Sawako Okada

Efficacy of sitafloxacin-based rescue therapy for Helicobacter pylori after failures of first- and second-line therapies

ABSTRACT Sitafloxacin-based triple therapy achieved 83.6% (per-protocol) and 78.2% (intention-to-treat) success in eradicating Helicobacter pylori among 78 Japanese patients after clarithromycin-based first-line and metronidazole-based second-line triple therapies failed. Eradication succeeded in 32 out of 43 patients, even with gyrA mutation-positive Helicobacter pylori (per protocol). The position of the gyrA mutation (N87 or D91) was determined to be a better marker than MIC levels for predicting outcomes of sitafloxacin-based treatment.

High frequency of overlap between functional dyspepsia and overactive bladder

Background  Overactive bladder syndrome (OAB) is defined as a symptom complex comprising urgency, with or without urge incontinence, and usually frequency and nocturia. The association between irritable bowel syndrome (IBS) and bladder symptoms has been reported. This study is designed to investigate whether functional dyspepsia (FD), like IBS, is associated with OAB.

Validation of the gerdQ questionnaire for the management of gastro-oesophageal reflux disease in Japan

Background The GerdQ scoring system may be a useful tool for managing gastro-oesophageal reflux disease. However, GerdQ has not been fully validated in Asian countries. Objective To validate the Japanese version of GerdQ and to compare this version to the Carlsson-Dent questionnaire (CDQ) in both general and hospital-based populations. Methods The questionnaires, including the Japanese versions of GerdQ and CDQ, and questions designed to collect demographic information, were sent to a general population via the web, and to a hospital-based population via conventional mail. The optimal cutoff GerdQ score and the differences in the characteristics between GerdQ and CDQ were assessed. Results The answers from 863 web-responders and 303 conventional-mail responders were analysed. When a GerdQ cutoff score was set at 8, GerdQ significantly predicted the presence of reflux oesophagitis. Although the GerdQ scores were correlated with the CDQ scores, the concordance rates were poor. Multivariate analysis results indicated that, the additional use of over-the-counter medications was associated with GerdQ score ≥ 8, but not with CDQ score ≥ 6. Conclusions The GerdQ cutoff score of 8 was appropriate for the Japanese population. Compared with CDQ, GerdQ was more useful for evaluating treatment efficacy and detecting patients’ unmet medical needs.

Proton-pump inhibitors for the treatment of functional dyspepsia

In the Rome III classification, functional dyspepsia (FD) has been further subcategorized into two different syndromes, namely, epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). Acid-related pathophysiology seems to be mainly responsible for EPS, and antisecretory agents such as proton-pump inhibitors (PPIs) seem to be effective mainly against EPS. However, recent information as to the relationship between initial duodenal acid sensitization in the early postprandial phase and delayed gastric emptying in the later postprandial phase would suggest the amelioration of PDS by antisecretory agents. In the present review, we summarized the recent literature on the direct and indirect effect of PPIs in FD (including not only Rome III, but also Rome II criteria). The effects of PPIs against FD are heterogeneous, depending on the protocol of the clinical studies, and the inclusion criteria of each randomized controlled trial (primary care or tertiary care population). As the placebo effects cannot be ignored in this disease, a placebo-controlled study would be necessary, at least for the evaluation of the effect of each agent on symptom relief in patients with FD. Further studies directly comparing PPIs with suitable placebos in terms of their effects in reducing the symptoms of endoscopically confirmed, Rome III-based FD are awaited.

Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy

The relationship between Helicobacter pylori (H. pylori) eradication therapy and the risk of developing gastroesophageal reflux disease (GERD) is controversial. We investigated the influence of H. pylori eradication on the risk of GERD by focusing on the quality of life (QOL) and evaluating reflux symptoms. Patients with H. pylori infection were administered triple therapy for H. pylori eradication. At 3 months and 1 year after the eradication therapy, surveys were conducted to determine the health-related QOL by quality of life in reflux and dyspepsia-Japanese version, (QOLRAD-J) and the severity of GERD symptoms by Carlsson-Dent questionnaire (CDQ). Forty patients were included in the analysis. Although no significant changes of these scores were apparent 3 months after H. pylori eradication, the QOLRAD-J and CDQ scores were significantly improved after 1 year. The degree of improvement was even more marked in cases with initially low scores. In conclusion, improved GERD-related QOL and reflux symptoms were noted 1 year after H. pylori eradication therapy. In addition, the degree of improvement was more marked in cases with severe reflux symptoms.

Role of enhanced visibility in evaluating polyposis syndromes using a newly developed contrast image capsule endoscope.

Background/Aims A flexible spectral imaging color enhancement system was installed in new capsule software for video capsule endoscopy. Contrast image capsule endoscopy (CICE) is a novel technology using light-emitting diodes selected for the main absorption range of hemoglobin. We assessed the feasibility and diagnostic effi cacy for small bowel surveillance in patients with polyposis syndromes. Methods Six patients with polyposis syndromes, four with familial adenomatous polyposis and one each with Cowden syndrome (CS) and Cronkhite-Canada syndrome (CCS) were examined using CICE. We conducted three evaluations to assess the effect on the numbers of the detected polyps; compare polyp diagnostic rates between adenoma and hamartoma; and assess polyp visibility. Results The numbers of detected polyps and diagnostic accuracy did not differ signifi cantly between pre-contrast and contrast images. However, 50% of the adenomatous polyps displayed enhanced visibility on contrast images. CICE contrast images exhibited clearly demarcated lesions and improved the visibility of minute structures of adenomatous polyps. Hamartomatous polyp micro-structures in patients with CS and CCS were more clearly visualized on contrast than pre-contrast images. Conclusions CICE is an effective tool for enhancing the visibility of polyps in patients with polyposis syndrome.

Biliary Findings Assist in Predicting Enlargement of Intraductal Papillary Mucinous Neoplasms of the Pancreas

BACKGROUND & AIMS There is controversy over the optimal management strategy for patients with branch-duct type intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs), precursors to pancreatic cancer. We aimed to identify factors associated with the presence of BD-IPMNs and changes in their diameter. METHODS Two separate analyses were conducted in a cohort of patients who underwent magnetic resonance cholangiopancreatography (MRCP) in a single year (2006). MRCP findings and clinical outcomes of these patients were followed for a maximum of 6 years. We evaluated initial MRCP findings and demographics associated with the presence of BD-IPMNs at baseline and increase in BD-IPMN diameter over time. RESULTS During the follow-up period, 154 patients developed BD-IPMN and 322 patients did not. Older age, diabetes mellitus, gallbladder adenomyomatosis, and absence of gallstones were associated with the presence of BD-IPMNs at baseline. Increases in diameter of BD-IPMNs were associated with 3 baseline factors: BD-IPMN diameter greater than 17 mm, gallbladder adenomyomatosis, and a common bile duct diameter less than 5.5 mm. Patients with BD-IPMNs could be stratified into 4 groups with varying risk for the enlargement of BD-IPMNs over time: those with 3 risk factors (hazard ratio [HR], 11.4; 95% confidence interval [CI], 3.4-37.8), 2 risk factors (HR, 4.7; 95% CI, 1.7-12.8), or 1 risk factor (HR, 3.1; 95% CI, 1.2-8.2) compared with those without risk factors. CONCLUSIONS For patients with BD-IPMNs, careful follow-up evaluation is particularly important for those with BD-IPMN >17 mm in size, common bile duct diameter <5.5 mm, or gallbladder adenomyomatosis.

Sa1933 Overexpression of CD44v9 in Gastric Cancer Cells Confers Resistance to Trastuzumab by Inducing Antioxidant Enzymes That Inhibit Tumor Cell Death Induced by Oxidative Stress

Background and aim: Aberrant DNA methylation plays critical roles in the development of colorectal cancers (CRCs). Laterally spreading tumors (LSTs) are generally defined as lesions greater than 10 mm in diameter with a low vertical axis that extend laterally along the luminal wall. Those flat lesions are thought to be less invasive because they are likely to be found in the adenoma stage or intramucosal CRCs. On the other hand, a subset of CRCs are known to develop from nonpolypoid lesions and the nonpolypoid submucosal invasive CRCs were smaller than did the polypoid cancers. We aimed to identify DNA methylation changes, which are associated with growth pattern and invasiveness of colorectal tumors. Methods: Methylated CpG island amplification coupled with CpG island microarray (MCAM) analysis was carried out to screen for differentially methylated genes between large (≥20 mm in diameter) noninvasive tumors (NTs) and small (<20 mm in diameter) invasive tumors (ITs). Bisulfite pyrosequencing was used to analyze methylation of the NTSR1 gene. Colony formation assay, MTT assay and Matrigel invasion assays were carried out to analyze the function of NTSR1. Results: MCAM analysis in large NTs (n = 3) and small ITs (n = 3) identified elevated levels of methylation of NTSR1 in large ITs. Quantitative bisulfite pyrosequencing analysis in a large set of clinical samples (large IT, n = 78; small IT, n = 13; large NT, n = 28; small NT, n = 96; normal colon, n= 66) revealed that NTSR1

Sa1900 CD44v9 Results in Resistance to Trastuzumab via Induction of ROS Resistance

Background: Twenty percent of advanced gastric cancers are HER2-positive. Trastuzumab(Tmab), a monoclonal antibody that interferes with the HER2 receptor, combined with cisplatin and a fluoropyrimidine has been shown to increase survival in HER2-positive gastric cancer. Tmab induces reactive oxygen species (ROS) in lung adenocarcinoma in vitro, and may have similar effects in other cancer types as well. CD44 variant 9 (CD44v9) expression is associated with a poor prognosis in gastric adenocarcinomas. The CD44v9 isoform interacts with and stabilizes xCT, a glutamate-cystine transporter, resulting in increased intracellular levels of reduced glutathione (GSH), and increased defense against ROS. The relationship between CD44v9 expression and HER2 status in the response of gastric cancer to various treatments, including Tmab has not been reported. The present study was conducted to investigate the role of CD44v9 in the effectiveness of Tmab treatment on gastric adenocarcinomas. We hypothesize that CD44v9 causes resistance to Tmab via induction of ROS resistance, and targeting CD44v9 may increase effectiveness of Tmab therapy. Methods: NCI-N87(high HER2), a gastric cancer cell line, was used for this study. Anti-HER2 siRNA was used to knockdown HER2 expression in NCI-N87 cells. The pRc/CMV expressing plasmid encoding human CD44v9 was transfected into NCI-N87 cells (CD44v9-NCI-N87). N-acetyl cysteine (NAC) (15mM) was used as a ROS scavenger for 72h in vitro. Cells were incubated for 72h with different concentrations of Tmab (a range of doses between 0, 10, 50 μg/ml), and cell viability was determined by MTS assay. Intracellular GSH levels were measured by luminescent based assay. Intracellular ROS were measured by flow cytometry with CM-H2DCFDA. Cells were cultured for 24h with different concentrations of Tmab (a range of doses between 0, 40, 80, 120, 200 μg/ml) in this assay. Results: Tmab caused a dose-dependent decrease in cell viability in NCI-N87 cells(10μg/ml 88.2%(p=0.015), 50μg/ml 73.3%(p<0.001)), but did not in anti-HER2 siRNA treated NCI-N87(10μg/ml 99.0%(p=0.879), 50μg/ml 93.0%(p= 0.495) and CD44v9-NCI-N87(10μg/ml 104.4%(p=0.442), 50μg/ml 97.3%(p=0.623)). Tmab increased intracellular ROS level in NCI-N87 cells (p=0.007), but did not in anti-HER2 siRNA treated NCI-N87 and CD44v9-NCI-N87. Intracellular GSH levels were significantly higher in CD44v9-NCI N87 than NCI-N87 (p=0.004). NAC decreased Tmab-induced cell death in NCI-N87. These data indicated that CD44v9 is associated with increased intracellular GSH level, and may protect against Tmab induced ROS damage and cell death. Conclusion: Knock down of CD44v9 expression in HER2 positive gastric cells restores Tmab sensitivity through the restoration of ROS mediated cell death.

66 Neural Stem Cell Transplantation Restored the Delayed Gastric Emptying in Apolipoprotein E-Knockout Mice

Background. Although the pathogenesis of delayed gastric emptying, namely gastroparesis, is still unclear, diabetes mellitus is major etiology of gastroparesis. Decreased neuronal nitric oxide synthase (nNOS), which induces relaxation of gastric smooth muscle through the production of nitric oxide, is supposed to be one of the mechanisms of gastroparesis (Gastroenterology 113:1535, 1997). However, the effective treatment for gastroparesis has not been developed. While dyslipidemia is a risk factor of diabetic neuropathy, the defect of apolipoprotein E (apoE), a lipid transporter secreted from glial cell, decreased the expression of nNOS in the stomach (Dig Dis Sci. 57:1504, 2012). Furthermore, transplantion of neural stem cell into gastric antral wall was reported to improve delayed gastric emptying in nNOS knockout mouse (Gastroenterology 129:1817, 2005). The aim of the present study is to explore the role of apoE on gastric emptying and evaluate the effect of neural stem cell transplantation against the model of gastroparesis. Methods. The model of type2 diabetes, db/db mice, and apoE knockout mice, which is the model of arteriosclerosis and hyperlipidemia, were used. For measurement of gastric emptying, 0.48 mg of 13C-acetic acid with 0.15 ml liquid meal (Lacol®) was orally administered. The gastric half emptying time (t1/2) measured by 13C breath test was used for evaluation. The expression levels of nNOS, pan-neuronal marker, PGP 9.5, glial fibrillary acidic protein (GFAP), and glia derived neurotrophic factor (GDNF) were examined by immunohistochemistry andWestern blotting. Neural stem cells were isolated from ffLuc-transgenic mouse, which fluorescent protein, venus, and luciferase gene was fused (BBRC 419; 188, 2012). After tertiary neurosphere was formed, it was injected into gastric antral wall by glass needle. Results. Delayed gastric emptying was observed in 27% of db/db mice, while the levels of blood glucose and body weight were not significantly different. The expression of nNOS in gastric antrum and serum level of apoE were significantly decreased in db/db mice which presented delayed gastric emptying. In apoE knockout mice, the gastric emptying was also delayed compared with control. Although, the expression of PGP 9.5 was not changed, the expression of nNOS was significantly decreased in apoE knockout mice. Furthermore, the expression levels of GFAP and GDNF were significantly decreased in apoE knockout mice. Transplantation of neural stem cell significantly improved the delayed gastric emptying in apoE knockout mice. Conclusion. Neural stem cell transplantation restored the delayed gastric emptying in apoE knockout mice, suggesting a promising application of regenerative therapy against gastroparesis.