Takeshi Azuma

Kobe University, Kōbe, Hyōgo, Japan

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Publications (430)2282.06 Total impact

  • No preview · Article · Jan 2016 · Endoscopy
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    ABSTRACT: CagA, encoded by cytotoxin-associated gene A (cagA), is a major virulence factor of Helicobacter pylori, a gastric pathogen involved in the development of upper gastrointestinal diseases. Infection with cagA-positive H. pylori may also be associated with diseases outside the stomach, although the mechanisms through which H. pylori infection promotes extragastric diseases remain unknown. Here, we report that CagA is present in serum-derived extracellular vesicles, known as exosomes, in patients infected with cagA-positive H. pylori (n = 4). We also found that gastric epithelial cells inducibly expressing CagA secrete exosomes containing CagA. Addition of purified CagA-containing exosomes to gastric epithelial cells induced an elongated cell shape, indicating that the exosomes deliver functional CagA into cells. These findings indicated that exosomes secreted from CagA-expressing gastric epithelial cells may enter into circulation, delivering CagA to distant organs and tissues. Thus, CagA-containing exosomes may be involved in the development of extragastric disorders associated with cagA-positive H. pylori infection.
    Preview · Article · Jan 2016 · Scientific Reports
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    ABSTRACT: Background and aim: Alcoholic liver disease (ALD) is the most common cause of hepatocellular carcinoma (HCC) worldwide. Des-gamma-carboxy prothrombin (DCP) is elevated in many patients with HCC, but also in severe alcoholics without HCC. We aimed to clarify whether the DCP/NX-DCP ratio (NX-DCP-R) could have a high specificity in ALD patients without HCC. Methods: We performed a prospective cohort study on a total of 703 consecutive outpatients of liver diseases including severe alcoholics and healthy volunteers, who underwent blood biochemical examinations at Kobe University Hospital. Serum DCP was measured by electrochemiluminescence immunoassay (ECLIA) using a monoclonal antibody, MU-3. A novel parameter, serum NX-DCP, which represents predominantly DCP caused by reduced vitamin K availability, was also measured by ECLIA using monoclonal antibodies P-16 and P-11. The diagnostic accuracy of DCP and NX-DCP-R in patients with and without excessive alcohol intake was statistically examined. Results: DCP was significantly higher in alcoholics than in non-alcoholics (p= 0.005), whereas the NX-DCP-R did not differ between alcoholics and non-alcoholics (p= 0.375). DCP was significantly increased in the serum of each patient with alcoholic hepatitis and alcoholic cirrhosis (p< 0.05), whereas the NX-DCP-R was not increased (p> 0.05). Conclusions: NX-DCP-R, but not DCP, was not increased in alcoholics without HCC. As for negative screening for HCC, the specificity of the NX-DCP-R in alcoholics without HCC was better than that of DCP in alcoholics without HCC, and so could be a useful negative screening tool for HCC in millions of alcoholics worldwide.
    No preview · Article · Nov 2015 · Cancer biomarkers: section A of Disease markers
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    ABSTRACT: Objective The standard treatment for submucosal esophageal cancer is esophagectomy or chemoradiotherapy (CRT). However, these treatment modalities could deteriorate the general condition and quality of life of the patients who are intolerant to invasive therapy. It is therefore important and beneficial to develop less invasive treatment protocols for these patients. Methods The study included 43 patients who were clinically suspected of mucosa or submucosal esophageal cancer but underwent endoscopic submucosal dissection (ESD) as a primary treatment, due to the patients’ poor performance statuses and/or preferences for less invasive therapy. According to the pathological findings and patient’s general condition, whether the patient underwent additional treatments or remained hospitalized without additional treatments was thereafter decided for each patient. We retrospectively analyzed the outcomes of these patients. Results Fifteen patients underwent additional surgery, 11 patients underwent CRT/radiation therapy (RT) and 17 patients were followed without additional treatments. During the 3-year follow-up period, the relapsefree survival rates in the patients who received or did not receive additional treatments were 88% and 64%, respectively (95% confidence interval, 0.45-0.76, p=0.04). The relapse-free and overall survival rates in the patients with additional treatments were equivalent or superior to those described in previous reports of the standard treatments. Preceding ESD contributed to reduce the local relapse significantly to approximately 3.5% and additional CRT-related toxicities. Conclusion Preceding ESD is very effective for the local control of cancer, and useful for histologically confirming the high-risk factors of relapse, such as ≥submucosal layer 2 (SM2) invasion and lymphovascular involvements. ESD with additional therapy may be a promising strategy for optimizing the selection of therapy depending on the patient’s general condition.
    No preview · Article · Nov 2015 · Internal Medicine

  • No preview · Article · Oct 2015 · Endoscopy
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    ABSTRACT: Recent studies have suggested that a peculiar tumor mimicking intraductal tubulopapillary neoplasms (ITPNs) of the pancreas can develop in the bile duct. Here, we present a similar case and review the literature on the newly proposed biliary neoplasm. A 68-year-old lady was referred to us for further evaluation of a liver mass. On imaging, the tumor was 40 mm in size and intraductal in location, and was enhanced slightly on the contrast-enhanced CT. No mucin overproduction was found. She underwent right hepatectomy for suspected intraductal papillary neoplasm of the bile duct (IPNB). The tumor histologically consisted of the biliary-type epithelium arranged in a tubular architecture within the dilated bile duct. Tumor cells had features of high-grade dysplasia but no stroma invasion. No expressions of MUC2 and MUC5AC were noted. On molecular studies, KRAS and GNAS appeared to be wild-type genotypes. These features were in keeping with ITPNs. In the literature review, "biliary ITPNs" described in four manuscripts were characterized by predominantly intrahepatic/hilar in location, histologic tubular architecture, negative expressions of MUC2 and MUC5AC, and uncommon alterations of KRAS, GNAS, and BRAF. Although invasive malignancy was present in 71%, the outcome was favorable with the 5-year survival expected to be around 90%. Biliary ITPNs are supposedly uncommon, but a greater awareness of this condition may give more chance to diagnose the under-recognized neoplasm.
    No preview · Article · Oct 2015 · Hepatology Research
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    ABSTRACT: Cancer cachexia, which is characterized by decreased food intake, weight loss and systemic inflammation, increases patient's morbidity and mortality. We previously showed that rikkunshito (RKT), a Japanese traditional herbal medicine (Kampo), ameliorated the symptoms of cancer cachexia through ghrelin signaling-dependent and independent pathways. To investigate other mechanisms of RKT action in cancer cachexia, we performed metabolome analysis of plasma in a rat model bearing the Yoshida AH-130 hepatoma. A total of 110 metabolites were detected in plasma and RKT treatment significantly altered levels of 23 of those metabolites in cachexia model rats. Among them, glucarate, which is known to have anticarcinogenic activity through detoxification of carcinogens via inhibition of β-glucuronidase, was increased in plasma following administration of RKT. In our AH-130 ascites-induced cachexia rat model, administration of glucarate delayed onset of weight loss, improved muscle atrophy, and reduced ascites content. Additionally, glucarate reduced levels of plasma interferon-γ (IFN-γ) in tumor-bearing rats and was also found to suppress LPS-induced IFN-γ expression in splenocytes in vitro. These results suggest that glucarate has anti-inflammatory activity via a direct effect on immune host cells and suggest that RKT may also ameliorate inflammation partly through the elevation of glucarate in plasma.
    Preview · Article · Oct 2015 · Evidence-based Complementary and Alternative Medicine
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    ABSTRACT: A 66-year-old woman presented to us with malaise, anorexia and rectal mucous discharge, and her laboratory data showed severe hyponatremia, hypokalemia, hypochloremia and renal failure. Computed tomography revealed massive occupation of the rectum by a large tumor. Colonoscopy revealed a mucus-rich villous tumor in the rectum. As there were no other factors that could cause an electrolyte disorder, she was diagnosed with McKittrick-Wheelock syndrome (MWS). The current standard treatment for MWS is partial surgical colectomy. However, surgeries are invasive and postoperative complications sometimes become an issue. After confirming no signs of submucosal invasion of the tumor by magnifying chromoendoscopic examination, endoscopic submucosal dissection (ESD) was indicated. The tumor was completely removed en bloc without adverse events. The histology showed a mucosal adenocarcinoma containing a villous component, 24.5 x 17.0 cm in size. This removal dramatically improved the patient's symptoms and the electrolyte abnormalities without medication. Although several sessions of endoscopic balloon dilation were required to treat postoperative stricture, she has been symptom-free and had no recurrence for 4 years after treatment. We experienced a case of MWS treated by ESD instead of surgery. ESD should be feasible and beneficial for the treatment of MWS.
    No preview · Article · Aug 2015 · Clinical Journal of Gastroenterology
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    ABSTRACT: The neuropsychiatric test (NP test) is a clinically available modality to confirm minimal hepatic encephalopathy (MHE), but it takes at least 30 minutes for outpatients to complete. An easier primary screening tool of the NP test would be helpful to predict MHE in routine testing on the public METHODS: We performed a prospective cohort study on 59 cirrhotic outpatients at Kobe University Hospital. Laboratory measurements, the NP test, and the chronic liver disease questionnaire (CLDQ) were performed. As an indicator of MHE, cases with and without two abnormal subsets or more in the NP test were compared, and the independent risk factors were statistically examined. Predictive scoring systems of the risk of MHE were established using multivariate logistic regression. CLDQ worry (WO) was the best predictive factor of MHE diagnosed by the NP test (p = 0.006). The predictive model using CLDQ WO discriminated well between patients with and without MHE (AUC: 0.714; 95% CI: 0.582 to 0.824). The predictive scores of MHE enable the patient-specific probability to be easily looked up. CLDQ WO was shown to be an independent factor associated with the NP test to diagnose MHE in cirrhotic patients. The easy predictive scoring system of the risk of MHE using CLDQ WO could become a primary screening tool before performing the NP test in a social setting. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Hepatology Research
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    ABSTRACT: A variety of treatment modalities including L-carnitine have been tried for cirrhotic patients with minimal hepatic encephalopathy (MHE), which improved MHE for some patients, but were not effective for the other patients. We aimed to identify pre-therapeutic independent factors to predict the amelioration of MHE after L-carnitine treatment. We performed a prospective cohort study on a total of 64 consecutive outpatients of cirrhotic patients who underwent blood biochemical examinations and neuropsychiatric (NP) test at Kobe University Hospital. MHE patients diagnosed by the NP test were orally administered L-carnitine for 3 months. The patients with and without MHE amelioration were compared, and the independent factors were statistically examined. Predictive scoring systems of the amelioration of MHE were established using multivariate logistic regression. The amelioration of MHE was found in 45.8% of MHE patients. Serum taurine before the treatment was the best predictive factor of the amelioration of MHE (p = 0.046). The predictive model using serum taurine discriminated well between patients with and without the amelioration of MHE (AUC: 0.748; 95% CI: 0.531 to 0.901). The predictive scores of the amelioration of MHE enable the patient-specific probability to be easily looked up. Serum taurine before L-carnitine treatment was shown to be an independent factor associated with the amelioration of MHE 3 months after the treatment. The easy pre-therapeutic prediction of MHE amelioration after L-carnitine treatment would help in improving awareness of the selection of MHE patients with good response to L-carnitine, thus being beneficial from a financial perspective. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · Hepatology Research
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    ABSTRACT: Background and study aims: Improvements in the endoscopic submucosal dissection (ESD) technique have made circumferential ESD in the rectum possible. However, little is known about the clinical course after extensive ESD in the rectum. The aim of this study was to determine the stricture risk in the rectum after total or subtotal circumferential ESD. Patients and methods: A total of 69 patients with 69 rectal tumors that required ≥ 75 % circumferential resection were identified at Kobe University Hospital and an affiliated hospital between April 2005 and May 2014. Among the patients, 61 were available for evaluation of stricture development, either by follow-up colonoscopy or by surgical specimens. The rate and possible risk factors of post-ESD strictures were investigated. Results: Post-ESD rectal strictures developed in 12 patients (19.7 %). Patients who underwent total circumferential ESD developed a stricture (5/7, 71.4 %) more frequently than those with subtotal (≥ 90 %) ESD (7/16, 43.8 %). Patients undergoing an ESD procedure that involved < 90 % of the circumference did not develop strictures. The strictures were membranous or < 10 mm long in all cases. Of the patients with stricture, 11 received endoscopic balloon dilation and one received bougie with short-caliber-tip transparent hood; all strictures improved following dilation therapy. Statistical analysis revealed that ≥ 90 % circumferential resection was an independent risk factor for stricture, whereas morphology and size were not. Conclusions: Patients who underwent total or subtotal circumferential ESD of a rectal tumor had a high risk of stricture formation. Dilation helped to alleviate the stenosis.Study registered at University Hospital Medical Information Network (UMIN 000016559). © Georg Thieme Verlag KG Stuttgart · New York.
    No preview · Article · Jul 2015 · Endoscopy
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    ABSTRACT: Quasispecies of hepatitis B virus (HBV) with variations in the major hydrophilic region (MHR) of the HBV surface antigen (HBsAg) can evolve during infection, allowing HBV to evade neutralizing antibodies. These escape variants may contribute to chronic infections. In this study, looked for the MHR variants in HBV quasispecies using ultra-deep sequencing and evaluated the relationship between these variants and clinical manifestations. We enrolled 30 Indonesian patients with hepatitis B infection (11 with chronic hepatitis and 19 with advanced liver disease). The most common sub-genotypes/subtypes of HBV were B3/adw (97%). The HBsAg titre was lower in patients with advanced liver disease than in those with chronic hepatitis. The MHR variants were grouped based on the percentage of the viral population affected: major, ≥ 20% of the total population; intermediate, 5%-20%; and minor, 1%-5%. The rate of MHR variation which present in the major and intermediate viral population were significantly greater in patients with advanced liver disease than in chronic patients. The most frequent MHR variants related to immune evasion in the major and intermediate populations were P120Q/T, T123A, P127T, Q129H/R, M133L/T, and G145R. The major population of MHR variants causing impaired of HBsAg secretion (e.g., G119R, Q129R, T140I, and G145R) was only detected in advanced liver disease patients. This is the first study to use ultra-deep sequencing for detecting MHR variants of HBV in Indonesian patients. We found that a greater number of MHR variation was related to disease severity and a reduced likelihood of HBsAg titre.
    No preview · Article · Jul 2015 · Journal of clinical microbiology

  • No preview · Article · Jun 2015 · Journal of Gastroenterology
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    ABSTRACT: Our understanding of the mechanism of cancer dormancy is emerging, but the underlying mechanisms are not fully understood. Here we analyzed mouse xenograft tumors derived from human breast cancer tissue and the human breast cancer cell line MDA-MB-231 to identify the molecules associated with cancer dormancy. In immunohistological examination using the proliferation marker Ki-67, the tumors included both proliferating and dormant cancer cells, but the number of dormant cells was remarkably increased when they metastasized to the lung. In the gene expression analysis of the orthotopic cancer cells by a single-cell multiplex real-time quantitative reverse transcription PCR followed by flow cytometric analysis, restrained cellular proliferation was associated with downregulation of the chemokine receptor CXCR4. In the immunohistological and flow cytometric analyses, the expression level of CXCR4 in the metastasized cancer cells was decreased compared with that in the cancer cells in orthotopic tumors, although the expression level of the CXCR4 ligand CXCL12 was not reduced in the lung. In addition, the proliferation of the metastasized cancer cells was further decreased by the CXCR4 antagonist administration. In the ex vivo culture of the metastasized cancer cells, the expression level of CXCR4 was increased, and in the xenotransplantation of ex vivo cultured cancer cells, the expression level of CXCR4 was again decreased in the metastasized cancer cells in the lung. These findings indicate that CXCR4 is downregulated in metastasized breast cancer cells and implicated in their dormancy.
    Preview · Article · Jun 2015 · PLoS ONE
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    ABSTRACT: During colorectal endoscopic submucosal dissection (ESD), the feature of a muscle layer being pulled toward a neoplastic tumor is sometimes detected. We call this feature the muscle-retracting sign (MR sign). The aim of this study was to evaluate whether the MR sign is associated with particular types of neoplastic lesions and whether it has any clinical significance for ESD sessions. A total of 329 patients underwent ESD for 357 colorectal neoplasms. The frequency of positivity for the MR sign was evaluated in different morphologic and histopathologic types of neoplasm. The success rate of complete resection and the incidence of complications were also evaluated according to whether lesions were positive or negative for the MR sign. The rates of positivity for the MR sign in the various lesion types were as follows: laterally spreading tumor - granular nodular mixed type (LST-G-M), 9.6 %; laterally spreading tumor - granular homogeneous type (LST-G-H) and laterally spreading tumor - nongranular type (LST-NG), 0 %; sessile type, 41.2 %. The resection rate was 100 % (329 /329) in lesions negative for the MR sign; however, it was 64.3 % (18 /28) in lesions positive for the MR sign, which was significantly lower (P < 0.001). The MR sign was present only in some protruding lesions, and more importantly, it was associated with a high risk of incomplete tumor removal by ESD. Our data indicate that lesions positive for the MR sign lesions should be dissected with great caution; alternatively, based on the features of the individual case, a switch to surgery should be considered for the benefit of the patient.
    Full-text · Article · May 2015

  • No preview · Article · May 2015 · Gastrointestinal Endoscopy
  • Yoshinori Morita · Tetsuya Yoshizaki · Takeshi Azuma

    No preview · Article · May 2015 · Gastrointestinal Endoscopy
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    ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is histologically characterized by the aberrant accumulation of lipid droplets in the liver, which is positively correlated with insulin resistance. Within the spectrum of this disease, patients can develop hepatitis and cirrhosis; i.e., non-alcoholic steatohepatitis (NASH). The mechanisms responsible for the progression of NAFLD are not fully understood. Triacylglycerol (TAG), which is mainly found in lipid droplets, is currently considered to act as a buffer against the accumulation of non-TAG toxic lipid species. In line with this, recent studies have revealed that insulin resistance is driven by the accumulation of phosphatidic acid and diacylglycerol in hepatocytes and that cholesterol-overloaded stellate cells are associated with fibrosis in the liver. Therefore, it is important to identify the toxic lipid species that contribute to NAFLD progression in order to clarify the pathogenesis of NASH and find novel targets for its treatment. In this review, we divided lipids into five classes; i.e., into fatty acyls, glycerophospholipids, glycerolipids, sphingolipids, and sterol lipids, and described their molecular structures, distributions, and metabolism under physiological conditions, as well as the contributions they make to the progression of NAFLD.
    No preview · Article · Apr 2015 · Current drug targets

  • No preview · Article · Apr 2015 · Gastroenterology
  • Yoshihiko Yano · Takeshi Azuma · Yoshitake Hayashi
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    ABSTRACT: Hepatitis B virus (HBV) infection is major global issue, because chronic HBV infection is strongly associated with liver cancer. HBV spread worldwide with various mutations and variations. This variability, called quasispecies, is derived from no proof-reading capacity of viral reverse transcriptase. So far, thousands of studies reported that the variety of genome is closely related to the geographic distribution and clinical characteristics. Recent technological advances including capillary sequencer and next generation sequencer have made in easier to analyze mutations. The variety of HBV genome is related to not only antigenicity of HBs-antigen but also resistance to antiviral therapies. Understanding of these variations is important for the development of diagnostic tools and the appropriate therapy for chronic hepatitis B. In this review, recent publications in relation to HBV mutations and variations are updated and summarized.
    No preview · Article · Mar 2015 · World Journal of Hepatology

Publication Stats

9k Citations
2,282.06 Total Impact Points


  • 2006-2016
    • Kobe University
      • • Department of Internal Medicine
      • • Division of Gastroenterology
      • • Graduate School of Medicine
      Kōbe, Hyōgo, Japan
  • 2010
    • Kobe Gakuin University
      Kōbe, Hyōgo, Japan
  • 2008
    • Tohoku University
      • Institute of Development, Aging and Cancer
      Sendai, Kagoshima, Japan
  • 2001-2008
    • University of Fukui
      Hukui, Fukui, Japan
  • 1984-2008
    • Kyoto Prefectural University of Medicine
      • Division of Preventive Medicine
      Kioto, Kyōto, Japan
  • 1999-2007
    • Fukui University
      Hukui, Fukui, Japan
  • 2002
    • Hokkaido University
      • Graduate School of Science
      Sapporo, Hokkaidō, Japan
    • Tokyo Medical University
      Edo, Tokyo, Japan
  • 2000-2001
    • Fukui Prefectural University
      Фукуй, Fukui, Japan
    • Shiga University of Medical Science
      Ōtu, Shiga Prefecture, Japan
  • 1998
    • Okinawa Chubu Hospital
      Okinawa, Okinawa, Japan
    • University Hospitals Of Leicester NHS Trust
      Leiscester, England, United Kingdom
  • 1988-1995
    • Wayne State University
      • School of Medicine
      Detroit, Michigan, United States
  • 1992-1993
    • Kyoto Prefectural University
      Kioto, Kyōto, Japan
    • University of Texas Southwestern Medical Center
      • Department of Pediatrics
      Dallas, TX, United States
    • Keio University
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan