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The Japan Gastroenterological Association (JGA) published the first version of clinical guidelines for chronic diarrhea 2023. These guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic diarrhea, and provide flowcharts for the diagnosis and treatment of chronic diarrhea based on the latest evidence. Treatment for chronic diarrhea begins by distinguishing secondary chronic constipation with a clear etiology, such as drug-induced diarrhea, food-induced diarrhea, systemic disease-associated diarrhea, infection-associated diarrhea, organic disease-associated diarrhea, and bile acid diarrhea. The first line of treatment for chronic diarrhea in the narrow sense, defined in these guidelines as functional diarrhea in routine medical care, is lifestyle modification and dietary therapy. The first medicines to be considered for oral treatment are probiotics for regulating the gut microbiome and antidiarrheals. Other medications, such as 5HT3 receptor antagonists, anticholinergics, Kampo medicine, psychotherapy, antibiotics, bulking agents, adrenergic agonists, and somatostatin analogues, lack sufficient evidence for their use, highlighting a challenge for future research. This Clinical Guidelines for Chronic Diarrhea 2023, which provides the best clinical strategies for treating chronic diarrhea in Japan, will also be useful for medical treatment worldwide., (The Author(s). Published by S. Karger AG, Basel.)

In July 2023 the Japan Gastroenterological Association published the first version of its clinical guidelines for chronic constipation 2023. Based on the latest evidence, these guidelines describe the definition, classification, diagnostic criteria, diagnostic testing methods, epidemiology, pathophysiology, and treatment of chronic constipation. They include flowcharts for both diagnosis and treatment of chronic constipation. In the treatment of chronic constipation, the first step involves differentiating between secondary forms, such as organic disease-associated constipation, systemic disease-associated constipation, and drug-induced constipation. The next step is to determine whether the chronic constipation stems from a motility disorder, a form of primary chronic constipation. For functional constipation and constipation-predominant irritable bowel syndrome, treatment should be initiated after evaluating symptoms like reduced frequency of bowel movement frequency type or defecation difficulty type. The first line of treatment includes improvement of lifestyle habits and diet therapy. The first drugs to consider for oral treatment are osmotic laxatives. If these are ineffective, secretagogues and ileal bile acid transporter inhibitors are candidates. However, stimulant laxatives are exclusively designated for as-needed use. Probiotics, bulk-forming laxatives, prokinetics, and Kampo medicine, for which there is insufficient evidence, are considered alternative or complementary therapy. Providing the best clinical strategies for chronic constipation therapy in Japan, these clinical guidelines for chronic constipation 2023 should prove useful for its treatment worldwide., (The Author(s). Published by S. Karger AG, Basel.)

Background: Belching disorders and rumination syndrome (RS) are disorders of gut-brain interaction (DGBIs) in Rome IV. Belching disorders are composed of excessive gastric belching (GB) and supragastric belching (SGB). Excessive GB is related to physiological phenomenon whereas excessive SGB and RS are behavioral disorders., Summary: A recent large internet survey found that prevalence of belching disorders and RS were 1% and 2.8%, respectively. It has been recognized that not a few patients with two behavioral disorders, excessive SGB and RS, could be misdiagnosed as proton pump inhibitors (PPI)-refractory gastroesophageal reflux disease (GERD). In patients with reflux symptoms, distinguishing these conditions is essential because they need psychological treatment (i.e., cognitive behavioral therapy (CBT) rather than acid suppressants. Clinicians should take a medical history meticulously first to identify possible excessive SGB and/or RS. High-resolution impedance manometry and/or 24-h impedance-pH monitoring can offer an objective diagnosis of the disorders. Several therapeutic options are available for excessive SGB and RS. The first-line therapy should be CBT using diaphragmatic breathing that can stop the behaviors involving complex muscle contraction (e.g., abdominal straining) to generate SGB or rumination. Overlap with eating disorders and/or other DGBIs such as functional dyspepsia can make management of the behavioral disorders challenging since such coexisting conditions often require additional treatments., Key Messages: Excessive SGB and RS are not unusual conditions. It is important to raise awareness of the behavioral disorders for appropriate management., (© 2023 S. Karger AG, Basel.)

Introduction: Frailty is a crucial health issue among older adults. Growth differentiation factor 15 (GDF15) is associated with inflammation, oxidative stress, insulin resistance, and mitochondrial dysfunction, which are possible pathogeneses of frailty. However, few longitudinal studies have investigated the association between GDF15 and the incidence of frailty. Therefore, we investigated whether high serum GDF15 levels are associated with the incidence of frailty., Methods: A total of 175 older adults (mean age: 77 ± 6 years; 63% women) with cardiometabolic diseases and no frailty out of the two criteria at baseline participated. Individuals with severe renal impairment or severe cognitive impairment were excluded. Serum GDF15 levels were measured at baseline. Patients were asked to assess frailty status at baseline and annually during follow-up using the modified version of the Cardiovascular Health Study (mCHS) and the Kihon Checklist (KCL). We examined the association between GDF15 tertiles and each frailty measure during follow-up (median 38-39 months). In the multivariate Cox regression analysis, with the GDF15 tertile groups as the explanatory variables, hazard ratios (HRs) and 95% confidence intervals (CIs) for incident frailty were calculated after adjusting for covariates and using the lowest tertile group as the reference., Results: During the follow-up period, 25.6% and 34.0% of patients developed frailty, as defined by the mCHS and KCL, respectively. The highest GDF15 tertile group had a significantly higher incidence of mCHS- or KCL-defined frailty than the lowest GDF15 tertile group. Multivariate Cox regression analysis revealed that the adjusted HRs for incident mCHS- and KCL-defined frailty in the highest GDF15 tertile group were 3.9 (95% CI: 1.3-12.0) and 2.7 (95% CI: 1.1-6.9), respectively., Conclusion: High serum GDF15 levels predicted the incidence of frailty among older adults with cardiometabolic diseases and could be an effective marker of the risk for frailty in interventions aimed at preventing frailty, such as exercise and nutrition., (© 2024 S. Karger AG, Basel.)

Introduction: We examined the relationship between previous fluctuations in Mini-Mental State Examination (MMSE) scores, future changes in MMSE scores, and attrition from follow-up surveys, which helps in a more comprehensive interpretation of repeatedly collected MMSE scores., Methods: This 4-year longitudinal study included 2,073 community-dwelling older adults aged ≥65 years in Japan. The MMSE was administered at baseline (T0), 2 years (T1), and 4 years (T2) follow-up. We performed multinomial logistic regression analysis with the dependent variable, indicating the change in MMSE score from T1 to T2 (categorized as increase, no change [reference category], and decrease) and attrition at T2. The independent variables included the change in MMSE scores from T0 to T1 and MMSE scores at T0 and T1., Results: The mean MMSE score was 29 across the three time points. A one-point decrease in MMSE score from T0 to T1 was associated with 79% (95% confidence interval: 1.62, 1.97) higher odds of an increase in MMSE score from T1 to T2 and 28% (1.17, 1.40) higher odds of attrition at T2. A one-point decrement in the MMSE score at T0 and T1 was also associated with an increase in the MMSE score from T1 to T2 and attrition at T2., Conclusion: Focusing on cognitive fluctuation for 2 years, rather than cognitive function at a point in time, would have no remarkable advantage when focusing on future cognitive function and attrition. Our results emphasize the need for further studies to identify factors that distinguish between those who continue to attend follow-up surveys and show improvements in cognitive test scores and those who drop out., (© 2023 S. Karger AG, Basel.)

Introduction: Synovial sarcoma (SS) predominantly affects adolescents and young adults. Doxorubicin with or without ifosfamide therapy is the standard first-line treatment for unresectable or metastatic SS. However, there is no standard second-line chemotherapy regimen. The purpose of the current study was to evaluate the outcomes of second-line chemotherapy for patients with SS., Methods: We retrospectively evaluated the outcomes of 61 patients with unresectable or metastatic SS who had received first-line chemotherapy at our institution between 1997 and 2017. Patients who received second-line chemotherapy were included in the analysis. Outcomes of the chemotherapy were evaluated., Results: Among the 61 patients treated with first-line chemotherapy, we identified 32 patients who received second-line chemotherapy. Most patients (62.5%) were under 40 years of age. Regarding second-line chemotherapy regimens, 6 (18.8%) patients were treated with doxorubicin with/without ifosfamide, 6 (18.8%) with ifosfamide and etoposide, 4 (12.5%) with docetaxel and gemcitabine, 5 (15.6%) with pazopanib, 2 (6.2%) with trabectedin, and 1 (3.1%) with eribulin. The overall response rate according to the Response Evaluation Criteria in Solid Tumors for all patients was 9.4%. Eleven patients (34.3%) achieved disease-control for >6 months. The median follow-up duration was 15.2 months. The 1-year progression-free and overall survival rates were 33.1% and 67.1%, respectively., Conclusion: Our exploratory study revealed that the response rate of second-line chemotherapy regimens for patients with SS was 9.4%. Therefore, there is an urgent need to develop more active therapeutic regimens for SSs., (© 2022 S. Karger AG, Basel.)

Background and Aim: Helicobacter pylori is the leading cause of gastric cancer, but it is still uncertain whether eradicating H. pylori in early gastric cancer (EGC) patients who underwent endoscopic resection can prevent metachronous gastric cancer (MGC). This study aimed to investigate the effect of H. pylori eradication to prevent MGC after endoscopic submucosal dissection (ESD)., Methods: In this propensity-matched retrospective observational study, 770 patients with EGC who received ESD were enrolled. The outcome was the incidence of MGC; this was compared between the persistent and eradicated groups., Results: MGC was detected in 27 patients (7.8%) during a median period of 39.0 months (range 26.0-64.0). After propensity matching, 126 pairs of patients in each group were analyzed. The 5-year cumulative incidence rates of MGC were 13.2 and 3.9% in the persistent and eradicated groups, respectively (p= 0.021, log-rank test). On multivariate analysis, H. pylori eradication prevented MGC significantly (hazard ratio [HR] 0.32; p = 0.029). The results remained robust after inverse probability of treatment weighting analysis (HR 0.30; p = 0.020)., Conclusions: Successful H. pylori eradication could prevent MGC after ESD for EGC., (© 2019 S. Karger AG, Basel.)

Background and Aim: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1β (IL-1β) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis., Methods: Small intestinal mucositis was induced in wild-type, NLRP3-/-, and caspase-1-/- mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1β or IL-18, or neutralizing antibody against IL-1β., Results: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1β and protein expression of cleaved caspase-1 and mature IL-1β. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3-/- mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1β and neutralized by IL-1β antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1β were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells., Conclusions: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1β maturation., (© 2019 S. Karger AG, Basel.)

Introduction: Endoscopic mucosal resection for small superficial nonampullary duodenal epithelial tumors is a noninvasive treatment; however, perforations can occur. Bipolar snares can reduce the risk of perforation due to small tissue damage. Currently, only few studies have reported endoscopic mucosal resection for small superficial nonampullary duodenal epithelial tumors using a bipolar snare and the effect of preoperative findings., Objective: To investigate (1) resectability and adverse events of endoscopic mucosal resection using a bipolar snare for small superficial nonampullary duodenal epithelial tumors and (2) the predictions of piecemeal resection., Methods: Between 2007 and 2017, 89 patients with 107 lesions underwent endoscopic mucosal resection using a bipolar snare. Among them, 88 lesions of 77 patients were evaluated. The primary outcome was the incidence of en bloc resection and R0 resection and adverse events. Risk factors associated with piecemeal resection, including preoperative lesion findings, were also examined., Results: The incidence rates of en bloc and R0 resections were 85.2 and 48.9%, respectively. Neither intraoperative or delayed perforations nor procedure-related mortality was noted. The nonlifting sign after submucosal injection was associated with an increase in piecemeal resection (odds ratio: 20.3, 95% confidence interval: 2.53-162; p = 0.005)., Conclusion: Endoscopic resection for small superficial nonampullary duodenal epithelial tumors can cause perforation; however, endoscopic mucosal resection using a bipolar snare can be a safe treatment option as it does not cause perforations. The nonlifting sign after submucosal injection is a predictive factor for piecemeal resection., (© 2020 S. Karger AG, Basel.)

Background: Patency confirmation is useful for avoiding the retention of capsule endoscopy (CE). We first evaluated the clinical utility of the tag-less PillCamTM Patency Capsule (PPC) for up to 72 h after ingestion prospectively., Methods: Excretion of an intact capsule or intact body within 72 h, or positive PPC image in the colon or negative PPC image by abdominal X-ray at 30 h was defined as confirmed functional patency. In patients with unconfirmed functional patency, balloon-assisted enteroscopy was performed to evaluate the reason., Results: Functional patency was confirmed in 44 of 57 patients. Patency was confirmed in 38 patients (66.7%) at 30 h. In 6 of 19 patients (31.6%) in whom patency was not confirmed at 30 h, patency was confirmed within 72 h and no capsule retention (CR) occurred. The rate of pan-enteroscopy did not differ between patients whose patency was confirmed at 30 h and those whose patency was confirmed within 72 h. Excretion time of the PPC significantly correlated with that of the capsule (r = 0.650). Severe adhesions (>5 cm) interfered with PPC passage in 2 patients, despite the absence of critical stricture. The rate of no CR in patients with functional patency confirmed by prior PPC was 97.7%. Misjudgment of the location of the PPC is a risk for CR., Conclusions: Extending the time to confirm functional patency to 72 h may be acceptable and increase the possibility to perform CE safely in whom CE can perform intrinsically. University Hospital Medical Information Network registration No: 000002564., (© 2019 S. Karger AG, Basel.)

Introduction: Current assays based on the 0-hour/1-hour (0-/1-h) algorithm using high-sensitivity cardiac troponin (hs-cTn) are limited to only Abbott Architect hs-cTnI, Siemens Vista hs-cTnI, and Roche Elecsys hs-cTnT., Objective: This study aimed to evaluate this new hs-cTnI assay, LumipulsePresto hs Troponin I, for diagnosis of acute myocardial infarction (AMI) on admission and on 0-/1-h algorithm to stratify AMI patients precisely., Methods: This prospective cohort study included 442 patients with suspected non-ST-elevation myocardial infarction in three hospitals in Japan and Taiwan from June 2016 to January 2019. We enrolled patients presenting to the emergency department with symptoms suggestive of AMI and collected blood samples on admission and 1 hour later. Two independent cardiologists centrally adjudicated final diagnoses; all clinical information was reviewed twice: first, using serial hs-cTnT (Roche-Elecsys, primary analysis) and Lumipulse Presto Lumipulse Presto, second, using the Lumipulse Presto hs-cTnI measurements. At first, we compared diagnostic accuracy quantified using receiver operating characteristic (ROC) curves for AMI. Then, we evaluated major adverse cardiovascular events (cardiac death, AMI) in the rule-out group according to a 0-hour/1-hour algorithm at the 30-day follow-up., Results: Diagnostic accuracy at presentation by the ROC curve for AMI was very high and similar for the LumipulsePresto hs-cTnI and hs-cTnT,(area under the curve [AUC]: LumipulsePresto hs-cTnI, 0.89, 95% confidence interval [CI] 0.86-0.93; hs-cTnT, 0.89, 95% CI 0.85-0.93; p = 0.82). In early presenters, the LumipulsePresto hs-cTnI appeared to maintain the diagnostic performance of hs-cTn for patients with <3 h (AUC: LumipulsePresto hs-cTnI, 0.87, 95% CI 0.81-0.92; hs-cTnT, 0.86, 95% CI 0.80-0.92; p = 0.81). The algorithm using the LumipulsePresto hs-cTnI ruled out AMI in 200 patients with negative predictive value and sensitivity of 100% (95% CI 97.3%-100%) and 100% (95% CI 92.7%-100%), respectively, in the rule-out group., Conclusion: Diagnostic accuracy and clinical utility of the novel LumipulsePresto hs-cTnI assay are high and comparable with the established hs-cTn assays., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT)., Objectives and Method: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria., Results: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant., Conclusions: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs., (© 2019 S. Karger AG, Basel.)

Introduction: Carcinosarcoma is a rare cancer, and its prognosis is poor. There are few reports on the prognostic factors of patients with carcinosarcoma who receive second-line chemotherapy., Objective: To investigate the outcome and prognostic factors of patients who received second-line chemotherapy for gynecologic carcinosarcoma., Methods: We retrospectively investigated patients with ovarian or uterine carcinosarcoma, who were treated at two institutions from July 2006 to March 2018. All patients who had received second-line chemotherapy for advanced or recurrent disease were eligible. The efficacy of second-line chemotherapy and prognostic factors were evaluated., Results: Forty-six patients were eligible. Combination chemotherapy was used in approximately half (52.2%) of the patients. The response rate and disease control rate of second-line chemotherapy were 32.6 and 60.9%, respectively. The median follow-up period was 11.0 (range, 8.8-107.5) months. The median progression-free survival and overall survival were 6.3 (95% CI, 3.2-7.5) months and 12.9 (95% CI, 7.8-16.0) months, respectively. In the multivariate analysis of overall survival, a treatment-free interval >180 days was a significant good prognostic factor. The median overall survival was 7.8 (95% CI, 5.1-10.5) months in the <180 days group and 16.4 (95% CI, 13.1-130.6) months in the >180 days group (p = 0.0052; hazard ratio, 0.26; 95% CI, 0.10-0.66), respectively., Conclusion: The outcome of gynecologic carcinosarcoma in the second-line setting is poor, especially in patients with a short treatment-free interval., (© 2020 S. Karger AG, Basel.)

Background/aims: Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal reflux. Recently, an EP1 receptor antagonist, ONO-8539, showed the reduction of TLESRs in monkeys. However, its effect on TLESRs in humans remains unclear. This study investigated the effect of ONO-8539 on postprandial TLESRs in healthy male subjects., Methods: Twenty-seven subjects participated in this placebo-controlled, cross-over study. The subjects received either placebo or ONO-8539 (450 mg) after a standardized breakfast. A 30-min basal recording was performed 4 h after drug administration. Subsequently, TLESR recordings were performed after a high-fat test meal for 3 h. The examination was repeated at least 7 days from the first evaluation for washout., Results: Thirteen patients were ultimately analyzed. The basal lower esophageal sphincter pressure was not different between the 2 groups (16.3 and 18.0 mm Hg for placebo and ONO-8539, respectively; p = 0.88). ONO-8539 significantly reduced the number of TLESRs from 15.0 to 12.0 for 3 h (p < 0.05). The proportion of terminating events of TLESRs was significantly different between the 2 groups (p < 0.05). No events and swallowing terminated more TLESRs with ONO-8539 than with placebo., Conclusions: ONO-8539 suppressed TLESRs mildly. EP1 receptor may be involved with the mechanism of human TLESRs., (© 2019 S. Karger AG, Basel.)

Background: Serum albumin and hemoglobin levels are independently associated with subsequent cognitive deterioration in older adults. This prospective study used repeated measures analysis to identify aging trajectories in serum albumin and hemoglobin levels and investigated if these trajectories were associated with incident disabling dementia among community-dwelling older Japanese., Methods: A total of 2,005 adults aged 65-90 years participated in annual geriatric health assessments during the period from June 2002 through July 2017; the total number of observations was 9,330. A review of a municipal database of the Japanese public long-term care insurance system identified 1,999 of 2,005 adults without dementia at baseline, 278 (13.9%) of whom developed disabling dementia during the follow-up period (June 2002 through December 2017)., Results: We identified three trajectory patterns (high, moderate, and low) for serum albumin and hemoglobin levels for the age period 65 through 90 years. After controlling for potential confounders, participants with moderate and low trajectories for serum albumin level had hazard ratios of 1.27 (95% confidence interval 0.94-1.72) and 2.07 (1.37-3.11), respectively, for the development of incident disabling dementia, with the high trajectory group as reference. The respective hazard ratios for hemoglobin level were 1.31 (0.93-1.85) and 1.58 (1.04-2.40), respectively., Conclusion: Dementia risk was higher for individuals with low trajectories for serum albumin and hemoglobin levels. This finding highlights the importance of interventions that improve nutritional status and control relevant diseases in middle-aged and older adults with low serum albumin and hemoglobin levels., (© 2019 S. Karger AG, Basel.)

Objective: Recent guidelines propose that both proton pump inhibitor (PPI) responders and nonresponders are included in eosinophilic esophagitis (EoE). Although multiple biopsies should be required to diagnose EoE because of patchy distribution of esophageal eosinophils, it is unclear whether multiple biopsies are required to evaluate histological effectiveness of PPI therapy. This study aimed to determine the optimal biopsy protocol after PPI therapy in patients with EoE., Methods: Of 110 EoE patients, 22 PPI nonresponders were enrolled. Intraepithelial eosinophils were counted in areas of high density in multiple biopsy specimens after PPI therapy. The prevalence of esophageal eosinophilia and peak eosinophil counts after PPI therapy was analyzed according to the biopsy sites and endoscopic findings. Positive predictive value (PPV) was calculated according to the number of biopsies., Results: Of 124 biopsies, 59 (47.6%) specimens showed esophageal eosinophilia (≥15 per high-power field). Eosinophil counts were significantly higher in specimens from the lower esophagus than in those from the upper esophagus but not in those from the middle esophagus. Prevalence of esophageal eosinophilia was 76.2, 40.9, and 24.3% in the lower, middle, and upper esophagus respectively. PPI nonresponders were diagnosed in all cases with 4 biopsy specimens obtained from the lower and middle esophagus, showing that PPV for non-effectiveness of PPI therapy was 0.910 (95% CI 0.773-1.000). The prevalence of esophageal eosinophilia and peak eosinophil counts was higher in cases with white plaques and linear furrows., Conclusion: Multiple biopsies should be required to evaluate histological effectiveness of PPI therapy in patients with EoE. Four biopsies from the lower and middle esophagus may be sufficient., (© 2018 S. Karger AG, Basel.)

Background and Objective: Esophagectomy, which is one of the most invasive operations among gastrointestinal surgeries, deteriorates the physical condition of patients. Such deterioration may be severe in elderly patients and advanced age may negatively affect long-term survival. However, elderly patients are more likely to die from cancer-unrelated causes than younger patients. Therefore, when comparing the survival of elderly patients after cancer surgery with that of younger patients, it is necessary to control the influence of cancer-unrelated death. To address this problem, we calculated the relative survival and applied the excess hazard model to control the influence of competing risk of death from cancer., Methods: We retrospectively analyzed 505 patients with thoracic esophageal cancer who underwent transthoracic esophagectomy. Prognostic information was followed up to 10 years after surgery or until death in all patients. Prognostic information of patients lost to follow-up was retrieved from the Osaka Cancer Registry's database. First, we identified prognostic variables as confounders of age by univariate and multivariate analysis. Then, we estimated age effects using the excess hazard model including the prognostic variables as confounders., Results: Univariate and multivariate analysis showed that clinical stage, residual tumor, and postoperative complications (p < 0.1) were confounders of age. Multivariate excess hazard model revealed that age was not a significant prognostic factor at any cutoff point. However, the excess hazard ratio of death tended to increase continuously in patients aged 70 years or older., Conclusions: When clinicians offer esophagectomy for esophageal cancer, age per se should not be a limiting factor. Strict evaluation of patients should be performed before surgery, especially in the elderly., (© 2019 S. Karger AG, Basel.)

Background: Adenocarcinoma of the esophagogastric junction (EGJ) is uncommon in Eastern countries, including Japan, but it is believed that the incidence of EGJ adenocarcinoma will increase in Asia in the future due to the decreasing incidence of Helicobacter pylori infection. Endoscopic submucosal dissection (ESD) is a minimally invasive and curative treatment that allows precise pathological assessment., Summary: Magnifying endoscopy with narrow-band imaging may be useful for differential diagnoses and for delineating the cancer margin of EGJ adenocarcinoma, but subsquamous carcinoma extension, which is the invasion of EGJ adenocarcinoma beneath the normal esophageal squamous epithelium, makes it difficult to detect cancer margins of the oral side in ESD for EGJ adenocarcinoma. Since subsquamous carcinoma extension was reported to be less than 1 cm in most cases, the oral safety margin that is placed 1 cm from the squamocolumnar junction is useful for negative cancerous horizontal margin. A multicenter retrospective study of esophageal adenocarcinoma including EGJ adenocarcinoma showed that mucosal and submucosal cancer within 500 μm from the muscularis mucosa without lymphovascular involvement, a poorly differentiated component, and lesion size over 3 cm were not associated with metastasis. Several retrospective studies about ESD for EGJ adenocarcinoma have suggested feasible short-term and long-term outcomes using curative criteria based on gastric cancer guidelines. Key Messages: ESD would be a good first-line treatment for superficial EGJ adenocarcinoma, including Barrett's adenocarcinoma. Additional information about the incidence of metastasis would help confirm the indication of ESD for EGJ adenocarcinoma., (© 2018 S. Karger AG, Basel.)

Activation of the NOD-Like Receptor Family, Pyrin Domain-Containing 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1, triggers pro-caspase-1 cleavage promoting the processing of pro-interleukin (IL)-1β into mature IL-1β, which is critical for the development of non-steroidal anti-inflammatory drug (NSAID)-induced enteropathy. We investigated the effects of isoliquiritigenin, a flavonoid derived from the roots of Glycyrrhiza species, on NSAID-induced small intestinal damage and the inflammasome activation. To induce enteropathy, mice were administered indomethacin by gavage with or without isoliquiritigenin pretreatment. Some mice received an intraperitoneal injection of recombinant murine IL-1β in addition to isoliquiritigenin and indomethacin. Indomethacin induced small intestinal damage and increased protein levels of cleaved caspase-1 and mature IL-1β in the small intestine. Treatment with 7.5 and 75 mg/kg isoliquiritigenin inhibited indomethacin-induced small intestinal damage by 40 and 56%, respectively. Isoliquiritigenin also inhibited the indomethacin-induced increase in cleaved caspase-1 and mature IL-1β protein levels, whereas it did not affect the mRNA expression of NLRP3, ASC, caspase-1, and IL-1β. Protection against intestinal damage in isoliquiritigenin-treated mice was completely abolished with exogenous IL-1β. NLRP3-/- and caspase-1-/- mice exhibited resistance to intestinal damage, and isoliquiritigenin treatment failed to inhibit the damage in NLRP3-/- and caspase-1-/- mice. Isoliquiritigenin prevents NSAID-induced small intestinal damage by inhibiting NLRP3 inflammasome activation., (© 2018 S. Karger AG, Basel.)

Background: Obscure gastrointestinal bleeding (OGIB) is a common but embarrassing problem for gastroenterologists. Most bleeding lesions associated with OGIB are present in the small intestine and sometimes cannot be identified due to the difficulty associated with physical accessibility. Capsule endoscopy (CE) and double-balloon enteroscopy (DBE) have enabled in the process of diagnosing and have evolved to become approaches to treating OGIB., Summary: CE is a minimally invasive procedure and has a high diagnostic yield in patients with OGIB. DBE offers additional advantage of biopsy collection for pathological diagnosis and therapeutic intervention, but it should be noted that it sometimes causes severe adverse events such as acute pancreatitis, intestinal bleeding, and intestinal perforation. CE should be performed early in the workup course of OGIB. Positive CE findings enhance the diagnostic yield of subsequent DBE, and the effective therapeutic intervention improves the clinical outcomes of OGIB patients. On the contrary, there are no clear guidelines for further investigation of patients with negative CE findings at the present. Although patients in stable general condition may only require follow-up, repeated CE is useful to detect positive findings in patients with evidence of sustained bleeding and progressing anemia. We have revealed that repeated CE has higher positive finding rate than DBE in OGIB patients with negative CE findings in a preliminary study. Key Messages: CE and DBE have complementary roles in the management of OGIB, and the precise timing and proper sequence may be important for the approach to treating OGIB., (© 2018 S. Karger AG, Basel.)

Objective: To investigate the efficacy and safety of pazopanib for recurrent or metastatic solitary fibrous tumor (SFT) in first- and second-line settings., Methods: Patients histologically diagnosed with SFT at our hospital who received pazopanib monotherapy for inoperable disease between January 2013 and November 2016 were eligible. We retrospectively investigated treatment outcomes according to the treatment lines and assessed adverse events., Results: Nine patients were eligible. The median age was 67 years (range 42-81), and 6 patients (66.7%) were male. Four patients (50%) received pazopanib as second-line treatment. According to the RECIST and Choi criteria, the respective response rates were 0 and 50%, while the respective disease control rates were 88.9 and 75%. The median progression-free survival (PFS) was 6.2 months (95% confidence interval 3.2-8.8). Treatment line and high frequency of mitosis were not predictive of PFS (p = 0.67, 0.92). Two patients (22.2%) experienced elevated liver enzymes of grade 3 or higher., Conclusion: Pazopanib is an effective treatment option for recurrent or metastatic SFT in first- and second-line settings. Liver injury is a major adverse event and adequate treatment withdrawal and dose reduction should be considered when necessary., (© 2018 S. Karger AG, Basel.)

Background/aims: Approximately 20-40% of patients with gastroesophageal reflux disease (GERD) are refractory to proton pump inhibitor (PPI) treatment. The acid-inhibitory effect of vonoprazan, a novel potassium-competitive acid blocker (P-CAB), is significantly greater when compared to the effect of PPIs. We investigated the efficacy of vonoprazan treatment for PPI-refractory GERD and factors associated with P-CAB non-response., Methods: We enrolled 277 GERD patients receiving continuous PPI therapy. Subjects completed a self-report questionnaire including the frequency scale for the symptoms of GERD (FSSG). Patients with PPI-refractory GERD received 20 mg of vonoprazan once daily for 8 weeks. After that, subjects completed the same questionnaire, and the results were used to identify P-CAB responders and non-responders., Results: Twenty-eight patients were identified as P-CAB responders and 26 were non-responders. Vonoprazan treatment significantly decreased scores of FSSG, nighttime symptom, and Athens Insomnia Scale. Multivariate analysis demonstrated co-existing functional dyspepsia (FD; OR 4.94) and the presence of sleep disturbances (OR 4.34) was associated with P-CAB non-response, whereas alcohol consumption was inversely associated., Conclusions: Vonoprazan treatment might be appropriate as a promising new strategy for PPI-refractory GERD. Co-existing FD, sleep disturbances, and alcohol abstinence were significantly associated with P-CAB non-response. Other therapeutic options should be considered in patients with these factors., (© 2017 S. Karger AG, Basel.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) damage the small intestine by causing multiple erosions and ulcers. However, to date, no established therapies and prophylactic agents are available to treat such damages. We reviewed the role of intestinal microbiota in NSAID-induced intestinal damage and identified potential therapeutic candidates., Summary: The composition of the intestinal microbiota is an important factor in the pathophysiology of NSAID-induced small intestinal damage. Once mucosal barrier function is disrupted due to NSAID-induced prostaglandin deficiency and mitochondrial malfunction, lipopolysaccharide from luminal gram-negative bacteria and high mobility group box 1 from the injured epithelial cells activate toll-like receptor 4-signaling pathway and nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome; this leads to the release of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Proton pump inhibitors (PPIs) are often used for the prevention of NSAID-induced injuries to the upper gastrointestinal tract. However, several studies indicate that PPIs may induce dysbiosis, which may exacerbate the NSAID-induced small intestinal damage. Our recent research suggests that probiotics and rebamipide could be used to prevent NSAID-induced small intestinal damage by regulating the intestinal microbiota. Key Messages: Intestinal microbiota plays a key role in NSAID-induced small intestinal damage, and modulating the composition of the intestinal microbiota could be a new therapeutic strategy for treating this damage., (© 2016 S. Karger AG, Basel.)

Background: Gastrointestinal endoscopy and Helicobacter pylori(H. pylori) eradication therapy are commonly performed even among the elderly population. The aim of this study was to understand the way endoscopists viewed the application of endoscopy and H. pylori eradication in the elderly of East Asian countries., Methods: Self-administered questionnaires containing 13 questions on endoscopy and H. pylori eradication in the elderly were distributed to major institutions in Japan, South Korea, China, Indonesia, and the Philippines., Results: Two hundred and fifteen endoscopists (111 in Japan, 39 in China, 24 in Korea, 21 in Indonesia, and 20 in the Philippines) participated in this study. In the institutions where these endoscopists were associated, around 50% of patients undergoing endoscopy were above the age of 60 years. The participating endoscopists indicated that the necessity of screening esophagogastroduodenoscopy and colonoscopy was lower in populations aged over 81 than the other age groups. They hesitated to perform therapeutic endoscopy, such as endoscopic submucosal dissection or endoscopic retrograde cholangiopancreatography, more often in patients over 85. They also hesitated to perform H. pylori eradication in patients aged over 81, especially in Japan., Conclusion: Endoscopists had significantly different attitudes regarding the indications for screening or therapeutic endoscopy and H. pylori eradication therapy in younger and elderly populations in East Asian countries., (© 2016 S. Karger AG, Basel.)

Background/aims: Modified neuroleptanalgesia (m-NLA) with midazolam is often used for sedation and analgesia during endoscopic submucosal dissection (ESD) for gastrointestinal neoplasia. However, interruption due to poor response to midazolam is often experienced during ESD for esophageal squamous cell carcinoma (ESCC) because most patients with ESCC have a history of heavy alcohol intake. We examined the incidence and risk factors for poor response to m-NLA with midazolam and pethidine hydrochloride., Methods: This retrospective cross-sectional study was conducted at a single institution. Between April 2007 and July 2013, 151 patients with superficial ESCC who underwent ESD under sedation using m-NLA with midazolam and pethidine hydrochloride were enrolled. Poor response to sedation was defined as the use of a second drug when Ramsay Sedation Score 1-2., Results: Poor response to sedation occurred in 66.2% patients. Most cases of poor response were controlled by using additional flunitrazepam. Multivariate logistic regression analysis showed that cumulative alcohol intake and major specimen size were independent risk factors for poor response to sedation (OR 3.63, 95% CI 1.20-10.99, and OR 3.23, 95% CI 1.26-8.25)., Conclusion: Our study indicated that cumulative alcohol intake and major specimen size were associated with poor response to m-NLA with midazolam and pethidine hydrochloride., (© 2016 S. Karger AG, Basel.)

Objects: Recently, we reported that diagnostic laparoscopy with photodynamic diagnosis using oral 5-aminolevulinic acid (ALA-PDD) is a promising tool for diagnosing early peritoneal metastases in gastric cancer. The present study evaluated the usefulness of adding ALA-PDD to conventional diagnostic laparoscopy and assessed the association of the ALA-PDD results with peritoneal fluid cytology and molecular diagnostic testing., Methods: Diagnostic laparoscopy using sequential white light (WL) and ALA-PDD observations was performed in 52 advanced gastric cancer patients, and the sensitivity of ALA-PDD for detecting peritoneal disease was compared to WL. Peritoneal fluid samples from the same patients were also subjected to cytological examination and molecular diagnosis using a transcription-reverse transcription concerted reaction (TRC)., Results: Twenty-four of the 52 patients (46%) had no macroscopic evidence of peritoneal metastases on WL examination; however, ALA-PDD detected dissemination in 5 of these 24 patients (21%) (pd-P). Cytological examination was negative in 4 of the 5 pd-P patients, and molecular testing using TRC was negative in 3 of the 5 pd-P patients., Conclusions: This study demonstrated that diagnostic laparoscopy with ALA-PDD improved the sensitivity for the detection of peritoneal metastases. ALA-PDD may be a useful technique for the preoperative staging of advanced gastric cancer and can complement examinations of peritoneal lavage fluids., (© 2014 S. Karger AG, Basel.)

Background and Aim: The prevalence and incidence of inflammatory bowel disease (IBD) are lower in East Asia than in Western countries; however, marked increases have recently been reported. The clinical diagnosis and medical management of IBD in East Asia differ from those in Western countries. A questionnaire-based survey was performed to gather physicians' current opinions on IBD in different East Asian countries., Methods: Representative International Gastrointestinal Consensus Symposium (IGICS) committee members provided a questionnaire to physicians in each East Asian country studied. The questionnaire mainly focused on the diagnosis and management of IBD., Results: There were 19 respondents from Japan, 10 from South Korea, 9 from the Philippines, 6 from China and 4 from Indonesia. Colonoscopy (100%) and histopathology (63%) were commonly used for the diagnosis in ulcerative colitis (UC). Conventional small bowel enteroclysis was still the most common diagnostic tool for assessing small bowel lesions in Crohn's disease (CD) in East Asia. The percentage of physicians who investigated the reactivation of Cytomegalovirus in severe or refractory patients with UC ranged from 0% in the Philippines and Indonesia to 100% in Japan and Korea. Most physicians in Korea, the Philippines, China and Indonesia chose thiopurines or anti-TNF therapy as the second-line treatment in severe refractory UC, whereas Japanese physicians preferred to use tacrolimus or leukocyte apheresis. Physicians in the Philippines and Indonesia preferred to use oral 5-aminosalicylic acid for newly diagnosed severe ileocecal CD. In contrast, Korean physicians chose oral steroids and most physicians in China and Japan preferred to use anti-TNF. Nutritional therapy to induce or maintain remission in patients with CD was commonly used in Indonesia, Japan and China. Targeted biopsies by conventional colonoscopy were the most preferred strategy for cancer surveillance in long-standing UC over random biopsies in this region., Conclusions: The present survey found that current diagnostic approaches and clinical management of IBD vary within East Asian countries.

Background: Nighttime acid reflux that influences refractory symptoms is strongly associated with sleep disturbances. The aim of this study was to examine the associations between sleep disturbances and refractory gastroesophageal reflux disease (GERD) symptoms in patients receiving once daily proton pump inhibitors (PPI) and the efficacy of twice-daily rabeprazole treatment., Method: In a multicenter survey, 433 GERD patients receiving once-daily PPI treatment completed a self-report questionnaire that included the Frequency Scale for the Symptoms of GERD (FSSG) and questions about sleep disturbances. Study cases were defined as patients with an FSSG score ≥8. Of the 222 study cases, 106 individuals received rabeprazole 10 mg twice daily for 4-8 weeks., Results: Of the 433 subjects, 222 patients revealed FSSG scores of ≥8. Use of a half dose of PPI was associated with such cases. PPI-refractory symptoms were found in 46% of patients with standard-dose PPI treatment. Nighttime symptoms (OR = 2.56), daytime sleepiness (OR = 1.64), and poorer sleep quality (OR = 1.67) were significantly associated with refractory GERD symptoms. Twice-daily rabeprazole treatment significantly improved FSSG scores and sleep disturbances., Conclusion: About half of the GERD patients receiving once-daily standard-dose PPI treatment had refractory GERD symptoms. Sleep disturbances were significantly associated with refractory GERD symptoms. Twice-daily rabeprazole treatment was effective in such cases., (Copyright © 2013 S. Karger AG, Basel.)

Background: Information regarding hematological toxicities in breast cancer chemotherapy patients with hepatitis B (HBV) or C virus (HCV) infection is limited., Methods: We retrospectively reviewed the presence of hepatotoxicities (i.e. aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin elevation) and hematotoxicities (i.e. leukopenia and thrombocytopenia) among breast cancer patients with HBV or HCV infection who received chemotherapy from 1999 to 2010. All of the patients included in this analysis were classified as Child-Pugh A., Results: Among 32 patients with HBV infection who underwent chemotherapy (total cycles, 378), 3 experienced grade 3/4 hepatotoxicities, requiring 2 treatment delays and 1 treatment revision. Further, 9 patients experienced grade 3/4 hematotoxicities; of these, 2 required treatment delays and 3 required treatment revisions. Fifty-two HCV patients underwent a total of 570 cycles of chemotherapy. Five patients experienced grade 3/4 hepatotoxicities and required treatment delays, whereas 10 patients experienced grade 3 hematotoxicities; 3 of these patients required treatment delays., Conclusion: Hematotoxicities requiring chemotherapy dose or treatment revision were not highly prevalent among breast cancer chemotherapy patients with HBV or HCV infection and a normal range of liver function. Under careful monitoring, chemotherapy dosage or schedule adjustments may not be necessary in similar patients positive for HBV or HCV., (Copyright © 2012 S. Karger AG, Basel.)

Background: The incidence of gastric cancer (GC) is high, and colorectal cancer (CRC) has significantly increased in Asian countries., Aim: To examine the current screening for GC and CRC within East Asia by means of a questionnaire survey., Methods: Representative members of the Committee of the International Gastrointestinal Consensus Symposium provided a questionnaire to physicians in six East Asian countries., Results: A total of 449 physicians participated in this survey. In all countries, more than 70% of physicians started GC screening between 40 and 59 years. The most popular method to screen for GC was endoscopy (92.7%), but combination methods such as Helicobacter pylori (HP) antibody, barium X-ray, and tumor marker with endoscopy differed by country. For HP-positive individuals, most physicians screened every year by endoscopy, and for individuals post-HP eradication, about half of physicians (56.3%) thought there was a need to follow-up with GC screening. Among all physicians, the most common age to start CRC screening was in the 40s (39.8%) and 50s (40.9%). Based on the American Cancer Society Recommendations, a fecal occult blood test every year was the most popular method for CRC screening overall. However, among each country, this test was most popular in only Japan (76.9%) and Indonesia. In other countries, sigmoidoscopy every 5 years and total colonoscopy every 10 years were the most popular methods., Conclusion: There are similarities and differences in the screening of GC and CRC among East Asian countries., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: Visceral obesity is commonly involved in the pathogenesis of gastroesophageal reflux disease (GERD) and non-alcoholic fatty liver disease (NAFLD). However, other characteristic factors different from visceral obesity are associated with the pathogenesis of NAFLD. We investigated the prevalence of GERD symptoms in patients with NAFLD and its associated risk factors., Methods: NAFLD (n = 96) and controls (n = 139) were enrolled in this study. GERD symptoms were evaluated by using a frequency scale for the symptoms of GERD., Results: GERD symptom score and its prevalence rate were higher in the NAFLD group (7.4 ± 0.7, 37%) than those seen in the control groups (4.5 ± 0.4, 20%), which was independent of sex, age, and body mass index (BMI). GERD symptoms were correlated with insulin resistance (r = 0.167, p = 0.011), total cholesterol (T-CHO) (r = 0.138, p = 0.034), triglyceride (TG) (r = 0.178, p = 0.006), or immunoreactive insulin (r = 0.173, p = 0.008) but not BMI (r = 0.089, p = 0.175). GERD symptoms of the NAFLD group were significantly severer in the higher group of T-CHO and TG levels than those in the lower group. Multivariate analysis proved that risk factors related to GERD symptoms were TG (OR 3.96, 95% CI 1.31-11.9) and T-CHO (OR 3.39, 95% CI 1.11-10.3)., Conclusion: The severity and prevalence of GERD symptoms in patients with NAFLD were high, which was associated with serum levels of TG and T-CHO but not BMI., (Copyright © 2012 S. Karger AG, Basel.)

Background: Reduced cerebrovascular reactivity (CVR) is an important step in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The present study utilized quantitative single photon emission computed tomography (SPECT) with the autoradiographic (ARG) method and reactive hyperemia peripheral arterial tonometry (RH-PAT) to assess vasoreactivity in intracranial arteries and in peripheral arteries in patients with CADASIL., Methods: Quantitative SPECT studies were conducted in eight patients with CADASIL, while RH-PAT analysis was conducted in eight CADASIL patients and in eight age-matched normal subjects. Quantitative SPECT studies with the ARG method were performed at baseline and after administration of acetazolamide. Regional cerebral blood flow (rCBF) values were measured using stereotactic extraction estimation (SEE) methods. The rCBF of CADASIL patients was averaged in the bilateral frontal, temporal, parietal, and occipital lobes as well as in the limbic system, cerebellar hemisphere, whole cerebral cortex and basal ganglia. The CVR index from acetazolamide stress of intracranial arteries was calculated in each area. Vasoreactivity of peripheral arteries was estimated by the reactive hyperemia index (RHI) measured with a PAT device before and after interruption of arterial flow., Results: Average RHI after post-deflation was lower in CADASIL patients than in normal subjects. RHI correlated significantly with CVR in all brain areas in CADASIL patients., Conclusions: Vasoreactivity is reduced in peripheral arteries and in intracranial arteries in patients with CADASIL., (Copyright © 2011 S. Karger AG, Basel.)

Background/aims: Endoscopic definitions and management of Barrett's esophagus vary widely among countries. To examine the current situation regarding diagnosis, epidemiology, management and treatment of Barrett's esophagus in East Asian countries using a questionnaire-based survey., Methods: Representative members of the Committee of the International Gastrointestinal Consensus Symposium developed and sent a questionnaire to major institutions in China, South Korea, Japan, Thailand, Indonesia, and the Philippines., Results: A total of 56 institutions in the 6 countries participated in the survey. We found that the presence of specialized columnar metaplasia is considered to be important for diagnosing Barrett's esophagus in East Asian countries except for Japan. C&M criteria have not been well accepted in East Asia. The palisade vessels are mainly used as a landmark for the esophagogastric junction in Japan. The prevalence of long segment Barrett's esophagus is extremely low in East Asia, while the prevalence of short segment Barrett's esophagus is very high only in Japan, likely due to different diagnostic criteria., Conclusion: Among East Asian countries, we found both similarities and differences regarding diagnosis and management of Barrett's esophagus. The findings in the present survey are helpful to understand the current situation of Barrett's esophagus in East Asian countries., (Copyright © 2012 S. Karger AG, Basel.)

Percutaneous coronary intervention (PCI) is now performed in a wide range of patients with coronary artery disease. Complications of PCI include in-stent re-stenosis and in-stent thrombosis. According to the recent 2005 guidelines of the American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions, dual antiplatelet therapy with low-dose aspirin and thienopyridine derivatives such as ticlopidine and clopidogrel should be used in patients who have undergone PCI. A serious complication of dual antiplatelet therapy is bleeding, most of which arise from the gastrointestinal (GI) tract. In this article we review published studies about GI bleeding in patients who have undergone PCI. The prevalence of GI bleeding in patients who are administered dual antiplatelet therapy following PCI is approximately 2%, and GI bleeding after PCI is associated with increased morbidity, mortality, duration of hospitalization and cost. Advanced age, a history of peptic ulcer disease, co-administration of non-steroidal anti-inflammatory drugs, co-administration of anticoagulants, and physiological stress are considered to be the major risk factors for GI bleeding in patients undergoing antiplatelet therapy following PCI. Recent clinical and experimental studies indicate that administration of low-dose aspirin may also increase the risk of adverse events in the small intestine. Although some prophylactic strategies such as proton-pump inhibitor, H₂ receptor antagonist and eradication of Helicobacter pylori are proposed, there are few randomized controlled trials assessing the best strategy for the prevention of GI bleeding after PCI. Further extensive studies are required to ascertain the beneficial effect of prophylactic agents for dual antiplatelet therapy following PCI., (Copyright © 2011 S. Karger AG, Basel.)

Objective: Several studies have shown associations between left-handedness and several chronic diseases such as bronchial asthma and inflammatory bowel disease. Perceptual responses within the brain-gut axis play a crucial role in the development of the cardinal symptoms of functional gastrointestinal (GI) diseases, including dyspepsia and irritable bowel syndrome (IBS). The aim of this study was to determine the association between left-handedness and GI symptoms or diseases., Methods: 2,447 Japanese who underwent a routine health check-up were asked to complete a self-report questionnaire regarding age, gender, writing handedness and GI symptoms experienced over the past 3 months, including heartburn, acid regurgitation, epigastric pain, postprandial fullness, abdominal pain/discomfort, nausea and/or chest pain. Symptoms were positive when their frequency was 2 to 3 days per month or more. Diagnosis of dyspepsia and IBS was performed according to the Rome III Integrative Questionnaire., Results: Left-handedness was observed in 177 (7.2%) subjects. Early satiation, abdominal pain/fullness and postprandial fullness were less commonly observed in left-handed individuals. After adjustment for age and sex, left-handedness was found to be significantly associated with decreased OR for early satiation (OR = 0.43; 95% CI: 0.23-0.78). There were no significant associations between left-handedness and GERD (gastroesophageal reflux disease), dyspepsia or IBS., Conclusions: This study demonstrated a significant negative association between left-handedness and early satiation. The findings suggest that cerebral lateralization may affect the development of GI symptoms., (Copyright © 2011 S. Karger AG, Basel.)

Objectives: The aim of this study was to analyze the prognostic impact of suboptimal treatment in patients with mediastinal primary nonseminomatous germ cell tumor (MNSGCT)., Methods: We retrospectively reviewed the clinical data of 23 consecutive MNSGCT patients who were referred to the National Cancer Center Hospital between 1999 and 2007. Optimal treatment was defined as a primary chemotherapy regimen comprising a standard dosage of bleomycin + etoposide + cisplatin or etoposide + ifosfamide + cisplatin with sufficient dose intensity according to the guidelines of the European Germ Cell Cancer Consensus Group., Results: Ten and 13 patients received optimal and suboptimal treatment, respectively. The progression-free survival was statistically different between the patients who received optimal and suboptimal treatment (p = 0.01), and the hazard ratio of the optimal treatment group relative to the suboptimal treatment group was 0.19 (95% CI, 0.04-0.89). Although the overall survival was not statistically different between the 2 patient groups (p = 0.12), the hazard ratio in this regard was 0.36 (95% CI, 0.10-1.38)., Conclusions: Patients who receive suboptimal treatment have poor clinical outcomes. Providing treatment after considering evidence-based guidelines may be important for improving the clinical outcomes of MNSGCT patients., (Copyright 2010 S. Karger AG, Basel.)

Background and Aim: Leptin, a key hormone in regulation of food intake and energy expenditure, exerts pleiotropic cytokine-like biological effects. Its role in gastric ulcer healing is unclear. In this study, we investigated the role of leptin in gastric ulcer healing., Methods: Experimental gastric ulcer was induced by focal serosal application of acetic acid in leptin-deficient ob/ob mice and wild-type mice. Healing of gastric ulcer and angiogenesis in the ulcer tissue was evaluated., Results: Gastric ulcer healing was delayed in ob/ob mice compared with that in wild-type mice. The impairment of ulcer healing observed in ob/ob mice was characterized by reduced expression of vascular endothelial growth factor (VEGF) and impairment of angiogenesis. Systemic administration of leptin to ob/ob mice reversed the impairment of gastric ulcer healing; this reversal was accompanied by an increase in VEGF expression and angiogenesis. Although mRNA for leptin was not expressed in normal gastric mucosa and not induced in ulcerous tissue, leptin receptor expression was markedly upregulated in gastric epithelial cells at ulcer margins, and was colocalized with VEGF., Conclusion: These findings suggest that leptin promotes gastric ulcer healing by induction of angiogenesis in the granular tissue of ulcers via upregulation of VEGF expression., (Copyright (c) 2010 S. Karger AG, Basel.)

Background and Aim: Several studies performed in Western countries demonstrate the association between sleep dysfunction and gastroesophageal reflux disease (GERD), especially when nighttime heartburn is present. The purpose of this study was to examine the prevalence and risk factors of sleep dysfunction, and the effect of rabeprazole on reflux symptoms and sleep dysfunction in Japanese GERD patients., Methods: A total of 134 GERD patients, including 82 patients with non-erosive reflux disease (NERD), were enrolled. Patients received rabeprazole 10 mg daily for 8 weeks. Patients were asked to complete both a frequency scale for symptoms of GERD (FSSG) questionnaire and a Pittsburgh Sleep Quality Index (PSQI) questionnaire at baseline and 8 weeks after treatment., Results: Sleep dysfunction defined as a PSQI score >5.5 was found in 70 (52.2%) of the GERD patients. NERD was significantly associated with sleep dysfunction compared to erosive reflux disease (OR 2.18, 95% CI 1.05-4.53). However, other factors, including nighttime heartburn, were not associated with sleep dysfunction. Rabeprazole treatment significantly decreased both the FSSG and the PSQI score., Conclusion: The prevalence of sleep dysfunction was high among GERD patients. NERD was identified as a risk factor for sleep dysfunction. Use of a proton-pump inhibitor led to an effective decrease in sleep dysfunction. These results suggest a different pathogenesis of sleep dysfunction in Japanese GERD patients compared to GERD patients in Western countries. However, acid plays an important role in sleep dysfunction in all patients with GERD., (Copyright 2010 S. Karger AG, Basel.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are widely used clinically but increase the risk of gastrointestinal (GI) complications., Aim: To examine the current prescription of NSAIDs and comedication to prevent GI complications from NSAIDs within East Asia by means of a questionnaire survey., Methods: Representative members of the Committee of the International Gastrointestinal Consensus Symposium provided a questionnaire to physicians in 6 East Asian countries., Results: A total of 1,568 physicians participated in this survey. Most physicians prescribed nonselective NSAIDs, cyclooxygenase-2 inhibitors (COXIBs) or aspirin for more than 5 patients per week in all countries, with the exception of the prescription of COXIBs in Japan. Of the nonselective NSAIDs, the drug most frequently prescribed as a first choice was loxoprofen (34%), which was mainly prescribed in Japan, followed by diclofenac (30%). The frequency of prescription of comedication with nonselective NSAIDs was higher compared with that for selective COXIBs or aspirin. Physicians in the northern region (China, Japan and Korea) preferred mucoprotective drugs for comedication with NSAIDs or aspirin, while those in southern region (Indonesia, Philippines and Thailand) frequently used proton-pump inhibitors., Conclusion: Among East Asian countries, there are both similarities and differences in the prescription of NSAIDs and of comedication to prevent GI complications.

Background/aims: Gastroesophageal reflux disease (GERD) is a common gastrointestinal disease. This study was designed to examine current epidemiology, diagnosis, management, and treatment of patients diagnosed with GERD by surveying physicians in several East Asian countries., Methods: A questionnaire-based survey was completed in six countries including China, Indonesia, Japan, Korea, the Philippines, and Thailand between July 2008 and December 2008., Results: In total, 876 physicians participated in the study. Most physicians in all countries, except Japan, frequently used international guidelines for the care of GERD patients, whereas approximately half of Japanese physicians did not use such guidelines. GERD was common among many patients, but Barrett's esophagus, particularly the long-segmental type, was rare. The incidence of esophageal cancer, particularly adenocarcinoma, was high in China, but low in other countries. Most physicians diagnosed GERD based on symptoms, followed by endoscopy in Japan and Korea, or in other countries, by the proton-pump inhibitor (PPI) test. Heartburn was recognized as the chief complaint in all countries except Korea. Most physicians in all countries used PPI as the first-line of treatment for GERD. Increasing the PPI dose was the treatment of choice for PPI-refractory erosive esophagitis in Korea, the Philippines, and Thailand. In contrast, in other countries, physicians used a combination of PPI and other drugs to treat PPI-refractory erosive esophagitis. Prescription of antidepressant drugs increased for PPI-refractory nonerosive reflux disease compared with PPI-refractory erosive esophagitis., Conclusion: The findings in the present survey are useful to understand the current epidemiology, diagnosis, and treatment of GERD in East Asian countries., (Copyright 2009 S. Karger AG, Basel.)

Background and Aim: The medical treatment of rheumatoid arthritis (RA) includes nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose corticosteroids, and disease-modifying antirheumatic drugs (DMARDs). We evaluated the incidence of small bowel injury in RA patients who were taking anti-RA drugs with or without concomitant NSAIDs by capsule endoscopy., Methods: A total of 28 RA patients who took low-dose corticosteroids and/or DMARDs for more than 1 year were enrolled., Results: The incidence of red spots did not differ between the 2 groups: 14 of 16 patients (87.5%) in the NSAID group and 11 of 12 patients (91.7%) in the non-NSAID group. In contrast, the incidence of mucosal breaks was significantly higher in the NSAID group than in the non-NSAID group: mucosal breaks were detected in 13 of 16 patients (81.3%) and 4 of 12 patients (33.3%) in the NSAID and non-NSAID groups, respectively. In the NSAID group, mucosal breaks developed in users of preferential cyclooxygenase-2 inhibitors at a frequency similar to that in users of traditional NSAIDs., Conclusion: Patients taking anti-RA drugs may have an increased frequency of small bowel injury regardless of NSAID use, and NSAID use may be associated with an increased incidence of severe small bowel injury.

Background: To explore predictors of functional improvement or decline in instrumental activities of daily living (IADL) among community-dwelling older people., Methods: Of all the residents (>or=65 years, n = 1,673) living in Yoita town, Niigata prefecture, Japan, in 2000, 1,544 subjects who participated in the baseline interview survey (T1) were followed up until 2002 (T2). A wide range of variables obtained in T1 was entered into the model predicting functional improvement or decline in IADL., Results: Among 1,274 individuals who participated in both T1 and T2, 105 subjects showed improvement, 194 decline, and the remaining 975 showed stability in IADL. Multiple logistic regression analyses indicated that good self-rated health and cognitive function (MMSE >or=24) at T1 were good predictors of both improvement and protection against decline in IADL. Independence in basic activities of daily living predicted improvement in IADL. Advanced age and poor walking ability predicted decline in IADL., Conclusions: Good self-rated health and cognitive function predicted both improvement and protection against decline in IADL. Thus, intervention programs aiming at maintaining both good self-rated health and cognitive function should be able to improve IADL., ((c) 2008 S. Karger AG, Basel.)

Objective: Tyrosine kinase B (TrkB) is associated with aggressive behavior and poor prognosis in various cancers. Here we examined the association between TrkB expression and distant metastases/prognosis in gastric carcinoma (GC)., Patients and Methods: We analyzed TrkB expression in 161 GC patients by immunohistochemistry and Western blot analysis. The correlation of TrkB mRNA and protein expression levels was examined in 10 patients by RT-PCR assay., Results: TrkB expression was of level 1 in 97 (60.2%) and level 2 in 64 (39.8%) patients. Patients with level 2 expression had a significantly higher incidence of distant metastases (p < 0.0001), well-differentiated tumors (p < 0.005), deeper depth of invasion (p < 0.005) and poorer disease-free and overall survival (p < 0.0001 each) compared to patients with level 1. Multivariate analysis identified the level of TrkB expression as an independent prognostic factor for both disease-free and overall survival (p < 0.01 and p < 0.0001, respectively). Both lymph node metastasis (odds ratio = 10.7) and TrkB expression (odds ratio = 9.3) were independent predictors of distant metastases., Conclusion: A high level of TrkB expression was observed in well-differentiated GC subtypes and is a predictor for distant metastases and prognosis in GC., (Copyright 2008 S. Karger AG, Basel.)

Objective: A phase I/II study of a combination of S-1 and weekly paclitaxel was conducted to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs) and objective response rate (RR) in patients with advanced or recurrent gastric cancer., Methods: S-1 was administered orally at a fixed dose of 80 mg/m(2) per day on days 1-14. Paclitaxel was injected intravenously on days 1, 8, and 15, starting with a dose of 50 mg/m(2). The dose was increased in a stepwise manner., Results: In phase I, level 2 (60 mg/m(2)) was considered the MTD, because 2 of 3 patients in level 2 developed DLTs (grade 3 neutropenia and anemia, and grade 4 diarrhea and stomatitis). Therefore, the RD was determined to be level 1 (50 mg/m(2)). In phase II, efficacy and safety were assessed in 18 patients treated with the RD. The RR was 64.7% and the median survival time was 13.5 months. The most severe toxicities were grade 3 leukopenia (5.5%) and grade 3 neutropenia (5.5%)., Conclusion: Our study showed that S-1 combined with 50 mg/m(2) paclitaxel is effective and safe in patients with advanced or recurrent gastric cancer., ((c) 2008 S. Karger AG, Basel)