研究者データベース

小川 浩司(オガワ コウジ)
北海道大学病院 内科
助教

基本情報

所属

  • 北海道大学病院 内科

職名

  • 助教

学位

  • 博士(医学)(北海道大学)

科研費研究者番号

  • 20735188

J-Global ID

所属学協会

  • 日本超音波医学会   日本消化器内視鏡学会   日本肝臓学会   日本消化器病学会   日本内科学会   

研究活動情報

論文

  • Takuya Sho, Goki Suda, Atsushi Nagasaka, Yoshiya Yamamoto, Ken Furuya, Kenichi Kumagai, Minoru Uebayashi, Katsumi Terashita, Tomoe Kobayashi, Izumi Tsunematsu, Manabu Onodera, Takashi Meguro, Megumi Kimura, Jun Ito, Machiko Umemura, Takaaki Izumi, Naoki Kawagishi, Masatsugu Ohara, Yuji Ono, Masato Nakai, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto
    Hepatology research : the official journal of the Japan Society of Hepatology 48 7 529 - 538 2018年06月 [査読有り][通常論文]
     
    AIM: The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. METHODS: The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. RESULTS: A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. CONCLUSIONS: Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction.
  • Goki Suda, Koji Ogawa, Kenichi Morikawa, Naoya Sakamoto
    Journal of gastroenterology 53 5 591 - 605 2018年05月 [査読有り][通常論文]
     
    Hepatitis C virus (HCV) infection is one of the primary causes of liver cirrhosis and hepatocellular carcinoma. In hemodialysis patients, the rate of HCV infection is high and is moreover associated with a poor prognosis. In liver transplantation patients with HCV infection, recurrent HCV infection is universal, and re-infected HCV causes rapid progression of liver fibrosis and graft loss. Additionally, in patients with HCV and human immunodeficiency virus (HIV) co-infection, liver fibrosis progresses rapidly. Thus, there is an acute need for prompt treatment of HCV infection in these special populations (i.e., hemodialysis, liver transplantation, HIV co-infection). However, until recently, the standard anti-HCV treatment involved the use of interferon-based therapy. In these special populations, interferon-based therapies could not achieve a high rate of sustained viral response and moreover were associated with a higher rate of adverse events. With the development of novel direct-acting antivirals (DAAs), the landscape of anti-HCV therapy for special populations has changed dramatically. Indeed, in special populations treated with interferon-free DAAs, the sustained viral response rate was above 90%, with a lower incidence and severity of adverse events.
  • Goki Suda, Jun Ito, Atsushi Nagasaka, Yoshiya Yamamoto, Ken Furuya, Munenori Okamoto, Katsumi Terashita, Tomoe Kobayashi, Izumi Tsunematsu, Junichi Yoshida, Takashi Meguro, Masatsugu Ohara, Naoki Kawagishi, Megumi Kimura, Machiko Umemura, Takaaki Izumi, Yoko Tsukuda, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto
    Hepatology research : the official journal of the Japan Society of Hepatology 48 3 E146-E154  2018年02月 [査読有り][通常論文]
     
    BACKGROUND: The Japan Society of Hepatology guidelines indicate that hepatitis C virus (HCV) protease inhibitor combination therapy with simeprevir (SMV), pegylated-interferon (Peg-IFN), and ribavirin (RBV) is a therapeutic option for patients who fail to respond to a direct direct-acting antiviral-containing regimen. However, treatment outcomes have room for improvement. Fluvastatin (FLV) add-on treatment in Peg-IFN and RBV combination therapy for HCV-infected patients significantly improved the sustained virologic response (SVR), but the add-on effect of FLV on SMV combination therapy is not well understood. METHODS: This was a prospective, randomized, multicenter study in which a total of 61 HCV genotype 1b-infected patients were recruited and 60 eligible patients were randomly allocated to two groups that received 12 weeks of SMV/Peg-IFN/RBV followed by 12 weeks of Peg-IFN/RBV with or without 24 weeks of FLV. The SVR rate and adverse events were compared between the two groups. RESULTS: Thirty-one patients were allocated to the FLV add-on group and 29 patients were allocated to the control group. Baseline clinical factors, including median age, baseline platelet count, alanine aminotransferase level, HCV RNA titer, Fibrosis-4 index, and rate of IL28B minor genotype, were all similar between the two groups. The rapid virologic response, end-of-treatment response rates, SVR rates at 24 weeks after treatment, and safety profiles were also similar between the two groups. CONCLUSIONS: This prospective, randomized, multicenter study indicated that FLV had no add-on effect when given with SMV/Peg-IFN/RBV combination therapy for genotype 1b HCV-infected patients.
  • Masato Nakai, Koji Ogawa, Rei Takeda, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Machiko Umemura, Jun Ito, Takuya Sho, Goki Suda, Kenichi Morikawa, Naoya Sakamoto
    Hepatology research : the official journal of the Japan Society of Hepatology 48 3 E311-E319  2018年02月 [査読有り][通常論文]
     
    AIM: Water retention, hepatic ascites, and peripheral edema are significant problems in patients with liver cirrhosis (LC). Although furosemide and spironolactone are commonly used as treatment, they are often insufficient to treat hyponatremia and renal insufficiency in patients with LC. Tolvaptan (TVP) could provide an effective treatment alternative. However, predictive factors of a therapeutic response to TVP are unclear. Our aim was to examine clinical predictors of the response to TVP in patients with LC and water retention. METHODS: Fifty-two patients were treated with TVP, with therapeutic effects judged by a decrease in body weight (≥2 kg) and increase in urinary volume (≥500 mL) within 7 days. Blood biochemical tests were carried out at baseline and post-treatment, including serum soluble CD14 (sCD14) and urinary aquaporin 2 (AQP2) levels. Clinical and laboratory predictive factors of a TVP response were evaluated by univariate and multivariate analyses. RESULTS: The overall response to TVP was 55.8%. On univariate analyses, serum C-reactive protein (CRP) level, the neutrophil-to-lymphocyte ratio, urinary blood urea nitrogen, and urinary AQP2 were predictors of the TVP response, with only serum CRP retained on multivariate analysis. A higher serum sCD14 level was strongly associated with a non-response to TVP. A decrease in urinary AQP2 to undetectable level was associated with a response. CONCLUSION: Tolvaptan provides a rapid and strong effect to improve water retention in patients with LC. Baseline serum sCD14 and CRP levels are useful predictors of a response to TVP, with a decrease in urinary AQP2 during treatment indicating an early response.
  • Goki Suda, Norihiro Furusyo, Hidenori Toyoda, Yoshiiku Kawakami, Hiroki Ikeda, Michihiro Suzuki, Keiko Arataki, Nami Mori, Keiji Tsuji, Yoshio Katamura, Koichi Takaguchi, Toru Ishikawa, Kunihiko Tsuji, Noritomo Shimada, Atsushi Hiraoka, Sho Yamsaki, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Mineo Kudo, Atsushi Nagasaka, Ken Furuya, Yoshiya Yamamoto, Kanji Kato, Yoshiyuki Ueno, Etsuko Iio, Yasuhito Tanaka, Masayuki Kurosaki, Takashi Kumada, Kazuaki Chayama, Naoya Sakamoto
    Journal of gastroenterology 53 1 119 - 128 2018年01月 [査読有り][通常論文]
     
    BACKGROUND: Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV). METHODS: Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events. RESULTS: Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12. CONCLUSIONS: This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).
  • Naoki Kawagishi, Goki Suda, Masahiro Onozawa, Megumi Kimura, Osamu Maehara, Jun Ito, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto
    JOURNAL OF HEPATOLOGY 67 5 1106 - 1108 2017年11月 [査読有り][通常論文]
  • Osamu Maehara, Goki Suda, Mitsuteru Natsuizaka, Shunsuke Ohnishi, Yoshito Komatsu, Fumiyuki Sato, Masato Nakai, Takuya Sho, Kenichi Morikawa, Koji Ogawa, Tomoe Shimazaki, Megumi Kimura, Ayaka Asano, Yoshiyuki Fujimoto, Shinya Ohashi, Shingo Kagawa, Hideaki Kinugasa, Seiji Naganuma, Kelly A. Whelan, Hiroshi Nakagawa, Koji Nakagawa, Hiroshi Takeda, Naoya Sakamoto
    CARCINOGENESIS 38 11 1073 - 1083 2017年11月 [査読有り][通常論文]
     
    In esophageal squamous cell carcinoma (ESCC), a subset of cells defined by high expression of CD44 and low expression of CD24 has been reported to possess characteristics of cancer stem-like cells (CSCs). Novel therapies directly targeting CSCs have the potential to improve prognosis of ESCC patients. Although fibroblast growth factor-2 (FGF-2) expression correlates with recurrence and poor survival in ESCC patients, the role of FGF-2 in regulation of ESCC CSCs has yet to be elucidated. We report that FGF-2 is significantly upregulated in CSCs and significantly increases CSC content in ESCC cell lines by inducing epithelial-mesenchymal transition (EMT). Conversely, the FGFR inhibitor, AZD4547, sharply diminishes CSCs via induction of mesenchym al-epithelial transition. Further experiments revealed that MAPK/Erk kinase (Mek)/extracellular signal-regulated kinases (Erk) pathway is crucial for FGF-2-mediated CSC regulation. Pharmacological inhibition of FGF receptor (FGFR)-mediated signaling via AZD4547 did not affect CSCs in Ras mutated cells, implying that Mek/Erk pathway, downstream of FGFR signaling, might be an important regulator of CSCs. Indeed, the Mek inhibitor, trametinib, efficiently suppressed ESCC CSCs even in the context of Ras mutation. Consistent with these findings in vitro, xenotransplantation studies demonstrated that inhibition of FGF-2-mediated FGFR/Erk signaling significantly delayed tumor growth. Taken together, these findings indicate that FGF-2 is an essential factor regulating CSCs via Mek/Erk signaling in ESCC. Additionally, inhibition of FGFR and/or Mek signaling represents a potential novel therapeutic option for targeting CSCs in ESCC.
  • Goki Suda, Atsushi Nagasaka, Yoshiya Yamamoto, Ken Furuya, Kenichi Kumagai, Mineo Kudo, Katsumi Terashita, Tomoe Kobayashi, Izumi Tsunematsu, Junichi Yoshida, Takashi Meguro, Megumi Kimura, Jun Ito, Machiko Umemura, Takaaki Izumi, Seiji Tsunematsu, Fumiyuki Sato, Yoko Tsukuda, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto
    HEPATOLOGY RESEARCH 47 11 1127 - 1136 2017年10月 [査読有り][通常論文]
     
    Aim: Hepatitis C virus (HCV) infection is a risk factor for end-stage renal disease, renal graft failure, and hemodialysis patient mortality. However, the efficacy of direct-acting antiviral therapy for HCV-infected patients with renal impairment is unclear. Additionally, the promising NS5B inhibitor sofosbuvir has not been recommended for patients with severe renal impairment. In this prospective, multicenter study, we evaluated the efficacy and safety of daclatasvir and asunaprevir combination therapy, with a focus on patients with renal impairment.Methods: The study included 322 genotype 1 HCV-infected patients who received daclatasvir and asunaprevir combination therapy. The safety and sustained virological response was examined at 12weeks after the end of treatment and safety was evaluated according to renal function.Results: Of 322 patients, 5% (16/322) and 2.5% (8/322) had chronic kidney disease stage G3b (estimated glomerular filtration rate [eGFR], 30-44mL/min/1.73m(2)) and stage G4/5 (eGFR, 15-29/<15mL/min/1.73m(2)), respectively. Baseline presence of the NS5A resistance-associated variant, previous simeprevir treatment, and HCV RNA titers, which were predictors of a sustained viral response, were similar between patients with eGFR <45mL/min/1.73m(2) and eGFR >45mL/min/1.73m(2). Notably, the 12-week sustained viral response rate was comparable in patients with eGFR <45mL/min/1.73m(2) (100%, 24/24) and those with eGFR >45mL/min/1.73m(2) (88.9%, 265/298; P=0.07). Treatment discontinuation rates and adverse events, including alanine aminotransferase elevation, anemia, and renal disorders, were similar between the two groups.Conclusion: Daclatasvir and asunaprevir combination therapy for patients with renal dysfunction was highly effective and safe.
  • Goki Suda, Koji Ogawa, Yoshiya Yamamoto, Masaki Katagiri, Ken Furuya, Kenichi Kumagai, Jun Konno, Megumi Kimura, Naoki Kawagishi, Masatsugu Ohara, Machiko Umemura, Jun Ito, Takaaki Izumi, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Akihito Tsubota, Noritomo Shimada, Etsuko Iio, Yasuhito Tanaka, Naoya Sakamoto
    JOURNAL OF GASTROENTEROLOGY 52 10 1122 - 1129 2017年10月 [査読有り][通常論文]
     
    Background The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy.Methods This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12 weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated.Results Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7%(13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92 K at baseline.Conclusions This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.
  • Takuya Sho, Mitsuru Nakanishi, Kenichi Morikawa, Masatsugu Ohara, Naoki Kawagishi, Takaaki Izumi, Machiko Umemura, Jun Ito, Masato Nakai, Goki Suda, Koji Ogawa, Makoto Chuma, Takashi Meguro, Michio Nakamura, Atsushi Nagasaka, Hiromasa Horimoto, Yoshiya Yamamoto, Naoya Sakamoto
    Drugs in R&D 17 3 381 - 388 2017年09月 [査読有り][通常論文]
     
    BACKGROUND AND AIMS: Sorafenib is the first molecular targeted drug approved for the treatment of advanced hepatocellular carcinoma (HCC) and is a potent small molecule inhibitor of multiple kinases. Combination therapy with sorafenib and other cytotoxic agents for HCC may result in additive anticancer activity. The purpose of this phase I study was to investigate the safety and tolerability of combination therapy with sorafenib and 5-fluorouracil (5-FU) and to determine the optimum dose of 5-FU for a phase II trial. METHODS: This phase I study used a conventional 3 + 3 dose-escalation design. The primary endpoint was to determine the maximum tolerated dose (MTD) of 5-FU in combination with sorafenib and to determine the recommended dosage (RD) for phase II. The secondary endpoints evaluated were toxicity and the tumor response rate. All patients received 800 mg of sorafenib daily and three different dosages of 5-FU (250, 350, and 450 mg/m2/day) for 20 days by intravenous infusion in 1 month as one cycle. RESULTS: Twelve patients with advanced HCC were evaluated. The MTD of 5-FU in combination with sorafenib was 450 mg/m2/day, and 350 mg/m2/day was selected as the RD for a phase II study. Thrombocytopenia, stomatitis, and hand-foot skin reaction were observed as grade 3 adverse events. Nine patients achieved stable disease (75%), and three patients (25%) were judged to have progressive disease. The disease control rate was 75%. CONCLUSIONS: Combination therapy with sorafenib and 5-FU appears to be well tolerated and may have the potential to be an option for advanced HCC.
  • Tsunematsu S, Suda G, Yamasaki K, Kimura M, Takaaki I, Umemura M, Ito J, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Kamiyama T, Taketomi A, Sakamoto N
    Hepatology research : the official journal of the Japan Society of Hepatology 47 6 533 - 541 2017年05月 [査読有り][通常論文]
     
    AimHepatic arterial infusion chemotherapy (HAIC) is a potent therapeutic option for advanced hepatocellular carcinoma (HCC). However, there are few known predictive factors of treatment response to HAIC. We clarified the most accurate predictive factors early on in treatment.MethodsStudy subjects were 70 patients with advanced HCC who had been treated with HAIC. We assessed the relationships between patient characteristics, change ratios of early tumor markers, tumor response, progression-free survival (PFS), and overall survival.ResultsAfter two courses of HAIC, 1 (1.4%), 16 (22.9%), 30 (42.8%), and 23 (32.9%) of the 70 patients showed complete response, partial response, stable disease, and progressive disease, respectively. Overall survival was related to Child-Turcotte-Pugh score, extrahepatic metastasis, and the des--carboxyprothrombin (DCP) response. Univariate and multivariate analyses identified the neutrophil-to-lymphocyte ratio (NLR) and DCP response as significant determinants of treatment response and PFS. Progression-free survival with a low NLR (<2.87) was significantly longer than with a high NLR (median, 8.4months vs. 2.8months, respectively). Progression-free survival was 7.2months for patients with a responsive DCP (<0.7) and 2.3months for an unresponsive DCP (0.7). Additionally, even with baseline high NLR, patients with responsive DCP achieved better PFS.ConclusionBaseline NLR and early DCP response were significant predictors of treatment response and PFS after HAIC for patients with advanced HCC. The combination of baseline NLR and early DCP response could be accurate and useful predictive factors of response to HAIC and could help optimize treatments for patients with advanced HCC.
  • Yoko Tsukuda, Goki Suda, Seiji Tsunematsu, Jun Ito, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Takuya Sho, Osamu Maehara, Tomoe Shimazaki, Megumi Kimura, Kenichi Morikawa, Mitsuteru Natsuizaka, Koji Ogawa, Shunsuke Ohnishi, Makoto Chuma, Naoya Sakamoto
    JOURNAL OF MEDICAL VIROLOGY 89 5 857 - 866 2017年05月 [査読有り][通常論文]
     
    Hepatitis C virus (HCV) has been reported to hijack fatty acid metabolism in infected hepatocytes, taking advantage of lipid droplets for virus assembly. In this study, we analyzed the anti-HCV activity of L-carnitine, a substance involved in the transport of fatty acids into mitochondria. JFH-1 or HCV replicontransfected Huh7.5.1 cells were treated with or without L-carnitine to examine its anti-HCV effects. The effects of L-carnitine on HCV entry, HCV-induced adipogenesis and lipid droplet formation, and HCV-induced oxidative stress were examined. Treatment of JFH1-infected cells with L-carnitine inhibited HCV propagation in a concentration-dependent manner. In contrast, L-carnitine had no antiHCV activity in the HCV replicon system, which is lacking viral assembly. In addition, Lcarnitine did not affect HCV entry. However, Lcarnitine treatment decreased intracellular lipid droplets, which are crucial for HCV assembly in JFH-1-infected cells. The expression level of CPT-1 was decreased in JFH-1-infected cells, and L-carnitine treatment restored this expression. HCV-infected cells exhibited increased production of reactive oxygen species and glutathione oxidation. L-carnitine decreased oxidative stress induced by JFH-1-infection, as shown by glutathione/glutathione disulfide assays and MitoSOX staining. L-carnitine exhibited anti-HCV activity, possibly by inhibiting HCV assembly and through its anti-adipogenic activity in HCV-infected cells. Moreover, L-carnitine has antioxidant properties in HCVinfected hepatocytes. Overall, these results indicated that L-carnitine may be an effective adjunctive agent in antiviral therapies to treat chronic hepatitis C. (C) 2016 Wiley Periodicals, Inc.
  • Tsunematsu S, Suda G, Yamasaki K, Kimura M, Izumi T, Umemura M, Ito J, Sato F, Nakai M, Sho T, Morikawa K, Ogawa K, Tanaka Y, Watashi K, Wakita T, Sakamoto N
    Journal of medical virology 89 2 267 - 275 2017年02月 [査読有り][通常論文]
     
    Hepatitis B Virus (HBV) causes liver cirrhosis and hepatocellular carcinoma. Standard therapy includes treatment with interferon (IFN); however, its efficacy is limited. HBV has been reported to impair IFN signaling; however, the mechanism is unclear. Here, the relationship between HBV X protein (HBx) and IFN signaling was investigated by establishing HepG2 cells, stably expressing HBx (HepG2/HBx) via retrovirus-mediated gene transfer. Subsequently, IFN negative-regulator expression and its mechanism were studied. HepG2/HBx cells showed reduced expression of IFN-stimulated genes and expressed higher levels of suppressor of cytokine signaling 3 (SOCS3) and protein phosphatase 2A (PP2A) suppressor compared with control cells. Knockdown of SOCS3 and PP2A restored IFN sensitivity. Moreover, HepG2/HBx cells showed higher phosphorylation levels of signal transducers and activators of transcription 3 and endoplasmic reticulum stress, which are inducers of SOCS3 and PP2A, respectively. Additionally, HBx-knockdown restored IFN sensitivity in HepG2.2.15.7 cells. It was also confirmed that SOCS3 and PP2A expression levels were up-regulated in the liver of patients with HBV infection. The results of this study demonstrated that HBx impairs IFN signaling via increased expression of SOCS3 and PP2A, a novel mechanistic insight, providing a potential therapeutic target to enhance the efficiency of IFN therapy. J. Med. Virol. 89:267-275, 2017. (c) 2016 Wiley Periodicals, Inc.
  • Nakai M, Morikawa K, Ohara M, Kawagishi N, Izumi T, Umemura M, Ito J, Tsunematsu S, Sato F, Sho T, Suda G, Ogawa K, Sakamoto N
    Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 114 5 839 - 845 2017年 [査読有り][通常論文]
  • Goki Suda, Koji Ogawa, Megumi Kimura, Masato Nakai, Takuya Sho, Kenichi Morikawa, Naoya Sakamoto
    Journal of clinical and translational hepatology 4 4 320 - 327 2016年12月28日 [査読有り][通常論文]
     
    Prevalence of hepatitis C virus (HCV) infection is high in patients with end-stage renal dysfunction, including patients undergoing hemodialysis (HD). The HCV infection itself can cause glomerulonephritis and puts individuals at increased risk of developing end-stage renal disease; fortunately, successful HCV eradication sometimes restore HCV-related renal dysfunction. Moreover, the prognosis of dialysis patients infected with HCV is significantly worse and the renal allograft survival in HCV-infected patients is also worse than in dialysis patients without HCV infection. If life prognosis is favorable, therefore, anti-HCV therapy is strongly recommended for HCV-infected patients with severe renal dysfunction. The standard therapy for HCV-infected patients with severe renal dysfunction has historically been interferon-based therapy. However, this therapy remains ineffective in achieving high, sustained viral response rates and the rate of adverse events and treatment discontinuation due to treatment-induced adverse events continues to be high in patients with severe renal dysfunction. Safe and effective anti-HCV therapies are urgently needed, and crucial, for patients with severe renal dysfunction. Recently, direct-acting antivirals (DAAs) that specifically target viral proteins have been developed, and these targets include the NS3, NS5A, and NS5B of HCV. Clinical trials have revealed high efficacy and safety of the DAA-based therapies, but patients with severe renal dysfunction were not included in the majority of these trials. However, several recent reports have shown high efficacy and safety for some regimens of DAA combination therapy for HCV-infected patients with severe renal dysfunction. In this review, we discuss novel treatments for HCV-infected patients with severe renal dysfunction and the pharmacokinetics of these drugs.
  • Jun Ito, Goki Suda, Yoshiya Yamamoto, Atsushi Nagasaka, Ken Furuya, Kenichi Kumagai, Hideaki Kikuchi, Takuto Miyagishima, Tomoe Kobayashi, Megumi Kimura, Kazushi Yamasaki, Machiko Umemura, Takaaki Izumi, Seiji Tsunematsu, Fumiyuki Sato, Yoko Tsukuda, Katsumi Terashita, Masato Nakai, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto
    HEPATOLOGY RESEARCH 46 13 1294 - 1303 2016年12月 [査読有り][通常論文]
     
    Aim: Sofosbuvir (SOF), a nucleotide analog pro-drug, targets hepatitis C virus (HCV) NS5B polymerase and shows potential for treating HCV infection, given its high efficacy and good barrier to resistance. However, in addition to the rare resistant-associated variant (RAV) of non-structural protein NS5B S282T, several new potential RAVs of SOF have been reported, especially related to HCV genotype 1b. However, the prevalence and characteristics of these RAVs have not been clarified.Methods: We analyzed the prevalence of variants in the NS3/NS5A/NS5B regions in 96 patients treated with simeprevir (SMV) combination therapy, and the prevalence of RAVs in patients showing treatment failure was determined by direct- or deep-sequencing methods. Associations between these potential RAVs and clinical factors were also analyzed.Results: Prevalence of NS5B RAV C316N was high (46.9%, 45/96), whereas that of NS5B L159F was relatively low (1.04%, 1/96); however, deep sequencing showed that 30.0% of patients with C316N also had NS5B RAV L159F. Additionally, there was no significant relationship between the existence of potential NS5B and NS5A or NS3 RAVs. However, the presence of NS5B C316N was significantly associated with an HCV core amino acid 91 substitution. No significant difference was detected between each RAV and sustained virological response in simeprevir combination therapy.Conclusion: We provide clear evidence of the high prevalence of two potential naturally occurring NS5B RAVs (C316N and L159F) in Japan. It may be important to pay particular attention to these new potential RAVs, especially when using SOF-based therapy in patients with RAVs due to previous direct-acting antiviral therapy failure.
  • Katsumi Terashita, Makoto Chuma, Yutaka Hatanaka, Kanako Hatanaka, Tomoko Mitsuhashi, Hideki Yokoo, Takumi Ohmura, Hiroyuki Ishizu, Shunji Muraoka, Atsushi Nagasaka, Takahiro Tsuji, Yoshiya Yamamoto, Nobuaki Kurauchi, Norihiko Shimoyama, Hidenori Toyoda, Takashi Kumada, Yuji Kaneoka, Atsuyuki Maeda, Koji Ogawa, Mitsuteru Natsuizaka, Hirofumi Kamachi, Tatsuhiko Kakisaka, Toshiya Kamiyama, Akinobu Taketomi, Yoshihiro Matsuno, Naoya Sakamoto
    JOURNAL OF CLINICAL PATHOLOGY 69 7 593 - 599 2016年07月 [査読有り][通常論文]
     
    Background/Aim Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignant tumours, so the identification of molecular targets for ICC is an important issue. Zinc finger E-box binding homeobox 1 (ZEB1) is a key inducer of epithelial-mesenchymal transition (EMT). The aim of the present study was to clarify the clinical significance of ZEB1 in ICC and the associations between ZEB1 expression and EMT-related proteins. Methods We immunohistochemically examined the expression of EMT-related proteins, namely ZEB1, vimentin and E-cadherin, in ICC specimens from 102 patients. The clinicopathological and prognostic values of these markers were evaluated. Results ZEB1 and vimentin were expressed in 46.1% and 43.1% of tumours, respectively, and E-cadherin expression was lost in 44.1% of tumours. ZEB1 expression showed a significant inverse correlation with E-cadherin expression (p=0.004) and a positive correlation with vimentin expression (p=0.022). Altered expression of ZEB1 was associated with aggressive tumour characteristics, including advanced tumour stage (p=0.037), undifferentiated-type histology (p=0.017), lymph node metastasis (p=0.024) and portal vein invasion (p=0.037). Moreover, overall survival rates were significantly lower for patients with high ZEB1 expression than for patients with low ZEB1 expression (p=0.027). Kaplan-Meier analysis also identified E-cadherin expression (p=0.041) and vimentin expression (p=0.049) as prognostic indicators for overall survival. Conclusions ZEB1 expression is associated with tumour progression and poor prognosis in patients with ICC through positive correlations with vimentin and negative correlations with E-cadherin. ZEB1 expression is associated with a poor prognosis and might be an attractive target for the treatment of ICC.
  • Goki Suda, Mineo Kudo, Atsushi Nagasaka, Ken Furuya, Yoshiya Yamamoto, Tomoe Kobayashi, Keisuke Shinada, Miki Tateyama, Jun Konno, Yoko Tsukuda, Kazushi Yamasaki, Megumi Kimura, Machiko Umemura, Takaaki Izumi, Seiji Tsunematsu, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuteru Natsuizaka, Kenichi Morikawa, Koji Ogawa, Naoya Sakamoto
    JOURNAL OF GASTROENTEROLOGY 51 7 733 - 740 2016年07月 [査読有り][通常論文]
     
    HCV infection in chronic hemodialysis patients is high, has a poor prognosis and high risk of renal graft failure, and requires nosocomial infection control measures. However, options of anti-HCV therapy in such patients are limited and unsatisfactory. In this study, we report effectiveness and safety of HCV-NS5A-inhibitor daclatasvir (DCV) and protease-inhibitor asunaprevir (ASV) combination therapy for hemodialysis patients with HCV infection.This study was registered at the UMIN Clinical Trials Registry as UMIN000016355. Thirty-four dialysis patients were treated with DCV/ASV combination therapy between January 2015 and November 2015. Of those, 21 patients who were followed more than 12 weeks after treatment ended were included. We evaluated the 12-week sustained virologic response (SVR12) and adverse events during treatment.Of the 21 patients, four had compensated liver cirrhosis and three had resistance-associated variant of NS5A (NS5A RAVs)-Y93H at baseline. Overall, total of 95.5 % (20/21) of the patients achieved SVR12. Of note, all patients with cirrhosis or NS5A RAVs achieved SVR12. One relapser patient at 4 weeks post-treatment had NS3 D168E RAVs at baseline. A total of 20 patients (95.5 %) completed the 24-week therapy. One patient discontinued treatment at week 12 due to ALT elevations and achieved SVR12.DAV and ASV combination therapy for chronic hemodialysis patients with HCV infection was highly effective and well tolerated, even in elderly patients and patients with liver cirrhosis and NS5A-RAVs.
  • Maehara O, Sato F, Natsuizaka M, Asano A, Kubota Y, Itoh J, Tsunematsu S, Terashita K, Tsukuda Y, Nakai M, Sho T, Suda G, Morikawa K, Ogawa K, Chuma M, Nakagawa K, Ohnishi S, Komatsu Y, Whelan KA, Nakagawa H, Takeda H, Sakamoto N
    Cancer biology & therapy 16 10 1453 - 1461 2015年10月 [査読有り][通常論文]
     
    In hepatocellular carcinoma (HCC), there exists a highly tumorigenic subset of cells defined by high expression of CD44 and CD133 that has been reported to contain cancer stem-like cells (CSCs). Kruppel-like factor 5 (KLF5) regulates many factors involved in cell cycle, migration, inflammation, angiogenesis and stemness and has cancer-promoting effects in some cancers. While some reports have indicated that KLF5 may have important roles in regulation of CSCs, what role, if any, KLF5 plays in regulation of CSCs in HCC remains to be elucidated. Flow cytometric analysis of CD44 and CD133 in HCC cell lines revealed subpopulations of CD44(High)/CD133(High) and CD44(Low)/CD133(Low) cells. We subsequently sorted these subpopulations and identified KLF5 as a gene that is significantly upregulated in CD44(High)/CD44(High) cells via RNA sequencing using next generation sequencing technology. Moreover, KLF5 overexpression enriched the CD44(High)/CD133(High) subpopulation and, consistent with the up-regulation of CD44(High)/CD133(High) cells, KLF5 overexpressing cells were more resistant to anti-cancer drugs and displayed enhanced colony-formation capacity. By contrast, knock-down of KLF5 by siRNA diminished the CD44(High)/CD133(High) subpopulation. When KLF5 was acetylated by TGF-1, the KLF5-mediated CD44(High)/CD133(High) subpopulation enrichment was abrogated. Oppositely, ectopic expression of an acetylation-deficient KLF5 mutant further increased CD44(High)/CD133(High) subpopulations as compared to cell expressing wild-type KLF5. These findings provide novel mechanistic insight into a pivotal role for KLF5 in the regulation of CSCs in HCC.
  • Seiji Tsunematsu, Makoto Chuma, Toshiya Kamiyama, Noriyuki Miyamoto, Satoshi Yabusaki, Kanako Hatanaka, Tomoko Mitsuhashi, Hirofumi Kamachi, Hideki Yokoo, Tatsuhiko Kakisaka, Yousuke Tsuruga, Tatsuya Orimo, Kenji Wakayama, Jun Ito, Fumiyuki Sato, Katsumi Terashita, Masato Nakai, Yoko Tsukuda, Takuya Sho, Goki Suda, Kenichi Morikawa, Mitsuteru Natsuizaka, Mitsuru Nakanishi, Koji Ogawa, Akinobu Taketomi, Yoshihiro Matsuno, Naoya Sakamoto
    ABDOMINAL IMAGING 40 6 1492 - 1499 2015年08月 [査読有り][通常論文]
     
    Differentiating intrahepatic cholangiocarcinoma (ICC) from poorly differentiated hepatocellular carcinoma (p-HCC) is often difficult, but it is important for providing appropriate treatments. The purpose of this study was to examine the features differentiating ICC from p-HCC on contrast-enhanced dynamic-computed tomography (CT).This study examined 42 patients with pathologically confirmed ICC (n = 19) or p-HCC (n = 23) for which contrast-enhanced dynamic CT data were available. CT images were analyzed for enhancement patterns during the arterial phase, washout pattern, delayed enhancement, satellite nodules, capsular retraction, lesion shape, and presence of an intratumoral hepatic artery, intratumoral hepatic vein, intratumoral portal vein, and bile duct dilation around the tumor, portal vein tumor thrombus, lobar atrophy, or lymphadenopathy.Univariate analysis revealed the presence of rim enhancement (p = 0.037), lobulated shape (p = 0.004), intratumoral artery (p < 0.001), and bile duct dilation (p = 0.006) as parameters significantly favoring ICC, while a washout pattern significantly favored p-HCC (p < 0.001). Multivariate analysis revealed intratumoral artery as a significant, independent variable predictive of ICC (p = 0.037), and 15 ICCs (78.9%) showed this feature. Washout pattern was a significant, independent variable favoring p-HCC (p = 0.049), with 15 p-HCCs (65.2%) showing this feature.The presence of an intratumoral artery in the arterial phase on contrast-enhanced dynamic CT was a predictable finding for ICC, and the presence of a washout pattern was a predictable finding for p-HCC, differentiating between ICC and p-HCC.
  • Kazuaki Harada, Kazuteru Hatanaka, Kenji Kinoshita, Yasuyuki Kawamoto, Hiroaki Yamato, Koji Ogawa, Yoshiya Yamamoto, Hirohito Naruse
    Japanese Journal of Cancer and Chemotherapy 41 7 897 - 900 2014年07月01日 [査読有り][通常論文]
     
    The prognosis for patients diagnosed with advanced colorectal cancer with liver metastases is poor. Chemotherapy should be administered with caution in such patients because of complications due to severe liver dysfunction. We report here the successful management of a case of advanced sigmoid colon cancer, with icterus due to severe liver metastases, treated with cetuximab as first-line therapy. A 72-year-old man presented at our institution with complaints of severe general fatigue, tarry stools, and abdominal distention. He was diagnosed with advanced sigmoid colon cancer with multiple liver metastases. Clinical examination revealed the presence of ascites. The patient had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 3. A biopsy specimen of the primary tumor showed well-moderately differentiated adenocarcinoma without KRAS mutation. He was diagnosed with advanced sigmoid colon cancer with multiple hepatic metastases. Cetuximab monotherapy was initiated as first-line treatment. After 4 courses of cetuximab monotherapy, results of laboratory tests showed an improvement, and a computed tomography (CT) scan revealed a regression in the size of the liver metastases. Because the results of liver function tests and the ECOG PS scores improved, we initiated combination chemotherapy with 5-fluorouracil, Leucovorin, oxaliplatin (FOLFOX), and cetuximab. This regimen was well tolerated up to 14 courses, during which the only adverse reaction reported was a rash of grade 2 toxicity. Thereafter, disease progression in the form of liver metastases resulted in a change in the combination therapy to irinotecan and S-1 (IRIS) as second-line chemotherapy. Thereafter, irinotecan and panitumumab were administered as third-line therapy. The patient continued chemotherapy on an outpatient basis however, he died due to disease progression 18 months after his first visit.
  • Hiroaki Yamato, Hiroshi Kawakami, Kikuko Takagi, Koji Ogawa, Kazuteru Hatanaka, Yoshiya Yamamoto, Hirohito Naruse, Kazumichi Kawakubo, Naoya Sakamoto
    Gastrointestinal Endoscopy 79 4 676 - 678 2014年 [査読有り][通常論文]
  • Tomoe Kobayashi, Shuhei Hige, Katsumi Terashita, Masato Nakai, Hiromasa Horimoto, Takuya Sho, Mitsuru Nakanishi, Koji Ogawa, Makoto Chuma, Naoya Sakamoto, Masahiro Asaka
    JOURNAL OF GASTROENTEROLOGY 47 11 1228 - 1237 2012年11月 [査読有り][通常論文]
     
    An inosine triphosphatase (ITPA) single-nucleotide polymorphism (SNP) is associated with anemia induced by pegylated interferon and ribavirin (RBV) combination therapy in patients with chronic hepatitis C (CHC). However, there are very few reports on the hematological effects of RBV monotherapy. Here, hematological changes were monitored in patients with CHC who received RBV monotherapy, and the mechanism of these changes was investigated. Patients with CHC (n = 30) received RBV monotherapy for 4 weeks. The RBV dose was determined on the basis of body weight. Complete blood count, and serum erythropoietin (EPO) and thrombopoietin (TPO) levels were assessed. The associations between these parameters and the ITPA SNP (rs1127354) were analyzed. Over the 4 weeks, the median hemoglobin level of all patients decreased significantly, from 13.6 (10.5-16.6) to 11.7 (9.4-14.9) g/dl (P < 0.001), and the platelet counts increased, from 14.0 x 10(4) (8.9-37.4 x 10(4)) to 15.8 x 10(4) (10.2-40.6 x 10(4)) /mm(3) (P = 0.003). At week 4, hemoglobin levels differed between patients with the ITPA CC genotype and those with the AA or AC genotypes [11.1 (9.4-13.5) vs. 12.9 (12.5-14.9) g/dl, P = 0.001]. The platelet change ratio (i.e., platelet count at week 4/platelet count at baseline) in the patients with developing anemia was correlated with the increase in the serum EPO level over 4 weeks (r = 0.88, P = 0.002), but not with the increase in the serum TPO level over 4 weeks. RBV monotherapy induced anemia and affected thrombocytosis in patients with CHC. Elevated endogenous EPO may stimulate platelet production.
  • Makoto Chuma, Hiroshi Taguchi, Yoshiya Yamamoto, Shinichi Shimizu, Mitsuru Nakanishi, Koji Ogawa, Takuya Sho, Hiromasa Horimoto, Tomoe Kobayashi, Masato Nakai, Katsumi Terashita, Yusuke Sakuhara, Daisuke Abo, Yoko Tsukuda, Seiji Tsunematsu, Shuhei Hige, Mototsugu Kato, Hiroki Shirato, Masahiro Asaka
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 26 7 1123 - 1132 2011年07月 [査読有り][通常論文]
     
    Background and Aim: To evaluate the efficacy of intra-arterial 5-fluorouracil (5-FU) and subcutaneous interferon (IFN) combined with image-guided radiation therapy (IGRT) in advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT). Methods: Twenty HCC patients with PVTT were treated with 5-FU and IFN combined with image-guided radiation therapy (IGRT) (IGRT group), and as controls, 20 patients with PVTT were treated with 5-FU and IFN alone (non-IGRT group). Overall survival (OS) time, response rates, time to progression (TTP) and safety were compared across groups. Results: Complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) of PVTT were 5%, 55%, 40% and 0% in the IGRT group and 0%, 30%, 35% and 35%, in the non-IGRT group, respectively. CR, PR, SD, and PD of the whole tumor were 0%, 35%, 45% and 20% in the IGRT group and 0%, 30%, 35% and 35%, in the non-IGRT group, respectively. Overall median survival was significantly longer in the IGRT group (12.0 months 95% confidence interval [CI], 9.3-17.6 months) than in the non-IGRT group (9.1 months [95% Cl, 5.5-11.1 months]) (P = 0.041). TTP was significantly longer in the IGRT group (6.9 months [95% CI, 5.6-10.2 months]) than in the non-IGRT group (4.0 months [95% Cl, 3.3-6.4 months]) (P = 0.034). Conclusions: The response rates, median OS time and TTP in patients with advanced HCC with PVTT who received this novel combination therapy of intra-arterial 5-FU and subcutaneous IFN with TORT are encouraging, and this combination therapy warrants further investigation.
  • Koji Ogawa, Shuhei Hige, Mitsuru Nakanishi, Yoshiya Yamamoto, Makoto Chuma, Atsushi Nagasaka, Masahiro Asaka
    ANTIVIRAL THERAPY 14 4 513 - 522 2009年 [査読有り][通常論文]
     
    Background: We aimed to investigate the effects of ribavirin on hepatitis C virus (HCV). Immunological and virological effects were analysed in patients undergoing treatment with ribavirin monotherapy prior to the initiation of combination therapy with interferon-alpha. Methods: A total of 25 patients with chronic HCV infection were enrolled in this study. All patients received ribavirin for 4 weeks during monotherapy; subsequently, interferon-alpha 2b was additionally given as combined therapy. Patients were divided into two groups according to virological response. A rapid viral responder (RVR) was defined as a patient in whom HCV RNA became undetectable within 4 weeks after combination therapy. The changes of the T-helper (Th)1/Th2 subset of peripheral blood CD4(+) T-cells, serum cytokine levels and the alignment of the interferon sensitivity-determining region (ISDR) during ribavirin monotherapy were analysed by flow cytometry, ELISAs and sequencing methods. Results: A total of 17 patients were classed as RVR. In the RVR group, the mean SD serum alanine aminotransferase levels significantly decreased (before treatment 103 +/- 92 IU/I and after treatment 57 +/- 46 IU/I; P<0.05) during ribavirin monotherapy. The mean +/- SD Th1/Th2 ratio significantly increased (before treatment 13.9 +/- 5.1 and after treatment 16.7 +/- 6.2; P<0.05), but did not change in the non-RVR group. The levels of Th2 cytokines (interleukin-10 and soluble CD30) significantly decreased, especially in the RVR group. The mean +/- SD mutation rates of ISDR at the nucleotide level increased in the RVR group (before treatment 2.6 +/- 0.9 sites/clone and after treatment 3.9 +/- 1.6 sites/clone; P<0.05), but did not change in the non-RVR group. Conclusions: Ribavirin administration might increase the efficacy of interferon therapy for patients with chronic hepatitis C by stimulating the host immune system and promoting HCV gene mutation.
  • Makoto Chuma, Shuhei Hige, Mitsuru Nakanishi, Koji Ogawa, Mitsuteru Natsuizaka, Yoichi Yamamoto, Masahiro Asaka
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 23 9 1431 - 1436 2008年09月 [査読有り][通常論文]
     
    Background and Aim: Increased production of reactive oxygen species, which cause oxidative DNA damage, is considered to be related to hepatocarcinogenesis. 8-Hydroxy-2 '-deoxy-guanosine (8-OHdG) is a useful marker of DNA damage induced by oxidative stress. The aim of this study was to determine whether expression of 8-OHdG is a risk factor for the development of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) infection. Methods: The expression of 8-OHdG in liver biopsy specimens was assessed immunohistochemically. In total, 104 patients with chronic HCV infection who were diagnosed on liver biopsy between January 1987 and December 2002 were studied retrospectively. Univariate and multivariate analyses using age, gender, habitual drinking, tobacco exposure, diabetes mellitus, serum alanine aminotransferase level, HCV genotype, hepatic fibrosis, inflammation, steatosis, and 8-OHdG expression in liver biopsy specimens were conducted to identify factors related to the development of HCC. Results: On multivariate analysis, 8-OHdG and fibrosis were independent and significant risk factors for HCC development (relative risk, 2.48; P = 0.023; relative risk, 5.35; P = 0.001, respectively). Furthermore, the cumulative incidence rate of HCC in 39 patients with high 8-OHdG expression levels was significantly greater than that in 65 patients with low 8-OHdG expression levels (P = 0.043). In addition, liver 8-OHdG expression was correlated with hepatic inflammation. Conclusions: 8-OHdG is a risk factor for the development of HCC in patients with chronic HCV infection. Patients with chronic HCV who express 8-OHdG should be monitored carefully for the development of HCC.

その他活動・業績

  • 中井 正人, 森川 賢一, 大原 正嗣, 川岸 直樹, 出水 孝章, 梅村 真知子, 伊藤 淳, 常松 聖司, 佐藤 史幸, 荘 拓也, 須田 剛生, 小川 浩司, 坂本 直哉 日本消化器病学会雑誌 114 (5) 839 -845 2017年05月 [査読無し][通常論文]
     
    ウイルソン病は原因不明の肝機能障害、肝硬変における鑑別診断の1つである。多くは幼少期に診断されるが、成人後に肝硬変として発見される症例も経験する。血清セルロプラスミン、尿中銅などの測定にて診断可能な症例もあるが、診断に苦慮し、ATP7B遺伝子変異検査や肝組織中銅含有量測定が必要な場合もある。米国肝臓病学会、ヨーロッパ肝臓学会から診断ガイドラインが提唱されており、本邦でも2015年にウイルソン病診断ガイドラインが発表され、診断困難例においても、各ガイドラインに従った診断が可能となった。当科でのウイルソン病症例を各ガイドラインの診断基準、フローチャートを用いて検討し、その有用性を報告する。(著者抄録)
  • 【ガイドラインには書いていない「肝炎・肝がん診療の最近の問題点」】 B型肝炎治療・核酸アナログの長期投与の留意点
    小川 浩司, 坂本 直哉 肝臓クリニカルアップデート 3 (1) 41 -46 2017年05月 [査読無し][通常論文]
     
    本邦ではB型肝炎に対する核酸アナログ治療としてラミブジン、アデホビル、エンテカビル、テノホビルが保険適用となり、B型肝炎診療の大きな役割を担っている。核酸アナログ治療は高い抗ウイルス効果を認めるものの、B型肝炎の最終治療目標であるHBs抗原の陰性化は容易ではない。また、長期的には薬剤耐性や腎機能障害といった副作用、さらには発癌にも注意が必要である。(著者抄録)
  • 日本におけるB型肝炎キャリアの実態とその診療
    中井 正人, 小川 浩司, 坂本 直哉 消化器の臨床 19 (3) 181 -186 2016年06月 [査読無し][通常論文]
     
    B型肝炎キャリア(=HBV持続感染者)は本邦に全人口の1%程度存在すると考えられる。HBVキャリアは垂直感染対策によって疫学的に減少傾向となっているが、いまだ感染者は多く存在し重要な感染症である。HBV持続感染者の自然史において、ALT正常の2種類のキャリア(無症候性キャリア、非活動性キャリア)が存在し、両者ともに通常は治療対象とならないが、長期経過にて肝炎を生じ、肝硬変や肝細胞癌発症のリスクとなるため、適切なフォローアップとタイミングでの治療介入の検討が必要である。(著者抄録)
  • 肝臓における超音波組織弾性測定の機種間差の検討 Shear wave with Smart mapsとFibroScanとの比較
    若林 倭, 工藤 悠輔, 西田 睦, 堀江 達則, 岩井 孝仁, 表原 里実, 佐藤 恵美, 高杉 莉佳, 小川 浩司, 坂本 直哉 超音波医学 43 (1) 131 -132 2016年01月 [査読無し][通常論文]
  • 当科における初発肝細胞癌に対するラジオ波焼灼術後の長期成績
    小川 浩司, 山梨 香菜, 木下 賢治, 山本 桂子, 畑中 一映, 山本 義也, 成瀬 宏仁 道南医学会大会並びに総会プログラム・抄録集 67回 91 -96 2014年11月 [査読無し][通常論文]
     
    ラジオ波焼灼術(RFA)で初回治療した初発肝細胞癌110例(男性71例、女性39例、年齢中央値65歳)を対象に、長期的な再発率、予後について検討した。背景肝は慢性肝炎14例、肝硬変96例、肝予備能はChild-Pugh Grade A:79例、B:30例、C:1例、肝障害度はA:63例、B:44例、C:3例であった。累積再発率/局所再発率/累積全生存率は1年:17.0/1.9/99.0%、2年:48.4/8.4/88.9%、3年:55.0/9.7/78.7%、4年:67.2/11.5/63.9%、5年:73.8/11.5/55.5%であった。サブグループの治療成績は、肝予備能A群ではB/C群に比べ有意に予後良好で、腫瘍進行度Stage I群(46例)ではII/III群(64例)に比べ有意に再発率が低かった。初回再発(67例)への治療は手術5例、RFA:45例、TACE:12例、その他5例で、著効率は全体で78%と良好であった。治療後死亡53例の内訳は癌死27例(51%)、肝不全死13例(25%)、他病死13例(25%、心不全4、肺炎2、他臓器癌4、その他3)であった。
  • Volume Navigation Systemによる超音波診断および治療支援
    福田 友美, 山田 遥子, 長谷川 智, 野呂 恵子, 平方 奈津子, 佐藤 正幸, 小川 浩司, 山本 義也, 中村 麻名美 函館医学誌 38 (1) 49 -54 2014年10月 [査読無し][通常論文]
     
    リアルタイムImage Fusion技術であるVolume Navigation System(V-navi)を搭載した超音波検査(US)装置LOGIQ E9の構成と測定原理を紹介し、使用実績を報告した。本システム導入の2011年12月から2013年11月末までの2年間に、肝病変を対象としてV-naviを使用したUSは258例に施行した。V-naviを起動した状態で、ソナゾイド造影超音波検査(CEUS)やラジオ波焼灼療法、エタノール注入療法などの経皮的局所療法を施行することが可能であった。内訳はV-navi下USによる観察が86例で、V-navi確認後単独CEUS(106例)またはV-navi下併用CEUS(20例)による精査を同日に施行し、穿刺経路を確認するケースが多かった。これらの代表例4例を提示し、病変部位・性状診断や、最善の穿刺経路確認などに有用であった。
  • 市中病院における進行肝細胞癌に対するソラフェニブ治療成績と副作用対策の現状 患者サポートプログラム・ネクサリンクの導入
    山本 義也, 山梨 香菜, 木下 賢治, 大和 弘明, 山本 桂子, 小川 浩司, 畑中 一映, 成瀬 宏仁 The Liver Cancer Journal 6 (2) 126 -127 2014年06月 [査読無し][通常論文]
  • 梅村 真知子, 渡邉 豊, 小川 浩司, 山本 義也, 矢和田 敦, 榮浪 克也, 長佐古 友和, 川村 直之, 工藤 峰生, 松林 桂二, 狩野 吉康, 姜 貞憲, 水尾 仁志, 岡本 宏明, 高橋 和明, 安倍 夏生, 新井 雅裕, 三代 俊治 肝臓 55 (6) 349 -359 2014年06月 [査読無し][通常論文]
     
    2007〜10年の4年間に、函館市内4病院で診療した13例、函館市内で感染し札幌で発症した1例の計14例のE型肝炎ウイルス(HEV)感染者を対象とし、E型肝炎の臨床像、感染経路の解析およびウイルス遺伝子の系統解析を行った。道南地区における有症状の非A非B非C型急性肝炎のうちE型の頻度は24.2%であった。E型肝炎14(男8:女6)例中、4(男1:女3)例が重症化しそのうち3例は劇症肝炎を呈し2例は死亡した。13例から分離されたHEV RNAゲノムのORF1 326塩基に対し遺伝子系統解析を行ったところ、3株はgenotype 3、10株はgenotype 4に属した。genotype 4の7株は既報のKitami/Abashiri strainに、2株は札幌圏小流行を起こしたNew Sapporo strainに属した。患者の職業、食肉嗜好、居住地等は共通点に乏しかった。感染源として、従来から指摘されている動物の内臓肉に加え、生の貝類が疑われた。(著者抄録)
  • 分子標的薬と殺細胞性薬剤併用による治療効果増強の検証 高度進行肝癌に対する5-FU+ソラフェニブ併用療法の臨床第I相試験
    荘 拓也, 中西 満, 中馬 誠, 中村 路夫, 永坂 敦, 小川 浩司, 山本 義也, 目黒 高志, 常松 聖司, 佐藤 史幸, 佃 曜子, 寺下 勝巳, 中井 正人, 小林 智絵, 夏井坂 光輝, 髭 修平, 坂本 直哉 The Liver Cancer Journal 5 (2) 142 -143 2013年06月 [査読無し][通常論文]
  • 小川 浩司, 山本 義也, 梅村 真知子, 姜 貞憲, 坂田 秀勝, 松林 圭二, 高橋 和明, 新井 雅裕, 三代 俊治 肝臓 53 (4) 206 -215 2012年04月 [査読無し][通常論文]
     
    2010年春函館地区ではE型劇症肝炎2例が同時期に発生したが、分離同定されたE型肝炎ウイルス(HEV)株(JFI-Hak10、JFS-Hak10)は何れもGenotype 4に属し、遺伝子系統解析により2009年秋に発生したE型急性肝炎札幌圏小流行で分離された"new Sapporo strain"と近縁な同一系統株であることが判明した。症例は63歳と73歳のいずれも女性で2010年3月下旬に発症し4月上旬に函館市内の2病院に入院となった。症例1は劇症肝炎急性型を呈するも速やかに改善し第22病日退院となった。しかし症例2は肝炎が遷延し劇症肝炎亜急性型を呈し第50病日死亡した。血中HEV RNAをretrospectiveに定量したところ生存例ではウイルス量が順調に減衰したが、死亡例では血中HEV RNA量の減衰を認めず、肝炎の遷延化に関連し不幸な転帰につながった可能性が考えられた。(著者抄録)
  • 当院におけるソナゾイド造影超音波検査の現況とその有用性について
    平方 奈津子, 福田 友美, 長谷川 智, 東出 恵子, 佐藤 正幸, 小川 浩司, 山本 義也, 成瀬 宏仁, 工藤 和洋 函館医学誌 34 (1) 18 -22 2010年10月 [査読無し][通常論文]
     
    著者らは2009年1年間にソナゾイド造影超音波(CEUS)を施行した198例(男性145例、女性53例、平均年齢69.1歳)を対象に有用性について検討した。その結果、CEUS施行の目的は肝内腫瘍の描出と質的診断117例(A群)、肝生検またはRFAなど穿刺治療支援および治療効果判定75例(B群)、全肝スクリーニング6例(C群)であり、A群ではHCCとHCCを疑う結節精査が87例、転移性肝癌やその他肝腫瘍精査30例で、全例において腫瘍の確定診断につながった。B群では穿刺治療支援27例(Vascularイメージでの穿刺1例・Kupfferイメージでの穿刺24例・視認性向上が得られずBモードでの穿刺2例)、治療効果判定は48例であった。一方、C群では全例で明らかなdefectは描出されず、CEUSで新規の結節を指摘し得た症例はなかった。以上より、CEUSによる精査の過程で主結節と異なる部位に数mm大の新たな結節を検出した例もあり、CTでの検出能を上回る可能性が示唆された。
  • Sonazoid Case Study ソナゾイドによるルーチン造影超音波検査 市中病院におけるソナゾイド造影超音波検査の現状
    山本 義也, 小川 浩司, 山本 文泰, 畑中 一映, 片桐 雅樹, 成瀬 宏仁, 東出 恵子, 平方 奈津子, 佐藤 正幸 INNERVISION 24 (5) 97 -99 2009年04月 [査読無し][通常論文]
  • 集学的治療が奏功した胃小細胞癌の1例
    中井 正人, 小川 浩司, 江藤 和範, 山本 文泰, 畑中 一映, 山本 義也, 片桐 雅樹, 成瀬 宏仁, 原 豊, 工藤 和洋, 下山 則彦 函館医学誌 32 (1) 23 -27 2008年10月 [査読無し][通常論文]
     
    上腹部痛と全身倦怠感を主訴とした50歳代男性症例について検討した。心窩部に圧痛を認め、炎症反応の軽度上昇、高度貧血がみられた。癌胎児性抗原(CEA)、CA 19-9は正常範囲であったが、NSEは高値であった。GIF・上部消化管造影では、胃前提部後壁を中心とする巨大な潰瘍底を伴う2型腫瘍を認めた。生検では、N/C比が高くクロマチンに富み、核の切れ込み像をもつ異型度の高い細胞の集塊を認めた。免疫染色はAE1/AE3陽性、synaptophisin(+)、chromogranin A(+)、NCAM(+)であった。胃小細胞癌、T4N3H0P0M0のcStage IVと診断した。シスプラチン(CDDP)+塩酸イリノテカン(CPT-11)、TS-1+CDDP、カルボプラチン(CBDCA)+エトポシド(VP-16)といった全身化学療法、放射線療法、姑息的手術を行った。これらには一定の効果を認めたが、腹腔内残存原発巣の増大、転移巣の増悪から全身状態が悪化し、第410病日に死亡した。胃小細胞癌の原発巣に対しても、積極的な放射線療法にて一定の効果が期待できる症例が存在することが示唆された。

教育活動情報

主要な担当授業

  • 医学総論
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 基本医学研究
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 肝炎ウイルス、癌ゲノミクス、H.pylori、食道癌 Hepatitis viruses、Cancer genomics、H.pylori、Esophageal cancer
  • 基本医学総論
    開講年度 : 2019年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 肝炎ウイルス、癌ゲノミクス、H.pylori、分子標的療法 Hepatitis viruses、Cancer genomics、H.pylori、Molecular targeting therapies
  • 医学総論
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 肝炎ウイルス、癌ゲノミクス、H.pylori、食道癌、膵癌、炎症性腸疾患 Hepatitis viruses、Cancer genomics、H.pylori、Esophageal cancer 、Pancrease cancer 、Inflammatory bowel diseases
  • 基盤医学研究
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 肝炎ウイルス、癌ゲノミクス、H.pylori、食道癌、膵癌、炎症性腸疾患 Hepatitis viruses、Cancer genomics、H.pylori、Esophageal cancer 、Pancrease cancer 、Inflammatory bowel diseases
  • 臨床医学研究
    開講年度 : 2019年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 肝炎ウイルス、癌ゲノミクス、H.pylori、分子標的療法、がんプロフェッショナル Hepatitis viruses、Cancer genomics、H.pylori、Molecular targeting therapies、Professional oncology


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