研究者詳細 - 石川　哲也

Treatment with hepatocyte transplantation in a novel mouse model of persistent liver failure. 査読有り国際誌

Tamaki Y, Shibata Y, Hayakawa M, Kato N, Machii A, Ikeda Y, Nanizawa E, Hayashi Y, Suemizu H, Ito H, Ishikawa T

Biochemistry and biophysics reports 32 巻頁： 101382 - 101382 2022年12月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemistry and Biophysics Reports

Background and Aim: Cell-based transplantation therapy using hepatocytes, hepatic stem cells, hepatocyte-like cells induced from stem cells, etc. is thought to be an attractive alternative to liver transplantation, and have been studied to date. For its clinical application, however, it is extremely important to develop a model that reproduces the pathological conditions with indication for treatment and enables the study for the ideal treatment strategy. Methods: The transgenic mice which express the thymidine kinase (TK) gene of human herpes simplex virus (HSV) in their hepatocytes with normal immunity has been developed (designated as HSVtk). After ganciclovir (GCV) administration which injure TK-expressing hepatocytes, the primary hepatocytes (PHs) isolated from green fluorescent protein (GFP) transgenic mouse (GFP-tg) were transplanted to HSVtk intrasplenically, and replacement index (RI) with transplanted PHs in the liver, liver histology, and mRNA expressions in the liver were analyzed up to 8 weeks after transplantation. Results: HSVtk without PH transplantation after GCV administration developed persistent liver failure with degenerated hepatocytes, persistent elevation of ALT and hepatic p16 mRNA levels, suggesting the existence of cellular senescence in the base of the disease. When autologous GFP-PHs were transplanted to HSVtk, the transplanted cells were successfully engrafted in the liver. Eight weeks after transplantation, serum ALT levels and liver histology were almost normalized, while RIs varied from 19.8 to 73.8%. Since the hepatic p16 mRNA levels were decreased significantly in these mice, the senescence of hepatocytes associated with liver injury was thought to be resolved. On the other hand, allogenic GFP-PHs transplanted to HSVtk were eliminated as early as 1 week after transplantation. In these mice, hepatic p16 mRNA levels were significantly increased at 8 weeks after transplantation, suggesting the aggravation of hepatocyte senescence. FK506 administration to HSVtk protected the transplanted hepatocytes with allogenic background from rejection at 2 weeks after transplantation, but the condition of mice and the senescent status in the liver seemed worsened. Conclusions: The mouse model with HSVtk/GCV system was useful for studying the mechanism of liver regeneration and the immune rejection responses in the hepatocyte transplantation treatment. It may also be utilized to develop the effective remedies to avoid immune rejection.

DOI： 10.1016/j.bbrep.2022.101382

Factors associated with the progression of myosteatosis in patients with cirrhosis. 査読有り

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Fujishiro M

Nutrition (Burbank, Los Angeles County, Calif.) 103-104 巻頁： 111777 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nutrition

Objectives: The presence of myosteatosis is one factor associated with poor prognosis for patients with cirrhosis; however, the factors contributing to worsening myosteatosis are, to our knowledge, unknown. The aim of this study was to clarify the changes in myosteatosis, and the factors involved in these changes. Methods: The present study enrolled 178 patients with cirrhosis who underwent computed tomography twice to measure changes in skeletal muscle attenuation (SMA) at the L3 level. Factors associated with SMA and those associated with changes in SMA were examined. Results: Using linear multiple regression analysis, age (β = –0.22), skeletal muscle index (SMI; skeletal muscle area divided by height squared; β = 0.25), and visceral and subcutaneous fat indices (VFI and SFI; the visceral and subcutaneous fat areas at the umbilical level divided by height squared; β = –0.08, β = –0.06, respectively) were identified as associated with SMA. The 100-d change in SMA was –0.21 ± 1.29 Hounsfield units (HU). Changes in SMI and SMA were positively associated (R = 0.183, P = 0.014), whereas those in VFI and SMA were negatively associated (R = –0.172, P = 0.022). No association was noted between the 100-d changes in SFI and SMA. In patients whose SMI increased and VFI decreased, the 100-d change in SMA was 0.24 ± 1.82 HU, which was marginally different from that in patients whose SMI decreased and VFI increased (–0.44 ± 1.32 HU, P = 0.077). Conclusions: In patients with cirrhosis, myosteatosis progressed, and decreases in SMI and increases in VFI were correlated with its progression.

DOI： 10.1016/j.nut.2022.111777

Effect of illness uncertainty on alanine transaminase levels and aspartate aminotransferase levels in patients with nonalcoholic fatty liver disease. 査読有り

Ozawa N, Sato K, Sugimura A, Maki S, Tanaka T, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishigami M, Fujishiro M, Ishikawa T, Ando S

Nagoya journal of medical science 84 巻 ( 4 ) 頁： 857 - 864 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nagoya Journal of Medical Science

Patients with nonalcoholic fatty liver disease (NAFLD) have illness uncertainty. The purpose of this longitudinal study was to investigate the effect of the degree of illness uncertainty in patients with NAFLD on liver function values. We conducted a questionnaire survey and collected blood samples from outpatients with NAFLD. The items in the questionnaire were measured for illness uncertainty using the Japanese version of the Mishel Uncertainty in Illness Scale-Community (MUIS-C). Blood samples were collected at baseline and after 1 year. We divided the patients into two groups: one with high illness uncertainty and the other with low illness uncertainty. We then compared changes in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels over time from baseline using multiple regression analysis. This study analyzed 148 patients with NAFLD; 75 were male and 73 were female, with a mean age of 58.4 ± 12.3 years. The group with higher illness uncertainty had significantly higher ALT and AST levels at 1 year (b =.185 and.183, respectively) than the group with lower illness uncertainty. High illness uncertainty in patients with NAFLD can lead to higher ALT and AST levels. Healthcare providers must focus on reducing illness uncertainty in patients with NAFLD.

DOI： 10.18999/nagjms.84.4.857

Decreased appetite is associated with the presence of sarcopenia in patients with cirrhosis. 査読有り

Ishizu Y, Ishigami M, Honda T, Imai N, Ito T, Yamamoto K, Yokoyama S, Ishikawa T, Kawashima H

Nutrition (Burbank, Los Angeles County, Calif.) 103-104 巻頁： 111807 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nutrition

Objectives: To our knowledge, the relationship between appetite and sarcopenia in patients with cirrhosis is unknown. The aims of this study were to examine the factors associated with decreased appetite and to clarify the relationship between appetite and sarcopenia. Methods: This study included 61 patients with cirrhosis. The patients were asked to describe their appetite using a numerical rating scale (NRS) from 0 (none at all) to 10 (most), with ≤5 defined as decreased appetite. The clinical characteristics, gastrointestinal symptoms as assessed using the Gastrointestinal Symptom Rating Scale, handgrip strength, and skeletal muscle area at the third vertebra were collected retrospectively. Sarcopenia was diagnosed according to the criteria of the Japan Society of Hepatology. The differences in these factors between patients with and without decreased appetite, and the factors associated with the presence of sarcopenia were examined. Results: Alcoholic liver disease was the most common etiology. The median Model for End-Stage Liver Disease score was 8 (interquartile range = 7 - 10) and hepatocellular carcinoma was present in 35 patients. Overall, 36% of the patients with cirrhosis had decreased appetite. Patients with decreased appetite had a higher frequency of abdominal pain and acid reflux–related symptoms and significantly lower handgrip strength than patients without, among both men (P = 0.034) and women (P = 0.017). The multivariate analysis identified a decrease in appetite as a significant factor associated with the presence of sarcopenia (NRS one increase, odds ratio, 0.701; 95% confidence interval, 0.502–0.977; P = 0.036). Conclusion: Decreased appetite was associated with the presence of sarcopenia.

DOI： 10.1016/j.nut.2022.111807

An improved method to assess skeletal muscle mass in patients with liver cirrhosis based on computed tomography images. 査読有り

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

Hepatology research : the official journal of the Japan Society of Hepatology 52 巻 ( 11 ) 頁： 937 - 946 2022年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hepatology Research

Aim: Conventionally, the skeletal muscle area with computed tomography (CT) attenuation ranging from −29 to +150 Hounsfield unit (HU) divided by height squared (the conventional skeletal muscle index [SMI]) was used as an index of skeletal muscle mass. However, it includes fat-infiltrated skeletal muscle, which is known to have poor function. This study aims to determine whether the low-fat SMI, which uses skeletal muscle mass with CT attenuation ranging from +30 to +150 HU, or conventional SMI appropriately reflects the function of skeletal muscle. Methods: We retrospectively analyzed 120 patients with cirrhosis whose handgrip strength was measured. Among them, 48 patients underwent a physical performance assessment such as liver frailty index (LFI) and short physical performance battery (SPPB), and 80 underwent quality of life (QOL) assessment. The relationships between each SMI and handgrip strength, LFI, SPPB, and QOL were evaluated. Results: Low-fat SMI was significantly correlated with handgrip strength (males, R = 0.393, p = 0.002; females, R = 0.423, p < 0.001) and LFI (males, R = −0.535, p = 0.035; females, R = −0.368, p = 0.039), whereas conventional SMI was not. When using low-fat SMI, patients with low skeletal muscle mass had significantly low handgrip strength, LFI, SPPB, and physical and social-related QOL score than those without. By contrast, no significant differences were found for any items when using conventional SMI. Conclusions: Low-fat SMI is a good index of skeletal muscle mass that appropriately reflects skeletal muscle function.

DOI： 10.1111/hepr.13820

Short-term high-fat and high-carbohydrate diets increase susceptibility to liver injury by inducing hepatic procoagulant and proinflammatory conditions with different balances. 査読有り国際誌

Nanizawa E, Otsuka S, Hatayama N, Tamaki Y, Hayashi Y, Ishikawa T, Hirai S, Naito M

Nutrition (Burbank, Los Angeles County, Calif.) 101 巻頁： 111710 - 111710 2022年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nutrition

Objectives: High-fat diet (HFD) and high-carbohydrate diet (HCD) are strongly linked to nonalcoholic fatty liver disease, a hepatic manifestation of metabolic syndrome. The mechanism of pathologic progression from nonalcoholic fatty liver disease to nonalcoholic steatohepatitis, which is a more severe form associated with inflammation and fibrosis, remains poorly understood. Thus, the aim of this study was to investigate and compare the inflammatory and coagulative state of the liver in short-term HFD- or HCD-fed mice with acute liver injury induced by concanavalin A (Con A). Methods: Histopathologic evaluation, real-time polymerase chain reaction, and immunohistochemical evaluation were performed on the liver of mice fed HFDs and HCDs for 4 d before and after Con A administration. Results: The liver of the HFD-fed mice had larger fibrinogen/fibrin depositions than those fed the HCD. HCD induced the expression of the proinflammatory cytokine tumor necrosis factor-α in the liver. Moreover, the expression of proinflammatory cytokines and chemokines was further enhanced after Con A stimulation in HCD (e.g., interleukin-1α, interleukin-6 at 1 h), with a strong tendency for inflammatory cell infiltration also found (24 h). Conclusions: Short-term HCD and HFD increased susceptibility to liver injury. HCD tended to induce more intense inflammation, whereas HFD tended to induce more intense hypercoagulation, suggesting that HCD and HFD may have different mechanisms of pathologic progression to nonalcoholic steatohepatitis.

DOI： 10.1016/j.nut.2022.111710

Functional cureを目指したインターフェロン治療の効果とコア領域の変異測定の有用性

本多隆, 豊田秀徳, 安田諭, 横山晋也, 山本健太, 伊藤隆徳, 今井則博, 石津洋二, 石川哲也, 石上雅敏

肝臓 63 巻 ( Suppl.2 ) 頁： A607 - A607 2022年9月

Safety, tolerability, and anti-fibrotic efficacy of the CBP/β-catenin inhibitor PRI-724 in patients with hepatitis C and B virus-induced liver cirrhosis: An investigator-initiated, open-label, non-randomised, multicentre, phase 1/2a study 査読有り

Kimura K, Kanto T, Shimoda S, Harada K, Kimura M, Nishikawa K, Imamura J, Ogawa E, Saio M, Ikura Y, Okusaka T, Inoue K, Ishikawa T, Ieiri I, Kishimoto J, Todaka K, Kamisawa T

EBioMedicine 80 巻頁： 104069 2022年7月

Changes in the gut microbiota after hepatitis C virus eradication. 国際誌

Honda T, Ishigami M, Yamamoto K, Takeyama T, Ito T, Ishizu Y, Kuzuya T, Nakamura M, Kawashima H, Miyahara R, Ishikawa T, Hirooka Y, Fujishiro M

Scientific reports 11 巻 ( 1 ) 頁： 23568 - 23568 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

DOI： 10.1038/s41598-021-03009-0

Obesity and myosteatosis: the two characteristics of dynapenia in patients with cirrhosis.

Sugiyama Y, Ishizu Y, Ando Y, Yokoyama S, Yamamoto K, Ito T, Imai N, Nakamura M, Honda T, Kawashima H, Ishikawa T, Ishigami M

European journal of gastroenterology & hepatology 33 巻 ( 1S Suppl 1 ) 頁： e916 - e921 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European journal of gastroenterology & hepatology

OBJECTIVE: In patients with liver cirrhosis, the clinical characteristics of dynapenia, a condition in which skeletal muscle mass is maintained but muscle strength is reduced, are not yet known. This study aimed to clarify the characteristics of dynapenia and its impact on quality of life (QOL) in patients with liver cirrhosis. METHODS: We retrospectively analyzed 116 patients with cirrhosis. Based on grip strength and skeletal muscle mass measured by the bioelectrical impedance analysis method, patients were divided into four groups: normal muscle status, dynapenia, pre-sarcopenia (a condition involving only low muscle mass), and sarcopenia. The characteristics of dynapenia and its influence on QOL were examined. RESULTS: Fourteen patients had dynapenia. Liver function did not differ among the four groups. In patients with dynapenia, BMI was highest and computed tomography attenuation of skeletal muscle at the third lumbar spine vertebra was lowest among the four groups. The percentage of patients with both BMI ≥25 kg/m2 and myosteatosis was significantly higher in patients with dynapenia [9/14 (64.3%)] than in those with sarcopenia [2/23 (8.7%), P = 0.004] and pre-sarcopenia [0/18 (0%), P < 0.001] and tended to be higher than those with normal muscle status [16/61 (26.2%), P = 0.065]. The physical QOL in patients with dynapenia was as low as that in those with sarcopenia and significantly lower than that in those with normal muscle status. CONCLUSION: Cirrhotic patients with dynapenia had high BMI and myosteatosis, and impaired physical QOL.

DOI： 10.1097/MEG.0000000000002303

All-atom molecular dynamics study of hepatitis B virus containing pregenome RNA in solution. 査読有り

Fujimoto K, Yamaguchi Y, Urano R, Shinoda W, Ishikawa T, Omagari K, Tanaka Y, Nakagawa A, Okazaki S

The Journal of chemical physics 155 巻 ( 14 ) 頁： 145101 2021年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Chemical Physics

Immature hepatitis B virus (HBV) captures nucleotides in its capsid for reverse transcription. The nucleotides and nucleotide analog drugs, which are triphosphorylated and negatively charged in the cell, approach the capsid via diffusion and are absorbed into it. In this study, we performed a long-time molecular dynamics calculation of the entire HBV capsid containing pregenome RNA to investigate the interactions between the capsid and negatively charged substances. Electric field analysis demonstrated that negatively charged substances can approach the HBV capsid by thermal motion, avoiding spikes. The substances then migrate all over the floor of the HBV capsid. Finally, they find pores through which they can pass through the HBV capsid shell. Free energy profiles were calculated along these pores for small ions to understand their permeability through the pores. Anions (Cl−) showed higher free energy barriers than cations (Na+ and K+) through all pores, and the permeation rate of Cl− was eight times slower than that of K+ or Na+. Furthermore, the ions were more stable in the capsid than in the bulk water. Thus, the HBV capsid exerts ion selectivity for uptake and provides an environment for ions, such as nucleotides and nucleotide analog drugs, to be stabilized within the capsid.

DOI： 10.1063/5.0065765

Conditioned medium from stem cells derived from human exfoliated deciduous teeth ameliorates NASH via the Gut-Liver axis. 査読有り

Muto H, Ito T, Tanaka T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Maeda K, Honda T, Ishikawa T, Kato A, Ohshiro T, Kano F, Yamamoto A, Sakai K, Hibi H, Ishigami M, Fujishiro M

Scientific reports 11 巻 ( 1 ) 頁： 18778 2021年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

DOI： 10.1038/s41598-021-98254-8

Transient deterioration of albumin-bilirubin scores in early post-dose period of molecular targeted therapies in advanced hepatocellular carcinoma with 50% or higher liver occupation: A STROBE-compliant retrospective observational study. 国際誌

Muto H, Kuzuya T, Ito T, Ishizu Y, Honda T, Ishikawa T, Ishigami M, Fujishiro M

Medicine 100 巻 ( 31 ) 頁： e26820 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Medicine (United States)

AbstractReal-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6weeks.Overall survival was significantly longer in patients with partial response (PR)+stable disease (SD) (13.7months) than in patients with progressive disease (PD) (1.7months, P<.001) in the ≥50% group. Patients with antitumor response of PR+SD at 6weeks in the ≥50% group showed more marked deterioration of ALBI score at 2weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6weeks. Focusing on patients with PD at 6weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR+SD patients, a significant increase in CRP levels at 1 and 2weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR+SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

DOI： 10.1097/MD.0000000000026820

Amino Acid Polymorphism in Hepatitis B Virus Associated With Functional Cure. 招待有り査読有り

Honda T, Yamada N, Murayama A, Shiina M, Aly HH, Kato A, Ito T, Ishizu Y, Kuzuya T, Ishigami M, Murakami Y, Tanaka T, Moriishi K, Nishitsuji H, Shimotohno K, Ishikawa T, Fujishiro M, Muramatsu M, Wakita T, Kato T

Cellular and molecular gastroenterology and hepatology 12 巻 ( 5 ) 頁： 1583 - 1598 2021年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cellular and Molecular Gastroenterology and Hepatology

Background & Aims: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. Methods: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen–negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. Results: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. Conclusions: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

DOI： 10.1016/j.jcmgh.2021.07.013

Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen. 査読有り国際共著国際誌

Baudi I, Isogawa M, Moalli F, Onishi M, Kawashima K, Ishida Y, Tateno C, Sato Y, Harashima H, Ito H, Ishikawa T, Wakita T, Iannacone M, Tanaka Y

PLoS pathogens 17 巻 ( 5 ) 頁： e1009228 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PLoS Pathogens

Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive machinery to ER stress, and the failure of UPR to cope with ER stress results in cell death. Mechanisms that regulate the balance between ER stress and UPR are poorly understood. Type 1 and type 2 interferons have been implicated in hepatic flares during chronic HBV infection. Here, we examined the interplay between ER stress, UPR, and IFNs using transgenic mice that express hepatitis B surface antigen (HBsAg) (HBs-Tg mice) and humanized-liver chimeric mice infected with HBV. IFNα causes severe and moderate liver injury in HBs-Tg mice and HBV infected chimeric mice, respectively. The degree of liver injury is directly correlated with HBsAg levels in the liver, and reduction of HBsAg in the transgenic mice alleviates IFNα mediated liver injury. Analyses of total gene expression and UPR biomarkers’ protein expression in the liver revealed that UPR is induced in HBs-Tg mice and HBV infected chimeric mice, indicating that HBsAg accumulation causes ER stress. Notably, IFNα administration transiently suppressed UPR biomarkers before liver injury without affecting intrahepatic HBsAg levels. Furthermore, UPR upregulation by glucose-regulated protein 78 (GRP78) suppression or low dose tunicamycin alleviated IFNα mediated liver injury. These results suggest that IFNα induces ER stress-associated cell death by reducing UPR. IFNγ uses the same mechanism to exert cytotoxicity to HBsAg accumulating hepatocytes. Collectively, our data reveal a previously unknown mechanism of IFN-mediated cell death. This study also identifies UPR as a potential target for regulating ER stress-associated cell death.

DOI： 10.1371/journal.ppat.1009228

Quality of Life in patients with nonalcoholic fatty liver disease: Structure and related factors focusing on illness uncertainty. 査読有り

Ozawa N, Sato K, Sugimura A, Maki S, Tanaka T, Yamamoto K, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishigami M, Fujishiro M, Ishikawa T, Ando S

Japan journal of nursing science : JJNS 18 巻 ( 3 ) 頁： e12415 2021年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Journal of Nursing Science

Aim: Patients with nonalcoholic fatty liver disease (NAFLD) have a low quality of life (QOL) and illness uncertainty. This study examined the structure of QOL and associated factors, including illness uncertainty, among individuals with NAFLD. Methods: A cross-sectional survey was conducted using a self-administered questionnaire for outpatients with NAFLD. QOL was measured using the Short Form-8. Dietary habits, physical activity level, illness uncertainty, health locus of control, and knowledge of NAFLD were assessed. Path analysis was used to study the associated factors of QOL and their structure, including uncertainty of disease. Results: Path analysis of 168 NAFLD patients indicated that a high Physical Component Summary score on the Short Form-8—representing physical QOL—was predicted by a body mass index <25 kg/m2 and high educational level. A high Mental Component Summary score—representing mental QOL—was predicted by being male, good dietary habits, low illness uncertainty, and presence of consultants. The model showed satisfactory goodness-of-fit without being rejected by the chi-square test (goodness-of-fit index =.947, adjusted goodness-of-fit index =.917, comparative fit index =.967, root mean square error of approximation = 0.023). Conclusions: Nurses need to work closely with NAFLD patients as consultants, providing adequate information about the causes, treatments, and dietary habits, and focusing on the individual's perception of health. This could reduce illness uncertainty and contribute to the improvement of QOL.

DOI： 10.1111/jjns.12415

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice. 査読有り国際誌

Kanbe A, Ishikawa T, Hara A, Suemizu H, Nanizawa E, Tamaki Y, Ito H

Journal of gastroenterology and hepatology 36 巻 ( 3 ) 頁： 782 - 789 2021年3月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Gastroenterology and Hepatology (Australia)

Background and Aim: The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV-specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV-TK-NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV-TK) mice in which the host immune system was not impaired. Methods: Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV-treated mice were transplanted with 1 × 106 hepatocytes from HBV-transgenic (HBV-Tg) mice. Results: Serum alanine aminotransferase levels in HSV-TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV-Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)-positive areas in the liver tissue were observed for at least 20 weeks after HBsAg-positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV-Tg hepatocyte-replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV-TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon-γ-producing cells were increased in non-replaced mice. Conclusions: A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV-infected patients and can be used to develop a new strategy to treat chronic HBV infection.

DOI： 10.1111/jgh.15142

進行肝細胞癌に対するレンバチニブPD後のラムシルマブ治療の初期経験

葛谷貞二, 石上雅敏, 杉山由晃, 吉岡直輝, 水野和幸, 武藤久哲, 横山晋也, 田中卓, 山本健太, 伊藤隆徳, 石津洋二, 本多隆, 石川哲也, 藤城光弘

Pharma Medica 39 巻 ( 2 ) 頁： 72 - 73 2021年2月

Free energy profile of permeation of Entecavir through Hepatitis B virus capsid studied by molecular dynamics calculation 招待有り査読有り

Fujimoto K., Fukai M., Urano R., Shinoda W., Ishikawa T., Omagari K., Tanaka Y., Nakagawa A., Okazaki S.

Pure and Applied Chemistry 92 巻 ( 10 ) 頁： 1585 - 1594 2020年10月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pure and Applied Chemistry

Entecavir, triphosphorylated in liver cells, is an antiviral reagent against Hepatitis B virus (HBV). The reagent inhibits reverse transcription of RNA inside the virus capsid. In the present study, free energy profile of an Entecavir triphosphate (ETVTP) molecule has been calculated when it passes through pores of the capsid along two- and three-fold rotational symmetry axes in order to investigate permeation pathway of the reagent to the inside of the capsid. The calculations have been done based on thermodynamic integration (TI) method combined with all-atomistic molecular dynamic (MD) calculations. A free energy minimum of -19 kJ/mol was found at the entrance of the pore from the outside along the three-fold symmetry axis. This stabilization is from the interaction of negatively charged ETVTP with positively charged capsid methionine residues. This excess free energy concentrates of the reagent at the entrance of the pore by a factor of about 2000. A free energy barrier of approximately 13 kJ/mol was also found near the exit of the pore to the inside of the capsid due to narrow space of the pore surrounded by hydrophobic wall made by proline residues and negatively charged wall by aspartic acid residues. There, ETVTP is partially dehydrated in order to pass through the narrow space, which causes the great free energy loss. Further, the negatively charged residues produce repulsive forces on the ETVTP molecule. In contrast, in the case of the pore along the two-fold symmetry axis, the calculated free energy profile showed shallower free energy minimum, -4 kJ/mol at the entrance in spite of the similarly high barrier, 7 kJ/mol, near the exit of the pore.

DOI： 10.1515/pac-2020-0109

非肝癌症例と肝発癌症例の違いに関与する腸内細菌の検討

本多隆, 石上雅敏, 山本崇文, 犬飼庸介, 杉山由晃, 吉岡直輝, 水野和幸, 武藤久哲, 横山晋也, 田中卓, 山本健太, 伊藤隆徳, 石津洋二, 葛谷貞二, 石川哲也, 藤城光弘

肝臓 61 巻 ( Suppl.2 ) 頁： A701 - A701 2020年9月

Short-term high-fat diet intake leads to exacerbation of concanavalin A-induced liver injury through the induction of procoagulation state. 査読有り国際誌

Nanizawa E, Tamaki Y, Sono R, Miyashita R, Hayashi Y, Kanbe A, Ito H, Ishikawa T

Biochemistry and biophysics reports 22 巻頁： 100736 - 100736 2020年7月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Biochemistry and Biophysics Reports

Obesity and high-fat diet (HFD) are known to cause proinflammatory and procoagulation states and suggested to become a risk of developing thromboembolic diseases. Non-alcoholic fatty liver disease (NAFLD) is usually associated with obesity and HFD, and a part of NAFLD is known to progress to nonalcoholic steatohepatitis (NASH), the pathogenesis of which has not been fully elucidated. In the current study, we examined the influence of short-term HFD on hepatic expression of the molecules related to inflammation, coagulation, metabolism, and cellular stresses from the perspective that HFD itself can be a risk for the development to NASH. In the analysis in short-term (4 days to 14 days) HFD-fed mice, we found out that HFD increased hepatic expression of IFN-γ, TNF-α, IL-10, monocyte chemotactic protein-1 (MCP-1), tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1) mRNAs, and fibrin/fibrinogen deposition in the liver tissues. And it was suggested that metabolic alterations and endoplasmic reticulum (ER) stresses induced by the HFD intake were associated with this proinflammatory and procoagulation states. When we administered concanavalin A (Con A) to these HFD-fed mice, the extent of liver injury was dramatically exacerbated in HFD-fed mice. Heparin treatment to Con A-administered, HFD-fed mice (for 4 days) profoundly ameliorated the extent of liver injury. These suggest that even short-term of HFD intake induces proinflammatory and procoagulation states in the liver and thereby increases the susceptibility of the liver to circulating inflammatory stimuli. We think that it may explain a part of NASH pathogenesis.

DOI： 10.1016/j.bbrep.2020.100736

A prospective trial of vaccine to prevent hepatitis B virus reactivation after hematopoietic stem cell transplantation. 招待有り査読有り国際誌

Nishikawa K, Kimura K, Kanda Y, Sugiyama M, Kakihana K, Doki N, Ohashi K, Bae SK, Takahashi K, Ishihara Y, Mizuno I, Onishi Y, Onozawa M, Onizuka M, Yamamoto M, Ishikawa T, Inoue K, Kusumoto S, Hashino S, Saito H, Kanto T, Sakamaki H, Mizokami M

Bone marrow transplantation 55 巻 ( 7 ) 頁： 1388 - 1398 2020年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Bone Marrow Transplantation

Hepatitis B virus (HBV) reactivation reportedly occurs frequently after hematopoietic stem cell transplantation (HSCT) in resolved HBV-infected patients. Here, 50 patients with resolved HBV infections and scheduled to undergo HSCT were enrolled; all subjects were vaccinated with three doses of hepatitis B vaccine 12 months after HSCT and the incidence of HBV reactivation was monitored. The patients’ characteristics were: median age, 61 (34–72) years; male/female, 27/19; allogeneic/autologous, 40/6; bone marrow/peripheral blood stem cells/cord blood, 26/16/4. Of the 46 patients who underwent HSCT, 19 were excluded and did not make it to vaccination due to relapse of underlying disease, HBV reactivation within 12 months of HSCT, or transfer of patients. The remaining 27 were vaccinated 12 months after HSCT and monitored for 2 years. Six showed HBV reactivation, with a 2-year cumulative reactivation incidence of 22.2%; the same incidence was 27.3% only in allogeneic HSCT patients. Factors associated with HBV reactivation included the discontinuation of immunosuppressants (P = 0.0379) and baseline titers of antibody against hepatitis B surface antigen (P = 0.004). HBV reactivation with vaccination following HSCT could occur despite maintenance of serum anti-HBs at more than protective levels.

DOI： 10.1038/s41409-020-0833-5

Complete response of advanced hepatocellular carcinoma achieved by sorafenib dose re-escalation after failure of long-term low-dose-sorafenib treatment combined with transcatheter arterial chemoembolization: a case report. 査読有り

Muto H, Kuzuya T, Ito T, Ishizu Y, Honda T, Ishikawa T, Ishigami M, Fujishiro M

Clinical journal of gastroenterology 13 巻 ( 3 ) 頁： 397 - 402 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Clinical Journal of Gastroenterology

Few reports have described dose re-escalation after long-term low-dose sorafenib leading to good outcomes. Here, we report the case of an 80-year-old woman with advanced hepatocellular carcinoma who achieved complete response from sorafenib dose re-escalation after the failure of long-term low-dose sorafenib treatment combined with transcatheter arterial chemoembolization. Sorafenib therapy was initiated at 400 mg once daily due to old age and low platelet count. 5 months later, this dose was reduced to 200 mg once daily because of adverse events. Best radiological antitumor response by sorafenib treatment alone was judged as stable disease according to the modified Response Evaluation Criteria in Solid Tumors. 1 year later, she showed progressive disease owing to the progression of intrahepatic lesions. She received combination therapy with low-dose sorafenib (200 mg every other day) and transcatheter arterial chemoembolization, which proved relatively effective for three and a half years. Antitumor response by the fourth transcatheter arterial chemoembolization and subsequent low-dose sorafenib was clearly progressive disease. At that time, sorafenib-related adverse events were well-controlled. Sorafenib dose was re-escalated to 200 mg once daily. After this re-escalation, tumor markers declined rapidly, and adverse events remained tolerable. 4 months later, complete response was achieved.

DOI： 10.1007/s12328-019-01066-7

Correlation of serum zinc levels with pathological and laboratory findings in patients with nonalcoholic fatty liver disease. 査読有り国際誌

Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M

European journal of gastroenterology & hepatology 32 巻 ( 6 ) 頁： 748 - 753 2020年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Gastroenterology and Hepatology

Objective Chronic liver diseases are associated with zinc (Zn) deficiency. However, no previous studies have examined the relationship between serum Zn levels and hepatic pathological findings in patients with nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the serum Zn levels in NAFLD patients based on pathological/laboratory findings. Methods We evaluated a total of 191 NAFLD patients who underwent liver biopsy with the goal of identifying laboratory markers and pathological findings associated with serum Zn levels. Results Zn levels significantly decreased along with progression of hepatic fibrosis (P = 0.039), but there were no significant differences among inflammatory grades. Zn levels were most strongly correlated with albumin levels (r = 0.410, P < 0.001). In addition, Zn levels were significantly correlated with homeostasis model assessment of insulin resistance (HOMA-IR) (r = -0.284, P < 0.001), hyaluronic acid (r = -0.230, P < 0.001), branched chain amino acid/tyrosine molar ratio (BTR) (r = 0.278, P < 0.001), FIB-4 index (r = -0.238, P < 0.001), and NAFLD fibrosis score (NFS) (r = -0.261, P < 0.001). In multivariate analysis, albumin [odds ratio (OR), 9.244 (per 1 g/dL decrease) [95% confidence interval (CI), 2.261-32.744]; P < 0.001], BTR [OR, 1.545 (per 1 decrease) (95% CI, 1.115-2.140); P = 0.009], and HOMA-IR [OR, 1.048 (per 1 increase) (95% CI, 1.019-1.167); P = 0.028] were significantly associated with Zn deficiency. Conclusion The progression of liver fibrosis, but not inflammation, is associated with lower serum Zn levels in biopsy-proven NAFLD patients. Serum Zn levels were correlated with nutrition markers and insulin resistance.

DOI： 10.1097/MEG.0000000000001587

Sorafenib vs. Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis. 査読有り国際誌

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Anticancer research 40 巻 ( 4 ) 頁： 2283 - 2290 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Anticancer Research

Background/Aim: We aimed to compare the outcomes between sorafenib and lenvatinib as first-line therapy for advanced hepatocellular carcinoma (HCC) with major portal vein tumor thrombosis (Vp3/4). Patients and Methods: This retrospective study enrolled 41 HCC patients with Vp3/4 and Child-Pugh A. Results: The outcomes in the lenvatinib group (n=13) were significantly better than those in the sorafenib group (n=28) [best objective response rate according to the modified Response Evaluation Criteria in Solid Tumors: 53.8% vs. 14.3%; p=0.0193, best disease control rate: 92.3% vs. 35.7%; p=0.0008, median overall survival (OS): not reached vs. 187 days; p=0.0040, respectively]. Lenvatinib treatment was the only significant predictor of better OS and time to tumor progression. No patient needed to discontinue lenvatinib treatment due to drug-related adverse events. Conclusion: Compared with sorafenib, lenvatinib treatment for advanced HCC with Vp3/4 may lead to more favorable outcomes.

DOI： 10.21873/anticanres.14193

Initial Experience of Ramucirumab Treatment After Lenvatinib Failure for Patients With Advanced Hepatocellular Carcinoma. 査読有り国際誌

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Anticancer research 40 巻 ( 4 ) 頁： 2089 - 2093 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Anticancer Research

Background/Aim: The outcomes of ramucirumab after lenvatinib failure for hepatocellular carcinoma (HCC) patients with alpha fetoprotein (AFP) levels of ≥400 ng/ml are unknown. Patients and Methods: Of 12 patients treated with ramucirumab after lenvatinib failure, 10 patients were enrolled in this retrospective study. Results: The disease control rate of 80% at 6 weeks and the median time to progression of 3.1 months were the same by both the Response Evaluation Criteria in Solid Tumors (RECIST) and the modified RECIST. AFP reduction was seen in 5 patients at 2 weeks and in 3 patients at 6 weeks. The incidence of grade 3 adverse events was low at 10%. The albumin.bilirubin scores within 6 weeks did not worsen. Conclusion: Ramucirumab might have potential therapeutic efficacy and safety in advanced HCC patients after lenvatinib failure. Further studies are needed to confirm the outcomes of ramucirumab after lenvatinib failure.

DOI： 10.21873/anticanres.14167

Favorable radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma. 査読有り国際誌

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Hepatology research : the official journal of the Japan Society of Hepatology 50 巻 ( 3 ) 頁： 374 - 381 2020年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hepatology Research

Aim: We aimed to investigate the radiological antitumor response at 2 weeks after starting lenvatinib for patients with advanced hepatocellular carcinoma in real-world practice. Methods: This retrospective study enrolled 40 patients who received lenvatinib. Radiological antitumor response was evaluated according to the modified Response Evaluation Criteria in Solid Tumors. Results: The objective response rate at 2 weeks and best overall response on confirmation of complete response, partial response (PR), and stable disease required (confirmed response) were 57.5% and 32.5%, respectively. Based on confirmed response, the overall survival rate was significantly longer in patients with an objective response rate than in those with stable disease or progressive disease after 12 months (73.2% and 54.2%, P = 0.0358). All 13 patients with an objective response rate on confirmed response were evaluated as PR at 2 weeks. The alpha-fetoprotein ratio at 2 weeks was a significant factor associated with PR of response rate at 2 weeks. The median relative dose intensity from 2 to 6 weeks was significantly lower than that from 0 to 2 weeks (69.6% vs. 100%, P < 0.0001). Stratified by the antitumor response at 6 weeks considering the image evaluation at 2 weeks, the median relative dose intensity from 2 to 6 weeks was significantly lower in patients with progressive disease than in those with PR or stable disease (45.2% vs. 72.6%, P = 0.0482). Conclusions: The radiological antitumor response at 2 weeks was favorable. Information on a favorable visible therapeutic response very early after lenvatinib initiation can help patients maintain their motivation for treatment, and allow physicians to continue treatment effectively and safely.

DOI： 10.1111/hepr.13452

Effect of weight change and lifestyle modifications on the development or remission of nonalcoholic fatty liver disease: sex-specific analysis. 査読有り国際誌

Yoshioka N, Ishigami M, Watanabe Y, Sumi H, Doisaki M, Yamaguchi T, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Haruta JI, Fujishiro M

Scientific reports 10 巻 ( 1 ) 頁： 481 - 481 2020年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Scientific Reports

The effects of changes in various lifestyle habits on nonalcoholic fatty liver disease (NAFLD) have not been well elucidated. We aimed to clarify how weight change and lifestyle modifications were associated with the development or remission of NAFLD. In this longitudinal cohort study, we reviewed the periodic health checkup data of 1,421 subjects with no causes of liver disease besides NAFLD who had received at least two health checkups between 2009 and 2018. The prevalence of NAFLD at baseline was 34.1% (484/1,421). During follow-up period (4.6 ± 2.8 years), 104 subjects developed NAFLD and 127 subjects demonstrated NAFLD remission. The frequency of NAFLD development or that of NAFLD remission significantly increased as the larger weight gain or weight loss was, respectively (both, p < 0.001). Approximately 40% of the subjects who maintained ≥ 1%/year weight loss achieved NAFLD remission. By multivariate analysis, quitting smoking were independently associated with NAFLD development (adjusted odds ratio [AOR], 2.86; 95% CI, 1.24–6.62). Subjects who quit smoking demonstrated large weight gain (≥1%/year) significantly more frequently than the other subjects (p < 0.001). In sex-specific analysis, starting to exercise was independently associated with NAFLD remission in men (AOR, 2.38; 95% CI, 1.25–4.53).

DOI： 10.1038/s41598-019-57369-9

Efficacy and Safety of Sorafenib in Unresectable Hepatocellular Carcinoma with Bile Duct Invasion. 国際誌

Tanaka T, Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Fujishiro M

Oncology 98 巻 ( 9 ) 頁： 621 - 629 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oncology (Switzerland)

Because the frequency of bile duct invasion in hepatocellular carcinoma (HCC) patients is very rare, there is limited clinical evidence to demonstrate the outcomes of systemic therapy in HCC with bile duct invasion. Our aim was to clarify the efficacy and safety of sorafenib treatment in patients with unresectable advanced HCC with bile duct invasion. Methods: One hundred and seventy-five patients with advanced HCC were enrolled in this study. We retrospectively compared the outcomes of sorafenib between patients without bile duct invasion [B (-) group, n = 165] and those with bile duct invasion [B (+) group, n = 10]. Results: There were no significant differences in the confirmed objective response rate (ORR) and the confirmed disease control (DC) rate between the B (-) and the B (+) groups (13.9 vs. 20.0%, p = 0.637 for ORR; 47.2 vs. 70.0%, p = 0.202 for DC rate, respectively). There were no significant differences in median overall survival (OS) and time to progression (TTP) between the B (-) group and the B (+) group (14.8 vs. 14.1 months, p = 0.780 for OS; 3.4 vs. 5.7 months, p = 0.277 for TTP, respectively). Post-treatment factors associated with good OS were changes in albumin-bilirubin score (0-6 weeks) of <0.25, and antitumor response at 6 weeks of DC. Though 5 of 10 patients (50%) in the B (+) group had bile duct complications, such as obstructive jaundice and biliary bleeding, these 5 patients were able to recover from biliary troubles by careful and vigorous management with biliary endoscopic intervention, and were able to continue sorafenib therapy safely. Conclusions: Our present results suggest that sorafenib might have potential therapeutic efficacy and safety in advanced HCC patients with bile duct invasion. In case of biliary tract troubles before and during sorafenib treatment, early biliary management may be important to continue sorafenib therapy safely. Further studies are needed to confirm the outcomes of sorafenib in advanced HCC patients with bile duct invasion.

DOI： 10.1159/000507051

Serum Nutritional Markers as Prognostic Factors for Hepatic and Extrahepatic Carcinogenesis in Japanese Patients with Nonalcoholic Fatty Liver Disease. 査読有り国際誌

Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Toyoda H, Kumada T, Fujishiro M

Nutrition and cancer 72 巻 ( 5 ) 頁： 884 - 891 2020年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nutrition and Cancer

Serum zinc (Zn) levels and the branched chain amino acid/tyrosine molar ratio (BTR) were reported to decrease with the progression of various chronic liver diseases. We investigated the impact of BTR and Zn on the incidence of malignancies in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). A total of 179 Japanese NAFLD patients who underwent liver biopsy were enrolled. Hepatocellular carcinoma (HCC) and extrahepatic malignancies developed in 7 (3.9%) and 10 (5.6%) patients, respectively, during the follow-up period (median 7.9 years). Patients with low BTR levels (<5.0) and Zn deficiency (<70 μg/dL) had significantly higher incidences of HCC and extrahepatic malignancies (P < 0.001 and 0.026), respectively. Multiple logistic regression analyses revealed the following risk factors: liver fibrosis (F3–4) (hazard ratio [HR] 24.292, 95% confidence interval [CI] 2.802–210.621, P = 0.004) and BTR < 5.0 (HR 5.462, 95% CI 1.095–27.253, P = 0.038) for HCC, and serum Zn level <70 μg/dL (HR 3.504, 95% CI 1.010–12.157, P = 0.048) and liver inflammation (A2–3) (HR 3.445, 95% CI 0.886–13.395, P = 0.074) for extra-hepatic malignancies. In conclusion, serum BTR and Zn levels were useful for predicting HCC and extrahepatic malignancies in NAFLD, respectively.

DOI： 10.1080/01635581.2019.1653474

Sarcopenia impairs health-related quality of life in cirrhotic patients. 査読有り国際誌

Ando Y, Ishigami M, Ito T, Ishizu Y, Kuzuya T, Honda T, Ishikawa T, Fujishiro M

European journal of gastroenterology & hepatology 31 巻 ( 12 ) 頁： 1550 - 1556 2019年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Gastroenterology and Hepatology

Aim Sarcopenia is associated with poor health-related quality of life (HRQOL) in the general population. However, in cirrhotic patients, as the development of sarcopenia is closely related to declined liver function, which also impairs HRQOL, whether sarcopenia deteriorates HRQOL independently from declined liver function remains unclear. The aim of this study was to clarify the impact of sarcopenia on HRQOL impairment in cirrhotic patients. Patients and methods A total of 88 cirrhotic patients [median age, 69 years; range: 31-79 years; 49 male (55.7%), 45 with hepatocellular carcinoma (51.1%)] were analyzed. We measured HRQOL using the 36-item Short-Form Health Survey version 2 questionnaire and identified factors contributing to scores lower than 50 in physical component summary (PCS), mental component summary, and role-social component summary (RCS) scores. Results Twenty-four (27.2%) patients had sarcopenia. PCS and RCS scores were significantly lower in patients with sarcopenia compared with those without sarcopenia. Patients with Child-Pugh (CP) classification B or C showed significantly lower scores in PCS and RCS than those with CP classification A. On multivariate analysis, the presence of sarcopenia was the only factor associated with low PCS scores [odds ratio (OR): 11.6; P = 0.031]. Female sex (OR: 3.34; P = 0.034), CP classification B or C (OR: 3.19; P = 0.037), and presence of sarcopenia (OR: 4.64; P = 0.016) were identified as independent factors for low RCS scores. Conclusion Sarcopenia independently impairs physical and role-social HRQOL in cirrhotic patients.

DOI： 10.1097/MEG.0000000000001472

Successful Treatment of Hepatocellular Carcinoma with Regorafenib after Sorafenib-induced Hypersensitivity. 査読有り

Yoshioka N, Kuzuya T, Ito T, Ishizu Y, Honda T, Ishikawa T, Ishigami M, Fujishiro M

Internal medicine (Tokyo, Japan) 58 巻 ( 19 ) 頁： 2803 - 2808 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Internal Medicine

Sorafenib and regorafenib are tyrosine kinase inhibitors that are used in the treatment of hepatocellular carcinoma and which have similar chemical structures and toxicity profiles. We herein report a case in which regorafenib treatment could be continued for 10 months and stable disease could be maintained for a long period despite the discontinuation of sorafenib due to grade 4 liver injury and grade 3 fever. The severe adverse events could be attributed to drug hypersensitivity, since a drug-induced lymphocyte stimulation test (DLST) indicated sensitivity to sorafenib. A DLST for regorafenib was negative. This is the first report showing that regorafenib could be safely administered after the discontinuation of sorafenib due to hypersensitivity.

DOI： 10.2169/internalmedicine.2812-19

Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment. 査読有り国際誌

Kuzuya T, Ishigami M, Ito T, Ishizu Y, Honda T, Ishikawa T, Hirooka Y, Fujishiro M

Hepatology research : the official journal of the Japan Society of Hepatology 49 巻 ( 9 ) 頁： 1054 - 1065 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Hepatology Research

Aim: This study aimed to investigate the clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma (HCC) after sorafenib treatment. Methods: Of 122 patients, 103 were radiologically confirmed as progressive disease (PD) (sorafenib-refractory group), and 19 discontinued sorafenib therapy due to adverse events prior to radiologic PD (sorafenib-intolerant group). Patients in the sorafenib-refractory group were divided into two subgroups each, according to their eligibility for second-line treatment (second-line-in and -out group), regorafenib (RESORCE-in and -out group), or ramucirumab (REACH-2-in and -out group). Results: Patients included in the non-candidate group were those with α-fetoprotein level <400 ng/mL (n = 51, 49.5%), daily sorafenib dose <400 mg (n = 44, 42.7%), Child–Pugh B or C (n = 40, 38.8%), and Eastern Cooperative Oncology Group performance status score ≥2 (n = 24, 23.3%). The percentages of candidates were 57.3% for second-line, 35.0% for regorafenib, and 23.3% for ramucirumab. The median post-progression survival (PPS) was significantly longer for the second-line-in and the RESORCE-in groups than in the non-candidate groups (12.6 and 11.0 months vs. 3.0 and 6.1 months, respectively). The PPS was not significantly different between the REACH-2-in and -out groups. A significant predictor of candidates for second-line treatment at sorafenib initiation was a Child–Pugh score of 5 (A5). Conclusions: Not all patients refractory to sorafenib were candidates for second-line therapy. A Child–Pugh score of A5 at sorafenib initiation was an important and favorable factor related to eligibility for second-line therapy and good outcomes.

DOI： 10.1111/hepr.13358

Induction of humoral and cellular immune response to HBV vaccine can be up-regulated by STING ligand. 査読有り国際誌

Ito H, Kanbe A, Hara A, Ishikawa T

Virology 531 巻頁： 233 - 239 2019年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Virology

A persistent hepatitis B virus (HBV) infection is characterized by a lack of or a weak immune response to HBV. Efficient induction of the HBV-specific immune response leads to the clearance of HBV. Stimulator of interferon (IFN) genes (STING) is a cytoplasmic sensor of intracellular DNA from microbes and host cells. In the present study, we examined the efficacy of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) that is a ligand of the STING pathway as an HBV vaccine adjuvant. Wild-type (WT) mice and HBV-transgenic (HBV-Tg) mice were immunized with hepatitis B surface antigen (HBsAg) and cGAMP. The vaccination with HBsAg and cGAMP significantly enhanced the humoral and cellular immune response to HBsAg in WT and HBV-Tg mice. Cytokine production related to Th1 and Th2 responses and the activation of antigen-presenting cells in lymphoid tissues were induced by cGAMP. Vaccination using cGAMP may overcome tolerance in patients with chronic HBV infection.

DOI： 10.1016/j.virol.2019.03.013

In utero exposure to di(2-ethylhexyl)phthalate suppresses blood glucose and leptin levels in the offspring of wild-type mice. 査読有り国際誌

Hayashi Y, Ito Y, Naito H, Tamada H, Yamagishi N, Kondo T, Ishikawa T, Gonzalez FJ, Nakajima T

Toxicology 415 巻頁： 49 - 55 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Toxicology

Exposure of pregnant mice to di(2-ethylhexyl)phthalate (DEHP) induces maternal lipid malnutrition and decreases the number of live fetuses/pups. In this study, we aimed to clarify the relationship between maternal lipid malnutrition and the nutritional status of the neonatal, lactational, and adult offspring, as well as the role of peroxisome proliferator-activated receptor α (PPARα) in these relationships. Sv/129 wild-type (mPPARA), Ppara-null, and PPARα-humanized (hPPARA) mice were fed diets containing 0, 0.01, 0.05, or 0.1% DEHP in utero and/or during the lactational stage. The male offspring were killed on postnatal day 2 or 21, or after 11 weeks. Exposure to either 0.05% or 0.1% DEHP during both the in utero and lactational periods decreased serum glucose concentrations in 2-day-old mPPARA offspring. These dosages also decreased both serum and plasma leptin levels in both 2- and 21-day-old mPPARA offspring. In contrast, exposure to DEHP only during the lactational period did not decrease leptin levels, suggesting the importance of in utero exposure to DEHP. Exposure to 0.05% DEHP during the in utero and lactational periods also increased food consumption after weaning in both mPPARA and hPPARA mice; this was not observed in Ppara-null offspring. In conclusion, in utero exposure to DEHP induces neonatal serum glucose malnutrition via PPARα. DEHP also decreases serum and plasma leptin concentrations in offspring during the neonatal and weaning periods, in association with PPARα which presumably results in increased of food consumption after weaning.

DOI： 10.1016/j.tox.2019.01.008

Corrigendum to "Intact metabolite profiling of mouse brain by probe electrospray ionization/triple quadrupole tandem mass spectrometry (PESI/MS/MS) and its potential use for local distribution analysis of the brain" [ACA 983 (2017) 160-165]. 国際誌

Hayashi Y, Zaitsu K, Murata T, Ohara T, Moreau S, Kusano M, Tanihata H, Tsuchihashi H, Ishii A, Ishikawa T

Analytica chimica acta 1031 巻頁： 196 - 196 2018年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Analytica Chimica Acta

The authors regret errors in Table 1 in the manuscript. The errors are now corrected as below. The authors would like to apologize for any inconvenience caused. We noticed that the polarity and SRM transition of some compounds in Table 1 are not correct in the published article. Herein, we report the correct polarity and SRM transition in the revised Table 1 as given below: [Table presented]

DOI： 10.1016/j.aca.2018.08.001

Effective Transplantation of 2D and 3D Cultured Hepatocyte Spheroids Confirmed by Quantum Dot Imaging 査読有り

Okumura H., Nanizawa E., Nakanishi A., Yukawa H., Hashita T., Iwao T., Baba Y., Ishikawa T., Matsunaga T.

Advanced Biosystems 2 巻 ( 8 ) 2018年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Advanced Biosystems

Liver transplantation is the most effective treatment for patients with end-stage liver diseases, but hepatocyte transplantation using spheroids is expected to become an alternative strategy owing to the limited number of liver donors. However, the effects of the transplantation route and spheroid size on cell dynamics and the organ-specific accumulation of hepatocytes are not well characterized. In this study, the influence of three delivery routes (tail vein, portal vein, and spleen) and three spheroid sizes (50, 100, and 150 µm in diameter) on the accumulation of human fetal hepatocytes labeled with quantum dots in the liver and other organs (heart, lung, kidney, and spleen) of recipient mice is investigated. Ex vivo fluorescence imaging reveals that the accumulation of transplanted cells in the liver is highest for transplantation via the portal vein compared with other routes. The accumulation efficiency depends on spheroid size, and spheroids with a diameter of 50 µm display greater accumulation than that of spheroids of other sizes. It is concluded that hepatocyte transplantation via the portal vein using small spheroids of 50 µm in diameter may be effective for clinical applications.

DOI： 10.1002/adbi.201800137

(-)-Epigallocatechin-3-gallate Down-regulates Doxorubicin-induced Overexpression of P-glycoprotein Through the Coordinate Inhibition of PI3K/Akt and MEK/ERK Signaling Pathways

Satonaka Hana, Ishida Kumiki, Takai Miho, Koide Ryoji, Shigemasa Ryota, Ueyama Jun, Ishikawa Tetsuya, Hayashi Kazuhiko, Goto Hidemi, Wakusawa Shinya

ANTICANCER RESEARCH 37 巻 ( 11 ) 頁： 6071-6077 2017年11月

Effects of Ursodeoxycholic Acid and Insulin on Palmitate-Induced ROS Production and Down-Regulation of PI3K/Akt Signaling Activity

Yokoyama Kunihiro, Tatsumi Yasuaki, Hayashi Kazuhiko, Goto Hidemi, Ishikawa Tetsuya, Wakusawa Shinya

BIOLOGICAL & PHARMACEUTICAL BULLETIN 40 巻 ( 11 ) 頁： 2001-2004 2017年11月

Utility of Doppler ultrasonography for diagnosing and assessing treatment effects in liver compartment syndrome. 査読有り

Ando Y, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Hayashi K, Ishikawa T, Goto H, Hirooka Y

Clinical journal of gastroenterology 10 巻 ( 3 ) 頁： 265 - 269 2017年6月

Coexistence of Copper in the Iron-Rich Particles of Aceruloplasminemia Brain. 査読有り国際誌

Yoshida K, Hayashi H, Wakusawa S, Shigemasa R, Koide R, Ishikawa T, Tatsumi Y, Kato K, Ohara S, Ikeda SI

Biological trace element research 175 巻 ( 1 ) 頁： 79 - 86 2017年1月

近赤外バイオイメージング-NIR-II:第2の生体の窓 NIR-II近赤外領域における移植幹細胞in vivo蛍光イメージング

湯川博, 小林香央里, 湯川博, 小林香央里, 新岡宏彦, 亀山達矢, 佐藤和秀, 鳥本司, 石川哲也, 馬場嘉信, 馬場嘉信

Bio Industry 34 巻 ( 1 ) 頁： 113 - 113 2017年

セロトニン症候群モデルラットにおける筋肉の異常収縮と血漿メタボローム・プロファイルの関連性

財津桂, 野田沙樹, 林由美, 大原倫美, 井口亮, 草野麻衣子, 佐藤貴子, 土橋均, 石川哲也, 鈴木廣一, 石井晃

日本毒性学会学術年会 44.1 巻 ( 0 ) 頁： O-38 2017年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

【目的】セロトニン症候群（SS）は、SSRIの過剰摂取等から脳内セロトニン濃度が上昇して発症するとされ、重篤の場合には異常高体温が観察される。我々は以前、SSモデルラットでは血漿中の多数のメタボライトが対照群に比べて有意に上昇することや、異常高体温と筋肉の異常収縮の関連を本学会で報告した。そこで、この原因を更に追究する為、SSモデルラットの血漿、肝臓及び骨格筋（腓腹筋）についてメタボローム解析を行った。【実験方法】6週齢のWistar系雄性ラットを投与2時間前から絶食し、5-HTP DMSO溶液、Clorgyline saline溶液を腹腔内投与してモデルを作成した。対照群には同量のDMSOとsalineを投与した。投与前後で直腸温を測定し、投与35分後に解剖を行い、血漿、肝臓および腓腹筋を採取後、急速凍結した。臓器試料は氷冷MeOHを加えてホモジナイズし、遠心分離後の上清及び血漿にISを加えて溶媒抽出した。遠心濃縮及び凍結乾燥後、誘導体化を行い、島津製作所製 GCMS-TQ8040を用いてメタボローム解析を行った。さらに腓腹筋についてはqRT-PCRによるUCP-3の遺伝子発現解析を行った。【結果】投与35分後にモデル群の直腸温は約40℃に上昇し、対照群と有意差を示した。メタボローム解析の結果、モデルの腓腹筋では異常収縮に伴い、嫌気呼吸が亢進していることが示唆され、かつ、UCP-3が有意に上昇したことから、筋肉の異常収縮が異常高体温に寄与することが示唆された。肝臓では尿素の蓄積に加え、尿素回路構成成分の有意な変動が観察され、筋肉の異常収縮に伴うタンパク質・アミノ酸の異化によって尿素回路に変動が生じたと考えられた。血漿ではアミノ酸やTCA回路構成成分を含めた79成分が有意に上昇し、筋肉の異常収縮とそれに伴う嫌気呼吸の亢進の結果、血漿中に上記のメタボライトが蓄積すると考えられた。

DOI： 10.14869/toxpt.44.1.0_o-38

Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 identified from Dental Pulp Stem Cells Synergistically Resolve Acute Liver Failure in Rats by Altering Macrophage Polarity 査読有り

Takanori Ito, Akihito Yamamoto, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Yoshiki Hirooka, Hidemi Goto

HEPATOLOGY 64 巻頁： 515A - 515A 2016年10月

脂質メディエーターとメタボローム解析によるPPARαノックアウトマウスを用いたコカイン誘発性肝障害の解析

篠田諭, 林由美, 財津桂, 酒井佑一朗, 山中麻友美, 那須民江, 石川哲也, 吉本高士, 草野麻衣子, 土橋均, 石井晃

日本毒性学会学術年会 43.1 巻 ( 0 ) 頁： P-90 2016年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本毒性学会

【目的】コカインは主としてミトコンドリアのβ酸化能を障害することにより肝障害を誘引することが示唆されており、その毒性の発現には核内受容体Peroxisome Proliferator-Activated Receptor α（PPARα）の関与が指摘されている。そこで、PPARαノックアウト（KO）マウスを用いてコカイン誘因性肝障害を解析した。 【実験方法】wildおよびKOマウスにコカイン塩酸塩（30mg/kg）を1日1回腹腔内に投与した。投与期間は1日あるいは3日間とし、最終投与3時間後に肝臓および血清を採取した。対照群にはsalineを投与した。血清ALT、ASTはニットーボーメディカル製BBxを用いて測定した。肝臓の組織切片を作成し、HE染色等により病理像を観察した。さらに、島津製作所製LCMS-8060およびGCMS-TQ8040（何れもタンデム質量分析計）を用いて、肝臓内の脂質メディエーターおよびメタボロームの解析を行った。 【結果】血清ALT、ASTは、wildマウスの3日間投与群において対照群に対して有意な上昇が認められた。一方、KOマウスでは、3日間投与群の半数(n=4)で極めて高い値を示したが、残りの半数(n=4)では対照群と同程度であった。HE染色による病理標本においても、wildマウスの3日間投与群では明らかな肝障害が認められたが、KOマウスの3日間投与群では、ALT・ASTが高値を示した個体では、微小脂肪滴の沈着やミトコンドリアの腫大と推定される病変が観察され、特に強い肝障害が認められたが、ALT、ASTが上昇しなかった個体では、このような肝障害は認められなかった。 【考察】PPARαは脂肪酸のβ酸化だけでなくNF-κBを基とする抗炎症作用にも関与するため、KOマウスでは強い肝障害が生じるものと予想される。しかし実際には、半数のKOマウスにおいてはコカイン誘因性の肝障害が認められなかった。そこで、KOマウスにおける肝障害の程度の差異について解析するため、アラキドン酸カスケードを主とした脂質メディエーターおよびメタボローム解析を行い、その主因を追及する。

DOI： 10.14869/toxpt.43.1.0_p-90

穿刺治療支援アプリケーションVirtuTRAXTMを用いた2ステップ法によるラジオ波焼灼術の試み査読有り

[Pathogenesis and disease state in hepatitis B virus infection].

Ishikawa T

Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 9 巻頁： 429 - 33 2015年12月

C型肝炎治療の現状招待有り

石川哲也

明日の臨床 27 巻 ( 1 ) 頁： 29-34 2015年6月

Kynurenine production mediated by indoleamine 2,3-dioxygenase aggravates liver injury in HBV-specific CTL-induced fulminant hepatitis. 査読有り

OHTAKI Hirofumi, ITO Hiroyasu, ANDO Kazuki, ISHIKAWA Tetsuya, HOSHI Masato, ANDO Tatsuya, TAKAMATSU Manabu, HARA Akira, MORIWAKI Hisataka, SAITO Kuniaki, SEISHIMA Mitsuru

Biochim Biophys Acta 1842 巻 ( 9 ) 頁： 1464–1471 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）

Indoleamine 2,3-dioxygenase (IDO), an enzyme that is ubiquitously distributed in mammalian tissues and cells, converts tryptophan to kynurenine, and is also known as a key molecule that promotes apoptosis in lymphocytes and neurons. In this study, we established hepatitis B virus (HBV)-transgenic (Tg)/IDO-knockout (KO) mice and examined the influence of IDO in a murine fulminant hepatitis model induced by HBV-specific cytotoxic T lymphocytes (CTL). An increase of IDO expression in the livers of HBV-Tg/IDO-wild-type (WT) mice administered HBV-specific CTL was confirmed by real-time polymerase chain reaction, western blotting, and evaluating IDO activity. Plasma alanine aminotransferase (ALT) levels in HBV-Tg/IDO-KO mice after HBV-specific CTL injection significantly decreased compared with those in HBV-Tg/IDO-WT mice. An inhibitor of IDO, 1-methyl-D-tryptophan (1-MT), could also attenuated the observed liver injury induced by this HBV-specific CTL. The expression levels of cytokine and chemokine mRNAs in the livers of HBV-Tg/IDO-WT mice were higher than those in the livers of HBV-Tg/IDO-KO mice. The administration of kynurenine aggravated the liver injury in HBV-Tg/IDO-KO mice injected with HBV-specific CTL. Simultaneous injection of recombinant murine interferon (IFN-γ) and kynurenine also increased the ALT levels in HBV-Tg/IDO-KO mice. The liver injury
induced by IFN-γ and kynurenine was improved in HBV-Tg/tumor necrosis factor-α-KO mice. Conclusion:
Kynurenine and IFN-γ induced by the administration with HBV-specific CTL are cooperatively involved in the
progression of liver injury in acute hepatitis model. Our results may lead to a new therapy for the acute liver injury caused by HBV infection.

Induction of hepatitis B virus surface antigen-specific cytotoxic T lymphocytes can be up-regulated by the inhibition of indoleamine 2, 3-dioxygenase activity. 査読有り

ITO Hiroyasu, ANDO Tatsuya, ANDO Kazuki, ISHIKAWA Tetsuya, SAITO Kuniaki, MORIWAKI Hisataka, SEISHIMA Mitsuru

Immunology 142 巻 ( 4 ) 頁： 614–623 2014年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Cytotoxic T lymphocytes (CTLs) are thought to be major effectors involved in viral clearance during acute infections, including hepatitis B virus (HBV) infection. A persistent HBV infection is characterized by a lack of or a weak CTL response to HBV, which may be reflective of tolerance to HBV. Efficient induction of HBV-specific CTLs leads to the clearance of HBV in patients with a chronic HBV infection. Previously, we
reported that a-galactosylceramide (a-GalCer), a specific natural killer T (NKT) cell agonist, enhanced the induction of HBV surface antigen (HBsAg)-specific CTLs. In the present study, we found that inhibition of
indoleamine 2,3-dioxygenase (IDO) activity enhanced the induction of HBsAg-specific CTLs after immunization with HBsAg and a-GalCer. The administration of HBsAg and a-GalCer increased the production of interleukin-2 and interleukin-12b, which are crucial for the induction of HBsAg-specific CTLs. The production of these cytokines was more strongly enhanced in IDO knockout mice compared with wild-type mice. In addition, a-GalCer induced the production of IDO in CD11b+ cells, and these cells inhibited proliferation of HBsAg-specific CTLs. Our results lead to strategies for improving the induction of HBsAg-specific CTLs.

Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced bydoxorubicin in HepG2 cells. 査読有り

KOMORI Yuki, ARISAWA Sakiko, TAKAI Miho, YOKOYAMA Kunihiro, HONDA Minako, HAYASHI Kazuhiko, ISHIGAMI Masatoshi, KATANO Yoshiaki, GOTO Hidemi, UEYAMA Jun, ISHIKAWA Tetsuya, WAKUSAWA Shinya.

European JournalofPharmacology 724 巻頁： 161-167 2014年2月

進行肝細胞癌に対するソラフェニブ投与後2週間以内の発熱と造影CT上の阻血性変化との関係査読有り

葛谷貞二、石上雅敏、新家卓郎、今井則博、阿知波宏一、荒川恭宏、山田恵一、中野聡、石津洋二、本多隆、林和彦、石川哲也、中野功、片野義明、伊藤彰浩、廣岡芳樹、後藤秀実.

肝臓 54 巻 ( 7 ) 頁： 505-506 2013年7月

満腹感を伴う便秘症状の原因にvildagliptinの関与が示唆された糖尿病合併末期腎不全の1例査読有り

綾田穣、森弘卓延、加藤ふみ、堀田直樹、黒川剛、中野達徳、石川哲也

腎と透析 74 巻 ( 3 ) 頁： 470-474 2013年3月

葛谷貞二, 林和彦, 石上雅敏, 石川哲也, 中野功, 片野義明, 伊藤彰浩, 廣岡芳樹, 泉並木, 後藤秀実, 石津洋二, 新家卓郎, 今井則博, 阿知波宏一, 荒川恭宏, 山田恵一, 中野聡, 本多隆

肝臓 54 巻 ( 12 ) 頁： 850 - 853 2013年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本肝臓学会

We performed percutaneous radio frequency ablation (RFA) therapy by two-step insertion method using VirtuTRAXTM (GE Healthcare, USA) instrument navigator. Subjects were 16 patients (23 nodules) with hepatocellular carcinoma. VirtuTRAXTM position sensor was attached to the hilt of 14-gauge outer needle. In all cases, we could perform 17- gauge Cool-tip RFA without the positional gap between the virtual tract and the actual needle which was caused by the deflection of the needle. The reasons without causing the positional gap were that the outer needle was more rigid than Cool-tip needle, and that it was inserted using initial insertion of a 21-gauge guided needle. RFA by two-step insertion method using VirtuTRAXTM is suggested to be more safe and effective than conventional RFA.

DOI： 10.2957/kanzo.54.850

その他リンク： http://search.jamas.or.jp/link/ui/2014089120

Quantum dots conjugated with transferrin for brain tumor cell imaging.

Yukawa H, Tsukamoto R, Kano A, Okamoto Y, Tokeshi M, Ishikawa T, Mizuno M, Baba Y

Journal of Cell Science and Therapy 4 巻 ( 3 ) 頁： 1 2013年

Immunoregulation of hepatitis B virus infection -rationale and clinical application- 招待有り

ISHIKAWA Tetsuya

Nagoya J Med Sci 74 巻頁： 217-232 2012年8月

担当区分：筆頭著者記述言語：英語

Hepatitis B virus (HBV) is susceptible to the cellular immune responses, especially to the signal of interferon (IFN)-g. The action of IFN-g is pleiotropic, and causes downregulation of HBV in protein, RNA, and possibly DNA levels. Therefore, therapeutic vaccination to induce cellular immune responses to HBV is a promising approach for controlling chronic HBV infection. A number of clinical trials with this approach have been conducted to date, however, they have not been as successful as initially expected. T-cell exhaustion induced by the excessive HBV antigens caused by persistent infection is thought to be one of the main causes of poor responses to therapeutic vaccination. In this review, the mechanisms behind immunoregulation of HBV replication and immunodysfunction during chronic HBV infection are summarized, and novel approaches to improve the efficacy of therapeutic vaccination, from basic research to clinical trials, are introduced.

機能性胃疾患診療における不安抑うつスコアの有用性と機能性胃疾患の発症および増悪因子としての心配性の関与について

洪繁、松浦俊博、木村宏之、石川哲也、京兼和宏、山田理

消化器内科 55 巻 ( 1 ) 頁： 42-49 2012年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）

HADS（Hospital Anxiety Depression Scale）スコアに本人の主観的性格分類（楽天的か心配性か）を組み合わせて解析することで、機能性胃腸症発症、増悪と心配性の性格の関わりについて解析した。職域検診を受診した健常者の解析からは、心配性の性格とHADSスコアが正に相関していた。更に、機能性胃腸症患者では、うつ病で治療中の患者と同様に心配性の患者の割合が非常に高く、患者の心配性の性格が機能性胃腸症発症及び増悪因子であることが疑われた。機能性胃腸症の診療においては、多くの患者が過度に心配性であり、胃腸症状の出現により更に心配性の度合いが高じていることを考慮し、患者の不安を取り除く診療を行うことが、患者の愁訴を減少させ、治療満足度を向上させる方法であると考えられる。

瀉血による慢性肝炎の進展予防

伊東和樹, 石川哲也

medicina 48 巻 ( 7 ) 頁： 1176-1178 2011年7月

今月の主題内科疾患の予防戦略消化器疾患の予防戦略瀉血による慢性肝炎の進展予防

伊東和樹, 石川哲也

medicina 48 巻 ( 7 ) 頁： 1176 - 1178 2011年7月

Association of interleukin 28B and mutations in the core and NS5A region of hepatitis C virus with response to peg-interferon and ribavirin therapy. 査読有り

HAYASHI Kazuhiko, KATANO Yoshiaki, HONDA Takashi, ISHIGAMI Masatoshi, ITOH Akihiro, HIROOKA Yoshiki, ISHIKAWA Tetsuya, NAKANO Isao, YOSHIOKA Kentaro, TOYODA Hidenori, KUMADA Takashi, GOTO Hidemi

Liver Int 頁： 1359-1365 2011年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

Background and aims: Mutations in the core and NS5A region of hepatitis C virus (HCV) genotype 1b have been associated with response to interferon (IFN) therapy. Genome-wide association studies have revealed that the singlenucleotide polymorphism (SNP) of interleukin 28B (IL28B) contributes to IFN response. The aim of this study was to investigate whether the SNP of IL28B (rs8099917) and amino acid substitutions in the core and NS5A region affect the response to IFN therapy. Methods: A total of 299 patients (157 men, 142 women; mean age, 55.910.3 years) infected with HCV genotype 1b were studied. The fibrosis stage was diagnosed as F0 (n = 23), F1 (n = 121), F2 (n = 62), F3 (n = 32) and F4 (n = 7) by liver biopsy. Results: Of the 299 patients, 138 achieved sustained virological response (SVR). On univariate analysis, predictors of SVR were age o60 years, male gender, higher platelet count, lack of fibrosis, non-Q at core 70, mutant-type interferon sensitivitydetermining region (ISDR) and IL28B genotype TT. The factors related to SVR on multivariate analysis were IL28B (P = 0.0001), fibrosis (P = 0.0111) and mutations in the core region70 (P = 0.0267) and ISDR (P = 0.0408). The best SVR was achieved in patients with non-Q70, mutant-type ISDR and T allele (74.5%), and the worst was achieved in patients with Q70, wild-type
ISDR and G allele (8.1%). Conclusions: The SNP of IL28B and mutations in the core region and NS5A are associated with IFN responsiveness. Both host and viral factors might be useful for predicting IFN response.

DOI： 10.1111/j.1478-3231.2011.02571.x.

バンコマイシン投与によって難治性肝性脳症が改善し肝細胞癌に対する肝動脈化学塞栓療法が可能となった1例

葛谷貞二, 竹田欽一, 宇都宮節夫, 多賀雅浩, 川田登, 池田誉, 今井則博, 水谷佳貴, 広瀬健, 石川哲也

癌と化学療法 38 巻 ( 6 ) 頁： 995 - 1001 2011年6月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：(株)癌と化学療法社

症例は80歳、男性。C型肝硬変、肝細胞癌で通院していた。2007年秋ごろから肝性脳症を繰り返すようになり、頻回の外来通院と入院加療を必要とした。肝予備能の低下により、肝細胞癌に対する治療は不可能となった。肝性脳症に対して緩下剤、ラクツロース、カナマイシン内服などの投与を行ったが、脳症のコントロールは困難であった。血中アンモニア値は130μg/dL前後で、時に200μg/dL以上となった。12月よりバンコマイシン内服(0.5g/回、3日に1回投与)を追加したところ、アンモニア値は速やかに50μg/dL低下となり、意識レベルの正常化、ADL、QOLの改善など著明な効果が得られた。バンコマイシン内服開始3ヵ月後には、Child C(10点)からChild B(7点)と肝予備能も改善、肝細胞癌に対し肝動脈化学塞栓療法が可能となった。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00296&link_issn=&doc_id=20110629470023&doc_link_id=%2Fab8gtkrc%2F2011%2F003806%2F025%2F0995-0997%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2011%2F003806%2F025%2F0995-0997%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Liver stiffness in extrahepatic cholestasis correlates positively with bilirubin and negatively with alanime aminotransferase

HARATA Masao, HASHIMOTO Senju, KAWABE Naoto, NITTA Yoshifumi, MURAO Michihito, NAKANO Takuji, ARIMA Yuko, SHIMAZAKI Hiroaki, ISHIKAWA Tetsuya, OKUMURA Akihiko, ICHINO Naohiro, OSAKABE Keisuke, NISHIKAWA Toru, YOSHIOKA Kentaro

Hepatology research : the official journal of the Japan Society of Hepatology 41 巻 ( 5 ) 頁： 423 - 429 2011年5月

沈降型B型肝炎ワクチン招待有り

石川哲也

肝胆膵 61 巻 ( 6 ) 頁： 1088-1094 2010年12月

Hypofractionated stereotactic body radiotherapy for primary and metastatic liver tumors using the novalis image-guided system: preliminary results regarding efficacy and toxicity. 査読有り国際誌

Hiromitsu Iwata, Yuta Shibamoto, Chisa Hashizume, Yoshimasa Mori, Tatsuya Kobayashi, Naoki Hayashi, Katsura Kosaki, Tetsuya Ishikawa, Teiji Kuzuya, Setsuo Utsunomiya

Technology in cancer research & treatment 9 巻 ( 6 ) 頁： 619 - 27 2010年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

www.tcrt.org The purpose of this study was to evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) for primary and metastatic liver tumors using the Novalis image-guided radiotherapy system. After preliminarily treating liver tumors using the Novalis system from July 2006, we started a protocol-based study in February 2008. Eighteen patients (6 with primary hepatocellular carcinoma and 12 with metastatic liver tumor) were treated with 55 or 50 Gy, depending upon their planned dose distribution and liver function, delivered in 10 fractions over 2 weeks. Four non-coplanar and three coplanar static beams were used. Patient age ranged from 54 to 84 years (median: 72 years). The Child-Pugh classification was Grade A in 17 patients and Grade B in 1. Tumor diameter ranged from 12 to 35 mm (median: 23 mm). Toxicities were evaluated according to the Common Terminology Criteria of Adverse Events version 4.0, and radiation-induced liver disease (RILD) was defined by Lawrence's criterion. The median follow-up period was 14.5 months. For all patients, the 1-year overall survival and local control rates were 94% and 86%, respectively. A Grade 1 liver enzyme change was observed in 5 patients, but no RILD or chronic liver dysfunction was observed. SBRT using the Novalis image-guided system is safe and effective for treating primary and metastatic liver tumors. Further investigation of SBRT for liver tumors is warranted. In view of the acceptable toxicity observed with this protocol, we have moved to a new protocol to shorten the overall treatment time and escalate the dose.

Role of tumor necrosis factor-α in acute hepatitis B virus infection

Ability of IDO to attenuate liver injury in α-galactosylceramide- induced hepatitis model 査読有り

Hiroyasu Ito, Masato Hoshi, Hirofumi Ohtaki, Ayako Taguchi, Kazuki Ando, Tetsuya Ishikawa, Yosuke Osawa, Akira Hara, Hisataka Moriwaki, Kuniaki Saito, Mitsuru Seishima

Journal of Immunology 185 巻 ( 8 ) 頁： 4554 - 4560 2010年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER ASSOC IMMUNOLOGISTS

IDO converts tryptophan to L-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in α-galactosylceramide (α-GalCer)-induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered α-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after α-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-D-tryptophan also exacerbated liver injury in this murine hepatitis model. In α-GalCer-induced hepatitis models, TNF-α is critical in the development of liver injury. The mRNA expression and protein level of TNF-α in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with α-GalCer were analyzed by flow cytometry, and the numbers of CD49b+ and CD11b+ cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with α-GalCer, TNF-α secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in α-GalCer-induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-α-producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the α-GalCer-induced hepatitis model. Copyright © 2010 by The American Association of Immunologists, Inc.

DOI： 10.4049/jimmunol.0904173

Ito Hiroyasu, Ando Kazuki, Ishikawa Tetsuya, SEISHIMA Mitsuru

炎症・再生 : 日本炎症・再生医学会雑誌 = Inflammation and regeneration 30 巻 ( 5 ) 頁： 445 - 450 2010年9月

PEG後栄養管理中の義歯誤嚥に対しネット鉗子とオーバーチューブを用い安全に異物除去が可能であった1例査読有り

綾田穣, 堀田直樹, 中野達徳, 内村正史, 花井恵美, 伊藤陽子, 徳永有姫, 吉田篤生, 石川哲也, 増子和郎

在宅医療と内視鏡治療 14 巻 ( 1 ) 頁： 46-51 2010年9月

著明な肝障害を伴ったプロトポルフィリン症の1例査読有り

嶋崎宏明, 有馬裕子, 中野卓二, 村尾道人, 新田佳史, 原田雅生, 川部直人, 橋本千樹, 長野健一, 石川哲也, 奥村明彦, 林和彦, 片野義明, 黒田誠, 吉岡健太郎

肝臓 51 巻 ( 4 ) 頁： 175 - 182 2010年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本肝臓学会

症例は29歳男性．小児期より光線過敏があった．父方の祖父，弟にも光線過敏を認める．2001年11月肝障害のため他院に入院し，プロトポルフィリン症（EPP）と診断され，肝生検では軽度線維化と色素沈着をみとめた．2005年8月腹痛，食欲不振，黄疸，肝障害のため同院に再入院した．肝生検では広範な線維化，多数の色素沈着をみとめた．2006年11月腹痛，食欲不振，便秘，微熱，黄疸のため当院に第1回目の入院をした．赤血球プロトポルフィリン13776 μg/dl ，ALT 287 IU/L，総ビリルビン5.1 mg/dl であった．2007年5月に同様の症状にて第2回目の入院をした．2008年8月に同様の症状にて第3回目の入院をし，肝不全が進行し11月死亡した．EPPは稀な遺伝性疾患であり，肝不全にて死亡する患者は多くない．しかし重症の肝障害の治療法としては肝移植しかなく，適切な時期に肝移植を考慮すべきと思われる．

DOI： 10.2957/kanzo.51.175

CiNii Books

その他リンク： http://search.jamas.or.jp/link/ui/2010194025

MUC1標的免疫細胞療法とGemcitabineとの併用が著効した膵頭部多発癌肝転移の1例査読有り

今井則博, 竹田欽一, 宇都宮節夫, 多賀雅浩, 川田登, 池田誉, 水谷佳貴, 広瀬健, 石川哲也, 吉田松年

癌と化学療法 37 巻 ( 3 ) 頁： 527-529 2010年3月

B型肝炎に対する免疫療法招待有り

石川哲也

medicina 47 巻 ( 3 ) 頁： 487-490 2010年3月

[A case of metastatic pancreatic cancer with a remarkable response to combination therapy of gemcitabine and adoptive immune cell therapy]. 査読有り

Norihiro Imai, Kinichi Takeda, Setsuo Utsunomiya, Masahiro Taga, Noboru Kawata, Takashi Ikeda, Yoshitaka Mizutani, Ken Hirose, Tetsuya Ishikawa, Shonen Yoshida

Gan to kagaku ryoho. Cancer & chemotherapy 37 巻 ( 3 ) 頁： 527 - 9 2010年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）

A 52-year-old woman with a chief complaint of epigastric distress was diagnosed as having pancreatic cancer with multiple liver metastases. After insertion of a metallic stent for biliary stenosis, combination therapy of gemcitabine (GEM) and adoptive immune cell therapy (AICT) was initiated. GEM 1,000 mg/m2 was administered on day 1, 8 and 15 every 4 weeks, while AICT using MUC1 peptide-pulsed dendritic cells (DC) and anti-CD3-activated T lymphocytes (CAT) was given biweekly. After 6 courses of GEM and 9 courses of DC-CAT, the patient was considered to have a complete response (CR) on CT and MRI examination. CR has still been maintained by the continuous administration of GEM and CAT. The combination therapy of GEM and AICT was suggested to be effective against advanced pancreatic cancer.

Role of tumor necrosis factor-.ALPHA. in acute hepatitis B virus infection

Ito Hiroyasu, Ando Kazuki, Ishikawa Tetsuya, Seishima Mitsuru

Inflammation and Regeneration 30 巻 ( 5 ) 頁： 445 - 450 2010年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：日本炎症・再生医学会

Tumor necrosis factor (TNF)-α is one of the most important factors in HBV infection and HBV infection-related diseases. Although TNF-α is critical and beneficial in HBV clearance, the liver injury is progressed by the up-regulation of TNF-α production. Taken together, TNF-α contribute to the cure and increase of severity in acute hepatitis caused by HBV. It is very important to understand the role of TNF-α, which has two-wedge sword in HBV infection, and the mechanism of TNF-α production. This review briefly overviews up to date about the role of TNF-α in HBV-induced liver injury and HBV clearance, including our results achieved recently.

DOI： 10.2492/inflammregen.30.445

Interaction between LPS-induced NO production and IDO activity in mouse peritoneal cells in the presence of activated Va14 NKT cells. 査読有り

Ohtaki H, Ito H, Ando K, Ishikawa T, Hoshi M, Tanaka R, Osawa Y, Yokochi T, Moriwaki H, Saito K, Seishima M.

Biochem Biophys Res Com 389 巻 ( 2 ) 頁： 229-234 2009年11月

BSCガストロストミーシステムを用いた胃瘻交換時における患者に与える影響についての検討

綾田穣, 堀田直樹, 中野達徳, 鮫島庸一, 吉田篤生, 花井恵美, 伊藤陽子, 徳永有姫, 石川哲也, 増子和郎

在宅医療と内視鏡治療 13 巻 ( 1 ) 頁： 19 - 24 2009年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：PEG・在宅医療研究会

BSCガストロストミーシステム:BSC gastrostomy system(以下BSCGSと略す)は、ガイドワイヤーを用いずに胃瘻造設後のカテーテル交換を行うことができるバンパータイプ・ボタン型カテーテルキットである。今回BSCGSに改良が加えられたため、交換に要する時間や、バイタルサインの変化について、ガイドワイヤーを用いる同タイプのキットとの比較検討を行った。BSCGSでは、有意に交換時間が短縮され(p<0.01)、バイタルサインの変化に有意差は認めず、有用かつ安全と考えられた。(著者抄録)

市販薬およびフルバスタチンナトリウムによる薬物性肝障害を発症したＧｉｌｂｅｒｔ症候群の１例査読有り

Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined direction. 査読有り

Ohashi T, Tanabe J, Ishikawa T, Okumura A, Sato K, Ayada M, Hotta N, Kuzuya K, Ito H, Nakao H, Yoneda M, Kakumu S.

Hepatol Res 39 巻 ( 5 ) 頁： 510-519 2009年5月

V alpha14 NKT cells activated by alpha-galactosylceramide augment lipopolysaccharide-induced nitric oxide production in mouse intra-hepatic lymphocytes. 査読有り

Ohtaki H, Ito H, Ando K, Ishikawa T, Saito K, Imawari M, Yokochi T, Moriwaki H, Seishima M

Biochem Biophys Res Com 378 巻 ( 3 ) 頁： 579-583 2009年1月

Role of TNF-alpha produced by nonantigen-specific cells in a fulminant hepatitis mouse model. 査読有り

Ito H, Ando K, Ishikawa T, Saito K, Takemura M, Imawari M, Moriwaki H, Seishima M.

J Immunol 182 巻 ( 1 ) 頁： 391-397 2009年1月

Usefulness of radiofrequency ablation with micro-convex probe for hepatocellular carcinoma. 査読有り

HOTTA Naoki, AYADA Minoru, MATSUMOTO Eiji, OKUMURA Akihiko, ISHIKAWA Tetsuya, SATO Ken, OOHASHI Tomohiko, KAKUMU Shinichi

Hepato-gastroenterology 56 巻 ( 93 ) 頁： 1127-1132 2009年

記述言語：英語掲載種別：研究論文（学術雑誌）

Background/Aims: It was aimed to assess whether a micro-convex probe is superior to the present conventional probe for ultrasonography from the points of safety and efficacy during percutaneous radiofrequency ablation therapy for hepatocellular carcinoma. Methodology: Twenty-one patients with 23 hepatocellular carcinoma lesions who had one or 2 lesions, each 4 cm or less in diameter, and liver function of Child-Pugh class A or B were enrolled. All the patients except for 2 patients were seropositive for hepatitis C virus. Radiofrequency ablation was carried out under a real-time US guidance. The cooled-tip electrodes used were single and clustered. Results: It was possible to perform safe and accurate percutaneous radiofrequency ablation procedure using micro-convex probes for the treatment of all hepatocellular carcinoma nodules. It was also possible to treat hepatocellular carcinoma located in the right subphrenic region without artificial pleural effusion under intercostal ultrasonography guide. Improved clustered needles were successfully applied to treat the nodules more than 3 cm in diameter with less resistance for penetration compared with the conventional needle. The findings of advanced dynamic flow image on ultrasonography to assess the therapeutic efficacy indicated the consistency with those of dynamic CT which was done 3 to 5 days later radiofrequency ablation. Major complication of radiofrequency ablation procedure was noted in none. Conclusions: These results suggest that micro-convex probe with clustered tips is superior to conventional probe for ultrasonography from the points of safety and efficacy during radiofrequency ablation for hepatocellular carcinoma nodule located in the right subphrenic region and for larger sized nodule more than 3 cm.

綾田穣, 石川哲也, 奥村明彦, 堀田直樹, 広瀬昭憲, 増子和郎, 各務伸一

肝臓 50 巻 ( 3 ) 頁： 139 - 144 2009年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人　日本肝臓学会

症例は，56歳女性．心窩部痛と嘔吐に対し市販薬を内服するも改善せず，外来を受診．黄疸，肝胆道系酵素の上昇を認めたため入院となった．市販薬による薬物性肝障害を疑い，内服を中止．肝障害は軽快した．退院後，高脂血症に対しフルバスタチンナトリウムを投与したところ再び肝障害が出現した．内服中止により，肝障害は改善したが，以後も持続する間接ビリルビン優位の高ビリルビン血症を認めた．Gilbert症候群を疑い，遺伝子解析により同症候群と確定診断した．Gilbert症候群は，bilirubin UDP-glucuronyl transferase（UGT1A1）活性の低下によるビリルビンのグルクロン酸抱合の障害が主たる病因と考えられている体質性黄疸である．UGT1A1は脂溶性薬物代謝の第II相に関与する酵素の遺伝子多型であり，UGT1A1活性の低下が，薬物性肝障害を発症した原因と推察された．

DOI： 10.2957/kanzo.50.139

Deficiency of forkhead box P3 and cytotoxic T-lymphocyte-associated antigen-4 gene expressions and impaired suppressor function of CD4+CD25+ T cells in patients with autoimmune hepatitis

OKUMURA Akihiko, ISHIKAWA Tetsuya, SATO Sayaka, YAMAUCHI Taeko, OSHIMA Hisae, OHASHI Tomohiko, SATO Ken, AYADA Minoru, HOTTA Naoki, KAKUMU Shinichi

Hepatology research : the official journal of the Japan Society of Hepatology 38 巻 ( 9 ) 頁： 896 - 903 2008年9月

Deficiency of forkhead box P3 and cytotoxic T-lymphocyte-associated antigen-4 gene expressions and impaired suppressor function of CD4+CD25+ T cells in patients with autoimmune hepatitis. 査読有り

Okumura A, Ishikawa T, Sato S, Yamauchi T, Oshima H, Ohashi T, Sato K, Ayada M, Hotta N, Kakumu S.

Hepatol Res 38 巻 ( 9 ) 頁： 896-903 2008年9月

Role of V alpha14+ NKT cells in the development of hepatitis B virus-specific CTL: Activation of V alpha14+ NKT cells promotes the breakage of CTL tolerance. 査読有り

Ito H, Ando K, Ishikawa T, Nakayama T, Taniguchi M, Saito K, Imawari M, Moriwaki H, Yokochi T, Kakumu S, Seishima M.

Int Immunol 20 巻 ( 7 ) 頁： 869-879 2008年7月

Use of the Model for End-Stage Liver Disease (MELD) score to predict 1-year survival of Japanese patients with cirrhosis and to determine who will benefit from living donor liver transplantation. 査読有り

Ishigami M, Honda T, Okumura A, Ishikawa T, Kobayashi M, Katano Y, Fujimoto Y, Kiuchi T, Goto H.

J Gastroenterol 43 巻 ( 5 ) 頁： 363-368 2008年5月

Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo. 査読有り

Iwamoto N, Ito H, Ando K, Ishikawa T, Hara A, Taguchi A, Saito K, Takemura M, Imawari M, Moriwaki H, Seishima M.

Liv Int 29 巻 ( 2 ) 頁： 277-283 2008年2月

Use of hepatitis B vaccine for the treatment of chronic hepatitis B

ISHIKAWA Tetsuya, KAKUMU Shinichi

Hepatology research : the official journal of the Japan Society of Hepatology 37 巻頁： S347 - S350 2007年10月

B型肝炎の新たな治療展開 B型肝炎の治療戦略　Adefovir pivoxil

石川哲也, 各務伸一

内科 100 巻 ( 4 ) 頁： 677 - 682 2007年10月

Expression of Toll-like receptors in chronic hepatitis C virus infection. 査読有り

Sato K, Ishikawa T, Okumura A, Yamauchi T, Sato S, Ayada M, Matsumoto E, Hotta N, Ohashi T, Fukuzawa Y, Kakumu S.

J Gastroenterol Hepatol 22 巻 ( 10 ) 頁： 1627-1632 2007年10月

Use of HB vaccine for the treatment of chronic hepatitis B. 招待有り

Ishikawa T, Kakumu S.

Hepatol Res 37 巻 ( S3 ) 頁： S347-S350 2007年10月

Effect of Vitamin K2 on the recurrence in patients with hepatocellular carcinoma. 査読有り

Hotta N, Ayada M, Sato K, Ishikawa T, Okumura A, Matsumoto E, Ohashi T, Kakumu S.

Hepato-gastroenterology 54 巻 ( 79 ) 頁： 2073-2077 2007年10月

今月の主題消化器薬の使い方Update 消化器疾患の薬物治療自己免疫性肝炎(AIH)

石川哲也

medicina 44 巻 ( 9 ) 頁： 1713 - 1715 2007年9月

Double filtration plasmapheresis and interferon combination therapy for chronic hepatitis C patients with genotype 1 and high viral load

FUJIWARA Kenji, KANEKO Shuichi, KAKUMU Shinichi, SATA Michio, HIGE Shuhei, TOMITA Eiichi, MOCHIDA Satoshi, IDE T., NISHIDA H., YOKOYAMA H., YAMASHITA T., MORIWAKI H., NAGAKI M., SUGIHARA J., TAKAHASHI H., ISHIKAWA T., MIYATA M., NISHIKAWA K., NAGOSHI S., SUGAHARA S., YAMAMOTO K., MIZUTA T., ANDO T., TAKEI Y., ENOMOTO N., TSUDA H., SUMINO Y., ISHII K., SAISHO H., YOKOSUKA O., EGUCHI K., HAMASAKI K., SAWADA K., FUKUNAGA K., ARAKAWA Y., MORIYAMA M., IMAWARI M., ITO T.

Hepatology research : the official journal of the Japan Society of Hepatology 37 巻 ( 9 ) 頁： 701 - 710 2007年9月

Combination therapy with lamivudine and HB vaccine on chronic hepatitis B

ISHIKAWA Tetsuya, KAKUMU Shinichi

Hepatology research : the official journal of the Japan Society of Hepatology 37 巻頁： S62 - S66 2007年7月

Combination thearpy with lamivudine and HB vaccine on chronic heaptitis B. 招待有り

Ishikawa T, Kakumu S.

Hepatol Res 37 巻 ( S1 ) 頁： S62-S66 2007年7月

今月の主題ウイルス肝炎実地診療A to Z 扉

石川哲也

medicina 44 巻 ( 5 ) 頁： 847 - 847 2007年5月

今月の主題ウイルス肝炎実地診療A to Z 座談会外来で診るウイルス肝炎-効果的な病診連携のために

八橋弘, 伊東和樹, 柴田実, 石川哲也

medicina 44 巻 ( 5 ) 頁： 972 - 983 2007年5月

今月の主題ウイルス肝炎実地診療A to Z ウイルス肝炎の的確な診断のために肝障害患者の診断の進め方

各務伸一, 石川哲也

medicina 44 巻 ( 5 ) 頁： 848 - 851 2007年5月

Sonazoid を用いての肝腫瘍の血流診断の有用性

綾田穣, 堀田直樹, 奥村明彦, 石川哲也, 木場久美子, 黒田康子, 丹羽幸佳, 井戸誠, 各務伸一

Journal of medical ultrasonics = 超音波医学 34 巻 2007年4月

Real Time 4D Ultrasound System を用いたRFAの有用性

堀田直樹, 綾田穣, 土方康孝, 大橋知彦, 佐藤顕, 奥村明彦, 石川哲也, 大野長行, 各務伸一

Journal of medical ultrasonics = 超音波医学 34 巻 2007年4月

Live 3D における肝腫瘍に対しての超音波検査の有用性

堀田直樹, 綾田穣, 大橋知彦, 佐藤顕, 奥村明彦, 石川哲也, 小崎正博, 各務伸一

Journal of medical ultrasonics = 超音波医学 34 巻 2007年4月

Effect of vitamin K2 on the recurrence in patients with hepatocellular carcinoma

Hotta Naoki, Ayada Minoru, Sato Ken, Ishikawa Tetsuya, Ohumura Ahihiko, Matsumoto Eiji, Ohashi Tomohiko, Kakumu Shinichi

HEPATO-GASTROENTEROLOGY 54 巻 ( 79 ) 頁： 2073 - 2077 2007年

減量再投与により肝障害再発の回避が可能であったメシル酸イマチニブによる薬物性肝障害の１例

綾田穣, 石川哲也, 奥村明彦, 堀田直樹, 古田恵子, 山内妙子, 土方康孝, 大橋知彦, 佐藤顕, 各務伸一

肝臓 48 巻 ( 10 ) 頁： 505 - 510 2007年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人　日本肝臓学会

症例は，72歳，女性．慢性骨髄性白血病（chronic myelogenous leukemia CML）に対し，抗悪性腫瘍薬であるメシル酸イマチニブ（imatinib mesilate：IM）の投与が開始された．約1年後の血液検査で肝障害を指摘されたため，当科に紹介入院となった．DDWJ-2004ワークショップの薬物性肝障害診断基準案での判定および肝病理組織診断より，IMによる薬物性肝障害と診断した．本症例は，CMLに対する有効な治療法が他にないため，起こりうる肝障害の危険性と，悪性腫瘍に対する治療効果の有益性を臨床的に検討し，休薬期間の後，IMの減量再投与を行った．減量再投与により，肝障害の再発の回避が可能となったIMによる薬物性肝障害の1例を経験したため，文献的考察を加え報告する．

DOI： 10.2957/kanzo.48.505

特発性肺線維症の経過中に発症した出血性胃 vascular ectasia に対し内視鏡的結紮術が有効であった1例

Combination therapy with lamvudine and HB vaccine on chronic hepatitis B.

石川哲也

Hepatology Research 37 2007年

綾田穣, 中野達徳, 堀田直樹, 奥村明彦, 石川哲也, 大橋知彦, 松本英司, 佐藤顕, 吉田香果, 各務伸一

日本消化器内視鏡学会雑誌 = Gastroenterological endoscopy 48 巻 ( 11 ) 頁： 2626 - 2631 2006年11月

Role of toll-like receptors in hepatitis C virus-infected chronic liver disease

Kakumu Shinichi, Okumura Akihiko, Ishikawa Tetsuya, Yamauchi Taeko, Sato Sayaka, Sato Ken, Ohashi Tomohiko, Ayada Minoru, Hotta Naoki, Fukuzawa Yoshitaka

HEPATOLOGY 44 巻 ( 4 ) 頁： 300A - 300A 2006年10月

Efficacy of non-invasive hepatic fibrosis quantificated-evaluation by liver elasticity measurement in nonalcoholic steatohepatitis (NASH) - Comparison of ultrasonic transient elastography and histopathological diagnosis

Fukuzawa Yoshitaka, Kizawa Senji, Ohashi Tomohiko, Matsumoto Eiji, Sato Ken, Ayada Minoru, Hotta Naoki, Okumura Akihiko, Ishikawa Tetsuya, Kakumu Shinichi

HEPATOLOGY 44 巻 ( 4 ) 頁： 649A - 650A 2006年10月

Expression of toll-like receptor family on regulatory T cells in the patients with autoimmune hepatitis

Okumura Akihiko, Ishikawa Tetsuya, Sato Sayaka, Yamauchi Taeko, Ohashi Tomohiko, Sato Ken, Ayada Minoru, Hotta Naoki, Fukuzawa Yoshitaka, Kakumu Shinichi

HEPATOLOGY 44 巻 ( 4 ) 頁： 640A - 641A 2006年10月

Four-dimensional ultrasonography for therapeutic radiofrequency ablation for heaptocellular carcinoma. 査読有り

Hotta N, Maeno T, Ayada M, Sato K, Ishikawa T, Okumura A, Matsumoto E, Fukuzawa Y, Kakumu S.

Hepato-gastroenterology 53 巻 ( 70 ) 頁： 521-525 2006年7月

経鼻的細経内視鏡を用いた経皮内視鏡的胃瘻造設術の試み

綾田穣, 中野達徳, 堀田直樹, 中江治道, 國井伸, 吉田香果, 奥村明彦, 石川哲也, 福沢嘉孝, 各務伸一

Gastroenterological Endoscopy 48 巻 ( 7 ) 頁： 1425 - 1430 2006年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：(一社)日本消化器内視鏡学会

脳神経障害を有する患者26例を対象に,細径内視鏡の経鼻挿入で経皮内視鏡的胃瘻造設術(PEG)施行13例(経鼻群)と経口的にPEG施行13例(経口群)に無作為に分けて比較した.1)胃瘻造設前の上部消化管内視鏡検査(GIF)の施行時間および胃瘻造設時間は両群で有意差はなかった.2)胃瘻造設中の嘔吐反射回数(平均)は経鼻群3.0回,経口群6.9回と経鼻群で有意に少なかった.3)検査前に比し,検査中の血圧ならびに脈拍数の上昇率はともに経鼻群で有意に低値であった.4)末梢血酸素飽和度は検査前,検査中とも両群で有意差はなかった.5)経鼻群では,鼻粘膜や咽頭・口腔内粘膜の損傷等は認めず,両群とも重篤な偶発症は認めなかった.以上,経鼻群では苦痛とストレスの緩和に有用であり,安全性も経口群と同等であると考えられた

DOI： 10.11280/gee1973b.48.1425

Alteration of serum cytokine balances among different phases of chronic hepatitis B virus infection. 査読有り

Ayada M, Ishikawa T, Okumura A, Tanabe J, Ito H, Ohashi T, Matsumoto E, Sato K, Hotta N, Fukuzawa Y, Kakumu S.

Hepatol Res 34 巻 ( 4 ) 頁： 214-221 2006年4月

慢性肝疾患の病態にせまる免疫学的アプローチ自己免疫性肝炎(AIH)における制御性T細胞(Tr)の機能低下

奥村明彦, 石川哲也, 伊藤弘康, 佐藤さやか, 山内妙子, 大橋知彦, 松本英司, 佐藤顕, 綾田穣, 堀田直樹, 福澤嘉孝, 各務伸一

消化器と免疫 42 巻 ( 42 ) 頁： 29 - 32 2006年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本消化器免疫学会

自己免疫性肝炎患者の制御性T細胞(Tr)について,Trの機能を調節しているFoxp3,TNF-R-SF18,CTLA-4,CD28の各遺伝子の発現を調べ調べ,自己免疫性肝炎(AIH)患者と健常者のTrのサイトカイン産生能を比較し,TrがAIHの病態に関与している可能性について検討した.AIH 15例,コントロールとしてC型慢性肝炎(CH-C)患者26例と健常人12例を対象とした.AIHではFoxp3,CTLA-4のmRNA量が減少し,TrによるIL-10の産生能が低下していることが明らかとなった.Trの機能異常が病態に関与している可能性が示唆された

Plasma amino acid profiles applied for diagnosis of advanced liver fibrosis in patients with chronic hepatitis C infection. 査読有り

Zhang Q, Takahashi M, Noguchi Y, Sugimoto T, Kimura T, Okumura A, Ishikawa T, Kakumu S.

Hepatol Res 34 巻 ( 3 ) 頁： 170-177 2006年3月

The SHAP-hyaluronan complex in serum from patients with chronic liver diseases caused by hepatitis virus infection. 査読有り

Shen L, Zhuo L, Okumura A, Ishikawa T, Miyachi M, Owa Y, Ishizawa T, Sugiura N, Nagata Y, Nonami T, Kakumu S, Kimata K.

Hepatol Res 34 巻 ( 3 ) 頁： 178-186 2006年3月

肝癌局所療法における超音波ドプラ法の新展開 Real Time 4D Ultrasoundを用いた肝細胞癌のラジオ波焼灼療法の有用性-マイクロコンベックスプローブ使用における検討も含めて

堀田直樹, 大橋知彦, 松本英司, 佐藤顕, 綾田穣, 奥村明彦, 石川哲也, 福沢嘉孝, 各務伸一

Rad Fan 4 巻 ( 3 ) 頁： 116 - 119 2006年2月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：(株)メディカルアイ

従来の2D modeのエコーではなく,Real Time 4D Ultrasound systemsを用いて肝細胞癌に対しラジオ波焼灼療法(RFA)を施行し,その有用性について検討した.また,マイクロコンベックスプローブにおいても検討した.肝細胞癌22例25結節を対象とした.RFA施行22例25結節において,全症例Real Time 4D Ultrasound systemにて穿刺可能であった.Real Time 4D Ultrasound使用によるRFAは多方向より針の留置部位を確認することができ,より正確に経皮的治療を施行することができた

特徴ある組織像を呈したリセドロン酸ナトリウムによる薬物性肝障害の1例

綾田穣, 石川哲也, 奥村明彦, 大橋知彦, 松本英司, 佐藤顕, 堀田直樹, 福沢嘉孝, 各務伸一

肝臓 47 巻 ( 1 ) 頁： 10 - 15 2006年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：(一社)日本肝臓学会

53歳女.患者は腰痛のため初め著者らの施設の整形外科へ入院していた.骨粗鬆症と診断され,アレンドロン酸ナトリウム(ASH)の内服を開始していたが,転医に伴い,内服薬がASHからリセドロン酸ナトリウム(SRH)に変更になった.その後,全身倦怠感を訴え,血液検査において肝胆道系酵素の上昇を認めた.SRHによる薬物性肝障害を疑い,内服を中止し,ウルソデオキシコール(UDCA)の内服を開始したところ,肝障害とも漸次改善した.DDW-J2004ワークショップの薬物性肝障害診断基準案を用いてスコアリングを行った結果では,病型は胆汁うっ帯型で,スコアは(+6):「可能性が高い」と判定された.肝機能が正常化した半年後の肝生検では,軽度の門脈域の線維性拡大をみるも,他の所見は消失していた

DOI： 10.2957/kanzo.47.10

特発性肺線維症の経過中に発症した出血性胃ｖａｓｃｕｌａｒ　ｅｃｔａｓｉａに対し内視鏡的結紮術が有効であった１例

Four-dimensional ultrasonography for therapeutic radiofrequency ablation for hepatocellular carcinoma

Hotta Naoki, Maeno Tadashi, Ayada Minoru, Sato Ken, Ishikawa Tetsuya, Okumura Akihiko, Matsumoto Eiji, Fukuzawa Yoshitaka, Kakumu Shinichi

HEPATO-GASTROENTEROLOGY 53 巻 ( 70 ) 頁： 521 - 525 2006年

綾田穣, 中野達徳, 堀田直樹, 奥村明彦, 石川哲也, 大橋知彦, 松本英司, 伊藤顕, 吉田香果, 各務伸一

日本消化器内視鏡学会雑誌 48 巻 ( 11 ) 頁： 2626 - 2631 2006年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：一般社団法人日本消化器内視鏡学会

症例は62歳の女性.特発性肺線維症の増悪のため入院中であった.黒色物を嘔吐したため,上部消化管内視鏡検査を施行したところ,胃体上部大彎後壁よりに出血性vascular ectasiaを認めた.内視鏡的結紮術(EBL)を応用した1回の治療で完全に止血し,病変は消失した.特発性肺線維症の経過中に発症した出血性胃vascular ectasiaの報告はみられず,EBLが止血に有用と考えられたため報告する.

DOI： 10.11280/gee1973b.48.2626

Rebamipide enemas-New effective treatment for patients with corticosteroid dependent or resistant ulcerative colitis-

Miyata M, Kasugai K, Ishikawa T, Kakumu S, Onishi M, Mori T.

Dig Dis Sci 50 巻 ( S1 ) 頁： S119-S123 2005年10月

Assessment of hepatic fibrosis in chronic liver disease - Usefulness of the strain rate imaging method

Hotta N, Okumura A, Ishikawa T, Kakumu S

HEPATOLOGY 42 巻 ( 4 ) 頁： 342A - 342A 2005年10月

出血性胃vascular ectasiaに対し内視鏡的結紮術が有効であった2例

綾田穣, 堀田直樹, 石川哲也, 奥村明彦, 恒川明久, 井澤晋也, 大橋知彦, 松本英司, 佐藤顕, 福沢嘉孝, 各務伸一

Gastroenterological Endoscopy 47 巻 ( Suppl.2 ) 頁： 1971 - 1971 2005年9月

Four-dimensional ultrasonogaraphy for therapeutic radiofrequency ablation for hepatocellular carcinoma

Hotta N, Okumura A, Ishikawa T, Fukuzawa Y, Kakumu S

AMERICAN JOURNAL OF GASTROENTEROLOGY 100 巻 ( 9 ) 頁： S106 - S106 2005年9月

門脈圧亢進症の新しい薬物療法難治性腹水に対するdocarpamineの有用性と安全性

綾田穣, 石川哲也, 堀田直樹, 奥村明彦, 大橋知彦, 松本英司, 佐藤顕, 福沢嘉孝, 各務伸一

日本門脈圧亢進症学会雑誌 11 巻 ( 1 ) 頁： 43 - 43 2005年7月

B型肝炎ウイルス(HBV)関連抗原が肝炎進展過程に与える影響について

佐藤顕, 石川哲也, 田邊純一, 大橋知彦, 松本英司, 前野禎, 綾田穣, 堀田直樹, 宮田充樹, 奥村明彦, 福沢嘉孝, 各務伸一

消化器と免疫 41 巻 ( 41 ) 頁： 159 - 162 2005年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本消化器免疫学会

標題の影響を明らかにするため,concanavalin A(Con A)を投与されたHBVトランスジェニックマウスの肝臓におけるサイトカイン,ケモカインの発現パターンを解析し,同系正常マウスと比較した.結果,トランスジェニックマウスではCon A投与後2時間から24時間にかけてIL-18,TGF-β,GM-CSF,fractalkineの発現が正常マウスよりも強く,24時間後にはTNF-αとINF-γの発現が強かった.これは,HBV関連抗原が免疫応答を制御あるいは修飾することで何らかの免疫異常を引き起こしている可能性を示すと考えられた

マイクロコンベックス使用におけるラジオ波焼灼療法の経験

マイクロコンベックス使用におけるラジオ波焼灼療法の経験

堀田直樹, 綾田穣, 佐藤顕, 松本英司, 奥村明彦, 石川哲也, 福沢嘉孝, 高橋忍, 各務伸一

Japanese journal of medical ultrasonics = 超音波医学 32 巻頁： S409 2005年4月

堀田直樹, 綾田穣, 佐藤顕, 松本英司, 奥村明彦, 石川哲也, 福沢嘉孝, 高橋忍, 各務伸一

Journal of medical ultrasonics = 超音波医学 32 巻頁： S409 2005年4月

Changes in natural killer T cells subsets during therapy in type C hepatitis and hepatocellular carcinoma. 査読有り

Okumura A, Ishikawa T, Maeno T, Sato K, Ayada M, Hotta N, Yamauchi T, Fukuzawa Y, Kakumu S.

Hepatol Res 32 巻 ( 4 ) 頁： 213-217 2005年4月

マイクロコンベックス使用におけるラジオ波焼灼療法の経験

堀田直樹, 綾田穣, 佐藤顕, 松本英司, 奥村明彦, 石川哲也, 福沢嘉孝, 高橋忍, 各務伸一

超音波医学 32 巻 ( Suppl. ) 頁： S409 - S409 2005年4月

内視鏡的結紮術が有用であった出血性十二指腸 vascular ectasia の1例

綾田穣, 福沢嘉孝, 堀田直樹, 松本英司, 前野禎, 佐藤顕, 奥村明彦, 石川哲也, 各務伸一

日本消化器内視鏡学会雑誌 = Gastroenterological endoscopy 47 巻 ( 1 ) 頁： 15 - 21 2005年1月

Advanced dynamic flow imaging with contrast-enhanced ultrasonography for the evaluation of tumor vascularity in liver tumors. 査読有り

Hotta N, Tagaya T, Maeno T, Ayata M, Sato K, Ishikawa T, Okumura A, Fukuzawa Y, Kakumu S.

Clin Imaging 29 巻 ( 1 ) 頁： 34-41 2005年1月

内視鏡的結紮術が有用であった出血性十二指腸vascular ectasiaの1例

綾田穣, 福沢嘉孝, 堀田直樹, 松本英司, 前野禎, 佐藤顕, 奥村明彦, 石川哲也, 各務伸一

Gastroenterological Endoscopy 47 巻 ( 1 ) 頁： 15 - 21 2005年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：(一社)日本消化器内視鏡学会

82歳女性.患者は全身倦怠感,浮遊感,心窩部不快感,黒色便の出現で受診となった.血糖値の上昇と著明な貧血を認め,上部消化管内視鏡検査では上十二指腸角より下行部にかけて新鮮血の流出を認め,粘膜面の洗浄で上十二指腸角に数個の毛細血管拡張と,うち2ヶ所からの出血を認めた.十二指腸vascular ectasiaによる出血と診断し,内視鏡的結紮術(EVL)を施行したところ,止血後6日目の内視鏡では完全に止血が確認され,1ヵ月後の検査では潰瘍は瘢痕化していた.尚,貧血と全身倦怠感は輸血により改善した.以上,EVLは小腸の微細な出血源に対しても確実で有効な止血法になり得ると考えられた

DOI： 10.11280/gee1973b.47.15

2) DFPPによるウイルス除去療法 : DFPPによるC型肝炎ウイルス減量療法の効果(日本アフェレシス学会第13回関東甲信越地方会抄録)

A case of hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) using 4D real-time ultrasound system

Hotta N, Fukuzawa Y, Ayada M, Sato K, Maeno T, Tagaya T, Okumura A, Ishikawa T, Ito Y, Kakumu S

HEPATO-GASTROENTEROLOGY 52 巻 ( 64 ) 頁： 1224-1227 2005年

Changes in natural killer T cell subsets during therapy in type C hepatitis and hepatocellular carcinoma.

石川哲也

Hepatol Res 32 頁： 213 - 217 2005年

【内科診療最前線2005　この1年の動向を踏まえて】　肝疾患

各務伸一, 福沢嘉孝, 石川哲也, 奥村明彦, 堀田直樹, 綾田穣

内科 94 巻 ( 6 ) 頁： 1030 - 1038 2004年12月

【内科診療最前線2005 この1年の動向を踏まえて】肝疾患

各務伸一, 福沢嘉孝, 石川哲也, 奥村明彦, 堀田直樹, 綾田穣

内科 94 巻 ( 6 ) 頁： 1030 - 1038 2004年12月

Usefulness of contrast-enhanced ultrasonography to evaluate therapeutic effects for hepatocellular carcinoma

Hotta N, Okumura A, Ishikawa T, Kakumu S

AMERICAN JOURNAL OF GASTROENTEROLOGY 99 巻 ( 10 ) 頁： S69 - S69 2004年10月

Dynamics of CD8(+)T cells, CD4(+)T cells, and CD4(+)CD25(+) regulatory T cells in the liver with autoimmune hepatitis(AIH) - Analysis using mice model for AIH type 2

Okumura A, Ishikawa T, Ito H, Sato K, Maeno T, Ayada M, Hotta N, Matsumoto E, Ohashi T, Fukuzawa Y, Kakumu S

HEPATOLOGY 40 巻 ( 4 ) 頁： 421A - 421A 2004年10月

Nutrition assessment and management in outpatients with liver cirrhosis caused by HCV (LC-C) - Usefulness of a branched chain amino acid (BCAA)-rich product as late evening snacks (LES)

Fukuaawa Y, Hotta N, Ayada M, Ohashi T, Matsumoto E, Sato K, Maeno T, Okumura A, Ishikawa T, Kakumu S

HEPATOLOGY 40 巻 ( 4 ) 頁： 512A - 512A 2004年10月

西川和裕, 宮田充樹, 奥村明彦, 石川哲也, 各務伸一

日本アフェレシス学会雑誌 23 巻 ( 3 ) 頁： 289-290 2004年

内科診療最前線2005－この１年の動向を踏まえて－非アルコール性脂肪性肝炎 (NASH)，アルコール性肝障害 (ALD)．査読有り

各務伸一, 福沢嘉孝, 石川哲也, 奥村明彦, 堀田直樹, 綾田穣

内科 94 巻頁： 1823 - 1829 2004年

Wilson病より発症した胃孤立性静脈瘤に対しballoon-occluded retrograde transvenous obliteration (B-RTO) が有効であった1例査読有り

綾田穣, 奥村明彦, 石川哲也, 堀田直樹, 松本英司, 佐藤顕, 福沢嘉孝, 各務伸一

日本門脈圧亢進症学会雑誌 10 巻 ( 10 ) 頁： 132 - 136 2004年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：The Japan Society for Portal Hypertension

胃孤立性静脈瘤を合併した24歳男性のWilson病患者に対しB-RTOを施行し, 良好な経過を得ている1例を経験した.胃孤立性静脈瘤は, 出血の頻度こそ少ないが一度出血すると致死的かつ難治性であることが知られている.B-RTO施行後, 3年を経過したが, 無再発であり, 良好な経過をたどっている.消化器内科的な症状が前面にでないWlson病症例においても, 慎重な経過観察と, B-RTOなどの予防的な処置を適切に行うことが重要であると考えられた.

DOI： 10.11423/jsph1999.10.3-4_132

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic heaptitis C virus infection. 査読有り

Maeno T, Okumura A, Ishikawa T, Kato K, Sakakibara F, Sato K, Ayada M, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S.

J Gastroenterol Hepatol 18 巻 ( 12 ) 頁： 1358-1363 2003年12月

生活習慣病を合併した著明な脂肪肝症例に対して茵ちん蒿湯・防風通聖散併用療法が奏効した1例

福沢嘉孝, 堀田直樹, 佐藤顕, 前野禎, 綾田穣, 多賀谷恒明, 奥村明彦, 石川哲也, 各務伸一, 加藤勝久

漢方医学 27 巻 ( 5 ) 頁： 221 - 224 2003年12月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：(株)協和企画

53歳女.全身倦怠感,後頭部不快感を主訴とした.身長161cm,体重81kg,普段から暑がりで便秘傾向があり,熱実証,腹壁が厚く弾力があった.臨床データは異常値を示し,臨床データ及び腹部超音波検査より,高脂血症,高血圧,肥満,耐糖能障害(IGT)を合併する著明な脂肪肝と診断した.高血圧にはアンジオテンシンII受容体拮抗薬バルサルタンを投与し,コントロール良好となった.肥満・高脂血症・脂肪肝・IGTに対しては食事・運動療法を開始したが,各種データの改善は乏しかった.その後,生活習慣の乱れによりデータが悪化し,体重も治療前値付近に戻ったため,従来法を継続しながら,茵ちん蒿湯を新たに処方し,強化療法も同時に行った.約5ヵ月後,各種データは改善傾向を示したが,体重は殆ど変化しなかった.患者が減量を切望したこと等より,10月末から防風通聖散を併用した.治療開始から漢方薬併用投与約3.5ヵ月後迄に体重は74kgになり,各種データも改善し,自覚症状も殆ど消失した.現在,大きな副作用は認めず,生活習慣病に対する病識も向上してきた.従来法は継続中である

慢性肝疾患患者における血清SHAP-HA濃度－肝細胞癌のマーカーとしての有用性の検討－

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection

Maeno T, Okumura A, Ishikawa T, Kato K, Sakakibara F, Sato K, Ayada M, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 18 巻 ( 12 ) 頁： 1358 - 1363 2003年12月

Usefulness of contrast-enhanced ultrasonography with dynamic flow imaging to evaluated therapeutic effects for hepatocellular carcinoma. 査読有り

Hotta N, Tagaya T, Maeno T, Ishikawa T, Okumura A, Fukuzawa Y, Kakumu S.

Hepato-gastroenterology 50 巻 ( 54 ) 頁： 1867-1871 2003年11月

Combination therapy of lamivudine and HB vaccine for the treatment of chronic hepatitis B.

Ishikawa T, Okumura A, Maeno T, Sato K, Ayada M, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 38 巻 ( 4 ) 頁： 717A - 717A 2003年10月

Establishment of a novel mouse model for AIH type 2.

Okumura A, Ishikawa T, Sato K, Ayada M, Maeno T, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 38 巻 ( 4 ) 頁： 485A - 485A 2003年10月

Involvement of CD4+ CD25+ regulatory T cells as immune modulators in chronic hepatitis C virus (HCV) infection.

Okumura A, Ishikawa T, Yamauchi T, Maeno T, Sato K, Ayada M, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 38 巻 ( 4 ) 頁： 463A - 463A 2003年10月

Nutrition is more important than Th1-dominated condition for better response in interferon alpha-2b/ribavirin therapy.

Okumura A, Ishikawa T, Ayada M, Sato K, Maeno T, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 38 巻 ( 4 ) 頁： 314A - 314A 2003年10月

肝細胞癌におけるFas/Fas Lの発現と浸潤リンパ球との関係

福澤嘉孝, 堀田直樹, 佐藤顕, 前野禎, 綾田穣, 多賀谷恒明, 奥村明彦, 石川哲也, 各務伸一

愛知医科大学医学会雑誌 31 巻 ( 2 ) 頁： 106 - 107 2003年6月

Prevalence of diabetes mellitus in Japanese patients infected chronically with hepatitis C virus. 査読有り

Arao M, Murase K, Kusakabe A, Yoshioka K, Fukuzawa Y, Ishikawa T, Tagaya T, Yamanouchi K, Ichimiya H, Sameshima Y, Kakumu S.

J Gastroenterol 38 巻 ( 4 ) 頁： 355-360 2003年4月

Lack of tumor necrosis factor alpha induces impaired proliferation of hepatitis B virus-specific cytotoxic T lymphocytes. 査読有り

Kasahara S, Ando K, Saito K, Sekikawa K, Ito H, Ishikawa T, Ohnishi H, Seishima M, Kakumu S, Moriwaki H.

J Virol 77 巻 ( 4 ) 頁： 2469-2476 2003年2月

申力, 卓麗聖, 奥村明彦, 石川哲也, 各務伸一, 木全弘治

日本分子腫瘍マーカー研究会誌 19 巻 ( 19 ) 頁： 70 - 71 2003年

Usefulness of contrast-enhanced ultrasonography with dynamic flow imaging to evaluate therapeutic effects for hepatocellular carcinoma

Hotta N, Tagaya T, Maeno T, Ishikawa T, Okumura A, Fukuzawa Y, Kakumu S

HEPATO-GASTROENTEROLOGY 50 巻 ( 54 ) 頁： 1867 - 1871 2003年

3. B型慢性肝炎へのラミブジン+HBワクチン併用療法

石川哲也, 奥村明彦, 各務伸一

肝臓 43 巻 ( 10 ) 頁： 470-471 2002年10月

Usefulness of contrast-enhanced ultrasonography with dynamic flow imaging to evaluate therapeutic effects for hepatocelluiar carcinoma.

Hotta N, Maeno T, Tagaya T, Ayata M, Satoh K, Okumura A, Fukuzawa Y, Ishikawa T, Kakumu S

HEPATOLOGY 36 巻 ( 4 ) 頁： 687A - 687A 2002年10月

Different distribution of antigenic B cell and T cell epitopes within HBV core region

Okumura A, Ishikawa T, Sato K, Maeno T, Ayada M, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 36 巻 ( 4 ) 頁： 620A - 620A 2002年10月

Combination of HB vaccine with lamivudine for the treatment of chronic hepatitis B.

Ishikawa T, Okumura A, Maeno T, Sato K, Ayada Y, Hotta N, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 36 巻 ( 4 ) 頁： 643A - 643A 2002年10月

Expression of glypican-3 (GPC 3) and its significance as a novel marker of the degree of dedifferentiation in hepatocellular carcinoma

Fukuzawa Y, Furuta K, Tagaya T, Sato K, Maeno T, Ayada M, Hotta N, Okumura A, Ishikawa T, Kakumu S

HEPATOLOGY 36 巻 ( 4 ) 頁： 691A - 691A 2002年10月

慢性肝疾患と免疫 B型慢性肝炎患者におけるHBc抗原領域のエピトープの同定とそれに対する免疫応答の質的解析

石川哲也, 田邊純一, 佐藤顕, 前野禎, 綾田穣, 堀田直樹, 多賀谷恒明, 奥村明彦, 福沢嘉孝, 各務伸一

消化器と免疫 ( 38 ) 頁： 20 - 23 2002年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本消化器免疫学会

B型慢性肝炎患者(B-CH)におけるHBc抗原特異的免疫応答の標的部位の解析,免疫応答の質的評価を行った.B-CH患者23例を対象に,HBc抗原領域をカバーする13〜15merのペプタイドを作製し,患者末梢血単核球を刺激後,細胞内サイトカイン/ケモカイン発現パターンをflow cytometry(FACS)及びRT-PCRにて解析した.FACS解析では,HBc91-105(p19)での刺激時に,FN-γ+細胞,IL-4+細胞とも有意な増加がみられた.また,RT-PCRを用いた解析ではp19による刺激で11例中8例で,多くの場合,同時に複数のサイトカイン/ケモカインの発現増強がみられた.これらのことから,B-CH患者においてはp19に主要なエピトープが存在している可能性が示唆された

Expression of Fas/Fas ligand (FasL) and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC)

FUKUZAWA Yoshitaka, TAKAHASHI Kiyoshi, FURUTA Keiko, TAGAYA Tsuneaki, ISHIKAWA Tetsuya, WADA Kaori, OMOTO Yasukazu, KOJI Takehiko, KAKUMU Shinichi

Journal of gastroenterology 36 巻 ( 10 ) 頁： 681 - 688 2001年10月

Expression of Fas/Fas ligand (FasL) and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC). 査読有り

Fukuzawa Y, Takahashi K, Furuta K, Tagaya T, Ishikawa T, Wada K, Omoto Y, Koji T, Kakumu S.

J Gastroenterol 36 巻 ( 10 ) 頁： 178-186 2001年10月

Expression of Fas/Fas ligand (FasL) and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC) 査読有り

Y Fukuzawa, K Takahashi, K Furuta, T Tagaya, T Ishikawa, K Wada, Y Omoto, T Koji, S Kakumu

JOURNAL OF GASTROENTEROLOGY 36 巻 ( 10 ) 頁： 681 - 688 2001年10月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER-VERLAG

Background. This study was conducted to examine the expression of Fas/Fas ligand (FasL), to elucidate its relationship with tumor-infiltrating lymphocytes (TILs), and to detect possible gene mutation of Fas/FasL in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). Methods. Indirect immunohistochemical staining was performed on formalin-fixed, paraffin-embedded sections of liver biopsy and surgery specimens from five normal livers, and from the livers of 30 patients with HCC. Fas/FasL mRNA-expressing cells and apoptotic cells were detected by in situ hybridization and DNA nick end labeling (TUNEL), respectively. We also performed polymerase chain reaction (PCR) -amplifying and direct sequencing for the Fas/FasL gene. Results. Fas/FasL and its mRNA were localized on the, membrane or in the cytoplasm in some HCC cells, as well as hepatocytes. Their expression was enhanced in areas with infiltrating inflammatory cells in the noncancerous regions of liver tissue and on the margins of the cancerous tissue. The positivity rate for TUNEL was elevated along these margins. The labeling index of Fas/FasL was lower in the cancerous liver tissue than in the surrounding noncancerous region (P < 0.01), and tended to decrease in proportion to the malignancy of tumor cells; Fas/FasL expression was not found on poorly differentiated type cancer cells. Fas(-)/FasL(+), FasL-mRNA(+) HCC cells were seen in one specimen of moderately differentiated type. Some CD8+T lymphocytes were TUNEL-positive around the cancerous region. In this study, cancerous and noncancerous tissues in HCC revealed no genetic mutations in any exons of Fas/FasL. Conclusions. These findings suggest that Fas/FasL expression was decreased in proportion to the malignancy of tumor cells, and that infiltrating CD8+T lymphocytes play a role in apoptosis in HCC. The apoptosis in HCC could be regulated by the suppression of Fas/FasL expression, or, sometimes, by the enhancement of FasL expression.

DOI： 10.1007/s005350170031

Web of Science

Expression of Fas/Fas ligand (FasL) and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC)

Fukuzawa Y, Takahashi K, Furuta K, Tagaya T, Ishikawa T, Wada K, Omoto Y, Koji T, Kakumu S

JOURNAL OF GASTROENTEROLOGY 36 巻 ( 10 ) 頁： 681 - 688 2001年10月

Identification of highly immunogenic T cell epitope within HBV core region and immune response triggered by the activation of HBV core specific T cells.

Ishikawa T, Tanabe J, Okumura A, Maeno T, Yamamoto K, Hotta N, Yoshida K, Ito M, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 34 巻 ( 4 ) 頁： 312A - 312A 2001年10月

Crosstalk between oxidative stress and apoptosis in hepatocellular carcinoma (HCC).

Fukuzawa Y, Hotta N, Furuta K, Maeno T, Yamamoto K, Yoshida K, Ito M, Tagaya T, Okumura A, Ishikawa T, Kakumu S

HEPATOLOGY 34 巻 ( 4 ) 頁： 515A - 515A 2001年10月

Experimental autoimmune hepatitis in mice following immunization with cytochrome P450IID6.

Ishikawa T, Tanabe JC, Okumura A, Ito M, Maeno T, Yamamoto K, Yoshida K, Hotta N, Tagaya T, Fukuzawa Y, Miyakawa H, Kakumu S

HEPATOLOGY 34 巻 ( 4 ) 頁： 286A - 286A 2001年10月

Increased insulin resistance in the patients with chronic HCV infection is mediated by elevated serum TNF alpha.

Maeno T, Okumura A, Ishikawa T, Yamamoto K, Hotta N, Yoshida K, Ito M, Tagaya T, Fukuzawa Y, Kakumu S

HEPATOLOGY 34 巻 ( 4 ) 頁： 552A - 552A 2001年10月

Impaired function of peripheral blood dendritic cell subsets of hepatitis C virus-infected patients.

Sobue S, Nomura T, Nakao H, Okumura A, Ishikawa T, Kakumu S, Itoh M

HEPATOLOGY 34 巻 ( 4 ) 頁： 482A - 482A 2001年10月

Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection. 査読有り

Sobue S, Nomura T, Ishikawa T, Ito S, Saso K, Ohara H, Joh T, Itoh M, Kakumu S.

J Gastroenterol 36 巻 ( 8 ) 頁： 544-551 2001年8月

消化器疾患の病態とTh1/Th2バランス肝細胞のケモカイン産生とTh1/Th2バランスへの影響

石川哲也, 田邊純一, 伊東正道, 奥村明彦, 多賀谷恒明, 福澤嘉孝, 各務伸一

消化器と免疫 ( 37 ) 頁： 5 - 8 2001年7月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：日本消化器免疫学会

肝細胞の炎症及びTh1/Th2 cytokine刺激に対する反応,その後のTh1/Th2バランスに与える影響を,肝細胞のchemokine産生を測定することにより検討した.肝細胞はIFN-γ(Th1)刺激により,更にTh1反応を促進する方向に働くこと,IL-4(Th2)刺激によりTh1反応を抑制し,Th2反応を間接的に促進する方向に働くことがわかった.IL-1O(Th2)刺激はTh2反応を間接的に促進する方向に働いた.肝炎においては肝細胞自身が免疫応答の方向性を制御している可能性が示された