Kendo Kiyosawa

Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia

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Publications (631)

  • [Show abstract] [Hide abstract] ABSTRACT: Background and aim: Past HBV infection is considered as a risk factor for hepatocarcinogenesis, but the clinicopathological characteristics of non-B non-C hepatocellular carcinoma (NBNC-HCC) excluding past HBV infection have not been investigated. This study aimed to clarify the clinicopathological features of strictly-defined NBNC-HCC. Methods: Among HCC patients who underwent surgical resection at our affiliated hospitals in Nagano prefecture, Japan, between 1996 and 2012, 77 were negative for serum anti-hepatitis B virus (HBV) core/surface antibodies in addition to HBV surface antigen and anti-hepatitis C virus antibody without signs of autoimmune liver disease, Wilson disease, or hemochromatosis. These patients were divided into the alcohol intake-positive group (AL-HCC; ethanol intake >20 g/day, n = 31), non-alcoholic fatty liver group (NAFL-HCC; steatosis >5% and ethanol intake <20 g/day, n = 30), and cryptogenic group (CG-HCC; no ethanol intake or steatosis, n = 16). Pre-operative clinical parameters, tumor and background liver pathology, and prognosis were analyzed. Results: Advanced fibrosis and steatosis were detected in 64% and 60% in all patients. Approximately 85% of AL-HCC patients had advanced fibrosis. NAFL-HCC subjects had the highest body mass index and prevalence of diabetes, but 30-40% had none-to-mild fibrosis. CG-HCC patients exhibited the lowest incidence of accompanying hepatic inflammation/fibrosis but the largest tumor size. Recurrence/survival rates were comparable among the groups. Conclusions: Liver fibrosis and steatosis are risk factors of HCC regardless of past HBV infection and ethanol consumption. The present results also indicate the possibility of hepatocarcinogenesis independent of hepatic steatosis, inflammation and fibrosis, ethanol intake, and past HBV infection.
    Article · Jun 2016 · Hepatology Research
  • Masafumi Maruyama · Daisuke Kubota · Masayuki Miyajima · [...] · Kendo Kiyosawa
    Article · Apr 2016 · Gastroenterology
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    [Show abstract] [Hide abstract] ABSTRACT: Background: The number of hepatocellular carcinoma (HCC) patients with non-viral etiologies is increasing in Japan. We conducted a nation-wide survey to examine the characteristics of those patients. Methods: After we assessed the trend of patients who were first diagnosed with HCC at 53 tertiary care centers in Japan from 1991 to 2010, we collected detailed data of 5326 patients with non-viral etiology. The etiologies were categorized as autoimmune hepatitis, primary biliary cirrhosis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), unclassified, and other. Baseline characteristics at initial diagnosis, the modality of the initial treatment, and survival status were collected via a website. Survival of the patients was assessed by the Kaplan-Meier method and Cox proportional hazard regression. Results: The proportion of patients with non-viral etiologies increased from 10.0% in 1991 to 24.1% in 2010. Of the patients, 92% were categorized as ALD, NAFLD, or unclassified. Body mass index (BMI) was ≥ 25 kg/m(2) in 39%. Diabetes was most prevalent in NAFLD (63%), followed by unclassified etiology (46%) and ALD (45%). Approximately 80% of patients underwent radical therapy, including resection, ablation, or transarterial chemoembolization. Survival rates at 3, 5, 10, 15, and 20 years were 58.2, 42.6, 21.5, 15.2, and 15.2%, respectively. Multivariate analysis revealed that patients with BMI > 22 and ≤ 25 kg/m(2) showed the best prognosis versus other BMI categories, after adjusting by age, gender, tumor-related factors, and Child-Pugh score. Conclusions: Most cases of non-B, non-C HCC are related to lifestyle factors, including obesity and diabetes. Slightly overweight patients showed the best prognosis.
    Full-text available · Article · Jun 2014 · Journal of Hepatology
  • [Show abstract] [Hide abstract] ABSTRACT: Natural killer cells play a key role in the immune control of viral infections. Killer immunoglobulin-like receptors (KIRs) regulate natural killer cell activation and inhibition through the recognition of their cognate HLA class I ligands. We assessed the predictive factors of a sustained virological response (SVR) in 200 Japanese patients with chronic genotype 1b hepatitis C who were treated with telaprevir (TVR), pegylated-interferon-α2b (PEG-IFN), and ribavirin (RBV) triple therapy (92 patients) or PEG-IFN/RBV therapy alone (108 patients). Sixteen KIR genotypes, HLA-A, -B and -C ligands, and an interleukin (IL) 28B polymorphism (rs8099917) were analyzed. We observed that triple therapy, white blood cell count, hemoglobin value, hepatitis C viral load, a rapid virological response (RVR), IL28B TT genotype, and KIR3DL1-HLA-Bw4 genotype were associated with an SVR. In multivariate regression analysis, we identified an RVR (P < 0.000001; odds ratio [OR] = 20.95), the IL28B TT genotype (P = 0.00014; OR = 5.53), and KIR3DL1-HLA-Bw4 (P = 0.004, OR = 3.42) as significant independent predictive factors of an SVR. In conclusion, IL28B and KIR3DL1/HLA-Bw4 are independent predictors of an SVR in Japanese patients infected with genotype 1b HCV receiving TVR/PEG-IFN/RBV or PEG-IFN/RBV therapy.
    Article · Jun 2014 · Human Immunology
  • Article · Apr 2014
  • Shigeyuki Kawa · Hideaki Hamano · Kendo Kiyosawa
    [Show abstract] [Hide abstract] ABSTRACT: A unique form of chronic pancreatitis characterized by elderly male preponderance, minimal abdominal pain, irregular narrowing of the pancreatic duct, and swelling of the pancreatic parenchyma has been referred to as autoimmune pancreatitis. Autoimmune pancreatitis is also characterized by hypergammaglobulinemia, histological evidence of lymphoplasmacytic inflammation and fibrosis, and a favorable response to glucocorticoid treatment. These findings suggest that autoimmune mechanisms are involved in the pathogenesis of this disease. Other characteristic features of this disease are a high serum IgG4 concentration and an abundance of IgG4-bearing plasma cell infiltration in the affected organ, with the former being closely associated with disease activity and the latter being a histological hallmark of this disease. A frequent misdiagnosis is pancreatic cancer, leading to unnecessary surgery. Autoimmune pancreatitis is associated with various extra-pancreatic lesions, which share the common pathologic features of IgG4-bearing plasma cell infiltration with pancreatic lesions, suggestive of the presence of a systemic disease, i.e., IgG4-related disease. Autoimmune pancreatitis is now recognized as the pancreatic manifestation of this IgG4-related disease process.
    Article · Dec 2013
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    [Show abstract] [Hide abstract] ABSTRACT: Unlabelled: The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. Conclusion: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.
    Full-text available · Article · Aug 2012 · Hepatology
  • [Show abstract] [Hide abstract] ABSTRACT: This prospective, non-randomized, multicenter cohort study analyzed the safety and efficacy of a steroid-free immunosuppressive (IS) protocol for hepatitis C virus (HCV)-positive living donor liver transplant (LDLT) recipients in Japan. Of 68 patients enrolled from 13 transplant centers, 56 fulfilled the inclusion/exclusion criteria; 27 were assigned the steroid-free IS protocol (Fr group) and 29 the traditional steroid-containing IS protocol (St group). Serum HCV RNA levels increased over time and were higher in the St group until postoperative day 90 (POD 14, p = 0.013). Preemptive anti-HCV therapy was started in a higher percentage of recipients (59.3%) in the Fr group than in the St group (31.0%, p = 0.031), mainly due to early HCV recurrence. The incidence of HCV recurrence at one yr was lower in the Fr group (22.2%) than in the St group (41.4%; p = 0.066). The incidence of acute cellular rejection was similar between groups. New onset diabetes after transplant, cytomegalovirus infection, and renal dysfunction were significantly less frequent in the Fr group than in the St group (p = 0.022, p < 0.0001, p = 0.012, respectively). The steroid-free IS protocol safely reduced postoperative morbidity and effectively suppressed both the HCV viral load in the early post-transplant period and HCV recurrence in HCV-positive LDLT recipients.
    Article · Apr 2012 · Clinical Transplantation
  • Norio Hayashi · Kendo Kiyosawa · Hirohito Tsubouchi · [...] · Hiromitsu Kumada
    Article · Jan 2012 · Kanzo
  • [Show abstract] [Hide abstract] ABSTRACT: Immunoglobulin (Ig) G4-associated autoimmune hepatitis (AIH) is a recently identified and possibly new disease entity. However, the epidemiology and clinical features of IgG4-associated AIH remain uncertain. The aim of this study was to determine the prevalence and the clinical, serological, and histological characteristics of IgG4-associated AIH. We examined the clinical features, serum IgG4 concentration, liver biopsy histology, and IgG4-bearing plasma cell infiltration of 60 patients with type 1 AIH and 22 patients with autoimmune pancreatitis. High serum IgG4 concentration (≥ 135 mg/dL) and IgG4-bearing plasma cell infiltration in the liver (≥ 10/high-power fields [HPFs]) were found in 2 of the 60 (3.3%) patients with type 1 AIH. These patients had high serum levels of IgE, giant cell change, and rosette formation in the liver. Although corticosteroid therapy reduced the serum IgG4 concentration and normalized liver enzymes and histology, one patient developed IgG4-related sclerosing cholangitis after 5 years of follow-up. Because IgG4-associated AIH was found in over 3% of Japanese patients with type 1 AIH in our cohort, further studies are needed on this possible new disease entity and its impact on the diagnostic guidelines of AIH.
    Article · Jan 2011 · Journal of Gastroenterology
  • Norio Hayashi · Kendo Kiyosawa · Hirohito Tsubouchi · [...] · Hiromitsu Kumada
    Article · Jan 2011 · Gastroenterology
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    Takeji Umemura · Yoh Zen · Yasuni Nakanuma · Kendo Kiyosawa
    [Show abstract] [Hide abstract] ABSTRACT: A 42-year-old man was admitted to our hospital because of elevated liver enzymes (aspartate aminotransferase, 642 IU/L [normal range: 12-37]; alanine aminotransferase, 788 IU/L [normal range: 7-45]; alkaline phosphatase, 605 IU/L [normal range: 124-367]; c-glutamyl transpeptidase, 180 IU/L [normal range: 6-30]; and total bilirubin, 8.6 mg/dL [normal range: 0.3-1.2]). His serum immunoglobulin G (IgG) concentration was 5622 mg/dL (normal range: 870-1700), and anti-nuclear antibody titer (1:20480), anti-double-stranded DNA (>400 IU/mL), and smooth muscle antibody titer (1:40) were all abnormal. Infection with hepatitis A, B, and C; cyto-megalovirus; and Epstein-Barr virus were excluded, and no drug use was noted. Ultrasonography, abdominal computed tomography, and magnetic resonance imaging showed no abnormalities of the extrahepatic. Abbreviations: AIH, autoimmune hepatitis; HE, hematoxylin and eosin; IgG, immunoglobulin G.
    Full-text available · Article · Jul 2010 · Hepatology
  • [Show abstract] [Hide abstract] ABSTRACT: To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients. One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples. After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset. Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.
    Article · Jun 2010 · Journal of Hepatology
  • T. Umemura · K. Kiyosawa · E. Tanaka
    Article · Apr 2010 · Journal of Hepatology
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    Yasuhiko Hashikura · Takafumi Ichida · Koji Umeshita · [...] · Kendo Kiyosawa
    [Show abstract] [Hide abstract] ABSTRACT: The Japanese Liver Transplantation Society presented its first report on donor morbidity in 2003. The Society has been continuing to survey outcomes in living liver donors in Japan. By using a uniform comprehensive medical record review process, data were collected on 3565 living liver donors who had donated grafts by the end of December 2006 at 38 Japanese centers. Preoperative problems were reported in 2 donors, intraoperative problems in 27, and postoperative complications in 270. In total, 299 donors (8.4%) suffered complications related to liver donation. Postoperative complications included biliary complications in 3.0%, reoperation in 1.3%, severe after-effects in two (0.06%), and death (apparently related to donor surgery) in one donor (0.03%). The incidence of postoperative complications in left and right lobe donors was 8.7% and 9.4%, respectively. The accumulated experience indicates a reduction in the incidence of donor complications, especially for right lobe resection. One donor death and two cases of severe after effects related to liver donation have been reported during 18 years of living donor liver transplantation experience in Japan.
    Full-text available · Article · Aug 2009 · Transplantation
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    [Show abstract] [Hide abstract] ABSTRACT: Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed two cases of genotypic ETVr with viral rebound and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). Case 1: A 44-year-old HBeAg-positive man received ETV 0.1 mg/day for 52 weeks and 0.5 mg/day for 96 weeks consecutively. HBV DNA was 10.0 log(10) copies/ml at baseline, declined to a nadir of 3.1 at week 100, and rebounded to 4.5 at week 124 and 6.7 at week 148. Alanine aminotransferase (ALT) level increased to 112 IU/l at week 148. Switching to a lamivudine (LVD)/adefovir-dipivoxil combination was effective in decreasing HBV DNA. Case 2: A 47-year-old HBeAg-positive man received ETV 0.5 mg/day for 188 weeks. HBV DNA was 8.2 log(10) copies/ml at baseline, declined to a nadir of 2.9 at week 124, and then rebounded to 4.7 at week 148 and 6.4 at week 160. ALT level increased to 72 IU/l at week 172. The ETVr-related substitution (S202G), along with LVD-resistance-related substitutions (L180M and M204V), was detected by sequence analysis at week 124 in both case 1 and case 2. ETVr emerged in two Japanese nucleoside-naive CHB patients after prolonged therapy and incomplete suppression and in one patient after <0.5 mg of dosing. ETV patients with detectable HBV DNA or breakthrough after extended therapy should be evaluated for compliance to therapy and potential emergence of resistance.
    Full-text available · Article · Jun 2009 · Hepatology International
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    [Show abstract] [Hide abstract] ABSTRACT: Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephosphatidylcholine (PPC), a major component of essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor alpha (Ppara)-null mice, showing several similarities to human ALD. Male wild-type and Ppara-null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months. PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara-null mice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-beta1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis. PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the anti-oxidant action of PPC.
    Full-text available · Article · May 2009 · Journal of Hepatology
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    [Show abstract] [Hide abstract] ABSTRACT: Hepatoprotective therapies that include regular glycyrrhizin injections (GIs) are beneficial for chronic hepatitis C patients, but are sometimes insufficient for normalizing serum alanine aminotransferase (ALT) levels. Here, we evaluated whether the addition of minor bloodletting, named petit phlebotomy (PP), prior to each GI could further reduce serum ALT concentrations in such patients. Seventy-six hepatitis C virus (HCV)-infected patients receiving regular GI, with persistently abnormal serum ALT levels, were randomly divided into GI + PP and GI groups and monitored for 12 months. PP was performed before every GI to a total 60 ml of blood a week. The primary PP endpoint was a serum ferritin level of less than 20 ng/ml. PP was suspended upon reaching the endpoint, but was resumed as needed. The efficacy of the addition of PP was evaluated by measuring changes in serum ALT levels. Two patients in each group dropped out because of the appearance of hepatocellular carcinoma. The remainder completed the 12-month treatment with no serious adverse events. Serum ALT and ferritin levels were significantly decreased in the GI + PP group (from 67 +/- 34 to 44 +/- 14 U/l and from 163 +/- 127 to 25 +/- 21 ng/ml, respectively, both P < 0.001), but these changes were not seen in the GI group. Although 20 patients in the GI + PP group had compensated cirrhosis, no significant reductions in serum albumin concentrations were observed. The addition of PP is effective and safe for improving serum aminotransferase levels in HCV-infected patients receiving regular GI, even in those with compensated cirrhosis.
    Full-text available · Article · Apr 2009 · Journal of Gastroenterology
  • Keiichi Kono · Shigeru Toda · Kazuhiko Hora · Kendo Kiyosawa
    [Show abstract] [Hide abstract] ABSTRACT: Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are characterized by a high mortality rate; therefore, ARDS/ALI in humans is a leading cause of morbidity and mortality in critically ill patients. As previously reported, cytokines play a critical role as signaling molecules that initiate, amplify, and perpetuate inflammatory responses on a local and systemic basis, and the polymyxin-B immobilized direct hemoperfusion system (PMX-DHP) is effective for the treatment of ARDS/ALI. Furthermore, another direct hemoperfusion system using the beta2-microglobulin-selective adsorbent column, Lixelle, the direct hemoperfusion treatment (Lixelle-DHP), has been applied in some cases to patients who are affected with systemic inflammatory response syndrome. The aim of this study is to evaluate the therapeutic efficacy of Lixelle-DHP in the treatment of ARDS/ALI. Four patients, aged 67-79 years old (mean 72 +/- 6.2 years), diagnosed with ARDS/ALI were treated with Lixelle-DHP. The P(a)O(2)/fraction of inspired oxygen (F(i)O(2)) ratio (PF ratio) was 90.0 +/- 22.9 before the treatment, and it increased to 129.9 +/- 5.6 at 72 h afterward the start of treatment. Inflammatory cytokines such as interleukin (IL)-1 beta, IL-6, soluble intercellular adhesion molecule 1 (sICAM-1) decreased significantly after the treatment. All patients were still alive after one month. However, while IL-2 had decreased significantly after the treatment, it had returned by the next treatment. It is possible that Lixelle-DHP might be able to improve the PF ratio and mortality rate as a result of decreased cytokines, and it has been suggested that Lixelle-DHP has a beneficial influence in the treatment of ARDS/ALI.
    Article · Mar 2009 · Therapeutic apheresis and dialysis: official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy
  • Hirohito Tsubouchi · Hiromitsu Kumada · Kendo Kiyosawa · [...] · Toshifumi Hibi
    Article · Jan 2009 · Kanzo

Publication Stats

18k Citations


  • 2010
    • Victorian Infectious Diseases Reference Laboratory
      Melbourne, Victoria, Australia
  • 1973-2009
    • Shinshu University
      • Department of Medicine
      Shonai, Nagano, Japan
  • 2006
    • The Japanese Red Cross College of Nursing
      Edo, Tōkyō, Japan
  • 2004
    • Matsumoto University
      Shonai, Nagano, Japan
  • 2003
    • Dokkyo Medical University
      Totigi, Tochigi, Japan
  • 2000
    • Kofu Municipal Hospital
      Kōhu, Yamanashi, Japan
    • Tokyo Medical University
      Edo, Tōkyō, Japan
    • University of Hamburg
      Hamburg, Hamburg, Germany
  • 1997
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      La Jolla, CA, United States
  • 1993
    • Post Graduate Medical Institute Peshawar
      Peshawar, Khyber Pakhtunkhwa, Pakistan
  • 1991
    • Aizawa Hospital
      Honjō, Saitama, Japan