Faculty Profiles - ISHIKAWA, Tetsuya

Deep proteomicsを用いた高脂肪食摂取マウスにおける腸管透過性亢進メカニズムの検討

Spermidine enhances the efficacy of adjuvant in HBV vaccination in mice Reviewed

Ito D, Ito H, Ando T, Sakai Y, Ideta T, Ishii KJ, Ishikawa T, Shimizu M.

Hepatology Communications Vol. 24 ( 4 ) page： e0104 2023.4

B型慢性肝炎患者における免疫要素を加味した機能的治癒(Functional Cure)予測因子としてのコアI97L変異の可能性

本多隆, 石上雅敏, 石川哲也

肝臓 Vol. 64 ( Suppl.1 ) page： A352 - A352 2023.4

Proteomic analysis reveals changes in tight junctions in the small intestinal eepithelium of mice fed a high-fat diet Reviewed

Muto H, Honda T, Tanaka T, Yokoyama S, Yamamoto K, Ito T, Imai N, Ishizu Y, Maeda K, Ishikawa T, Adachi S, Sato C, Tsuji NM Ishigami M, Fujishiro M, Kawashima H.

Nutrients Vol. 15 ( 6 ) page： 1473 2023.3

武藤久哲, 本多隆, 水野史崇, 松田宣賢, 犬飼庸介, 山本崇文, 水野和幸, 横山晋也, 田中卓, 山本健太, 伊藤隆徳, 今井則博, 石津洋二, 石川哲也, 石上雅敏, 川嶋啓輝

日本消化器病学会雑誌 Vol. 120 ( 臨増総会 ) page： A308 - A308 2023.3

In Vivo Real-Time Quantum Dots Imaging to Track Transplanted Adipose Stem Cells in Different Inflammatory States of Acute Liver Failure Mice. International journal

Shota Yamada, Hiroshi Yukawa, Koudai Kitamura, Toshiki Mizumaki, Yasuma Yoshizumi, Tomomi Oohara, Eri Nanizawa, Fumika Hirano, Kazuhide Sato, Ayae Sugawara-Narutaki, Tetsuya Ishikawa, Yoshinobu Baba

Cell transplantation Vol. 32 page： 9636897231176442 - 9636897231176442 2023.1

Language：English Publishing type：Research paper (scientific journal)

Stem cell therapy plays an important role in regenerative therapy; however, there is little information on the in vivo dynamics of transplanted stem cells and the influence of the inflammation of affected tissues or organs on these dynamics. In this study, we revealed real-time dynamics of transplanted adipose tissue-derived stem cells (ASCs) and the influence of the inflammatory states on these dynamics in acute liver failure mice. Quantum dots (QDs) labeling did not affect the cytokine profile of ASCs, and intravenously transplanted ASCs labeled with QDs could be detected in real time with high efficiency without laparotomy. Until 30 min after ASC transplantation, no marked differences in the behavior or accumulation of transplanted ASCs in the liver were observed among the three groups with different degrees of liver damage (normal, weak, and strong). However, significant differences in the engraftment rate of transplanted ASCs in the liver were observed among the three groups from 4 h after transplantation. The engraftment rate was inversely correlated with the extent of the liver damage. These data suggested that QDs are useful for in vivo real-time imaging of transplanted cells, and the inflammatory state of tissues or organs may affect the engraftment rate of transplanted cells.

DOI： 10.1177/09636897231176442

Treatment with hepatocyte transplantation in a novel mouse model of persistent liver failure. Reviewed International journal

Yuki Tamaki, Yuria Shibata, Misaki Hayakawa, Nodoka Kato, Ami Machii, Yuma Ikeda, Eri Nanizawa, Yumi Hayashi, Hiroshi Suemizu, Hiroyasu Ito, Tetsuya Ishikawa

Biochemistry and biophysics reports Vol. 32 page： 101382 - 101382 2022.12

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

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. Reviewed

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

Nutrition (Burbank, Los Angeles County, Calif.) Vol. 103-104 page： 111777 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed

Naoki Ozawa, Kazuki Sato, Ayumi Sugimura, Shigeyoshi Maki, Taku Tanaka, Kenta Yamamoto, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Masatoshi Ishigami, Mitsuhiro Fujishiro, Tetsuya Ishikawa, Shoko Ando

NAGOYA JOURNAL OF MEDICAL SCIENCE Vol. 84 ( 4 ) page： 857 - 864 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：NAGOYA UNIV, SCH MED

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. Reviewed

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

Nutrition (Burbank, Los Angeles County, Calif.) Vol. 103-104 page： 111807 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

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 Vol. 52 ( 11 ) page： 937 - 946 2022.11

Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed International journal

Eri Nanizawa, Shun Otsuka, Naoyuki Hatayama, Yuki Tamaki, Yumi Hayashi, Tetsuya Ishikawa, Shuichi Hirai, Munekazu Naito

Nutrition (Burbank, Los Angeles County, Calif.) Vol. 101 page： 111710 - 111710 2022.9

Language：English Publishing type：Research paper (scientific journal)

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 Vol. 63 ( Suppl.2 ) page： A607 - A607 2022.9

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 Reviewed

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 Vol. 80 page： 104069 2022.7

Changes in the gut microbiota after hepatitis C virus eradication. International journal

Takashi Honda, Masatoshi Ishigami, Kenta Yamamoto, Tomoaki Takeyama, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Masanao Nakamura, Hiroki Kawashima, Ryoji Miyahara, Tetsuya Ishikawa, Yoshiki Hirooka, Mitsuhiro Fujishiro

Scientific reports Vol. 11 ( 1 ) page： 23568 - 23568 2021.12

Language：English Publishing type：Research paper (scientific journal)

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 Vol. 33 ( 1S Suppl 1 ) page： e916 - e921 2021.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

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

The Journal of chemical physics Vol. 155 ( 14 ) page： 145101 2021.10

Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

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 Vol. 11 ( 1 ) page： 18778 2021.9

Language：English Publishing type：Research paper (scientific journal) Publisher：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. International journal

Hisanori Muto, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro

Medicine Vol. 100 ( 31 ) page： e26820 2021.8

Language：English Publishing type：Research paper (scientific journal)

ABSTRACT: Real-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 6 weeks.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 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, 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 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.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. Invited Reviewed

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 Vol. 12 ( 5 ) page： 1583 - 1598 2021.8

Language：English Publishing type：Research paper (scientific journal) Publisher：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. Reviewed International coauthorship International journal

Ian Baudi, Masanori Isogawa, Federica Moalli, Masaya Onishi, Keigo Kawashima, Yuji Ishida, Chise Tateno, Yusuke Sato, Hideyoshi Harashima, Hiroyasu Ito, Tetsuya Ishikawa, Takaji Wakita, Matteo Iannacone, Yasuhito Tanaka

PLoS pathogens Vol. 17 ( 5 ) page： e1009228 2021.5

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed

Japan journal of nursing science : JJNS Vol. 18 ( 3 ) page： e12415 2021.3

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Ayumu Kanbe, Tetsuya Ishikawa, Akira Hara, Hiroshi Suemizu, Eri Nanizawa, Yuki Tamaki, Hiroyasu Ito

Journal of gastroenterology and hepatology Vol. 36 ( 3 ) page： 782 - 789 2021.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

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 Vol. 39 ( 2 ) page： 72 - 73 2021.2

Free energy profile of permeation of Entecavir through Hepatitis B virus capsid studied by molecular dynamics calculation Invited Reviewed

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

Pure and Applied Chemistry Vol. 92 ( 10 ) page： 1585 - 1594 2020.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 61 ( Suppl.2 ) page： A701 - A701 2020.9

Short-term high-fat diet intake leads to exacerbation of concanavalin A-induced liver injury through the induction of procoagulation state. Reviewed International journal

Eri Nanizawa, Yuki Tamaki, Reika Sono, Rintaro Miyashita, Yumi Hayashi, Ayumu Kanbe, Hiroyasu Ito, Tetsuya Ishikawa

Biochemistry and biophysics reports Vol. 22 page： 100736 - 100736 2020.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

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. Invited Reviewed International journal

Koji Nishikawa, Kiminori Kimura, Yoshinobu Kanda, Masaya Sugiyama, Kazuhiko Kakihana, Noriko Doki, Kazuteru Ohashi, Sung Kwan Bae, Kazuhiro Takahashi, Yuko Ishihara, Ishikazu Mizuno, Yasushi Onishi, Masahiro Onozawa, Makoto Onizuka, Masahide Yamamoto, Tetsuya Ishikawa, Kazuaki Inoue, Shigeru Kusumoto, Satoshi Hashino, Hidetsugu Saito, Tatsuya Kanto, Hisashi Sakamaki, Masashi Mizokami

Bone marrow transplantation Vol. 55 ( 7 ) page： 1388 - 1398 2020.7

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed

Hisanori Muto, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro

Clinical journal of gastroenterology Vol. 13 ( 3 ) page： 397 - 402 2020.6

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Takanori Ito, Masatoshi Ishigami, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Tetsuya Ishikawa, Hidenori Toyoda, Takashi Kumada, Mitsuhiro Fujishiro

European journal of gastroenterology & hepatology Vol. 32 ( 6 ) page： 748 - 753 2020.6

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro

Anticancer research Vol. 40 ( 4 ) page： 2283 - 2290 2020.4

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro

Anticancer research Vol. 40 ( 4 ) page： 2089 - 2093 2020.4

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 50 ( 3 ) page： 374 - 381 2020.3

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Naoki Yoshioka, Masatoshi Ishigami, Yasuko Watanabe, Hajime Sumi, Masao Doisaki, Takeo Yamaguchi, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Tetsuya Ishikawa, Jun-Ichi Haruta, Mitsuhiro Fujishiro

Scientific reports Vol. 10 ( 1 ) page： 481 - 481 2020.1

Language：English Publishing type：Research paper (scientific journal)

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. International journal

Taku Tanaka, Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro

Oncology Vol. 98 ( 9 ) page： 621 - 629 2020

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: 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. OBJECTIVE: 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. Reviewed International journal

Takanori Ito, Masatoshi Ishigami, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Tetsuya Ishikawa, Hidenori Toyoda, Takashi Kumada, Mitsuhiro Fujishiro

Nutrition and cancer Vol. 72 ( 5 ) page： 884 - 891 2020

Language：English Publishing type：Research paper (scientific journal)

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

Successful Treatment of Hepatocellular Carcinoma with Regorafenib after Sorafenib-induced Hypersensitivity. Reviewed

Sarcopenia impairs health-related quality of life in cirrhotic patients. Reviewed International journal

Yusuke Ando, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Tetsuya Ishikawa, Mitsuhiro Fujishiro

European journal of gastroenterology & hepatology Vol. 31 ( 12 ) page： 1550 - 1556 2019.12

Language：English Publishing type：Research paper (scientific journal)

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

Naoki Yoshioka, Teiji Kuzuya, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Masatoshi Ishigami, Mitsuhiro Fujishiro

Internal medicine (Tokyo, Japan) Vol. 58 ( 19 ) page： 2803 - 2808 2019.10

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Teiji Kuzuya, Masatoshi Ishigami, Takanori Ito, Yoji Ishizu, Takashi Honda, Tetsuya Ishikawa, Yoshiki Hirooka, Mitsuhiro Fujishiro

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 49 ( 9 ) page： 1054 - 1065 2019.9

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Hiroyasu Ito, Ayumu Kanbe, Akira Hara, Tetsuya Ishikawa

Virology Vol. 531 page： 233 - 239 2019.5

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Yumi Hayashi, Yuki Ito, Hisao Naito, Hazuki Tamada, Nozomi Yamagishi, Takaaki Kondo, Tetsuya Ishikawa, Frank J Gonzalez, Tamie Nakajima

Toxicology Vol. 415 page： 49 - 55 2019.3

Language：English Publishing type：Research paper (scientific journal)

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]. International journal

Yumi Hayashi, Kei Zaitsu, Tasuku Murata, Tomomi Ohara, Stéphane Moreau, Maiko Kusano, Hiroshi Tanihata, Hitoshi Tsuchihashi, Akira Ishii, Tetsuya Ishikawa

Analytica chimica acta Vol. 1031 page： 196 - 196 2018.11

Effective Transplantation of 2D and 3D Cultured Hepatocyte Spheroids Confirmed by Quantum Dot Imaging Reviewed

Hiroki Okumura, Eri Nanizawa, Anna Nakanishi, Hiroshi Yukawa, Tadahiro Hashita, Takahiro Iwao, Yoshinobu Baba, Tetsuya Ishikawa, Tamihide Matsunaga

Advanced Biosystems Vol. 2 ( 8 ) 2018.8

Language：English Publishing type：Research paper (scientific journal)

© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 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 Vol. 37 ( 11 ) page： 6071-6077 2017.11

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 Vol. 40 ( 11 ) page： 2001-2004 2017.11

Utility of Doppler ultrasonography for diagnosing and assessing treatment effects in liver compartment syndrome. Reviewed

Yusuke Ando, Masatoshi Ishigami, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Kazuhiko Hayashi, Tetsuya Ishikawa, Hidemi Goto, Yoshiki Hirooka

Clinical journal of gastroenterology Vol. 10 ( 3 ) page： 265 - 269 2017.6

Language：English Publishing type：Research paper (scientific journal)

Liver compartment syndrome is a life-threatening complication of hepatic subcapsular hematoma; diagnosis and assessment of treatment effects are therefore important. We report a rare case of liver compartment syndrome due to spontaneous hepatic subcapsular hematoma without any underlying conditions, in which Doppler ultrasonography (US) proved useful in both diagnosis and assessment of treatment effects. A 32-year-old woman experienced sudden epigastralgia and was diagnosed with hepatic subcapsular hematoma in the right lobe, based on contrast-enhanced computed tomography. Hepatic arteriography showed active hemorrhage and Doppler US showed retrograde flow in the right portal vein. From these findings, we diagnosed hepatic subcapsular hematoma complicated with liver compartment syndrome, and performed embolization of the bleeding point and percutaneous hematoma drainage. After these medical procedures, normalized antegrade flow in the right portal vein was observed on Doppler US. No underlying conditions contributing to hematoma were identified. In this case, Doppler US was useful for both diagnosis and assessment of treatment effects in liver compartment syndrome. When we examine patients with hepatic subcapsular hematoma, Doppler US should be used to diagnose the presence of liver compartment syndrome and assess treatment effects.

DOI： 10.1007/s12328-017-0741-4

Web of Science

Coexistence of Copper in the Iron-Rich Particles of Aceruloplasminemia Brain. Reviewed International journal

Kunihiro Yoshida, Hisao Hayashi, Shinya Wakusawa, Ryota Shigemasa, Ryoji Koide, Tetsuya Ishikawa, Yasuaki Tatsumi, Koichi Kato, Shinji Ohara, Shu-Ichi Ikeda

Biological trace element research Vol. 175 ( 1 ) page： 79 - 86 2017.1

Language：English Publishing type：Research paper (scientific journal)

The interaction between iron and copper has been discussed in association with human health and diseases for many years. Ceruloplasmin, a multi-copper oxidase, is mainly involved in iron metabolism and its genetic defect, aceruloplasminemia (ACP), shows neurological disorders and diabetes associated with excessive iron accumulation, but little is known about the state of copper in the brain. Here, we investigated localization of these metals in the brains of three patients with ACP using electron microscopes equipped with an energy-dispersive x-ray analyzer. Histochemically, iron deposition was observed mainly in the basal ganglia and dentate nucleus, and to lesser degree in the cerebral cortex of the patients, whereas copper grains were not detected. X-ray microanalysis identified two types of iron-rich particles in their brains: dense bodies, namely hemosiderins, and their aggregated inclusions. A small number of hemosiderins and most inclusions contained a significant amount of copper which was enough for distinct Cu x-ray images. These copper-containing particles were observed more frequently in the putamen and dentate nucleus than the cerebral cortex. Coexistence of iron and copper was supported by good correlations in the molecular ratios between these two metals in iron-rich particles with Cu x-ray image. Iron-dependent copper accumulation in iron-rich particles may suggest that copper recycling is enhanced to meet the increased requirement of cuproproteins in iron overload brain. In conclusion, the iron-rich particles with Cu x-ray image were found in the ACP brain.

DOI： 10.1007/s12011-016-0744-x

Web of Science

Ursodeoxycholic acid inhibits overexpression of P-glycoprotein induced bydoxorubicin in HepG2 cells. Reviewed

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 Vol. 34 ( 1 ) page： 113 - 113 2017

Metabolome analysis revealed that abnormal muscular contraction is related to both metabolic alterations and hyper-thermogenesis in the serotonin syndrome

ZAITSU Kei, NODA Saki, HAYASHI Yumi, OHARA Tomomi, IGUCHI Akira, KUSANO Maiko, SATO Takako, TSUCHIHASHI Hitoshi, ISHIKAWA Tetsuya, SUZUKI Koichi, ISHII Akira

Annual Meeting of the Japanese Society of Toxicology Vol. 44.1 ( 0 ) page： O-38 2017

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 Reviewed

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

HEPATOLOGY Vol. 64 page： 515A - 515A 2016.10

Investigation of cocaine-induced hepatic injury in PPARα-null mice on the basis of lipid mediators and metabolome analyses

SHINODA Satoshi, HAYASHI Yumi, ZAITSU Kei, SAKAI Yuichiro, YAMANAKA Mayumi, NASU Tamie, ISHIKAWA Tetsuya, YOSHIMOTO Takashi, KUSANO Maiko, TSUCHIHASHI Hitoshi, ISHII Akira

Annual Meeting of the Japanese Society of Toxicology Vol. 43.1 ( 0 ) page： P-90 2016

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

Ishikawa T

Nihon rinsho. Japanese journal of clinical medicine Vol. 73 Suppl 9 page： 429 - 33 2015.12

C型肝炎治療の現状 Invited

石川哲也

明日の臨床 Vol. 27 ( 1 ) page： 29-34 2015.6

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

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 Vol. 1842 ( 9 ) page： 1464–1471 2014.9

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed

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

Immunology Vol. 142 ( 4 ) page： 614–623 2014.8

Language：English Publishing type：Research paper (scientific journal)

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.

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 Vol. 724 page： 161-167 2014.2

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 Reviewed

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 Vol. 54 ( 7 ) page： 505-506 2013.7

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 Reviewed

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 Vol. 74 ( 3 ) page： 470-474 2013.3

Clinical trial of percutaneous radio frequency ablation therapy by two-step insertion method using VirtuTRAXTM instrument navigator Reviewed

Kuzuya Teiji, Hayashi Kazuhiko, Ishigami Masatoshi, Ishikawa Tetsuya, Nakano Isao, Katano Yoshiaki, Itoh Akihiro, Hirooka Yoshiki, Izumi Namiki, Goto Hidemi, Ishizu Yoji, Niinomi Takurou, Imai Norihiro, Achiwa Kouichi, Arakawa Takahiro, Yamada Keiichi, Nakano Satoshi, Honda Takashi

Kanzo Vol. 54 ( 12 ) page： 850 - 853 2013

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japan Society of Hepatology

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

Other Link： 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 Vol. 4 ( 3 ) page： 1 2013

Immunoregulation of hepatitis B virus infection -rationale and clinical application- Invited

ISHIKAWA Tetsuya

Nagoya J Med Sci Vol. 74 page： 217-232 2012.8

Authorship：Lead author Language：English

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 Vol. 55 ( 1 ) page： 42-49 2012.7

Language：Japanese Publishing type：Research paper (scientific journal)

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 Vol. 48 ( 7 ) page： 1176-1178 2011.7

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 Vol. 48 ( 7 ) page： 1176 - 1178 2011.7

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

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 page： 1359-1365 2011.6

Language：English Publishing type：Research paper (scientific journal)

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 Vol. 38 ( 6 ) page： 995 - 1001 2011.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(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)

Other Link： 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 Vol. 41 ( 5 ) page： 423 - 429 2011.5

沈降型B型肝炎ワクチン Invited

石川哲也

肝胆膵 Vol. 61 ( 6 ) page： 1088-1094 2010.12

Hypofractionated stereotactic body radiotherapy for primary and metastatic liver tumors using the novalis image-guided system: preliminary results regarding efficacy and toxicity. Reviewed International journal

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 Vol. 9 ( 6 ) page： 619 - 27 2010.12

Language：English Publishing type：Research paper (scientific journal)

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 Reviewed

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 Vol. 185 ( 8 ) page： 4554 - 4560 2010.10

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Vol. 30 ( 5 ) page： 445 - 450 2010.9

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 Reviewed

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 Vol. 14 ( 1 ) page： 46-51 2010.9

A case of erythropoietic protoporphyria with severe liver damage Reviewed

SHIMAZAKI Hiroaki, ARIMA Yuko, NAKANO Takuji, MURAO Michihito, NITTA Yoshifumi, HARATA Masao, KAWABE Naoto, HASHIMOTO Senju, NAGANO Kenichi, ISHIKAWA Tetsuya, OKUMURA Akihiko, HAYASHI Kazuhiko, KATANO Yoshiaki, KURODA Makoto, YOSHIOKA Kentaro

Kanzo Vol. 51 ( 4 ) page： 175 - 182 2010.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japan Society of Hepatology

Case is a 29-yr-old man, whose complaint was abdominal pain. He had photosensitivity since childhood. The paternal grandfather and the younger brother have photosensitivity. In November 2001, he admitted in the other hospital with liver dysfunction and was diagnosed as erythropoietic protoporphyria (EPP). In August 2005, he admitted with abdominal pain and jaundice and recovered with antibiotics. In January 2006, he was referred to our hospital with mild elevation of ALT. In November 2006 and in May 2007, he admitted in our hospital with abdominal pain and jaundice, and recovered with antibiotics. In August 2008, he admitted with the same symptoms. Erythrocyte protoporphyrin and total bilirubin continually elevated. He died from liver failure in November 2008. A small portion of EPP patients suffer from liver failure. The only effective treatment for liver failure of EPP is liver transplantation, which should be considered at appropriate timing of the disease course.

DOI： 10.2957/kanzo.51.175

CiNii Books

Other Link： http://search.jamas.or.jp/link/ui/2010194025

A case of metastatic pancreatic cancer with a remarkable response to to combination therapy of gemcitabine and adoptive immune cell therapy. Reviewed

Vol. 37 ( 3 ) page： 527-529 2010.3

B型肝炎に対する免疫療法 Invited

石川哲也

medicina Vol. 47 ( 3 ) page： 487-490 2010.3

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

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 Vol. 37 ( 3 ) page： 527 - 9 2010.3

Language：Japanese Publishing type：Research paper (scientific journal)

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-a in acute hepatitis B virus infection.

ITO Hiroyasu, ANDO Kazuki, ISHIKAWA Tetsuya, SEISHIMA Mitsuru.

Inflammation and Regeneration Vol. 30 ( 5 ) page： 445 - 450 2010

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

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 Vol. 389 ( 2 ) page： 229-234 2009.11

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 Vol. 13 ( 1 ) page： 19 - 24 2009.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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)

A patient with Gilbert's syndrome complicated with drug-induced liver injury by the over-the-counter drug and Fluvastatin Sodium: A case report Reviewed

Inflammatory cytokines modulate chemokine production patterns of HepG2 cells toward initially inclined direction. Reviewed

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 Vol. 39 ( 5 ) page： 510-519 2009.5

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

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

Biochem Biophys Res Com Vol. 378 ( 3 ) page： 579-583 2009.1

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

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

J Immunol Vol. 182 ( 1 ) page： 391-397 2009.1

Usefulness of radiofrequency ablation with micro-convex probe for hepatocellular carcinoma. Reviewed

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

Hepato-gastroenterology Vol. 56 ( 93 ) page： 1127-1132 2009

Language：English Publishing type：Research paper (scientific journal)

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.

Minoru Ayada, Tetsuya Ishikawa, Akihiko Okumura, Naoki Hotta, Akinori Hirose, Kazuo Masuko, Shinichi Kakumu

Acta Hepatologica Japonica Vol. 50 ( 3 ) page： 139 - 144 2009

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japan Society of Hepatology

A 56-year-old female was admitted to our hospital because of epigastralgia, vomiting, hyperbilirubinemia, and abnormalities in the hepatic function tests. After the discontinuation of an over-the-counter drug, her symptoms and the abnormalities in the blood tests were improved. Thus she was diagnosed as drug-induced liver injury by the over-the-counter drug. The second episode of drug-induced liver injury occurred when she took Fluvastatin Sodium for her hyperlipemia. The liver injury was improved by the discontinuation of the drug
however, only serum indirect bilirubin level remained abnormal. She was suspected to have constitutional jaundice, and diagnosed as Gilbert's syndrome by the analysis of gene polymorphism for UDP-glucuronyl transferase (UGT1A1). The polymorphism of UGT1A1 affects the efficiency of the lipophilic drug metabolism, and the activity of UGT1A1 is known to be low in the patients with Gilbert's syndrome Therefore the present case suggests that the recurrent drug-induced liver injury might be related to the low UGT1A1 activity due to Gilbert's syndrome. We here report the case with Gilbert's syndrome complicated with the recurrent drug-induced liver injuries. © 2009 The Japan Society of Hepatology.

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 Vol. 38 ( 9 ) page： 896 - 903 2008.9

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. Reviewed

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

Hepatol Res Vol. 38 ( 9 ) page： 896-903 2008.9

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. Reviewed

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

Int Immunol Vol. 20 ( 7 ) page： 869-879 2008.7

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. Reviewed

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

J Gastroenterol Vol. 43 ( 5 ) page： 363-368 2008.5

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

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

Liv Int Vol. 29 ( 2 ) page： 277-283 2008.2

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 Vol. 37 page： S347 - S350 2007.10

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 Vol. 100 ( 4 ) page： 677 - 682 2007.10

Expression of Toll-like receptors in chronic hepatitis C virus infection. Reviewed

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 Vol. 22 ( 10 ) page： 1627-1632 2007.10

Use of HB vaccine for the treatment of chronic hepatitis B. Invited

Ishikawa T, Kakumu S.

Hepatol Res Vol. 37 ( S3 ) page： S347-S350 2007.10

Effect of Vitamin K2 on the recurrence in patients with hepatocellular carcinoma. Reviewed

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

Hepato-gastroenterology Vol. 54 ( 79 ) page： 2073-2077 2007.10

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 Vol. 44 ( 9 ) page： 1713 - 1715 2007.9

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 Vol. 37 ( 9 ) page： 701 - 710 2007.9

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 Vol. 37 page： S62 - S66 2007.7

Combination thearpy with lamivudine and HB vaccine on chronic heaptitis B. Invited

Ishikawa T, Kakumu S.

Hepatol Res Vol. 37 ( S1 ) page： S62-S66 2007.7

今月の主題ウイルス肝炎実地診療A to Z 扉

石川哲也

medicina Vol. 44 ( 5 ) page： 847 - 847 2007.5

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 Vol. 44 ( 5 ) page： 972 - 983 2007.5

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 Vol. 44 ( 5 ) page： 848 - 851 2007.5

Usefulness of a Bloodflow Diagnosis at Liver Tumors Using Sonazoid

AYADA Minoru, HOTTA Naoki, OKUMURA Akihiko, ISHIKAWA Tetsuya, KIBA Kumiko, KURODA Yasuko, NIWA Sachiyo, IDO Makoto, KAKUMU Sinichi

Vol. 34 2007.4

Four-Dimensional Ultrasonography for Therapeutic Radiofrequency Ablation for Hepatocellular Carcinoma

HOTTA Naoki, AYADA Minoru, HIJIKATA Yasutaka, OOHASHI Tomohiko, SATO Ken, OKUMURA Akihiko, ISHIKAWA Tetsuya, OONO Nagayuki, KAKUMU Shinichi

Vol. 34 2007.4

Usefulness of ultrasonography to Liver Tumor in Live 3D

HOTTA Naoki, AYADA Minoru, OOHASHI Tomohiko, SATO Ken, OKUMURA Akihiko, ISHIKAWA Tetsuya, KOSAKI Masahiro, KAKUMU Shinichi

Vol. 34 2007.4

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 Vol. 54 ( 79 ) page： 2073 - 2077 2007

Management of imatinib mesilate (IM)-related hepatic injury by adjusting the dose of the drug in a patient with chronic myelogenous leukemia (CML): A case report

Ayada Minoru, Ishikawa Tetsuya, Okumura Akihiko, Hotta Naoki, Furuta Keiko, Yamauchi Taeko, Hijikata Yasutaka, Ohashi Tomohiko, Sato Ken, Kakumu Shinichi

Kanzo Vol. 48 ( 10 ) page： 505 - 510 2007

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japan Society of Hepatology

A 72-year-old female, with chronic myelogenous leukemia (CML) treated successfully with 400mg/day of imatinib mesilate (IM), developed laboratory signs of a cholestatic type of liver injury after one-year administration of IM, and was admitted to our hospital. We decided to stop the administration of IM to the patient. Thereafter the abnormalities in liver function tests recovered to the normal level promptly. However, with a necessity to use IM for preventing the recurrence of CML, we re-started administration of IM at a lower dose, by weighing the risk for liver injury and the benefit for CML in a balance. With careful monitoring of liver function tests, the dose of IM was gradually increased and reached 300mg/d, and the recurrence of liver injury or CML has not been observed. Here, we report the case of IM-related liver injury, controlled well after the re-administration of IM with the lower dose.

DOI： 10.2957/kanzo.48.505

A CASE OF HEMORRHAGIC GASTRIC VASCULAR ECTASIA TO BE ACCOMPANIED BY IDIOPATHIC PULMONARY FIBROSIS : SUCCESSFULLY TREATED BY ENDOSCOPIC BAND LIGATION

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

石川哲也

Hepatology Research 37 2007

AYADA Minoru, NAKANO Tatsunori, HOTTA Naoki, OKUMURA Akihiko, ISHIKAWA Tetsuya, OHASHI Tomohiko, MATSUMOTO Eiji, SATO Ken, YOSIDA Kagumi, KAKUMU Shinichi

Gastroenterol Endosc Vol. 48 ( 11 ) page： 2626 - 2631 2006.11

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 Vol. 44 ( 4 ) page： 300A - 300A 2006.10

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 Vol. 44 ( 4 ) page： 649A - 650A 2006.10

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 Vol. 44 ( 4 ) page： 640A - 641A 2006.10

Four-dimensional ultrasonography for therapeutic radiofrequency ablation for heaptocellular carcinoma. Reviewed

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

Hepato-gastroenterology Vol. 53 ( 70 ) page： 521-525 2006.7

TRIALS OF PERCUTANEOUS ENDOSCOPIC GASTROSTOMY BY TRANSNASAL ENDOSCOPY USING A SMALL-CALIBER ENDOSCOPE

AYADA Minoru, NAKANO Tatsunori, HOTTA Naoki, NAKAE Harumichi, KUNII Shin, YOSHIDA Kagumi, OKUMURA Akihiko, ISHIKAWA Tetsuya, FUKUZAWA Yoshitaka, KAKUMU Shinichi

GASTROENTEROLOGICAL ENDOSCOPY Vol. 48 ( 7 ) page： 1425 - 1430 2006.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

We performed percutaneous endoscopic gastrostomy (PEG) by transnasal endoscopy using a small-caliber endoscope for the purpose of relieving the pain and stress of gastrointestinal endoscopy and PEG without conscious cedation. The usefulness and safety were compared between cases performed PEG by transnasal endoscopy and those by transoral endoscopy. Cases with dysphagia by neurological diseases were divided into two groups randomly. The pull technique was used for both groups. We observed vital signs etc to compare pain and stress in transnasal insertion group and transoral insertion group. An increase in blood pressure and pulse rate was significantly small during PEG in the transnasal insertion group compared to the transoral group. There was no major complication in the transnasal insertion group as well as the transoral group. Our experience suggested that PEG by transnasal endoscopy using a smallcaliber endoscope is more useful than PEG by transoral endoscopy to relieve the pain and stress, and PEG by transnasal endoscopy is a safe method as well as PEG by transoral endoscopy.

DOI： 10.11280/gee1973b.48.1425

Alteration of serum cytokine balances among different phases of chronic hepatitis B virus infection. Reviewed

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

Hepatol Res Vol. 34 ( 4 ) page： 214-221 2006.4

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 Vol. 42 ( 42 ) page： 29 - 32 2006.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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. Reviewed

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

Hepatol Res Vol. 34 ( 3 ) page： 170-177 2006.3

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

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 Vol. 34 ( 3 ) page： 178-186 2006.3

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 Vol. 4 ( 3 ) page： 116 - 119 2006.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(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

Cholestatic hepatic injury related to administration of sodium risedronate hydrate. A case report with distinctive histological findings

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

Kanzo Vol. 47 ( 1 ) page： 10 - 15 2006.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：The Japan Society of Hepatology

A 53-year-old woman was hospitalized because of general fatigue, jaundice, and the elevation of serum hepatic and biliary enzymes. She was suffering from osteoporosis, and had undergone treatment with oral administration of sodium risedronate hydrate (SRH) for 6 months before admission. Liver injury related to SRH was suspected, and the medication was stopped. After cessation of the medication, she recovered from her illness, and the elevated enzymes gradually declined. According to the diagnostic scale for drug-induced hepatic injury at the workshop in Digestive Disease Week-Japan 2004, her liver injury was classified into cholestatic type and judged “highly possible.” Liver biopsy showed the distinctive findings, such as diffuse rosette formations of hepatocytes in liver parenchyma, and strongly supported the diagnosis. Liver biopsy gives us important, sometimes critical information as the present case, thus it should be considered for execution as an auxiliary measure for accurate diagnosis of drug-related liver injury.

DOI： 10.2957/kanzo.47.10

A CASE OF HEMORRHAGIC GASTRIC VASCULAR ECTASIA TO BE ACCOMPANIED BY IDIOPATHIC PULMONARY FIBROSIS: SUCCESSFULLY TREATED BY ENDOSCOPIC BAND LIGATION

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 Vol. 53 ( 70 ) page： 521 - 525 2006

AYADA Minoru, NAKANO Tatsunori, HOTTA Naoki, OKUMURA Akihiko, ISHIKAWA Tetsuya, OHASHI Tomohiko, MATSUMOTO Eiji, SATO Ken, YOSIDA Kagumi, KAKUMU Shinichi

GASTROENTEROLOGICAL ENDOSCOPY Vol. 48 ( 11 ) page： 2626 - 2631 2006

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

A 62-year-old-woman was admitted our hospital for treatment of idiopathic pulmonary fibrosis and treated with methylprednisolon on the 9th day of admission hematemesis and melena were noted. On gastrointestinal fiberscopy examination, gastric vascular ectsia with a bleeding spot was found at greater curvature of stomach near posterior wall of the upper gastric body. After a single procedure of endoscopic band ligation (EBL), vascular ectasia successfully disappeared without any complications. EBL could be one of the effective treatments for hemorrhagicgastric vascular ectasia.

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 Vol. 50 ( S1 ) page： S119-S123 2005.10

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

Hotta N, Okumura A, Ishikawa T, Kakumu S

HEPATOLOGY Vol. 42 ( 4 ) page： 342A - 342A 2005.10

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 Vol. 47 ( Suppl.2 ) page： 1971 - 1971 2005.9

Four-dimensional ultrasonogaraphy for therapeutic radiofrequency ablation for hepatocellular carcinoma

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

AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 100 ( 9 ) page： S106 - S106 2005.9

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 Vol. 11 ( 1 ) page： 43 - 43 2005.7

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 Vol. 41 ( 41 ) page： 159 - 162 2005.5

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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

Effort of micro-convex array for RFA to liver cancer

Effort of micro-convex array for RFA to liver cancer

HOTTA Naoki, AYADA Minoru, SATO Ken, MATSUMOTO Eiji, OKUMURA Akihiko, ISHIKAWA Tetsuya, FUKUZAWA Yoshitaka, TAKAHASHI Shinobu, KAKUMU Shinichi

Vol. 32 page： S409 2005.4

HOTTA Naoki, AYADA Minoru, SATO Ken, MATSUMOTO Eiji, OKUMURA Akihiko, ISHIKAWA Tetsuya, FUKUZAWA Yoshitaka, TAKAHASHI Shinobu, KAKUMU Shinichi

Vol. 32 page： S409 2005.4

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

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

Hepatol Res Vol. 32 ( 4 ) page： 213-217 2005.4

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 Vol. 32 ( Suppl. ) page： S409 - S409 2005.4

A CASE OF HEMORRHAGIC DUODENAL VASCULAR ECTASIA : SUCCESSFULLY TREATED BY ENDOSCOPIC VARICEAL LIGATION

AYADA Minoru, FUKUZAWA Yoshitaka, HOTTA Naoki, MATSUMOTO Eiji, MAENO Tadashi, SATO Ken, OKUMURA Akihiko, ISHIKAWA Tetsuya, KAKUMU Shinichi

Gastroenterol Endosc Vol. 47 ( 1 ) page： 15 - 21 2005.1

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

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

Clin Imaging Vol. 29 ( 1 ) page： 34-41 2005.1

A CASE OF HEMORRHAGIC DUODENAL VASCULAR ECTASIA: SUCCESSFULLY TREATED BY ENDOSCOPIC VARICEAL LIGATION

AYADA Minoru, FUKUZAWA Yoshitaka, HOTTA Naoki, MATSUMOTO Eiji, MAENO Tadashi, SATO Ken, OKUMURA Akihiko, ISHIKAWA Tetsuya, KAKUMU Shinichi

GASTROENTEROLOGICAL ENDOSCOPY Vol. 47 ( 1 ) page： 15 - 21 2005.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Gastroenterological Endoscopy Society

A 82-year-old-woman was hospitalized because of the hemorrhagic small intestinal an-giodysplasia with general malaise. On emergent gastrointestinal fiberscopy, we formed a duodenal vascular ectasia with two bleeding spots among several vascular ectasia at the superior duodenal angle. We successfully treated the two hemorrhagic vascular ectasia using a ligating device for endoscopic variceal ligation (EVL). Permanent hemostasis was obtained with one procedure with out side effects. EVL appeared to be useful for small hemorrhagic lesions of small intestine.

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 Vol. 52 ( 64 ) page： 1224-1227 2005

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

石川哲也

Hepatol Res 32 page： 213 - 217 2005

【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 Vol. 94 ( 6 ) page： 1030 - 1038 2004.12

【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 Vol. 94 ( 6 ) page： 1030 - 1038 2004.12

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

Hotta N, Okumura A, Ishikawa T, Kakumu S

AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 99 ( 10 ) page： S69 - S69 2004.10

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 Vol. 40 ( 4 ) page： 421A - 421A 2004.10

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 Vol. 40 ( 4 ) page： 512A - 512A 2004.10

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 Vol. 23 ( 3 ) page： 289-290 2004

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)． Reviewed

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 Vol. 94 page： 1823 - 1829 2004

Successful treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration (B-RTO) for a patient with Wilson disease Reviewed

Japanese Journal of Portal Hypertension Vol. 10 ( 10 ) page： 132 - 136 2004

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

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 Vol. 18 ( 12 ) page： 1358-1363 2003.12

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 Vol. 27 ( 5 ) page： 221 - 224 2003.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(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

Levels of SHAP-HA complex in the sera of patients with chronic liver diseases -Usefulness as an indicator for diagnosis of hepatocellular carcinoma-

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 Vol. 18 ( 12 ) page： 1358 - 1363 2003.12

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

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

Hepato-gastroenterology Vol. 50 ( 54 ) page： 1867-1871 2003.11

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 Vol. 38 ( 4 ) page： 717A - 717A 2003.10

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 Vol. 38 ( 4 ) page： 314A - 314A 2003.10

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 Vol. 38 ( 4 ) page： 463A - 463A 2003.10

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 Vol. 38 ( 4 ) page： 485A - 485A 2003.10

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 Vol. 31 ( 2 ) page： 106 - 107 2003.6

Prevalence of diabetes mellitus in Japanese patients infected chronically with hepatitis C virus. Reviewed

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

J Gastroenterol Vol. 38 ( 4 ) page： 355-360 2003.4

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

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

J Virol Vol. 77 ( 4 ) page： 2469-2476 2003.2

Shen L., Zhou L., Okumura A., Ishikawa T., Kakumu S., Kimata K.

Japan Journal of Molecular Tumor Marker Research Vol. 19 ( 19 ) page： 70 - 71 2003

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 Vol. 50 ( 54 ) page： 1867 - 1871 2003

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 Vol. 43 ( 10 ) page： 470-471 2002.10

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 Vol. 36 ( 4 ) page： 687A - 687A 2002.10

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 Vol. 36 ( 4 ) page： 643A - 643A 2002.10

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 Vol. 36 ( 4 ) page： 691A - 691A 2002.10

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 Vol. 36 ( 4 ) page： 620A - 620A 2002.10

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 ) page： 20 - 23 2002.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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 Vol. 36 ( 10 ) page： 681 - 688 2001.10

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

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

J Gastroenterol Vol. 36 ( 10 ) page： 178-186 2001.10

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

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

JOURNAL OF GASTROENTEROLOGY Vol. 36 ( 10 ) page： 681 - 688 2001.10

Language：English Publishing type：Research paper (scientific journal) Publisher：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 Vol. 36 ( 10 ) page： 681 - 688 2001.10

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 Vol. 34 ( 4 ) page： 312A - 312A 2001.10

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 Vol. 34 ( 4 ) page： 515A - 515A 2001.10

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 Vol. 34 ( 4 ) page： 286A - 286A 2001.10

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 Vol. 34 ( 4 ) page： 552A - 552A 2001.10

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 Vol. 34 ( 4 ) page： 482A - 482A 2001.10

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

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

J Gastroenterol Vol. 36 ( 8 ) page： 544-551 2001.8

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 ) page： 5 - 8 2001.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：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