Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy.

BACKGROUND: A study reported that rebamipide was effective at reducing short-term nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. The purpose of this study was to re-evaluate the effect of the co-administration of rebamipide on small intestinal injuries induced by short-term NSAID treatment. METHODS: Eighty healthy male volunteers were randomly assigned to two study groups: a control group (N = 40), which received NSAID (diclofenac sodium, 75 mg/day) and omeprazole (20 mg/day) treatment along with a placebo; and a rebamipide group, which received NSAID, omeprazole and rebamipide (300 mg/day). Small intestinal injuries (mucosal breaks plus denuded areas) were evaluated by capsule endoscopy before and after 14 days of treatment. RESULTS: A total of 38 control subjects and 34 rebamipide subjects completed the treatment and were evaluated by capsule endoscopy. NSAID therapy increased the mean number of mucosal injuries per subject from a basal level of 0.1 ± 0.3 to 16 ± 71 and 4.2 ± 7.8 in the control and rebamipide groups, respectively, but the difference was not significant. The difference in the percentage of subjects with at least one mucosal injury post-treatment was also not significant (control 63%; rebamipide 47%). Limiting our analysis to subjects with mucosal injuries, rebamipide co-treatment had the tendency to reduce the mean number of mucosal injuries per subject from 25 in the control group to 8.9 in the rebamipide group (multiple comparisons test; p = 0.088, Mann-Whitney U test; p = 0.038). CONCLUSIONS: Rebamipide co-therapy had the potential to reduce the intensity of small intestinal injury induced by 2-week administration of diclofenac.

[Carcinoma of the small intestine diagnosed by double balloon endoscopy].

There are no specific symptoms of patients with carcinoma of the small intestine. Therefore, it is difficult to diagnose in the early stage by imaging modalities such as radiological enteroclysis, computed tomography, and classical endoscopy. However, double balloon endoscopy makes it possible to diagnose the carcinoma of the entire small bowel by taking tissue samples for pathological assessment. The characteristic of endoscopic findings is irregular ulcerated tumor with malignant stricture. It is still difficult to find carcinoma of small intestine in patients without symptoms and most cases are advanced when diagnosis is achieved. We should try to diagnose in early stage by combining images modalities, capsule endoscopy and double balloon endoscopy safely and efficiently, resulting in improving the patients' prognosis.

Prevention of traditional NSAID-induced small intestinal injury: recent preliminary studies using capsule endoscopy.

Capsule endoscopy and balloon endoscopy, advanced modalities that now allow for full investigation of the entire small intestine, have revealed that non-steroidal anti-inflammatory drugs (NSAIDs) can cause a variety of abnormalities in the small intestine. Traditional NSAIDs can induce small intestinal injuries in over 50% of patients. Several studies have shown that the preventive effect of proton pump inhibitors does not extend to the small intestine, suggesting that concomitant therapy may be required to prevent small intestinal side effects associated with traditional NSAIDs use. Recently, several randomized controlled trials used capsule endoscopy to evaluate the preventive effect of certain drugs on NSAID-induced small intestinal injuries. These studies show that misoprostol and rebamipide have a preventive effect for NSAID-induced small intestinal mucosal injuries. However, these studies included only a small series of healthy volunteers and tested short-term NSAID treatment. Therefore, further extensive studies are clearly required to ascertain the beneficial effect of these drugs.

Distribution of small intestinal mucosal injuries as a result of NSAID administration.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce small intestinal mucosal injuries. The concentrations of NSAIDs, bile acids and intestinal flora may differ in the proximal and distal parts of the small intestine. This study aimed to analyse types and distributions of NSAID-induced small intestinal injuries. SUBJECTS AND METHODS: In total 55 healthy male volunteers were examined using baseline capsule endoscopy (CE). Subjects then undertook a 14-day regimen of NSAID medication (diclofenac sodium, 75 mg day(-1)) with proton-pump inhibitors (omeprazole 20 mg day(-1)) as gastroprotection. After 14 days, subjects underwent post-treatment CE and were assessed for three types of small intestinal injuries: denuded areas, erosions and ulcers. The proximal and distal parts of the small intestine were arbitrarily classified according to CE transit time from the duodenal bulb. RESULTS: Baseline CE revealed six mucosal lesions in 6 of 55 subjects (11%), consisting of three denuded areas and three erosions. Post-treatment CE identified 636 lesions in 32 of 53 subjects (60%); including 115 denuded areas in 16 subjects, 498 erosions in 22 subjects and 23 ulcers in 8 subjects. The distribution of small intestinal injuries differed according to type; denuded areas (90%: 103/115) were predominantly located in the proximal part, erosions throughout the small intestine and all ulcers in the distal part. The location of ulcers and denuded areas differed statistically (P < 0.0001). CONCLUSIONS: The impact of short-term NSAID medication on the small intestine differed according to intestinal site, with most denuded areas identified in the proximal part and all ulcers in the distal part.

Heregulin-induced VEGF expression via the ErbB3 signaling pathway in colon cancer.

BACKGROUND/AIMS: Heregulin (HRG/NRG) ligation to erbB3/4 promotes their respective heterodimerization with erbB2, and consequent erbB2 tyrosine phosphorylation. Although HRG has been shown to be expressed in a variety of cancer tissues, its expression and role in colon cancer have yet to be clarified. We therefore examined the link between the expression of these erbB receptors, and the relationship between HRG and vascular endothelial growth factor (VEGF) expression in colon cancer. METHODS: We analyzed the effects of HRG on VEGF secretion in 6 colorectal cancer cell lines by enzyme-linked immunosorbent assay, and HRG-induced p85 subunit of phosphatidylinositol 3-kinase (p85 PI-3K), Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) activation in Caco-2 colon cancer cell lines by Western blot. We also examined HRG and VEGF mRNA expression in 16 colon cancer biopsy samples by real-time PCR. The localization of HRG and VEGF protein expression in colon cancer tissue was detected by immunohistochemistry. RESULTS: Exogenous HRG stimulated VEGF secretion in all cell lines examined, and VEGF mRNA expression in Caco-2 cells. HRG also activated p85 PI-3K, Akt, ERK1/2, and p38 MAPK. VEGF secretion was inhibited by both specific p38 MAPK inhibitor and proteasome inhibitor that inhibit nuclear factor kappa B (NF-kappaB) activation. In colon cancer biopsy samples, HRG mRNA expression correlated with VEGF mRNA expression. HRG immunoreactivity was observed both in cancer cells and in mesenchymal cells in colon cancer tissues. CONCLUSION: These data suggest that HRG might affect colon cancer growth by regulating VEGF secretion via the erbB3 signaling pathway through autocrine and paracrine mechanisms.

Microsomal prostaglandin E synthase protein levels correlate with prognosis in colorectal cancer patients.

The aim of this study is to investigate the expression of three prostaglandin E synthase (PGES) isomers in colorectal cancer (CRC) tissue and to evaluate their relationship to clinicopathological factors and patient prognosis. Microsomal PGES (mPGES)-1, mPGES-2, cytosolic PGES (cPGES) and cyclooxygenase (COX)-2 protein expression were analyzed by real-time polymerase chain reaction and Western blot. The localization of each PGES and COX-2 protein was examined by immunohistochemistry in 155 surgical resections and correlated to clinicopathological factors and patient prognosis. mPGES-1 mRNA and protein levels were significantly higher in CRC than in paired normal tissues. mPGES-1 immunoreactivity localized in cancer cells in 43% of cases. mPGES-2 immunoreactivity was significantly more pronounced in cancer cells than in adjacent normal epithelium in 36% of cases. cPGES immunoreactivity was homogeneous in cancer cells and thus determined constitutive. mPGES-1 and mPGES-2 correlated with significantly worse prognosis in stage I-III patients. These results indicate that mPGES-1 and mPGES-2 may each play a role in CRC progression.

A randomized controlled trial on the efficacy of synbiotic versus probiotic or prebiotic treatment to improve the quality of life in patients with ulcerative colitis.

OBJECTIVE: Studies suggest that synbiotic therapy could prove more effective in the treatment of ulcerative colitis (UC) than therapies limited to probiotics or prebiotics. This study compared the effect of each of these therapies in the treatment of UC. METHODS: One hundred twenty outpatients with UC were randomly sorted into three groups of 40 patients each for probiotic, prebiotic, or synbiotic therapy. The probiotic group ingested one daily capsule consisting of Bifidobacterium longum 2 x 10(9) colony-forming units and the prebiotic group ingested daily 8.0-g doses of psyllium. The synbiotic group underwent both treatments. All patients completed Inflammatory Bowel Disease Questionnaires (IBDQs) at the onset of the trial, at the 2-wk midpoint, and at the 4-wk end of the trial. Blood variables were also evaluated in a subset of 32 patients randomly selected from all groups and values were compared with IBDQ scores. RESULTS: Thirty-one patients in the probiotic group, 31 in the prebiotic group, and 32 in the synbiotic group qualified for analyses. The remaining 26 patients had incomplete questionnaires. Total IBDQ scores improved within groups by the end of the trial (probiotics 162 to 169, NS; prebiotics 174 to 182, NS; synbiotics 168 to 176, P = 0.03). Individual scores improved as follows: probiotics, emotional function (P = 0.03); prebiotics, bowel function (P = 0.04); and synbiotics, systemic and social functions (P = 0.008 and P = 0.02). C-reactive protein decreased significantly only with synbiotic therapy (from 0.59 to 0.14 mg/dL, P = 0.04). There were no adverse events. CONCLUSION: Patients with UC on synbiotic therapy experienced greater quality-of-life changes than patients on probiotic or prebiotic treatment. These data suggest that synbiotic therapy may have a synergistic effect in the treatment of UC.

Prevention of nonsteroidal anti-inflammatory drug-induced small-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluated by capsule endoscopy.

BACKGROUND: There is no known preventive agent against nonsteroidal anti-inflammatory drug (NSAID) induced small-intestinal injury. OBJECTIVE: To evaluate by capsule endoscopy whether coadministration of prostaglandin (PG) can prevent small-intestinal damage induced by short-term NSAID treatment. DESIGN: Single-blind, randomized, controlled trial. SETTING: All procedures were performed at Nippon Medical School. SUBJECTS: Thirty-four healthy male volunteers. METHODS: All subjects were randomly assigned to 2 groups: an NSAID-control group, who underwent NSAID (diclofenac sodium, 25 mg 3 times daily) and omeprazole (20 mg once daily) treatment, and an NSAID-PG group, who received PG (misoprostol, 200 microg 3 times daily) in addition to the same NSAID-omeprazole treatment. Eligible subjects, 15 per group, underwent capsule endoscopy before and 14 days after treatment. MAIN OUTCOME MEASUREMENTS: The number of mucosal breaks at capsule endoscopy. RESULTS: NSAID treatment significantly increased the mean (SD) number of mucosal breaks per subject, from a basal level of 0.1 +/- 0.3 up to 2.9 +/- 6.3 lesions in the NSAID-control group (P = .012). In contrast, there was no significant change in the mean number of mucosal breaks before and after PG cotreatment (P = 0.42). Thus, the mean number of posttreatment mucosal breaks per subject was significantly higher in the NSAID-control group than in the NSAID-PG group (P = .028). There was a significant increase in the percentage of subjects in the NSAID-control group, with at least 1 mucosal break after treatment (from 6.7% to 53.3%), whereas there was no change in the incidence of mucosal breaks in the NSAID-PG group, which remained at 13.3%. (P = .002). LIMITATIONS: Single-center, open-label study. CONCLUSIONS: PG cotherapy reduced the incidence of small-intestinal lesions induced by a 2-week administration of diclofenac sodium.

[Primary small intestinal malignant tumors].

Small intestinal primary adenocarcinomas, carcinoids, gastrointestinal stromal tumors (GISTs) were cleared up inadequately because it was hard to examine for small intestine by modalities in the 20th century. Obscure gastrointestinal bleeding (OGIB) is often caused by these tumors. In future, these tumors will be more diagnosed in patients with OGIB by new modalities such as capsule endoscopy and double balloon endoscopy. We attempt to present these small intestinal malignant tumors using by capsule endoscopy and double balloon endoscopy.

Diagnostic yield of double-balloon endoscopy in patients with obscure GI bleeding.

BACKGROUND: Double-balloon endoscopy (DBE) is a new method that allows visualization, tissue sampling, and therapeutic intervention of a variety of pathologies throughout the small-intestinal tract. OBJECTIVE: In the present study, we evaluated the diagnostic yield of DBE and its impact on the final diagnosis, treatment, and clinical outcome of patients with obscure GI bleeding (OGIB). DESIGN AND SETTING: A hospital-based cross-sectional, follow-up study. PATIENTS: We studied 108 consecutive patients (66 men and 42 women) referred to our hospital from July 2003 to February 2007 for the evaluation of OGIB: 13 patients with overt-ongoing bleeding, 76 with overt-previous bleeding, and 19 with occult OGIB. MAIN OUTCOME MEASUREMENTS: Diagnostic yield, a final diagnosis, treatment, and clinical outcome were all analyzed in each group. RESULTS: DBE diagnostic rates for patients with overt-ongoing, overt-previous, and occult bleeding were 100.0%, 48.4% and 42.1%, respectively. The difference in diagnostic yields between the overt-ongoing group and the 2 other groups was statistically significant (P < .005). The most common sources of bleeding were ulcers and tumor lesions. Small-intestinal lesions were identified in 52 of 108 patients; of which 36 patients (69.2%) were biopsied and 49 patients (94.2%) received treatment. Eight patients (7.4%) had recurrent bleeding during the mean follow-up period of 28.5 months. Sensitivity, specificity, and positive and negative predictive values of DBE in the diagnoses of small-intestinal lesions in patients with OGIB were 92.7%, 96.4%, 98.1%, and 87.1%, respectively. No serious complications were encountered. CONCLUSIONS: DBE was proven to be a very useful diagnostic tool and had a therapeutic impact in the majority of patients with OGIB. The best candidates for the procedure were patients with overt-ongoing bleeding.

High dose probiotic and prebiotic cotherapy for remission induction of active Crohn's disease.

BACKGROUND: Clinical trials of probiotic treatment for Crohn's disease (CD) have yielded conflicting results. This study assessed the clinical usefulness of combined probiotic and prebiotic therapy in the treatment of active CD. METHOD: Ten active CD outpatients without history of operation for CD were enrolled. Their mean (+/-SD) age was 27 +/- 7 years and the main symptoms presented were diarrhea and abdominal pain. Patients' initial therapeutic regimen of aminosalicylates and prednisolone failed to achieve remission. Patients were thus initiated on a synbiotic therapy, consisting of both probiotics (75 billion colony forming units [CFU] daily) and prebiotics (psyllium 9.9 g daily). Probiotics mainly comprised Bifidobacterium and Lactobacillus. Patients were free to adjust their intake of probiotics or prebiotics throughout the trial. Crohn's disease activity index (CDAI), International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score and blood sample variables were evaluated and compared before and after the trial. RESULTS: The duration of the trial was 13.0 +/- 4.5 months. By the end of therapy, each patient had taken a 45 +/- 24 billion CFU daily probiotic dose, with six patients taking an additional 7.9 +/- 3.6 g daily psyllium dose. Seven patients had improved clinical symptoms following combined probiotic and prebiotic therapy. Both CDAI and IOIBD scores were significantly reduced after therapy (255-136, P = 0.009; 3.5-2.1, P = 0.03, respectively). Six patients had a complete response, one had a partial response, and three were non-responders. Two patients were able to discontinue their prednisolone therapy, while four patients decreased their intake. There were no adverse events. CONCLUSION: High-dose probiotic and prebiotic cotherapy can be safely and effectively used for the treatment of active CD.

Helicobacter pylori infection increases the risk of colorectal adenoma and adenocarcinoma, especially in women.

BACKGROUND: Recent reports suggest that Helicobacter pylori infection can potentially increase the risk of colorectal cancer. The purpose of this study was to assess the association between H. pylori infection and the risk of colorectal adenoma and adenocarcinoma, and to evaluate any differences on the basis of sex. METHODS: The subjects were 669 (40- to 80-year-old) patients who underwent both barium enema examination and total colonoscopy, and who were evaluated for H. pylori infection by (13)C-urea breath test, urease test, or histological diagnosis of biopsied gastric specimens. There were 142 H. pylori-negative and 527-positive patients. The odds ratios (ORs) for H. pylori-positive patients with colorectal adenoma and adenocarcinoma, and for tumor patients with either adenoma or adenocarcinoma were calculated. RESULTS: Among the H. pylori-negative patients, there were 52 patients without tumor, 63 with adenoma, 27 with adenocarcinoma, and 90 with tumor. Among the H. pylori-positive patients, there were 136, 264, 127, and 391 patients respectively. Pooling all subjects, those infected with H. pylori had a significantly increased OR for adenoma, adenocarcinoma, or tumor, compared to H. pylori-free patients (OR, 1.60, 1.80, and 1.66, respectively). For female H. pylori-positive subjects, the risk of having adenocarcinoma or tumor was significantly higher than that for their H. pylori-free counterparts, while for male H. pylori-positive and -negative subjects, there was no such significant difference. CONCLUSIONS: The results therefore suggest that, in patients aged 40-80 years, H. pylori infection increased the risk of colorectal adenoma and adenocarcinoma, with significantly higher risks for female patients.

Mean corpuscular volume (MCV) and the risk of colorectal adenoma in menopausal women.

BACKGROUND/AIMS: It has been reported that alcohol intake and folate deficiency are associated with an increased risk of colorectal adenomas and carcinomas. Mean corpuscular volume is increased under these conditions. We have reported that the mean corpuscular volume was higher in patients with adenoma than without adenoma in middle-aged men. The aim of this study was to assess the association between mean corpuscular volume and risk of colorectal adenoma in menopausal women. METHODOLOGY: The subjects were 415 menopausal women who underwent both barium enema examination and total colonoscopy, and their blood samples were analyzed. The subjects were divided into two groups with or without adenoma, and were divided into four groups according to the mean corpuscular volume value. Various variables were compared among the groups, and the odds ratios of adenoma were calculated. RESULTS: The mean corpuscular volume was higher in patients with adenoma than without adenoma (P = 0.002). As for the mean corpuscular volume value, the odds ratio (95% CI) of patients with adenoma was 1.00 (referent); (mean corpuscular volume (fl) < 90), 1.50 (0.93-2.07); (> or = 90 but < 92.5), 1.52 (0.97-2.07); (> or = 92.5 but < 95) and 2.87 (2.25-3.45); (> or = 95). CONCLUSIONS: Mean corpuscular volume > or = 95 may be used as an index of the risk for colorectal adenomas in menopausal women.