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Background and Aim Endoscopy‐based Kyoto classification predicts the risk of Helicobacter pylori infection and gastric cancer; however, the change in score following H. pylori eradication remains unknown. We retrospectively compared the Kyoto score before and after H. pylori eradication. Methods H. pylori‐positive patients who underwent baseline esophagogastroduodenoscopy (EGD), successful H. pylori eradication, and surveillance EGD were enrolled. The Kyoto score is a sum of scores for atrophy (Kimura‐Takemoto atrophic‐border classification none or C1: 0, C‐II or C‐III: 1, O‐I to O‐III: 2), intestinal metaplasia (none: 0, antrum: 1, corpus and antrum: 2), enlarged folds (absence: 0, presence: 1), nodularity (absence: 0, presence: 1), and diffuse redness (none: 0, mild: 1, severe: 2) and ranges from 0 to 8. Results Eighty‐three patients (mean age: 54.9 years; 65.1% women) were enrolled. The mean duration from successful eradication to surveillance EGD was 256 days. The Kyoto score significantly decreased from 3.90 to 2.78 following H. pylori eradication (P, The Kyoto classification score on endoscopic gastritis (sum of scores for atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness with or without regular arrangement of collecting venules) is associated with Helicobacter pylori infection status and gastric cancer risk. We found that the Kyoto classification score improved with H. pylori eradication. Improvement in the scores for enlarged folds, nodularity, and diffuse redness might be predictors for successful H. pylori eradication.

We compared recurrence patterns between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) after stereotactic body radiotherapy (SBRT) for early-stage lung cancer. Patients with ADC and SCC histology, who were treated with SBRT for clinical stage IA1-IIA lung cancer at our institution, were included in the analysis. The rates of disease-free survival (DFS), overall survival (OS), local recurrence (LR), lymph node metastasis (LNM), and distant metastasis (DM) were calculated using the Kaplan–Meier method or the cumulative incidence function. Among the 204 patients analyzed, 138 and 66 were in the ADC and SCC groups, respectively. The median follow-up period was 60 months. The five-year DFS and OS rates were 57% vs. 41% and 69% vs. 48% in the ADC and SCC groups, respectively (p = 0.015 and 0.019, respectively). In the multivariate analysis, the histological type was not associated with DFS or OS. Five-year LR, LNM, and DM rates were 10% vs. 24%, 12% vs. 20%, and 25% vs. 27% in the ADC and SCC groups, respectively (p = 0.0067, 0.074, and 0.67, respectively). The multivariate analysis identified the histological type of SCC as an independent factor for LR (hazard ratio, 2.41; 95% confidence interval, 1.21–4.77; p = 0.012). The present results suggest that the risk of LR after SBRT is higher for SCC than for ADC.

Background Despite advances in chemotherapy, curing multiple liver metastases is quite rare. Even when response is obtained, regrowth of the tumors is almost inevitable. We aimed to evaluate the efficacy and adverse events of helical tomotherapy for chemo‐refractory multiple liver metastases. Methods Forty‐five patients with chemo‐refractory multiple (3‐10) liver metastases after standard systemic chemotherapy entered the single‐institutional prospective study. Liver metastases were the major disease; however, 31 also had uncontrolled primary lesions and/or other metastases. The prescribed dose was 55 Gy in 25 fractions. The median planning target volume (PTV) and normal liver volume (NLV) of first treatment were 128 cm3 and 1175 cm3, respectively. The median of V15Gy, V30Gy, and mean dose to NLV were 45%, 23%, and 19.4 Gy, respectively. Results Forty‐two patients (93%) completed the planned treatment. Median survival time (MST) for all patients was 8 months, and the 1‐year survival rate was 29%. The median local control (LC) period was 5 months and the 6‐month control rate of irradiated tumors was 33%. A ≥30% decrease in tumor markers was observed in 31%. The most common grade 3 toxicity was lymphocytopenia (40%), followed by fatigue (6%). Radiation‐induced liver disease (RILD) was not observed. Pancreatic cancer as the primary tumor, distant metastases outside the liver, low pretreatment neutrophil‐to‐lymphocyte ratio (NLR), and low pretreatment monocyte‐to‐lymphocyte ratio (MLR) were associated with poorer prognoses. Conclusions Helical tomotherapy for chemo‐refractory multiple liver metastases is a feasible and potentially effective treatment. Incorporating tomotherapy into the first‐line treatment in combination with systemic chemotherapy should be considered. Trial registration number CROG 12005., Despite the remarkable advances of systemic chemotherapy for multiple liver metastases, the efficacy is still limited and cure of the multiple lesions is difficult. Helical tomotherapy for chemo‐refractory multiple liver metastases was suggested to be a feasible and potentially effective treatment with acceptable adverse events.

Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.

Background To treat multiple targets separated in the craniocaudal direction within a short time, we invented a new technique using multiple static‐port tomotherapy with the dynamic‐jaw mode and named it the pseudo‐DJDC (pDJDC) technique. We compared the pDJDC plans and helical tomotherapy plans using the dynamic‐jaw mode (HDJ) for multiple targets. In the pDJDC plans, we used a beam set with 2–7 ports to the targets at the same level in the craniocaudal direction, and employed another beam set for other targets using different port angles (9–12 angles in total). Methods In seven patients, two plans using the pDJDC and HDJ techniques were compared. For multiple targets (n = 2–6), 20–60 Gy in 2‐ to 7.5‐Gy fractions were prescribed for the planning target volumes at D50%. The conformity index, uniformity index (D5%/D95%), dose distribution in the lung, and treatment time were evaluated. Results The median conformity index of all seven patients was 3.0 for the pDJDC plans and 2.4 for the HDJ plans (P = 0.031). The median uniformity indices of the planning target volume (n = 25) for the two plans were 1.048 and 1.057, respectively (P = 0.10). For five patients with thoracic targets, the median mean lung doses were 2.6 Gy and 2.4 Gy, respectively (P = 0.63). The median V5Gy and V20Gy of the lungs in the five patients were 11.8% and 8.5% (P = 0.63), and 1.6% and 2.1% (P = 0.31), respectively. The pDJDC plans reduced the treatment time by 48% compared to the HDJ plans (median: 462 and 884 sec, respectively, P = 0.031). Conclusion The pDJDC technique allows treatment of multiple targets in almost half the time of the HDJ technique. The pDJDC plans were comparable to the HDJ plans in dose distribution, although the conformity index deteriorated.

Background and Aim Helicobacter pylori (H. pylori) infection is a strong risk factor for the development of gastric cancer. In 2013, the Japanese government approved H. pylori eradication therapy in patients with chronic gastritis as well as peptic ulcer. However, the continuing decline in eradication rates for first-line H. pylori eradication therapies is an urgent problem. In this study, we investigated changes in the first-line eradication rate from 2001 to 2010. Methods Eradication rates for 7-day triple therapy [proton pump inhibitor (rabeprazole 20 mg, lansoprazole 60 mg, or omeprazole 40 mg) + amoxicillin 1500 mg + clarithromycin (CAM) 400 or 800 mg, daily] were collated from 14 hospitals in the Tokyo metropolitan area. The urea breath test was used for the evaluation of eradication. The cut-off value was less than 2.5%. Results The yearly eradication rates (intention to treat/per protocol) were 78.5/79.5% (2001, n = 242), 71.2%/72.9% (2002, n = 208), 67.8%/70.5% (2003, n = 183), 75.6%/84.6% (2004, n = 131), 56.4%/70.5% (2005, n = 114), 70.5%/75.8% (2006, n = 271), 67.4%/82.0% (2007,n = 135), 64.0%/76.3% (2008, n = 261), 60.5%/74.3% (2009, n = 329), and 66.5%/78.8% (2010, n = 370), respectively. Examination of eradication rates according to CAM dosage revealed an eradication rate of 65.6% (383/584) for CAM 400 mg daily, and 68.5% (1124/1642) for CAM 800 mg daily, with no significant difference seen between dosages. Conclusion In recent years, eradication rates for first-line triple therapy have obviously decreased, but no noticeable decrease has occurred after 2001.

Background: The environment surrounding Helicobacter pylori eradication treatment is dramatically changing. Recently, vonoprazan, a first-in-class potassium-competitive acid blocker (P-CAB), was introduced onto the market in 2015. The aging of Japan’s demographic structure is becoming pronounced. In this study, we examined the trend of the eradication rate of H. pylori in the metropolitan area and examined factors concerning successful eradication. Methods: We collected data from 20 hospitals in the Tokyo metropolitan area on patients who received first-line eradication therapy with a proton-pump inhibitor (PPI)/P-CAB, amoxicillin, and clarithromycin for 1 week and second-line eradication therapy with a PPI/P-CAB, amoxicillin, and metronidazole for 1 week from 2013 to 2018. The annual eradication rate and associated factors for successful eradication were analyzed. Results: We collected data of 4097 and 3572 patients in the first- and second-line eradication therapies, respectively. The eradication rate decreased from 2013 to 2014 and increased again from 2015 to 2018 with the first-line therapy [the eradication rates in 2013, 2014, 2015, 2016, 2017 and 2018 were 71.8%, 63.7%, 78.5%, 84.6%, 89.7 and 90.1%, respectively, in the per protocol (PP)]. The second-line eradication rates were 90.0%, 82.6%, 88.8%, 87.5%, 91.8% and 90.1% in 2013, 2014, 2015, 2016, 2017 and 2018, respectively, in PP. Vonoprazan was an independent factor for successful eradication in not only first-line, but also second-line eradication. Age over 75 years was an independent factor for eradication failure in both first- and second-line eradication therapies. Conclusion: The eradication rate improved from 2015 to 2018 with the first-line therapy because of the introduction of vonoprazan in the market. The eradication rates with first- and second-line regimens in elderly patients were lower than those in younger patients.

Background In Japan, the eradication rate of first-line therapy for Helicobacter pylori (H. pylori) with a proton pump inhibitor (PPI), amoxicillin (AMPC) and clarithromycin (CAM) has been decreasing because of a high prevalence of CAM resistance. A possible decrease of the eradication rate for second-line therapy with a PPI, AMPC and metronidazole (MNZ) is of concern. The aim of this study is to assess the trends in second-line eradication therapy for H. pylori in Japan. Materials and Methods We accumulated data retrospectively on patients administered second-line eradication therapy for Helicobacter pylori with a PPI, AMPC, and MNZ for 1 week after failure of first-line eradication therapy with a PPI, AMPC and CAM at 15 facilities in the Tokyo metropolitan area in Japan from 2007 to 2011. Trends for second-line eradication rates in modified intention-to-treat (ITT) analyses were investigated. Second-line eradication rates were categorized by three PPIs (rabeprazole (RPZ), lansoprazole (LPZ) or omeprazole (OMZ)) and evaluated. Results We accumulated data on 1373 patients. The overall second-line eradication rate was 92.4%. Second-line eradication rates in 2007, 2008, 2009, 2010 and 2011 were 97.7, 90.6, 94.5, 91.8 and 91.8%, respectively, with no significant trends revealed. Second-line eradication rates categorized by three PPIs for the entire 5-year period were 91.6, 93.4 and 92.4% (RPZ, LPZ and OPZ, respectively) with no significant differences among the three PPIs. Conclusions From 2007 to 2011, there were no significant trends in the second-line eradication rates and the rates remained consistently high. From the viewpoint of high prevalence of CAM resistance in Japan, triple therapy with PPI, AMPC and MNZ may be a better strategy for first-line therapy compared to triple therapy with PPI, AMPC and CAM.

Background and aim The risk of developing colorectal cancer is higher in patients with ulcerative colitis (UC) than in the general population. Guidelines recommend surveillance colonoscopy (SCS) to reduce mortality; however, few studies have assessed physicians’ adherence to guidelines. This study was aimed to clarify the current status of SCS and adherence to guidelines through the characteristics of cancer/dysplasia surveillance for UC patients in Japan. Methods A questionnaire was mailed to 541 physicians who attended meetings on inflammatory bowel disease. Results The respondents encountered a median of 100 UC cases. Thirty percent of the respondents had never managed a UC patient with cancer. Fifty-one percent of the respondents had never diagnosed colorectal cancer with UC. Forty-seven percent of the respondents considered total colitis and left-sided colitis as indications for SCS, and 38% performed SCS regardless of the disease extent. Sixty-three percent of the respondents started SCS at 7–10 years after UC onset, whereas 20% started SCS at 3 years or less. Fifty-two percent of the respondents obtained targeted biopsies only, and chromoendoscopy was employed by 49% of the respondents as a special technique for surveillance. The median number of biopsies at SCS was 5 per patient; it was 3 among patients performed by physicians who obtained targeted biopsies only and 7 among those performed by physicians who obtained step biopsies and targeted biopsies (p < 0.0001). Conclusion A considerable proportion of the respondents did not follow the guidelines when selecting patients for surveillance and performing SCS. This article is protected by copyright. All rights reserved.

The gold standard for breast cancer treatment is surgery, but many women may desire to avoid surgery if possible. The purpose of this study was to evaluate whether breast cancer could be cured with modern sophisticated radiation techniques with good cosmetic outcome. We have treated 18 patients with operable breast cancer by conventional whole-breast irradiation followed by stereotactic body radiotherapy (primary tumor only) or intensity-modulated radiotherapy (tumor plus axillary nodes) boost. The planned doses were 50 Gy in 25 fractions, 18 to 25.5 Gy in 3 fractions, and 20 Gy in 8 fractions, respectively, for the 3 modalities. Stereotactic body radiotherapy was delivered with 7 to 9 coplanar and noncoplanar fixed beams, and intensity-modulated radiotherapy was given by tomotherapy. Chemotherapy and/or hormone therapy was used depending on the stage and receptor status. In 9 recent patients, hydrogen peroxide was intratumorally injected twice a week before whole-breast irradiation. All treatments were well tolerable and there were no grade ≥3 toxicities. With a median follow-up period of 35 months (range, 8-120 months), only 1 patient developed local recurrence and 2 patients developed distant metastasis. Overall survival, progression-free survival, and local control rates were 93%, 85%, and 92%, respectively, at 3 years. In 50% of the patients, the irradiated breast became better rounded, and the position of the nipple of the irradiated breast became ≥1 cm higher compared to that of the unirradiated breast. Thus, the treated breasts may be more aesthetically favorable than before irradiation in these patients. This may become a treatment option for patients with operable breast cancer.

Background and Goals: The prevalence of irritable bowel syndrome (IBS) among Japanese patients who visit hospitals departments of internal medicine is thought to be high. However, no clear statistical evidence has been provided to support such a claim. We tested the hypotheses that the prevalence of IBS in medical outpatients clinics in Japan is high, and that IBS patients feel more psychosocial stress than patients without IBS. Study: The subjects in this study were 633 patients who visited participating physicians. Patients were asked to fill in the Japanese version of the Rome II Modular Questionnaire (RIIMQ) for IBS diagnosis, the Self-reported Irritable Bowel Syndrome Questionnaire (SIBSQ) for severity of the disease and the demographic questionnaire for perceived stress and life style. Results: Rome II-defined IBS was diagnosed in 196 patients (31%). Analysis of variance revealed significant difference in the IBS scores of SIBSQ among IBS subjects (39.0 ± 11.1, mean ± SD), functional bowel disorder subjects (27.1 ± 10.2), and normal subjects (24.0 ± 10.0, P < 0.01). The prevalence of IBS depending on age formed 2 peaks, one among adolescents and the other among the elderly. IBS patients had significantly more perceived stress (P < 0.0001), irregular sleep habit (P < 0.0001), and irregular meal habit (P < 0.0001) than those without IBS. Conclusions: The prevalence of IBS among medical outpatients in Japan is high (31%). IBS subjects among medically ill patients are thought to have more perceived stress and less regular life styles.

Corticotropin-releasing factor (CRF) and urocortin I (UcnI) have been shown to accelerate colonic transit after central nervous system (CNS) or peripheral administration, but the mechanism of their peripheral effect on colonic motor function has not been fully investigated. Furthermore, the localization of UcnI in the enteric nervous system (ENS) of the colon is unknown. We investigated the effect of CRF and UcnI on colonic motor function and examined the localization of CRF, UcnI, CRF receptors, choline acetyltransferase (ChAT), and 5-HT. Isometric tension of rat colonic muscle strips was measured. The effect of CRF, UcnI on phasic contractions, and electrical field stimulation (EFS)-induced off-contractions were examined. The effects of UcnI on both types of contraction were also studied in the presence of antalarmin, astressin2-B, tetrodotoxin (TTX), atropine, and 5-HT antagonists. The localizations of CRF, UcnI, CRF receptors, ChAT, and 5-HT in the colon were investigated by immunohistochemistry. CRF and UcnI increased both contractions dose dependently. UcnI exerted a more potent effect than CRF. Antalarmin, TTX, atropine, and 5-HT antagonists abolished the contractile effects of UcnI. CRF and UcnI were observed in the neuronal cells of the myenteric plexus. UcnI and ChAT, as well as UcnI and 5-HT, were colocalized in some of the neuronal cells of the myenteric plexus. This study demonstrated that CRF and UcnI act on the ENS and increase colonic contractility by enhancing cholinergic and serotonergic neurotransmission. These peptides are present in myenteric neurons. CRF and, perhaps, to a greater extent, UcnI appear to act as neuromodulators in the ENS of the rat colon.

Urocortin 3 (Ucn 3) or stresscopin (SCP) is a new member of the corticotropin-releasing factor (CRF) neuropeptide family and is a specific ligand for CRF type 2 receptor (CRF2). CRF receptors are known to be expressed in the gastrointestinal tract and are considered to play pathophysiological roles, for example, in gastrointestinal motility under stress. We, therefore, examined Ucn 3 expression in the normal human large intestine obtained from surgery and autopsy in order to clarify this local response to stress in human intestine. Both immunohistochemistry and mRNA in situ hybridization demonstrated Ucn 3 expression in myenteric and submucosal nervous plexus, in vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) of blood vessels in subserosa, in smooth muscle layers of the large intestine, and in enterochromaffin cells. In contrast to Urocortin 1 (Ucn 1), Ucn 3 was hardly detected in lamina propria (LP) inflammatory cells in colonic mucosa. In addition, immunohistochemistry demonstrated CRF2 expression in myenteric and submucosal nervous plexus, in smooth muscle layers, in VECs, in VSMCs and in lamina propria inflammatory cells. Immunoreactive Ucn 3 was also detected in the large intestine by RIA, with high concentrations detected in the rectum (15.4+/-9.5 pmol/g wet weight, mean+/-SEM, n=3) and sigmoid colon (6.5+/-3.5 pmol/g wet weight, n=5). Reverse-phase HPLC of the human large intestine disclosed peaks eluting in the position of synthetic Ucn 3 or SCP. These findings all suggest that Ucn 3 plays some physiological or pathological roles in the modulation of gastrointestinal functions during stressful conditions in different manners from Ucn 1.

Interleukin-18 (IL-18) is believed to be one of the most important cytokines in the pathogenesis of inflammatory bowel disease (IBD). The aim of the study was to clarify the significance of single-nucleotide polymorphisms (SNPs) at the 5′-end of the IL-18 gene in the development of IBD. DNA was obtained from peripheral blood of 99 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 102 healthy controls. All participants were Japanese. SNPs at −656G/T, −607C/A, −137G/C, +113T/G, and +127C/T were determined by means of direct sequencing, and a genetic association with IBD was examined. The frequencies of the G allele at +113 and the T allele at +127 were significantly higher in patients with CD and UC compared with controls. The differences in allelic frequencies were more striking in patients with CD than in patients with UC, and at position +127 than at position +113. The haplotype estimation, according to the E-M algorithm, suggested that TACGT is closely associated with IBD, especially with CD. It was concluded that SNPs at the 5′-end of IL-18 gene might be closely related to the etiology of IBD.

Human metastatic colorectal carcinomas (CRCAs) express carcinoembryonic antigen (CEA) and/or MUC1 tumor-associated antigens as potential targets for the induction of active specific immunity. In the present study, freshly isolated metastatic CRCA cells were successfully fused with immature autologous human monocyte-derived dendritic cells (DCs). The created heterokaryons (DC/CRCA) coexpress the CRCA-derived CEA and MUC1 antigens and DC-derived MHC class II and costimulatory molecules. The fusion cells were functional in stimulating the proliferation of autologous T cells. In addition, both CD4+ and CD8+ T cells were activated by fusion cells, as demonstrated by the production of high levels of IFN-γ. More importantly, coculture of fusion cells with patient-derived peripheral blood mononuclear cells (PBMCs) resulted in the induction of antigen-specific cytotoxic T lymphocytes (CTLs). CTLs were effective at lysis of not only autologous CRCA cells but also the CEA and/or MUC1-positive and HLA partially matched target cells. Antigen-specific CTL responses were confirmed by tetrameric analysis. Coculture of PBMCs with fusion cells resulted in increased frequency of CEA- and MUC1-specific CTLs simultaneously. Taken together, these results indicate that freshly isolated human metastatic CRCA cells expressing the CEA and/or MUC1 may represent a potential partner for the creation of DC/tumor fusion cells targeting induction of antigen-specific CTL responses. Our report demonstrates the simultaneous induction of CRCA-specific CTL responses restricted by HLA-A2 and -A24. © 2005 Wiley-Liss, Inc.

Vascular smooth muscle cells and pericytes express MMP-1, MMP-9, TIMP-1 and type I procollagen in inflammatory bowel disease Aims: Matrix metalloproteinases (MMPs) are involved in tissue remodelling, which is one of the important aspects of inflammatory disease. To assess the balance between the matrix degradation and production, we analysed the in situ expression of MMP-1, -3, -8 and -9, tissue inhibitor of metalloproteinases (TIMP)-1 and -2, and type I procollagen (PC-I) in inflammatory bowel disease. Methods and results: Immunohistochemistry using frozen sections was performed in 17 patients with ulcerative colitis (UC) and 16 with Crohn’s disease (CD). In both UC and CD, MMPs and TIMPs were expressed by inflammatory cells as well as by fibroblastic cells most prominently in actively inflamed areas in ulcer bases, but sparsely in intact inflamed mucosa in both UC and CD. In UC, inflamed mucosa with erosions expressed these substances focally. Fibroblasts also expressed PC-I. We identified that vascular smooth muscle cells of venules in ulcer bases expressed MMP-1 and -9, TIMP-1 and PC-I. These venules also expressed E-selectin, a cell adhesion molecule to facilitate the leucocyte extravasation, and vascular endothelial growth factor (VEGF) receptor 2, consistent with their property of newly formed vessels. Conclusions: Our results suggest that MMPs are involved in the tissue remodelling, angiogenesis and promotion of leucocyte extravasation in the actively inflamed area in the ulcer base in both UC and CD. MMP-1 expression in the mucosa may be related to the initial step of ulceration in UC. Therapeutic manipulation of extracellular matrix turnover would be an effective therapy to alleviate active inflammation and accelerate ulcer healing.

Myofibroblasts in the periacinar area of the pancreas have been demonstrated to mediate fibrogenesis in pancreatic fibrosis. However, only a few reports have described myofibroblasts in the pancreatic duct. To elucidate the presence of myofibroblasts in the pancreatic ductal wall, we performed an immunohistochemical study, using immunostains for both alpha-smooth muscle actin (alphaSMA) and desmin, and an electron microscopic study on surgically resected pancreatic specimens from 10, 23, 23, and 56 cases of focal pancreatitis (FP), chronic pancreatitis (CP), pancreatic carcinoma (PCa), and carcinoma of the papilla of Vater (VPCa), respectively. All cases showed localized stenosis of the main pancreatic duct by means of preoperative pancreatography. As controls, 20 autopsy cases were studied. alphaSMA-positive and desmin-negative cells existed in the ductal walls of controls and were revealed as myofibroblasts by means of electron microscopy. In six FPs, proliferation of myofibroblasts was observed at the stenotic portion. In VPCas, myofibroblasts mainly proliferated in the pancreatic ductal wall. In CPs and PCas, no myofibroblast proliferation was observed at the stenotic portion. The proliferation of myofibroblasts might occur as a wound healing process in FP, while acting against elevation of intraductal pressure in VPCa. In conclusion, proliferation of myofibroblasts plays an important role in ductal changes in various pathological situations.

The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and beta-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the beta-catenin gene were observed in any patient. One patient lacked beta-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic beta-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributable to environmental factors such as Helicobacter pylori infection.

A new model of MnSiF6.6H2O is presented which reproduces the `weak' h0l reflections not explained with the `anti­phase domain' model by Chevrier [Acta Cryst. (1991), B47, 224–228]. Good agreement for the `weak' reflections was obtained by assuming a sort of submicroscopic twinning. The average distances are Mn—O 2.15, Si—F 1.69 and O⋯F 2.78 A.

We have developed a new decompression brake, which incorporates an original operation mechanism, in answer to user demands for more powerful brake performance. This decompression brake improves braking power by more than 50% compared with a conventional exhaust brake, when operated in tandem with an exhaust brake. The decompression brake contributes to safe driving, to alleviate driver fatigue, and to prolong brake lining life. This paper reports on the following subjects: 1. (1)The principle and development of the original operation system. 2. (2) Test results of performance and load analysis.

A new model of MnSiF6.6H2O is presented which reproduces the `weak' h0l reflections not explained with the `anti­phase domain' model by Chevrier [Acta Cryst. (1991), B47, 224–228]. Good agreement for the `weak' reflections was obtained by assuming a sort of submicroscopic twinning. The average distances are Mn—O 2.15, Si—F 1.69 and O⋯F 2.78 A.

In the palladium-catalyzed asymmetric hydrosilylation of styrene (3a) with trichlorosilane, several chiral monophosphine ligands, (R)-2-diarylphosphino-1,1‘-binaphthyls (2a−g), were examined for their enantioselectivity. The highest enantioselectivity was observed in the reaction with (R)-2-bis[3,5-bis(trifluoromethyl)phenyl]phosphino-1,1‘-binaphthyl (2g), which gave (S)-1-phenylethanol (5a) of 98% ee after oxidation of the hydrosilylation product, 1-phenyl-1-(trichlorosilyl)ethane (4a). The palladium complex of 2g also efficiently catalyzed the asymmetric hydrosilylation of substituted styrenes on the phenyl ring or at the β position to give the corresponding chiral benzylic alcohols of over 96% ee. Deuterium-labeling studies on the hydrosilylation of regiospecifically deuterated styrene revealed that β-hydrogen elimination from 1-phenylethyl(silyl)palladium intermediate is very fast compared with reductive elimination giving hydrosilylation product when ligand 2g is used. The reaction of o-allylstyrene ...

In prostaglandin E2 (PGE2)-, pirenzepine-, and indomethacin-administered rats, the incorporation of N-[methyl-3H]-N'-nitro-N-nitrosoguanidine ([methyl-3H]MNNG) into gastric mucosal DNA was measured quantitatively by liquid scintillation counting after intragastric instillation of [methyl-3H]MNNG. The amount of incorporation was 25.4 +/- 5.9 pmol/mg DNA in control rats, 11.7 +/- 3.8 pmol/mg DNA in PGE2-administered rats, 6.2 +/- 5.6 pmol/mg DNA in pirenzepine-administered rats, and 42.9 +/- 14.4 pmol/mg DNA in indomethacin-administered rats. PGE2 and pirenzepine significantly decreased the incorporation as compared with the control group. In contrast, indomethacin increased the incorporation. In addition, gastric mucosa of these drug-treated rats was studied histochemically. PGE2 and pirenzepine increased secretion of gastric mucus whereas indomethacin decreased it. It is possible that gastric mucus has a protective effect not only against ulcerogenic agents but also against carcinogens. It is considered that gastric mucus plays an important role in the defense mechanism against carcinogenesis.

Irritable bowel syndrome (IBS) is considered a biopsychosocial disorder resulting from a combination of 3 interacting mechanisms: psychosocial factors, altered motility and transit, which may reflect severity of bowel dysfunction, and increased sensitivity of the intestine or colon. In other words, mechanism in IBS is biopsychosocial disorders; psychosocial factors, altered motility, and heightened sensory function. Understanding the brain-gut axis is the key to the eventual development of effective therapies for IBS.

The aim of antitumor immunotherapy is to induce CTL responses against autologous tumors. Previous work has shown that fusion of human dendritic cells and autologous tumor cells induce CTL responses against autologous tumor cells in vitro. However, in the clinical setting of patients with colorectal carcinoma, a major difficulty is the preparation of sufficient amounts of autologous tumor cells. In the present study, autologous dendritic cells from patients with colorectal carcinoma were fused to allogeneic colorectal tumor cell line, COLM-6 (HLA-A2−/HLA-24−), carcinoembryonic antigen (CEA)+, and MUC1+ as an alternative strategy to deliver shared colorectal carcinoma antigens to dendritic cells. Stimulation of autologous T cells by the fusion cells generated with autologous dendritic cells (HLA-A2+ and/or HLA-A24+) and allogeneic COLM-6 resulted in MHC class I– and MHC class II–restricted proliferation of CD4+ and CD8+ T cells, high levels of IFN-γ production in both CD4+ and CD8+ T cells, and the simultaneous induction of CEA- and MUC1-specific CTL responses restricted by HLA-A2 and/or HLA-A24. Finally, CTL induced by dendritic cell/allogeneic COLM-6 fusion cells were able to kill autologous colorectal carcinoma by HLA-A2- and/or HLA-A24-restricted mechanisms. The demonstration of CTL activity against shared tumor-associated antigens using an allogeneic tumor cell line, COLM-6, provides that the presence of alloantigens does not prevent the development of CTL with activity against autologous colorectal carcinoma cells. The fusion of allogeneic colorectal carcinoma cell line and autologous dendritic cells could have potential applicability to the field of antitumor immunotherapy through the cross-priming against shared tumor antigens and provides a platform for adoptive immunotherapy.

Ulcerative colitis (UC) is characterized by a long-standing chronic inflammation of the bowel with intermittent periods of exacerbation and remission. Its acute exacerbation appears to be related to various stresses. Urocortin 1 (Ucn1) may play important roles in integrated local responses to stress. We therefore examined local production of Ucn1 in patients with UC by immunohistochemistry and mRNA in situ hybridization. Ucn1 immunoreactivity was predominantly detected in lamina propria plasma cells and enterochromaffin cells. In UC patients without glucocorticoid treatment, Ucn1-positive cells and plasma cells increased in proportion to the severity of inflammation (P0.0001). Ucn1-positive cells significantly increased in UC patients with advanced inflammatory grades, compared with a control group (P0.0001) and nonspecific colitis group (P0.0001). In glucocorticoid-treated patients, Ucn1-positive cells were significantly lower in number, compared with the nonglucocorticoid-treated group. Ucn1 mRNA was expressed in lamina propria plasma cells, and both corticotropin-releasing factor(1) and corticotropin-releasing factor(2(a)) mRNAs were also partially coexpressed in these cells and macrophages. The present study showed that Ucn1-positive cells were correlated with the severity of inflammation in colonic mucosa with UC, and glucocorticoid treatment decreased these cells. Ucn1 therefore may act as a possible local immune-inflammatory mediator in UC.

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. The prevalence rate is 10-20% and women have a higher prevalence. IBS adversely affects quality of life and is associated with health care use and costs. IBS comprises a group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habit, and with features of disordered defecation. The consensus definition and criteria for IBS have been formalized in the “Rome II criteria”. Food, psychiatric disorders, and gastroenteritis are risk factors for developing IBS. The mechanism in IBS involves biopsychosocial disorders; psychosocial factors, altered motility, and heightened sensory function. Brain-gut interaction is the most important in understanding the pathophysiology of IBS. Effective management requires an effective physician-patient relationship. Dietary treatment, lifestyle therapy, behavioral therapy, and pharmacologic therapy play a major role in treating IBS. Calcium polycarbophil can benefit IBS patients with constipation or alternating diarrhea and constipation.

Helicobacter species can induce carcinoma in the liver of certain mice. Furthermore, Helicobacter pylori (H. pylori) exhibits hepatotoxicity in vitro. These reports indicate that H. pylori may play a role in hepatocarcinogenesis. The aim of this study was to assess the presence of H. pylori in human hepatocellular carcinoma (HCC) to determine if H. pylori may affect the development of this disease. Liver specimens from 15 HCC patients dissected into tumor and non-tumor tissues were examined for H. pylori by PCR using two sets of primers for 16S rRNA and urease B. DNA sequencing analysis was performed to confirm that PCR products with 16S rRNA primers were derived from H. pylori DNA. The specimens were also examined for H. pylori by immunohistochemistry using anti-H. pylori antibody. H. pylori was found in 13 of 15 tumor tissues, not in the non-tumor tissues. By contrast, Escherichia coli and Bacteroides fragilis, frequent colonizers of gut, were not detected by PCR in the HCC tumors. Ten cirrhotic liver tissue specimens and seven normal liver tissue specimens were also negative for H. pylori DNA by PCR. The nucleotide sequence of the amplified fragment shared 100% identity with the 16S rRNA gene of H. pylori. H. pylori was also detected in HCC tissue by immunohistochemical analysis. The presence of H. pylori in human HCC tissue was demonstrated by PCR and immunohistochemical analysis. These findings suggest that H. pylori might contribute to the development of HCC. Further study is needed to prove the pathogenetic role of H. pylori in the development of human HCC.

Publisher Summary This chapter investigates palladium charcoal-catalyzed cross-coupling for the synthesis of ethynylpyridines and arylpyridines. The chapter examines reactions using a bromopyridine with either an electron-donating group or an electron-withdrawing group. Both reactions gave the coupling products in excellent yields. Although the reaction of 2-chloropyridine produced 2-ethynylpyridine in moderate yield, 2-chloropyridine with an electron-donating group gave the products in good yields. Suzuki–Miyaura coupling could be catalyzed by palladium charcoal, but only phenylbromides were used as a substrate, and the reactions occurred regardless of the presence of added PPh 3 . When the reaction using phenylchlorides was carried out under these conditions, the products were not obtained in good yields. The phenylchlorides has been coupled in the past, which have an electron-withdrawing group on the ring. The reaction was conducted in dimethylacetamide (DMA) in the presence of palladium charcoal, but, without a ligand.

The prevalence of the peptic ulcer in the aged associated with liver cirrhosis is not so high in comparison with that of the younger. But if bleeding occurs, it is very difficult to stop it and it influences the prognosis of the patients. The factors of liver cirrhosis which influence the therapy of peptic ulcer are bleeding tendency, hypoalbuminemia, hepatic encephalopathy, and hepatorenal syndrome. The therapies on the peptic ulcer of the aged associated with liver cirrhosis are consisted with rest therapy, diet therapy, and drug therapy. It is necessary to consider the level of liver function to decide the therapies. If bleeding occurs, the endoscopic therapy is effective, and if the patient fall to the shock status, it is necessary to consider the operation as soon as possible. It is important to evaluate the liver function to select the therapies.