced colitis was attenuated by oral administration of lactoferrin in a dose-dependent manner, as reflected by improvement in clinical disease activity index, white blood cell count and hemoglobin concentration, macroscopic and histological scores, and myeloperoxidase activity. Reduced inflammation in response to lactoferrin was correlated with the significant induction of the anti-inflammatory cytokines, interleukin-4 and interleukin-10, and with significant reductions in the pro-inflammatory cytokines, tumor necrosis factor α, interleukin-1β, and interleukin-6. Conclusions: We concluded that oral administration of lactoferrin exerts a protective effect against the development of colitis in rats via modulation of the immune system and correction of cytokine imbalance. Lactoferrin has potential as a new therapeutic agent for inflammatory bowel disease. © 2002 Blackwell Publishing Asia Pty Ltd

Background. Peroxisome proliferator activator receptor-gamma (PPARγ) is a member of the nuclear receptor superfamily. Ligands of PPARγ, thiazolidione derivatives, have been reported to be the one of the candidates for the treatment of inflammatory bowel disease (IBD). Given the fact that PPARγ is a transcription regulator, expression pharmacogenomics, including differential gene expression profiling of drug responses in a colitis model, is thought to be a useful approach for finding relevant genes that can serve as the target for new drug treatment of IBD. Methods. We performed a global analysis for differential gene expression of the intestine in a dextran sodium sulfate (DSS) colitis mouse model following PPARγ ligand administration. By applying a high-density oligonucleotide array method, the expression patterns of approximately 12000 genes were analyzed, and selected genes were confirmed by a real-time quantitative PCR method. Results. The analysis of downregulated genes in the DSS mice following PPARγ administration revealed several functional gene clusters with altered expression: (1) oncogene families such as GRO1 oncogenes, (2) inflammatory mediator-related genes such as the interferon-gamma gene, (3) water electrolyte-associated genes, and (4) others. Conclusions. This is the first demonstration of global gene expression analysis using the DSS colitis mouse model with a PPARγ ligand, and these results provide new insight for finding novel target genes for treating IBD.

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.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.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-1β were also observed following lactoferrin administration.We concluded that lactoferrin exerts a protective effect against acute acid reflux-induced esophageal damage in rats.

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

Introduction We report the case of a patient who was diagnosed as having pneumatosis cystoides intestinalis while being treated with prednisolone for bronchial asthma. Even before we had experienced a case of this, the relationship between pneumatosis cystoides intestinalis and prednisolone was unclear. In this case, pneumatosis cystoides intestinalis was improved with the reduction of prednisolone, and therefore we thought a direct relationship between pneumatosis cystoides intestinalis and prednisolone might become clear, such as whether it is dose dependent. Case presentation A 62-year-old Japanese woman had been treated for bronchial asthma for approximately 40 years. She presented with abdominal distension, and a radiographic examination showed intraperitoneal free gas and intramural gas, suggestive of pneumatosis cystoides intestinalis. However, when her prednisolone dose was decreased from 30mg to 0mg for approximately a year because of improvement in her asthma symptoms, her abdominal symptom resolved, and the frequency of her bowel movements returned to normal. Conclusion Amelioration of pneumatosis cystoides intestinalis was observed with tapering of the prednisolone, suggesting that prednisolone may have been involved in the pathogenesis of pneumatosis cystoides intestinalis in this patient.

Obscure gastrointestinal bleeding (OGIB) is one of the common complications in patients with chronic kidney disease (CKD), especially those who are on maintenance hemodialysis (HD). However, little is known about the characteristics of the small-bowel lesions in these patients, or of the factors that could predict the presence of such lesions. Therefore we enrolled a total of 42 CKD patients (including 19 HD patients and 23 non-HD patients), and compared the incidence of the small-bowel lesions among two groups. Furthermore, to identify predictive factors for the presence of small-bowel lesions, we performed multivariate logistic-regression-analyses. The incidence of small-bowel vascular lesions was significantly higher in CKD patients than in age-and-sex matched non-CKD patients (P<0.001). On the other hand, there was any significant difference of the incidence of small-bowel lesions between HD and non-HD patients. In CKD patients, past history of blood transfusion (OR 5.66; 95% CI 1.10–29.1,P=0.04) was identified as an independent predictor of the presence of vascular lesions, and history of low-dose aspirin use (OR 6.00; 95% CI 1.13–31.9,P=0.04) was identified as that of erosive/ulcerated lesions. This indicated that proactive CE examination would be clinically meaningful for these patients.

The prognosis of metastatic or recurrent gastrointestinal stromal tumors (GISTs) accompanied by multiple hepatic metastases and peritoneal dissemination is very poor. We encountered a case of stage IV small intestinal GIST with multiple hepatic metastases and peritoneal dissemination that were observed after resection of the primary lesion. Multidisciplinary treatments were performed over time, including hepatic resection, radiotherapy, imatinib therapy, sunitinib therapy, and transcatheter arterial chemoembolization, and the disease had been brought under control following resection of a primary lesion 14 years ago. The patient was a 49-year-old woman diagnosed with hemorrhagic stool in July 1998, when a computed tomography scan revealed an 8-cm-diameter tumor in her small bowel. Partial resection of her small bowel was performed and the pathological diagnosis was a high-risk GIST showing 15 mitoses per 50 high power fields. Several metastases developed in the S4 and S5 segments of the patient's liver 3 years after resection of the primary lesion, and a central two-segmental resection of the liver was performed. Furthermore, 1 year after this procedure, peritoneal dissemination developed near the pancreas, for which radiotherapy was performed. Four months later, the patient again developed multiple liver metastases and was started on treatment with 400 mg imatinib per day, achieving a partial response(PR). Five years and 6 months after imatinib initiation, resistance emerged in one of the liver metastases. The patient was switched to sunitinib(50 mg per day), but was diagnosed with progressive disease at the end of the second course and the procedure was discontinued. Treatment with 400 mg of imatinib per day was resumed, and transcatheter arterial chemoembolization was performed twice over a 17-month period for the resistant hepatic region and a PR was achieved each time. We were able to maintain a PR in this patient; other metastases indicated the effectiveness of imatinib therapy. Therefore, a multidisciplinary team approach can be effective in achieving long-term disease control in patients with metastatic or recurrent GIST.

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.

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.

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

The patient was a 74-year-old man who suffered from epigastric abdominal pain. He visited our hospital in April 2008. An esophageal endocrine cell carcinoma was pointed out by gastrointestinal endoscopy, and he was diagnosed as esophageal endoscopic cell carcinoma with mediastinum lymph node by CT scan(Stage IVa: cT3N4M0). Concurrent chemoradiotherapy using CDDP+EP was started. After two courses, the primary tumor was markedly reduced, and endoscopy showed only a scar. We diagnosed the patient as being in complete remission. However, CT showed a liver metastasis relapse in June 2009, and we started AMR as second-line chemotherapy. His general condition went into a decline, however, He died on October 2, 2009.

Enterostatin selectively inhibits the intake of dietary fat after both peripheral and central administration. We have investigated the role of the hepatic vagus nerve in modulating the peripheral response to enterostatin in Sprague-Dawley rats adapted to a high fat (HF) diet. Intraperitoneal (ip) enterostatin reduced intake of HF diet after overnight starvation. This response was abolished by selective vagal hepatic branch transection. Immunohistochemical techniques were used to identify the location of Fos protein in brain nuclei after ip enterostatin. Fos protein was evident in the nucleus tractus solitarius (NTS), parabrachial, paraventricular and supraoptic nuclei. The pattern of expression of Fos-like immunoreactivity differed from that induced by the lipoprivic agent beta-mercaptoacetate. Transection of the hepatic vagus blocked the central Fos responses to ip enterostatin. We conclude that afferent hepatic vagal nerve activity is required for the feeding response to peripheral enterostatin.

Low-dose aspirin is widely used for the prevention of cardiovascular and cerebrovascular diseases. However, administration of low-dose aspirin is associated with an increased risk of upper gastrointestinal complications, such as upper gastrointestinal erosions, ulcers and bleeding. The aim of this study was to clarify the prevalence and various clinical factors of upper gastrointestinal complications associated with low-dose aspirin treatment.A total of 1213 patients taking low-dose aspirin were evaluated with upper endoscopic examinations. We studied retrospectively the incidence of and risk factors for upper gastrointestinal complications associated with low-dose aspirin use.Of the 1213 patients taking low-dose aspirin, 598 patients and 72 patients were found to have gastroduodenal erosions (57.3%) and peptic ulcers (5.9%), respectively. Of these 72 peptic ulcers, 27 were diagnosed as hemorrhagic ulcers. Previous ulcer history was identified as a risk factor for peptic ulcer and upper gastrointestinal bleeding during low-dose aspirin therapy. Upper gastrointestinal symptoms and no use of gastroprotective agents were also identified as risk factors for peptic ulcers. In this study, the use of a histamine-2 receptor antagonist was indicated as a protective factor for peptic ulcers.Low-dose aspirin therapy is associated with an increased risk of developing upper gastrointestinal complications. Administration of a histamine-2 receptor antagonist was effective for the prevention of low-dose aspirin induced peptic ulcers.

To clarify the physiological role of vagal amino acid sensors in the liver, the effect of hepatic vagotomy and/or celiac vagotomy (sectioning of the hepatic branch and/or celiac branches of the vagus nerve) on the secretion of insulin and glucagon after intraperitoneal injection of neutral ( l -alanine, l -leucine, and l -phenylalanine), acidic ( l -glutamate), or nonmetabolized (cycloleucine) acids, was examined in rats. Hepatic vagotomy enhanced both plasma glucose and glucagon concentrations after intraperitoneal injection of alanine more than those in sham-vagotomized (control) rats, while after intraperitoneal injection of leucine, hepatic vagotomy decreased plasma glucose concentrations and enhanced plasma insulin concentrations more than in control animals. These effects, following both alanine and leucine administration, were blocked by celiac vagotomy. Glutamate, phenylalanine, and cycloleucine stimulation in hepatic-vagotomized rats caused no significant differences in plasma glucose, insulin, or glucagon levels as compared to those in sham-vagotomized rats. Celiac vagotomy alone did not affect plasma glucose, insulin, or glucagon concentrations after stimulation by these five amino acids. The physiological role of alanine and leucine sensors may be to prevent amino acid-induced exaggerated pancreatic hormone secretion and to maintain blood glucose homeostasis, while glutamate, phenylalanine, and cycloleucine have no effect on this pancreatic neuroendocrine system.

Vagal glucose receptor and arginine sensor have been found to exist in the liver of normal rats. The present study was designed to examine whether these sensory receptor systems function in streptozotocin-induced mildly diabetic rats. One week after streptozotocin injection (35 mg/kg body wt. iv), hepatic vagotomy and installation of a jugular vein catheter were performed. Three days after the surgery, intraperitoneal glucose (1 g/kg body wt.) or arginine (1 g/kg body wt.) stimulation was done with the rat in an unanesthetized and unrestrained state. Hepatic vagotomy significantly reduced glucose-induced insulin release with an increase in plasma glucose in control and diabetic rats. The rate of reduction of plasma insulin release was similar in the two groups. Hepatic vagotomy also significantly enhanced arginine-induced insulin release in both groups, but in control rats there was no change in the response to plasma glucose, while in diabetic rats there was a significant reduction. The rate of enhancement of plasma insulin release by hepatic vagotomy was significantly greater in diabetic than in control rats. The results indicate that streptozotocin-induced mildly diabetic rats have hyperfunction of the arginine sensor and normofunction of the glucose receptor and modulate insulin release through these receptor systems in the liver.

Endoscopic injection sclerotherapy is in widespread use for patients with esophageal varices. It is well known that pleural effusions are among complications following endoscopic sclerotherapy. However, there are few studies regarding the proportion of patients developing pleural effusions after sclerotherapy.Between August 1991 and September 1998, 575 endoscopic injection sclerotherapies were carried out in 128 patients. Chest radiographs were obtained prior to and 24 hours after all procedures. We also obtained other clinical data from all patients.In total, 17.7% of post-sclerotherapy patients were diagnosed as having small amounts of pleural effusions. Logistic regression revealed pleural effusions after sclerotherapy to be associated with ascites, chest pain for 24 hours, total volume of sclerosant and submucosal injection of more than 4mL of sclerosant. In parallel with injection of an increasing amount of submucosal sclerosant, the proportion of patients with pleural effusion increased.Pleural effusions were related to ascites, chest pain for 24 hours, total sclerosant volume and submucosal injection of sclerosant.

Nitric oxide (NO) production is elevated in the intestine and may contribute to intestinal injury during inflammation. However, how the expression of inducible NO synthase (iNOS) mRNA and endothelial NO synthase (eNOS) mRNA in the esophageal mucosa contribute to mucosal damage caused by reflux esophagitis remains unknown. Since vascular endothelial growth factor (VEGF) exerts its action on microcirculation, contributing to angiogenesis and inflammation, we examined the role of VEGF together with iNOS and eNOS on development of reflux esophagitis.The mRNA expression levels of iNOS, eNOS and VEGF were measured in biopsy specimens from 25 patients with reflux esophagitis, using TaqMan PCR and reverse transcription PCR.The expression of iNOS mRNA in the esophageal mucosa increased parallel to the severity of the esophagitis. There were no significant differences between both eNOS and VEGF mRNA expression levels and the severity of the esophagitis. The existence of gastric mucosal atrophy, hiatus hernia, therapy and Helicobacter pylori infection did not affect the levels of mRNA expression.The accumulation of NO, produced by iNOS, was considered to be related to the exacerbation of reflux esophagitis. Therapeutic intervention that reduces NO production may thus be of use in preventing development of esophageal mucosal injury in patients with reflux esophagitis.

Galanin and enterostatin, which are distributed in both the central nervous system and the gastrointestinal tract, regulate the feeding behavior. In the first set of experiments, we investigated the effects of galanin and enterostatin, injected into the third ventricle, on food intake, gastric emptying, and the sympathetic activity of nerves innervating interscapular brown adipose tissue in rats. Galanin dose-dependently increased the intake of a high-fat diet after overnight starvation, but it did not affect low-fat diet intake. In contrast, enterostatin suppressed the intake of the high-fat diet, while intake of the low-fat diet was not affected. Galanin significantly and dose-dependently suppressed gastric emptying rate. However, gastric emptying showed no response to enterostatin. Galanin produced a dose-dependent suppression of sympathetic firing rate. In rats fed a high-fat diet, the injection of enterostatin showed a dose-dependent increase in firing rate. In contrast, animals fed a chow diet showed almost no response. In the second set of experiments, we investigated the role of the hepatic vagus nerve in modulating the peripheral response to enterostatin in rats. Intraperitoneal (i.p.) enterostatin reduced the intake of a high-fat diet. Immunohistochemical identification indicated that the Fos protein was present in the nucleus tractus solitarius, and parabrachial, paraventricular, and supraoptic nuclei after IP enterostatin. These responses to i.p. enterostatin were blocked by hepatic vagotomy. These results suggest that galanin and enterostatin coordinate to regulate feeding behavior, gastric emptying, and sympathetic activity to interscapular brown adipose tissue via central and peripheral sites of action, one of which was the interaction which was found to exist through the vagal system.

Background: Recent studies have shown that the number of patients with reflux esophagitis is increasing in Japan, but the prevalence and risk factors associated with reflux esophagitis in Japanese patients are not well defined. Methods: By using all endoscopic records in the Katta General Hospital from April through to September 1999, we identified 392 patients. We examined the Los Angeles classification, peptic ulcer, gastric mucosal atrophy, hiatal hernia and other medical variable factors for their contribution to esophagitis in the patients. Results: Patients (13.8%) were diagnosed as having reflux esophagitis with a mucosal break. In a multivariate analysis, reflux esophagitis was associated with hiatal hernia (odds ratio (OR) 2.276, 95% confidence interval (CI) 1.164–4.450), with patients over 65 years of age (OR 2.521, 95% CI 1.238–5.134) and the open type of gastric mucosal atrophy (OR 0.420, 95% CI 0.225–0.785). There was no significant difference between esophagitis and Helicobacter pylori infection and peptic ulcer. Conclusions: We observed that age, hiatal hernia and a lower rate of gastric mucosal atrophy were associated with the proportion of mucosal breaks accompanying esophagitis.

Although dehydroepiandrosterone (DHEA) is recognized as one of the major adrenal androgens, its precise physiological role in the human endocrine system remains to be elucidated. In particular, the effect of DHEA on carcinogenesis has not been fully characterized. We undertook this study to determine whether DHEA has a chemopreventative effect on the precursors of colon cancer in a murine model of azoxymethane (AOM)-induced aberrant crypt foci (ACF). The number of ACF was significantly decreased in mice treated with 0.4% (p < 0.001) and 0.8 % DHEA (p < 0.001), but there were no significant differences between DHEA-treated and control mice in terms of the ACF size, β-catenin expression or level of dysplasia. This is the first study of colon cancer carcinogenesis demonstrating that DHEA treatment can decrease the number of ACF without apparently modifying their malignant potential. These data strongly suggest that DHEA might be a potential chemopreventative agent against human colon cancer.

Natural immunomodulator lactoferrin is known to exert an anti-inflammatory effect. However, there have been no studies that examine the mode of action of lactoferrin in reducing intestinal damage. We investigated the effect of lactoferrin on a trinitrobenzenesulfonic acid (TNBS)-induced colitis model in rats. Bovine lactoferrin was given once daily through gavage, starting 3 days before (preventive mode) or just after TNBS administration (treatment mode) until death. The distal colon was removed to be examined. Colitis was attenuated by lactoferrin via both modes in a dose-dependent manner, as reflected by improvement in macroscopic and histological scores and myeloperoxidase activity. Lactoferrin caused significant induction of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, significant reductions in the proinflammatory cytokines tumor necrosis factor-α and IL-1β, and downregulation of the nuclear factor-κB pathway. We concluded that lactoferrin exerts a protective effect against colitis in rats via modulation of the immune system and correction of cytokine imbalance. Lactoferrin has potential as a new therapeutic agent for inflammatory bowel disease.