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Duodenal tumors with a sporadic adenoma-carcinoma sequence are extremely rare. For such clinically suspected cases without a specific family history, performing a comprehensive gene search is important to understand the germline mutation background. We present a 68-year-old woman without a genetic or familial history of familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, or Lynch syndrome who presented to Kosei Hospital, Japan, with exertional dyspnea induced by abdominal pain lasting 3 weeks. A duodenal tumor was suspected by contrast-enhanced computed tomography. Esophagogastroduodenoscopy showed a lesion accompanied by a white microprotuberance on the descending part of the duodenum opposite the papilla, with a giant ulcerative lesion at the center of the white lesion. Biopsy revealed a low-grade adenoma, high-grade adenoma, and adenocarcinoma. Immunohistochemical analysis of the adenoma and adenocarcinoma showed Ki-67, p53, cytokeratin 20, caudal-type homeobox 2, and carcinoembryonic antigen positivity and cytokeratin 7 negativity. The findings suggested the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma. However, in the mutational analysis using next-generation sequencing, c.4348C>T (p.Arg1450Ter) mutation in APC was detected in all normal mucosal, adenoma, and carcinoma tissues. This mutation is common in FAP patients. Even if the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma is suggested in cases without a familial FAP history, as in this case, genetic analysis may reveal FAP. Thus, performing a comprehensive genetic analysis of duodenal carcinoma patients with a possible adenoma-carcinoma sequence is necessary to explore their genetic background.

Background/Aims: To elucidate the current management of ulcerative colitis (UC)-associated cancer, a questionnaire-based survey was conducted to gather current opinions on colitis-associated cancer in different East Asian countries. Methods: The questionnaire, based on physicians, contains 9 questions focused on UC management and cancer surveillance. In addition, the questionnaire based on neoplastic cases, which contains 17 questions, was collected and analyzed. Results: With regard to the diagnosis of UC-associated cancer, most respondents started surveillance colonoscopy within 10 years from onset, favored targeted biopsies, and thought advanced imaging was useful. As for morphology, the frequency of elevated lesion and type 4 lesions was most common in early and advanced cancer, respectively. Peritoneal metastasis was frequently observed, and undifferentiated tumor was frequently developed. Laparoscopic surgery was widely used because it is less invasive. The prognostic outcome was poor, particularly in stage III and undifferentiated type. Conclusions: The current survey elucidated the current management in Asian countries and characteristics of colitis-associated cancer in these countries.

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.

Helicobacter (H.) suis is capable of infecting various animals including humans, and H. suis infections can lead to gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Recently, we reported that interferon-γ (IFN-γ) was highly expressed in the stomachs of H. suis-infected mice, but the direct relationship between the upregulation of IFN-γ expression and the formation of gastric lymphoid follicles after H. suis infection remains unclear. Here, we demonstrated that the IFN-γ produced by B cells plays an important role in the formation of gastric lymphoid follicles after H. suis infection. In addition, IFN-γ-producing B cells evoked gastric lymphoid follicle formation independent of T-cell help, suggesting that they are crucial for the development of gastric MALT induced by Helicobacter infection.

Background and Aim The hepatocyte growth factor (HGF)/c-Met pathway has attracted attention in the formation of malignant tumors, as HGF secreted from the microcirculatory components as well as residing macrophages has been suggested to act on the c-Met receptors of cancer cells to decrease apoptosis and increase proliferation, invasion, and metastasis. The present study was undertaken to elucidate the interaction of the gastric, hepatic, and pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma induced by Helicobacter heilmannii infection with c-Met and HGF. Methods C57BL/6 female mice, infected with H. heilmannii for 3 months were used. The localization of the HGF, c-Met, and HGF activator immunoreactivities was observed by the indirect immunohistochemical methods. In addition, the effect of c-Met antibody and c-Met inhibitor, PHA-665752, was also investigated. Results c-Met immunoreactivity was found in the lymphocytes composing the MALT lymphoma, and HGF immunoreactivity was recognized mostly in the endothelial cells and macrophages in the MALT lymphoma. HGFA was localized on mesenchymal cells other than the lymphocytes. The administration of the antibody against c-Met or the c-Met inhibitor to the infected mice induced the significant suppression of hepatic and pulmonary MALT lymphoma, while the gastric MALT lymphoma showed only a tendency to decrease in size, while the active caspase 3 positive cells markedly decreased in the gastric, hepatic, and pulmonary MALT lymphoma after the treatment with the c-Met antibody or the c-Met antagonist. Conclusions HGF and c-Met pathway were suggested to contribute to the lymphomagenesis in the MALT lymphoma after H. heilmannii infection.

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.

Helicobacter suis infects the stomachs of both animals and humans, and can induce gastric mucosa-associated lymphoid tissue (MALT) lymphomas. It is known that CXC chemokine ligand 13 (CXCL13) is highly expressed in the Helicobacter-infected mice and gastric MALT lymphoma patients, but the pathway that links the activation of CXCL13 and the formation of gastric MALT lymphomas remains unclear. In this study, we examined whether CXCL13 neutralization would interfere with the formation of gastric lymphoid follicles including B cells, CD4+T cells, dendritic cells (DCs), and follicular DCs (FDCs) in germinal centers to determine the role of CXCL13 in the formation of B-cell aggregates after H. suis infection. Moreover, the expression of genes associated with the lymphoid follicle formation was also effectively suppressed by anti-CXCL13 antibody treatment. These results suggest that the upregulation of CXCL13 has an important role in the development of gastric MALT lymphomas and highlight the potential of anti-CXCL13 antibody for protection against Helicobacter-induced gastric diseases.

Background: Since the publication of the Rome III criteria for functional dyspepsia (FD), the evidence about the efficacy of half-dose of proton pump inhibitors for dyspepsia symptoms have been limited. Objective: To examine the efficacy of lansoprazole for functional dyspepsia (FD) diagnosed with the Rome III criteria by the multicentre, double-blind, randomized, placebo-controlled study in Japan. Methods: A total of 54 FD participants were randomized to lansoprazole 15 mg once daily or placebo for a 4-week doubleblind treatment period. The primary efficacy endpoint was an overall dyspeptic symptom relief rate evaluated by 5-point Likert scale scores. The alteration of dyspeptic symptom scores during the study period was also assessed. Results: At week 4, the overall dyspeptic symptom relief rates were higher in the lansoprazole group (30.4%) than in the placebo group (6.7%) (p ¼ 0.045). The scores for epigastric pain (p ¼ 0.045) and epigastric burning (p ¼ 0.03) were significantly improved in the lansoprazole group compared to the placebo group, whereas the improvement of the scores for postprandial fullness (p ¼ 0.81) and early satiation (p ¼ 0.33) was not different between lansoprazole and placebo groups. Conclusions: Lansoprazole 15 mg ameliorates dyspeptic symptoms, particularly the epigastric pain syndrome-related symptoms of FD.

Neonatal Fc receptors for immunoglobulin (Ig)G (FcRn) assume a central role in regulating host IgG levels and IgG transport across polarized epithelial barriers. We have attempted to elucidate the contribution of FcRn in controlling Helicobacter infection in the stomach. C57BL/6J wild-type or FcRn(-/-) mice were infected with Helicobacter heilmannii, and gastric lesions, bacterial load and the levels of antigen-specific IgG in serum and gastric juice were analyzed. The elevated levels of anti-H. heimannii IgG in gastric juice were observed exclusively in wild-type mice but not in FcRn(-/-) mice. In contrast, an increase in lymphoid follicles and bacterial loads along with deeper gastric epithelium invasion were noted in FcRn(-/-) mice. C57BL/6J wild-type or FcRn(-/-) mice were also infected with Helicobacter pylori SS1, and the results of the bacterial load in stomachs of these mice and the anti-H. pylori IgG levels in serum and gastric juice were similar to those from H. heilmannii infection. Our data suggest that FcRn can be functionally expressed in the stomach, which is involved in transcytosis of IgG, and prevent colonization by H. heilmannii and the associated pathological consequences of infection.

In this study, we aimed to assess the role of helper T cells in the development of gastric lymphoid follicles induced by Helicobacter suis infection. C57BL/6J mice were orally inoculated with H. suis. Six weeks after infection, gastric lymphoid follicles were observed in the gastric mucosa by hematoxylin and eosin staining, and the number of follicles was increased throughout the infection period. An immunohistological examination showed that the lymphoid follicles were composed of B cells, CD4-positive helper T cells, and dendritic cells (DC). It was also revealed that the mRNA expression level of interferon-γ (IFN-γ) in the gastric mucosa was significantly increased at 12 weeks after infection. No gastric lymphoid follicles were detected in IFN-γ-deficient mice that had been infected with H. suis at 12 weeks after infection, although the development of lymphoid follicles in IL-4-deficient mice infected with H. suis was similar to that seen in the wild-type mice. In conclusion, IFN-γ, a Th1 cytokine, is deeply involved in the pathogenesis of gastric lymphoid follicles induced by H. suis infection, and it is suggested that CD4-positive T cells and DC aid in the expansion of gastric lymphoid follicles.

Little information is available on the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in patients of advanced age (≥80 years).A multicenter study was conducted at 10 Japanese institutions concerning their results for ESD. Data on 440 patients of advanced age (≥80 years) with EGC (470 lesions) were collected and reviewed. Early and long-term outcomes of ESD were assessed. We compared the overall survival rates between 3 patient groups, those with curative ESD, additional surgery after noncurative ESD, and nonsurgical follow-up after noncurative ESD.Bleeding and perforation rates were 3.2 and 2.8%, respectively. Curative ESD was achieved in 366 of the 470 lesions (77.9%). Of the 104 patients with noncurative ESD, 12 patients (11.5%) underwent additional surgery and 91 patients (87.5%) were followed without surgery. The 5-year survival rate in the patients with nonsurgical follow-up after noncurative ESD (66.7%) was significantly lower than that in the patients with curative ESD (80.3%, p = 0.0001). There was no significant difference in the 5-year survival rates between the patients with curative ESD and those with surgery after noncurative ESD (100%, p = 0.21), nor was there a difference in these rates between the patients with surgery after noncurative ESD and those with nonsurgical follow-up after noncurative ESD (p = 0.061). None of the patients developed cancer recurrence after curative ESD, and none developed cancer recurrence following the additional surgery after noncurative ESD. In the patients with curative ESD and in those with surgery after noncurative ESD, the cumulative observed survival was better than the expected survival for the general population of similar age and gender.ESD is safe for the treatment of EGC in patients 80 years of age or older. Both curative ESD and additional surgery after noncurative ESD may contribute to the extension of life expectancy.

Helicobacter heilmannii induces gastric lymphoid follicles in mice. However, the pathogenic mechanisms behind the induction of gastric lymphoid follicles by H. heilmannii infection have not been elucidated. The aim of this study was to investigate the roles of Peyer's patches (PP) in H. heilmannii-induced immune responses and the development of gastric lymphoid follicles. C57BL/6J and PP deficient mice were infected with H. heilmannii, and in addition to histological and immunohistological examinations, the expression levels of cytokines and chemokines in gastric mucosa were investigated. Gastric lymphoid follicle formation and the infiltration of dendritic cells, B cells, and helper T cells were milder in the PP-deficient mice 1 month after infection, but they were similar in both types of mice after 3 months. The mRNA expression levels of tumor necrosis factor α and CC chemokine ligand 2 were significantly high in the H. heilmannii-infected groups, and CXC chemokine ligand 13 expression was significantly increased in the infected C57BL/6J wild-type mice 1 month after infection. These results suggest that PP are not essential for the formation and development of gastric lymphoid follicles induced by H. heilmannii infection, although they are involved in the speed of gastric lymphoid follicle formation.

Surveillance of Helicobacter pylori antimicrobial susceptibility reflecting the general population in Japan is limited. The antimicrobial susceptibilities of 3,707 H. pylori strains isolated from gastric mucosa samples of previously untreated patients diagnosed with gastroduodenal diseases at 36 medical facilities located throughout Japan between October 2002 and September 2005 were evaluated. Using an agar dilution method for antimicrobial susceptibility testing of H. pylori , the MIC distributions and trends during the study period for clarithromycin, amoxicillin, and metronidazole were studied. While the MIC 50 and MIC 90 for clarithromycin did not change during the 3-year period, the MIC 80 showed a 128-fold increase. Furthermore, the rate of resistance increased yearly from 18.9% (2002 to 2003) to 21.1% (2003 to 2004) and 27.7% (2004 to 2005). With a resistance rate of 19.2% among males compared to 27.0% among females, a significant gender difference was observed ( P < 0.0001). Our study shows that in Japan, there is an evolving trend towards increased resistance to clarithromycin with geographical and gender differences as well as between clinical disease conditions. No significant changes in resistance were observed for amoxicillin and metronidazole during the period. While the benefit of H. pylori antimicrobial susceptibility testing has been debated in Japan, current empirical regimens are not based on susceptibility data representative of the general population. The development of an effective H. pylori eradication regimen in Japan will require continued resistance surveillance as well as a better understanding of the epidemiology of resistance.

Helicobacter heilmannii has been reported to cause gastric low-grade mucosa-associated lymphoid tissue-type (MALT) lymphoma, but its precise pathophysiological mechanism remains to be clarified. We recently established a model of gastric B-cell MALT lymphoma in C57BL/6 mice by means of peroral infection of H. heilmannii primarily obtained from cynomolgus monkeys. Using this model, macroscopic, immunohistochemical, and electron microscopic observations of MALT lymphomas were carried out in order to examine the development of apoptosis and angiogenesis. Enhancement of the microvascular network and an increase in vascular endothelial growth factor-A were detected in the central region of the MALT lymphoma tissue in the infected mouse stomach, while vascular endothelial growth factor-C was detected at the margins of the MALT lymphomas. In addition, many H. heilmannii-invaded parietal cells showed caspase-3 immunoreactivity in the fundic mucosal tissue surrounding the MALT lymphoma. In conclusion, in H. heilmannii-induced MALT lymphoma, enhanced immunoreactivity of vascular endothelial growth factor-A and factor-C was observed in areas encircled by increased parietal cell apoptosis, which indicates the pathophysiological relevance of both angiogenesis and apoptosis in MALT lymphoma formation.

Aim: Sociocultural factors are important because their different effects on the features of irritable bowel syndrome (IBS) between countries will provide clues towards solving this problem. The aims of this study were to depict the clinical realities of IBS in East Asian countries and test the hypothesis that the diagnosis and treatment of IBS differ between countries. Subjects and Methods: Study participants were 251 physicians involved in the clinical practice of IBS at major institutions in Japan, South Korea, China, the Philippines, Indonesia and Singapore. The questionnaire contained 45 questions focused on the clinical practice of IBS. Results: Subjects in Japan, South Korea, China, Indonesia, the Philippines and Singapore accounted for 55.4, 17.9, 8.8, 8.0, 6.4 and 3.6% of the study cohort, respectively. Amongst East Asian physicians, the most important symptom was considered to be abdominal pain by 33.4%, whilst 24.3% regarded alternating diarrhea and constipation to be the most important symptoms. Total colonoscopy and histopathology use showed no difference among countries. Prescriptions given for mild (p < 0.0001), moderate (p < 0.0001), severe (p < 0.0001), intractable (p = 0.002), diarrheal (p < 0.0001) and constipating (p < 0.0001) patients with IBS significantly differed between the countries. Except for several minor points, IBS specialists showed no significant difference in their diagnosis and treatment of IBS when compared to nonspecialists. Conclusion: This survey provided data on the clinical treatment of IBS among East Asian countries. The results supported the hypothesis that the diagnosis and treatment of IBS differs between countries.

原発性胆汁性肝硬変における線維化の程度をより客観的に評価するために, 画像解析装置を用いて肝組織内膠原線維を定量化し, 各種肝機能検査, 病期の進展, 肝表面および肝組織所見との関連について検討した.Ludwig 分類における肝線維化率は stage の進展に従い増加し, 各病期間に有意差を認めた. 一方, Scheuer 分類では病早期の肝線維化率に有意差はなかった. 検査データでは, GPT, T-bil, IV型コラーゲン7Sドメイン, ICG R 15においていずれも有意な正の相関を, albumin, CHEase, platelets では有意な負の相関を認めた. 赤色紋理や piecemeal necrosis を有する例の肝線維化率は, 有意に高率であった. 経過観察例では, 病期の進展に伴い, 肝線維量は増加していた.原発性胆汁性肝硬変の肝線維化率は, 臨床検査値と良好な対応を示しており, その進展を評価するには, 線維化の程度を把握することも重要であると考えられた.

In addition to eradication of Helicobacter pylori, chemotherapy with anticancer agents, and radiation therapy, the treatment with molecular target drugs including rituximab, a CD20 antagonist, is one of the promising new regimens. The mucosa-associated lymphoid tissue (MALT) lymphoma is histologically characterized by rich distribution of the microvascular network consisting of the immature capillaries, lymphatics and venules, and this microvascular network could be the target of the new pharmacotherapy in addition to the direct action on the accumulated B lymphocytes. We have established the animal model of the gastric MALT lymphoma by the Helicobacter heilmannii (H. heilmannii) peroral infection of C57BL/6 mice. The disease induced by this model is very similar to the human counterpart, because of the lymphoepithelial lesion characteristic of the human MALT lymphoma as well as the rich vascularization and localization of vascular endothelial growth factor (VEGF) and its receptors, Flt-1, Flk-1 and Flt-4. By administering VEGF receptor antibodies or celecoxib, one of the cyclooxygenase 2 inhibitors, we were able to induce a significant decrease in the size of the tumor and the apoptotic changes of the endothelial cells of the microvascular network. These antiangiogenic strategies were suggested to be candidates for the new pharmacological treatment of gastric MALT lymphoma, when other treatments are not effective.

The specific aim of this work is to clarify the characteristics of an ice/water mixture flowing in a horizontal circular pipe which will be used potentially in a district cooling system (DCS) utilizing the latent heat of ice. Sample ice was made by a chip-ice making machine, and the experimental result was compared with that of a natural snow/water mixture. The flow pattern was observed, and the pressure drop was measured in polyvinylchrolide pipes with diameters of 40, 80 and 150 mm, as well as in an 80 mm-diameter steel pipe and an 80 mm shot-blasted steel pipe. It has been shown that the empirical formula for the excess pressure loss coefficient of a snow/water mixture proposed by the present authors holds also for that of an ice/water mixture, and also applies to large-diameter pipes which will be used in DCS. The pipe material and surface roughness have shown to affect the pressure drop through friction between ice clusters and pipe wall, and a constant in the formula is related to the friction coefficient. Based on this relationship, a method to predict the pressure drop of an ice/water mixture flow in an arbitrary pipe is proposed.

Background and Aim. New diagnostic or therapeutic methods in endoscopy have been used. Current clinical application of these procedures is not well known. The aim of this study is to investigate the present situation on endoscopic diagnosis and treatment of gastrointestinal disorders in East Asian countries. Method. A representative member from the International Gastrointestinal Consensus Symposium Committee provided a questionnaire to physicians in China, Indonesia, Japan, Korea, the Philippines, and Thailand. Results. In total, 514 physicians including gastroenterologists, surgeons, and general practitioners enrolled. The most frequently occurring disorder as the origin of upper gastrointestinal bleeding is gastric ulcer. Capsule endoscopy is selected as the first choice for the diagnosis of small intestine bleeding. The second choice was double-balloon endoscopy or angiography. For patients with gastric adenoma, the number of physicians who choose endoscopic mucosal resection is larger than those selecting endoscopic submucosal dissection (ESD) in China, Indonesia, the Philippines, and Thailand. ESD is chosen first in Japan and Korea. Conclusion. New instruments or techniques on endoscopy have not come into wide use yet, and there is diversity in the situation on it in Asian countries. We should unify the endoscopic diagnostic criteria or treated strategy in patients with GI disease.

Physiological saline solutions, each adjusted to pH 1.0, pH 2.0 and pH 7.2, and added urea and urease inhibitor (Acetohydroxamic acid), were inoculated with a culture solution of Helicobacter pylori NCTC11637 strain derived from man, and allowed to react for 10, 30, 60 and 120 minutes. After five days of incubation on a blood agar medium, remaining viable H. pylori was counted. Survival of H. pylori was inadequate under the conditions of pH 1.0 and pH 2.0, but survival up to 120 min was observed on addition of urea. Further, on addition of urease inhibitor the survival time was reduced. H. pylori survived under the condition of pH 7.2 independent of addition of urea and urease inhibitor. Urea is essential for survival of H. pylori under strongly acidic conditions, and utility of urease inhibitor was observed for inhibition of survival of H. pylori.

胆嚢結石を合併し,繰り返す胆管・胆嚢炎に対して内視鏡下バルーン総胆管拡張術が有効であった原発性硬化性胆管炎(以下PSC)の1症例を経験したので報告する.症例は39歳男性.2年来繰り返す腹痛・発熱を主訴に来院した.胆石・胆嚢炎の診断にて治療していたが,1年後の腹部超音波検査にて肝内胆管に多発性の不整な拡張を認めたため,入院した.入院時肝機能検査は正常であったが,内視鏡的逆行性胆道造影では総胆管は全長にわたり狭窄しており,肝内胆管は不整に拡張していた.PSCを疑い腹腔鏡下肝生検を施行したところ,組織像はPSCに合致した所見を示していた.大腸内視鏡にて炎症性腸疾患の合併もあり,胆嚢結石及び胆管・胆嚢炎を合併したPSCと診断した.一旦外来管理としたが,胆管・胆嚢炎にて再入院した.入院後,内視鏡下にバルーン総胆管拡張術を2回施行した.その後胆管・胆嚢炎の発症はなく,現在外来通院中である.

The major cause of chemotherapy failure in patients with chronic gastritis and peptic ulcers caused by Helicobacter pylori is clarithromycin (CAM) resistance due to a mutation in the 23S rRNA gene. This study describes a non-invasive and accurate method for the detection of mixed CAM-resistant and -susceptible H. pylori by sequencing of the H. pylori 23S rRNA gene. Faeces were crushed with beads and the 23S rRNA gene was amplified using a nested PCR on the extracted DNA. Mutation analysis of this gene using this method showed that 20.4 % of patients carried mixed CAM-susceptible (wild type) and -resistant (A2142G or A2143G mutant) H. pylori. Furthermore, it was found that 66.6 % of patients who had been treated unsuccessfully carried one of these mutations in the 23S rRNA gene (including the mixed type), whilst standard culture detected CAM-resistant isolates in only 22.2 % of patients with unsuccessful treatment. These data suggest that, for successful therapy, the diagnosis method described here would more accurately detect CAM-resistant H. pylori, including mixed infections.

Both Helicobacter pylori and “ Candidatus Helicobacter heilmannii” infections are associated with peptic ulcers, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. However, good animal models of H. pylori clinical diseases are rare. In this study, we aimed to establish an animal model of “ Candidatus Helicobacter heilmannii” gastric MALT lymphoma. We used a urease-positive gastric mucosal and mucus homogenate from a cynomolgus monkey maintained in C57BL/6 mouse stomachs. The bacterium in the homogenate was identified as “ Candidatus Helicobacter heilmannii” based on a DNA sequence analysis of the 16S rRNA and urease genes. Mucosal and mucus homogenates were used to inoculate C57BL/6 mice, which were then examined for 24 months. We observed a gradual increase in the surface area of protrusive lesions in almost all infected C57BL/6 mouse fundic stomachs 6 months after infection. Light microscopic observations revealed an accumulation of B lymphocytes along with destruction of glandular elements and the presence of lymphoepithelial lesions consistent with low-grade MALT lymphomas. Electron microscopic observation revealed numerous “ Candidatus Helicobacter heilmannii” bacilli in the fundic glandular lumen, the intracellular canaliculi, and the cytoplasm of intact cells, as well as damaged parietal cells. In conclusion, “ Candidatus Helicobacter heilmannii” induced gastric MALT lymphomas in almost 100% of infected C57BL/6 mice after a 6-month period associated with the destruction of parietal cells.

After official acceptance of eradication therapy for Helicobacter pylori infected peptic ulcer disease in 2000, this treatment has been generalized as ulcer therapy in Japan. In 2003 the consensus statement of the Japanese Society for Helicobacter Research (JSHR) for Helicobacter pylori infection was presented. According to this statement MALT lymphoma was recommended to treat H. pylori infection because of the efficacy of its out come. Atrophic gastritis was also advised to treat H. pylori infection for the purpose of preventing gastric cancer development. The extra alimentary disease such as idiopathic thrombocytopenic purpura was still under evaluation. In diagnostic method the importance of drug susceptibility test is rising because of the increase of drug resistant H. pylori strain in Japan. The false positive case of urea breath test, the accuracy of new Japanese original serology tests and the stool antigen test are also under investigation. The standard regimen of H. pylori eradication therapy in Japan is proton pomp inhibitor (PPI) + amoxicilin (AMPC) + clarithromycin (CAM). The problem of this regimen is the decrease of eradication rate. The reason of this trend might be increase of CAM resistant strain. JSHR recommended a rescue regimen as PPI + AMPC + metronidazole for the patient whose first eradication therapy was unsuccessful result. The eradication of this second line regimen was reported as about 90%.

Background/Aim: One of the features of gastroesophageal reflux disease (GERD) in Japan is that its frequency and severity tend to increase in elderly women. In addition, elderly patients (≥65 years) with non-erosive reflux disease (NERD) present with typical symptoms more frequently than do non-elderly patients with NERD. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and enhances gastric emptying and improves gastric accommodation. Our previous prospective randomized multicenter placebo-controlled study, the G-GRIDE study, showed that RKT combined with a standard-dose of rabeprazole (RPZ) therapy significantly improved the acid-related dysmotility (ARD) symptoms in elderly patients with PPI-refractory NERD. The aim of this study was to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. Methods: Two hundred forty-two patients with PPI-refractory NERD were enrolled from August 2011 to July 2012 at 71 hospitals in Japan. Patients were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) plus rikkunshito (7.5 g/t.i.d.) (RKT group) or RPZ plus placebo (PL group) therapy. Of the 242 patients, 95 were elderly patients (≥65 years) with ARD (RKT group: n=52, PL group: n=43). We analyzed the changes using the 12 subscale score of the frequency scale for the symptoms of GERD (FSSG) at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. Results: No significant differences were seen between the 2 groups in terms of subject background. The FSSG score (mean±SD; at 0, 4, and 8 weeks) in both the RKT [16.0±7.0; 9.9±8.4; 7.0±6.4] and PL [15.1±6.4; 10.9±6.7, 11.1±8.5] groups significantly decreased after the treatment. However, the degree of improvement of total and ARD scores of FSSG after 8 weeks of treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach after meals, and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. Conclusion: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. RKT was especially effective for resolving postprandial GERD symptoms (heavy feeling in stomach after meals, sick feeling after meals, and heartburn after meals).

We determined the MICs of clarithromycin for 32 Helicobacter pylori strains isolated from gastric mucosa of patients, by using microdilution broth method under different microaerobic conditions (CO2: 5% and 15%). The pH of broth was more acidic at 15% CO2 than that of at 5% CO2. The MICs of clarithromycin for all H. pylori strains at 15% CO2 condition were higher than that of clarithromycin at 5% CO2 condition. Comparing the MICs with the results of eradication therapy, we concluded that the measurement of MIC under 5%CO2 condition is more useful for expecting the clinical outcome.

Triple-agent therapy with lansoprazole (15 mg/kg)-clarithromycin (50 mg/kg)-amoxicillin (50 mg/kg) twice daily for 7 days fully cleared “ Candidatus Helicobacter heilmannii” from infected mouse stomachs. Moreover, gastric mucosa-associated lymphoid tissue lymphoma-like lesions in the stomach nearly disappeared in the treated mice 4 months after the therapy.