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Featured researches published by Mitsuaki Sato.


Hepatology | 2010

Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection

Yasuhiro Asahina; Kaoru Tsuchiya; Nobuharu Tamaki; Itsuko Hirayama; Tomohiro Tanaka; Mitsuaki Sato; Yutaka Yasui; Takanori Hosokawa; Ken Ueda; Teiji Kuzuya; H. Nakanishi; Jun Itakura; Yuka Takahashi; Masayuki Kurosaki; Nobuyuki Enomoto; Namiki Izumi

An increase in the aging population is an impending problem. A large cohort study was carried out to determine the influence of aging and other factors on hepatocarcinogenesis in patients treated with interferon. Biopsy‐proven 2547 chronic hepatitis C patients registered at our referral center since 1992 were included. Of these, 2166 were treated with interferon‐based therapy. Incidences of hepatocellular carcinoma (HCC) associated with interferon were analyzed by Kaplan‐Meier and person‐years methods for an average follow‐up of 7.5 years. Factors associated with HCC risk were determined by Cox proportional hazard analysis. HCC developed in 177 interferon‐treated patients. The risk for HCC depended on age at primary biopsy and increased more than 15‐fold after 65 years of age. Even when stratified by stage of fibrosis, the cumulative and annual incidences of HCC were significantly higher in older patients than in younger patients (P < 0.001) at the same stage of fibrosis, except for cirrhosis. Progression of fibrosis over time was significantly accelerated in older patients. The impact of viral eradication on HCC prevention was less significant in older patients than in younger patients. Multivariate analysis confirmed that age, gender, liver fibrosis, liver steatosis, total cholesterol level, fasting blood sugar level, baseline and postinterferon alpha‐fetoprotein level, and virological response to interferon were independent risk factors associated with HCC. Aging was the strongest risk factor for a nonvirological response to interferon‐based antiviral therapy. Conclusion: Elderly patients are at a higher risk for HCC. Hepatitis C viral eradication had a smaller effect on hepatocarcinogenesis in older patients. Patients should therefore be identified at an earlier age and treatment should be initiated. HEPATOLOGY 2010


Hepatology Research | 2010

A predictive model of response to peginterferon ribavirin in chronic hepatitis C using classification and regression tree analysis.

Masayuki Kurosaki; Kotaro Matsunaga; Itsuko Hirayama; Tomohiro Tanaka; Mitsuaki Sato; Yutaka Yasui; Nobuharu Tamaki; Takanori Hosokawa; Ken Ueda; Kaoru Tsuchiya; H. Nakanishi; Hiroki Ikeda; Jun Itakura; Yuka Takahashi; Yasuhiro Asahina; Megumu Higaki; Nobuyuki Enomoto; Namiki Izumi

Aim:  Early disappearance of serum hepatitis C virus (HCV) RNA is the prerequisite for achieving sustained virological response (SVR) in peg‐interferon (PEG‐IFN) plus ribavirin (RBV) therapy for chronic hepatitis C. This study aimed to develop a decision tree model for the pre‐treatment prediction of response.


Hepatology Research | 2010

Hepatic steatosis in chronic hepatitis C is a significant risk factor for developing hepatocellular carcinoma independent of age, sex, obesity, fibrosis stage and response to interferon therapy

Masayuki Kurosaki; Takanori Hosokawa; Kotaro Matsunaga; Itsuko Hirayama; Tomohiro Tanaka; Mitsuaki Sato; Yutaka Yasui; Nobuharu Tamaki; Ken Ueda; Kaoru Tsuchiya; Teiji Kuzuya; H. Nakanishi; June Itakura; Yuka Takahashi; Yasuhiro Asahina; Nobuyuki Enomoto; Namiki Izumi

Aim:  Hepatic steatosis is linked to development of hepatocellular carcinoma (HCC) in non‐viral liver disease such as non‐alcoholic steatohepatitis. The present study aimed to assess whether hepatic steatosis is associated with the development of HCC in chronic hepatitis C.


Gastroenterology | 2008

Potential Relevance of Cytoplasmic Viral Sensors and Related Regulators Involving Innate Immunity in Antiviral Response

Yasuhiro Asahina; Namiki Izumi; Itsuko Hirayama; Tomohiro Tanaka; Mitsuaki Sato; Yutaka Yasui; Nobutoshi Komatsu; Naoki Umeda; Takanori Hosokawa; Ken Ueda; Kaoru Tsuchiya; H. Nakanishi; Jun Itakura; Masayuki Kurosaki; Nobuyuki Enomoto; Megumi Tasaka; Naoya Sakamoto; Shozo Miyake

BACKGROUND & AIMS Clinical significance of molecules involving innate immunity in treatment response remains unclear. The aim is to elucidate the mechanisms underlying resistance to antiviral therapy and predictive usefulness of gene quantification in chronic hepatitis C (CH-C). METHODS We conducted a human study in 74 CH-C patients treated with pegylated interferon alpha-2b and ribavirin and 5 nonviral control patients. Expression of viral sensors, adaptor molecule, related ubiquitin E3-ligase, and modulators were quantified. RESULTS Hepatic RIG-I, MDA5, LGP2, ISG15, and USP18 in CH-C patients were up-regulated at 2- to 8-fold compared with nonhepatitis C virus patients with a relatively constitutive Cardif. Hepatic RIG-I, MDA5, and LGP2 were significantly up-regulated in nonvirologic responders (NVR) compared with transient (TR) or sustained virologic responders (SVR). Cardif and RNF125 were negatively correlated with RIG-I and significantly suppressed in NVR. Differences among clinical responses in RIG-I/Cardif and RIG-I/RNF125 ratios were conspicuous (NVR/TR/SVR = 1.3:0.6:0.4 and 2.3:1.3:0.8, respectively). Like viral sensors, ISG15 and USP18 were significantly up-regulated in NVR (4-fold and 2.3-fold, respectively). Multivariate and receiver operator characteristic analyses revealed higher RIG-I/Cardif ratio, ISG15, and USP18 predicted NVR. Lower Cardif in NVR was confirmed by its protein level in Western blot. Also, transcriptional responses in peripheral blood mononuclear cells to the therapy were rapid and strong except for Cardif in not only a positive (RIG-I, ISG15, and USP18) but also in a negative regulatory manner (RNF125). CONCLUSIONS NVR may have adopted a different equilibrium in their innate immune response. High RIG-I/Cardif and RIG-I/RNF125 ratios and ISG15 and USP18 are useful in identifying NVR.


Hepatology Research | 2014

Deep sequencing analysis of variants resistant to the non-structural 5A inhibitor daclatasvir in patients with genotype 1b hepatitis C virus infection

Mika Miura; Shinya Maekawa; Mitsuaki Sato; Nobutoshi Komatsu; Akihisa Tatsumi; Shinichi Takano; Fumitake Amemiya; Yasuhiro Nakayama; Taisuke Inoue; Minoru Sakamoto; Nobuyuki Enomoto

Daclatasvir, a non‐structural (NS)5A replication complex inhibitor, is a potent and promising direct antiviral agent (DAA) for hepatitis C virus (HCV), being most effective in genotype 1b infection. Although it is known that genotype 1b viruses with Y93H and/or L31M/V/F mutations have strong resistance to daclatasvir, it is not known whether there are some clinical background conditions that favor the occurrence of HCV carrying those NS5A mutations.


Journal of Hepatology | 2008

The presence of steatosis and elevation of alanine aminotransferase levels are associated with fibrosis progression in chronic hepatitis C with non-response to interferon therapy

Masayuki Kurosaki; Kotaro Matsunaga; Itsuko Hirayama; Tomohiro Tanaka; Mitsuaki Sato; Nobutoshi Komatsu; Naoki Umeda; Takanori Hosokawa; Ken Ueda; Kaoru Tsuchiya; H. Nakanishi; Jun Itakura; Yasuhiro Asahina; Shozo Miyake; Nobuyuki Enomoto; Namiki Izumi

BACKGROUND/AIMS Interferon (IFN) therapy leads to regression of hepatic fibrosis in chronic hepatitis C patients who achieve a sustained virologic response (SVR), while the beneficial effect is limited in those who fail to do so. The aim of the present study was to define factors associated with progression of fibrosis in patients who do not achieve a SVR. METHODS Fibrosis staging scores were compared between paired liver biopsies before and after IFN in 97 chronic hepatitis C patients who failed therapy. The mean interval between biopsies was 5.9 years. Factors associated with progression of fibrosis were analyzed. RESULTS Fibrosis progressed in 23%, remained unchanged in 47% and regressed in 29%. Steatosis and a high average alanine aminotransferase (ALT) between biopsies were independent factors for progression of fibrosis with risk ratios of 5.53 and 4.48, respectively. Incidence and yearly rate of progression of fibrosis was 64% and 0.22+/-0.29 fibrosis units per year in those with both risk factors compared to 8% and -0.04+/-0.17 fibrosis units per year in those negative for both factors. CONCLUSIONS Hepatic steatosis and elevated ALT levels are risk factors for progression of fibrosis in chronic hepatitis C patients who fail to achieve a SVR to IFN therapy and therefore may be therapeutic targets to halt the potentially progressive disease.


Hepatology Research | 2014

Hepatocellular carcinoma risk assessment using gadoxetic acid-enhanced hepatocyte phase magnetic resonance imaging.

Nobutoshi Komatsu; Utaroh Motosugi; Shinya Maekawa; Kuniaki Shindo; Minoru Sakamoto; Mitsuaki Sato; Akihisa Tatsumi; Mika Miura; Fumitake Amemiya; Yasuhiro Nakayama; Taisuke Inoue; Mitsuharu Fukasawa; Tomoyoshi Uetake; Masahiko Ohtaka; Tadashi Sato; Yasuhiro Asahina; Masayuki Kurosaki; Namiki Izumi; Tomoaki Ichikawa; Tsutomu Araki; Nobuyuki Enomoto

To investigate whether the patients with hypovascular liver nodules determined on the arterial phase and hypointensity on the hepatocyte phase gadoxetic acid‐enhanced magnetic resonance imaging (hypovascular hypointense nodules) are at increased risk of hepatocarcinogenesis, we assessed subsequent typical hepatocellular carcinoma (HCC) development at any sites of the liver with and without such nodules.


Journal of Virology | 2015

Deep Sequencing and Phylogenetic Analysis of Variants Resistant to Interferon-Based Protease Inhibitor Therapy in Chronic Hepatitis Induced by Genotype 1b Hepatitis C Virus

Mitsuaki Sato; Shinya Maekawa; Nobutoshi Komatsu; Akihisa Tatsumi; Mika Miura; Masaru Muraoka; Yuichiro Suzuki; Fumitake Amemiya; Shinichi Takano; Mitsuharu Fukasawa; Yasuhiro Nakayama; Tatsuya Yamaguchi; Tomoyoshi Uetake; Taisuke Inoue; Tadashi Sato; Minoru Sakamoto; Atsuya Yamashita; Kohji Moriishi; Nobuyuki Enomoto

ABSTRACT Because of recent advances in deep sequencing technology, detailed analysis of hepatitis C virus (HCV) quasispecies and their dynamic changes in response to direct antiviral agents (DAAs) became possible, although the role of quasispecies is not fully understood. In this study, to clarify the evolution of viral quasispecies and the origin of drug-resistant mutations induced by interferon (IFN)-based protease inhibitor therapy, the nonstructural-3 (NS3) region of genotype 1b HCV in 34 chronic hepatitis patients treated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) was subjected to a deep sequencing study coupled with phylogenetic analysis. Twenty-six patients (76.5%) achieved a sustained viral response (SVR), while 8 patients did not (non-SVR; 23.5%). When the complexity of the quasispecies was expressed as the mutation frequency or Shannon entropy value, a significant decrease in the IFNL3 (rs8099917) TT group and a marginal decrease in the SVR group were found soon (12 h) after the introduction of treatment, whereas there was no decrease in the non-SVR group and no significant decrease in mutation frequency in the IFNL3 TG/GG group. In the analysis of viral quasispecies composition in non-SVR patients, major populations greatly changed, accompanied by the appearance of resistance, and the compositions were unlikely to return to the pretreatment composition even after the end of therapy. Clinically TVR-resistant variants were observed in 5 non-SVR patients (5/8, 62.5%), all of which were suspected to have acquired resistance by mutations through phylogenetic analysis. In conclusion, results of the study have important implications for treatment response and outcome in interferon-based protease inhibitor therapy. IMPORTANCE In the host, hepatitis C virus (HCV) consists of a variety of populations (quasispecies), and it is supposed that dynamic changes in quasispecies are closely related to pathogenesis, although this is poorly understood. In this study, recently developed deep sequencing technology was introduced, and changes in quasispecies associated with telaprevir (TVR)/pegylated interferon (PEG-IFN)/ribavirin (RBV) triple therapy and their clinical significance were investigated extensively by phylogenetic tree analysis. Through this study, the associations among treatment response, changes in viral quasispecies complexity in the early stage of treatment, changes in the quasispecies composition, and origin of TVR-resistant variant HCV were elucidated.


Hepatology Research | 2015

Liver stiffness measurement for risk assessment of hepatocellular carcinoma

Akihisa Tatsumi; Shinya Maekawa; Mitsuaki Sato; Nobutoshi Komatsu; Mika Miura; Fumitake Amemiya; Yasuhiro Nakayama; Taisuke Inoue; Minoru Sakamoto; Nobuyuki Enomoto

Liver fibrosis is a risk factor for hepatocellular carcinoma (HCC), but at what fibrotic stage the risk for HCC is increased has been poorly investigated quantitatively. This study aimed to determine the appropriate cut‐off value of liver stiffness for HCC concurrence by FibroScan, and its clinical significance in hepatitis B virus (HBV), hepatitis C virus (HCV) and non‐B, non‐C (NBNC) liver disease.


Hepatology Research | 2011

Changes in hepatitis C viral load during first 14 days can predict the undetectable time point of serum viral load by pegylated interferon and ribavirin therapy.

Jun Itakura; Yasuhiro Asahina; Nobuharu Tamaki; Itsuko Hirayama; Yutaka Yasui; Tomohiro Tanaka; Mitsuaki Sato; Ken Ueda; Teiji Kuzuya; Kaoru Tsuchiya; H. Nakanishi; Masayuki Kurosaki; Gretchen S. Gabriel; George J. Schneider; Namiki Izumi

Aim:  In the treatment of chronic hepatitis C, pegylated interferon (PEG‐IFN) and ribavirin combination therapy must be continued for an adequate duration to improve the rate of sustained virological response. We attempted to predict the time point at which serum hepatitis C virus (HCV) RNA are undetectable during combination therapy.

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Yasuhiro Asahina

University of Connecticut Health Center

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Jun Itakura

University of Yamanashi

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Namiki Izumi

Tokyo Medical and Dental University

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H. Nakanishi

University of Texas MD Anderson Cancer Center

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Masayuki Kurosaki

Tokyo Medical and Dental University

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