Faculty Profiles - ONISHI Hideki

Papers - ONISHI Hideki

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Application of radiofrequency ablation for the treatment of intermediate-stage hepatocellular carcinoma. Reviewed International journal

Kazuhiro Nouso, Kazuya Kariyama, Shinichiro Nakamura, Ayano Oonishi, Akiko Wakuta, Atsushi Oyama, Soichiro Ako, Chihiro Dohi, Nozomu Wada, Yuki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

Journal of gastroenterology and hepatology 32 ( 3 ) 695 - 700 2017.3

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

BACKGROUND AND AIM: Transcatheter arterial chemoembolization (TACE) is a standard therapy for the treatment of intermediate-stage hepatocellular carcinoma (HCC). In this study, we tried to elucidate the possibility of using radiofrequency ablation (RFA) as an alternative treatment of intermediate-stage HCC. METHODS: Among 246 patients who were initially diagnosed with intermediate-stage HCC, 76 who were treated with TACE (TACE group) and 91 who were treated with RFA (RFA group) were enrolled in this study. The risk for survival was analyzed with the Cox Proportional Hazard Model, and the survival rates were compared using propensity score matching. RESULTS: About half (50.6%) of the intermediate-stage HCC patients in the RFA group were diagnosed with Barcelona Clinic Liver Cancer substage-B1 (BCLC-B1) compared with only 19.7% of the patients in the TACE group. Survival of the RFA group was longer than that of TACE group in patients with BCLC-B1 and BCLC-B2. In contrast, no difference between groups was observed in patients with BCLC-B3/4. Multivariate analysis revealed that large tumor size (>30 mm, hazard ratio = 1.685, P = 0.043), high des-γ-carboxyprothrombin (>100 mAU/mL, hazard ratio = 1.920, P = 0.012), and TACE group (hazard ratio = 1.896, P = 0.016) were significant risk factors for survival. Overall 3-year survival of the patients in the RFA group (69.5%) was significantly longer than that of patients in the TACE group (51.5%) after propensity score matching (P = 0.032). No significant adverse events were observed in either group. CONCLUSIONS: RFA was useful for the treatment of less advanced intermediate-stage HCC and could be an alternative to TACE in selected cases.

DOI： 10.1111/jgh.13586

[Corrigendum] Loss of Runt‑related transcription factor 3 induces resistance to 5‑fluorouracil and cisplatin in hepatocellular carcinoma. Reviewed International journal

Junro Kataoka, Hidenori Shiraha, Shigeru Horiguchi, Hiroaki Sawahara, Daisuke Uchida, Teruya Nagahara, Masaya Iwamuro, Hiroki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto, Hiroyuki Okada

Oncology reports 37 ( 3 ) 1921 - 1921 2017.3

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

Following the publication of this article, we realize that there were some errors in the manuscript. Details of the experiments describing the gene silencing of RUNX3 with small interfering RNA (siRNA) were erroneously included in this paper, and all references to siRNA should have been deleted from the manuscript prior to publication. In the subsection entitled 'Cell lines and cell culture' on page 2577, the left‑hand column, the text should have indicated that the human HCC cell lines Hep3B and Huh7 were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA), whereas HLF cells were obtained from the Japanese Cancer Resources Bank (Tokyo, Japan). Lastly, an error was made in describing the calculation of the IC50 values, which did not correlate with the data shown in Fig. 2. Therefore, the subsection entitled 'Ectopic RUNX3 protein expression suppresses cell growth...' should have been entitled 'Ectopic RUNX3 protein expression increases 5‑FU and CDDP sensitivity', and the text herein should have read as follows: We analyzed the effects of RUNX3 on chemosensitivity in the RUNX3‑ or CAT (mock)‑transfected Hep3B and Huh7 cells. RUNX3 expression enhanced 5‑FU sensitivity in both cell lines; the cell viability with 5‑FU (100 nM) decreased from 66.3±4.6 to 34.3±5.0%, and from 71.0±4.7% to 27.0±5.5% in the Hep3B and Huh7 cells, respectively (Fig. 2A). RUNX3 expression also enhanced CDDP sensitivity in both cell lines; the cell viability with CDDP (100 nM) decreased from 58.7±2.6% to 25.7±4.9%, and from 67.7±4.1% to 25.7±7.5% in the Hep3B and Huh7 cells, respectively (Fig. 2B). We sincerely apologize for these errors and oversights, which have not affected any of the overall conclusions reported in the study, and regret any inconvenience they may have caused. [the original article was published in the Oncology Reports 35: 2576-2582, 2016; DOI: 10.3892/or.2016.4681].

DOI： 10.3892/or.2017.5419

The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma. Reviewed

Yasuyuki Shimomura, Akinobu Takaki, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Takayuki Maruyama, Naofumi Tamaki, Daisuke Uchida, Hideki Onishi, Kenji Kuwaki, Shinichiro Nakamura, Kazuhiro Nouso, Yasuhiro Miyake, Kazuko Koike, Takaaki Tomofuji, Manabu Morita, Kazuhide Yamamoto, Hiroyuki Okada

Internal medicine (Tokyo, Japan) 56 ( 3 ) 243 - 251 2017

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

Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

DOI： 10.2169/internalmedicine.56.7002

A case of unresectable combined hepatocellular cholangiocarcinoma showing favorable response to LFP therapy. Reviewed

Sayuri Kato, Yasuto Takeuchi, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Hideki Ohnishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology 113 ( 12 ) 2050 - 2056 2016.12

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

A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma. Therefore, sorafenib was administered;however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J01118&link_issn=&doc_id=20161222160009&doc_link_id=130005179285&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130005179285&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Potential of alpha-fetoprotein as a prognostic marker after curative radiofrequency ablation of hepatocellular carcinoma. Reviewed International journal

Chihiro Dohi, Kazuhiro Nouso, Koji Miyahara, Yuki Morimoto, Nozomu Wada, Hideaki Kinugasa, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

Hepatology research : the official journal of the Japan Society of Hepatology 46 ( 9 ) 916 - 23 2016.8

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

AIM: Recurrence of hepatocellular carcinoma (HCC) is observed frequently, even after curative treatments. The aim of this study is to elucidate the risk factors for recurrence of HCC after radiofrequency ablation (RFA), focusing on the carcinogenic potential of the liver assessed by α-fetoprotein (AFP). METHODS: We enrolled 357 consecutive patients who underwent complete ablation by RFA for primary HCC (≤3 cm, ≤3 tumors) and analyzed the correlation between 17 critical parameters, including AFP and HCC recurrence. RESULTS: Recurrence was observed in 236 patients during a mean observation period of 54.3 months. Multivariate analysis revealed that multiple tumors (risk ratio [RR] = 1.70, 95% confidence interval [CI] = 1.27-2.26, P < 0.001), high AFP (>10 ng/mL, RR = 1.45, 95% CI = 1.09-1.94, P < 0.001) and high des-γ-carboxyprothrombin (>40 mAU/mL, RR = 1.52, 95% CI = 1.13-2.02, P < 0.005) were significantly correlated with recurrence. AFP was selected as a significant factor even when the cut-off level was set lower (≤5 ng/mL). The risk of recurrence increased linearly according to the increase of the lowest AFP level after RFA and the adjusted ratios relative to AFP less than 5 ng/mL were 1.56, 2.14, 2.57 and 3.13 in AFP 5-10 ng/mL, 10-20 ng/mL, 20-50 ng/mL and over 50 ng/mL, respectively. In addition, the recurrence rate was predicted by the AFP level after RFA, regardless of the level before the treatment. CONCLUSION: AFP less than 5 ng/mL after curative RFA was an important predictor of a better prognosis and was considered to indicate the low carcinogenic potential of the non-cancerous liver.

DOI： 10.1111/hepr.12636

Loss of Runt-related transcription factor 3 induces resistance to 5-fluorouracil and cisplatin in hepatocellular carcinoma. Reviewed International journal

Junro Kataoka, Hidenori Shiraha, Shigeru Horiguchi, Hiroaki Sawahara, Daisuke Uchida, Teruya Nagahara, Masaya Iwamuro, Hiroki Morimoto, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Kazuhide Yamamoto, Hiroyuki Okada

Oncology reports 35 ( 5 ) 2576 - 82 2016.5

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

Runt-related transcription factor 3 (RUNX3) is known to function as a tumor suppressor in gastric cancer and other types of cancers, including hepatocellular carcinoma (HCC). However, its role has not been fully elucidated. In the present study, we aimed to evaluate the role of RUNX3 in HCC. We used the human HCC cell lines Hep3B, Huh7 and HLF; RUNX3 cDNA was introduced into Hep3B and Huh7 cells, which were negative for endogenous RUNX3 expression, and RUNX3 siRNA was transfected into HLF cells, which were positive for endogenous RUNX3. We analyzed the expression of RUNX3 and multidrug resistance-associated protein (MRP) by immunoblotting. MTT assays were used to determine the effects of RUNX3 expression on 5-fluorouracil (5-FU) and cisplatin (CDDP) sensitivity. Finally, 23 HCC specimens resected from patients with HCC at Okayama University Hospital were analyzed, and correlations among immunohistochemical expression of RUNX3 protein and MRP protein were evaluated in these specimens. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, MRP3 and MRP5 in the RUNX3-negative cells, whereas knockdown of RUNX3 in the HLF cells stimulated the expression of these MRPs. An inverse correlation between RUNX3 and MRP expression was observed in the HCC tissues. Importantly, loss of RUNX3 expression contributed to 5-FU and CDDP resistance by inducing MRP expression. These data have important implications in the study of chemotherapy resistance in HCC.

DOI： 10.3892/or.2016.4681

Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C. Reviewed International journal

Shintaro Nanba, Fusao Ikeda, Nobuyuki Baba, Koichi Takaguchi, Tomonori Senoh, Takuya Nagano, Hiroyuki Seki, Yasuto Takeuchi, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

Journal of clinical pathology 69 ( 3 ) 226 - 33 2016.3

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

BACKGROUND: Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established. METHODS: We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera. RESULTS: Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation. CONCLUSIONS: Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients. TRIAL REGISTRATION NUMBER: UMIN 000001031.

DOI： 10.1136/jclinpath-2015-203215

Alpha-fetoprotein before and after pegylated interferon therapy for predicting hepatocellular carcinoma development. Reviewed International journal

Yasuto Takeuchi, Fusao Ikeda, Toshiya Osawa, Yasuyuki Araki, Kouichi Takaguchi, Youichi Morimoto, Noriaki Hashimoto, Kousaku Sakaguchi, Tatsuro Sakata, Masaharu Ando, Yasuhiro Makino, Shuji Matsumura, Hiroki Takayama, Hiroyuki Seki, Shintarou Nanba, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

World journal of hepatology 7 ( 19 ) 2220 - 8 2015.9

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

AIM: To investigate factors that accurately predict hepatocellular carcinoma (HCC) development after antiviral therapy in chronic hepatitis C (CHC) patients. METHODS: CHC patients who received pegylated interferon and ribavirin were enrolled in this cohort study that investigated the ability of alpha-fetoprotein (AFP) to predict HCC development after interferon (IFN) therapy. RESULTS: Of 1255 patients enrolled, 665 developed sustained virological response (SVR) during mean follow-up period of 5.4 years. HCC was occurred in 89 patients, and 20 SVR patients were included. Proportional hazard models showed that HCC occurred in SVR patients showing AFP ≥ 5 ng/mL before therapy and in non-SVR patients showing AFP ≥ 5 ng/mL before and 1 year after therapy besides older age, and low platelet counts. SVR patients showing AFP ≥ 5 ng/mL before therapy and no decrease in AFP to < 5 ng/mL 1 year after therapy had significantly higher HCC incidence than non-SVR patients showing AFP ≥ 5 ng/mL before therapy and decreased AFP (P = 0.043). AFP ≥ 5 ng/mL before therapy was significantly associated with low platelet counts and high values of alanine aminotransferase (ALT) in stepwise logistic regression analysis. After age, gender, platelet count, and ALT was matched by propensity score, significantly lower HCC incidence was shown in SVR patients showing AFP < 5 ng/mL before therapy than in those showing AFP ≥ 5 ng/mL. CONCLUSION: The criteria of AFP < 5 ng/mL before and 1 year after IFN therapy is a benefical predictor for HCC development in CHC patients.

DOI： 10.4254/wjh.v7.i19.2220

Alteration of N-glycan profiles in patients with chronic hepatitis and hepatocellular carcinoma. Reviewed International journal

Koji Miyahara, Kazuhiro Nouso, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

Hepatology research : the official journal of the Japan Society of Hepatology 45 ( 9 ) 986 - 993 2015.9

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

AIM: Most of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application. METHODS: We analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters. RESULTS: The total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (>3), large tumor size (>3 cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver-operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC. CONCLUSION: We demonstrate the full spectrum of the alterations of serum N-glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression.

DOI： 10.1111/hepr.12441

Hepatic stellate cells promote upregulation of epithelial cell adhesion molecule and epithelial-mesenchymal transition in hepatic cancer cells. Reviewed International journal

Teruya Nagahara, Hidenori Shiraha, Hiroaki Sawahara, Daisuke Uchida, Yasuto Takeuchi, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Takeshi Kuwaki, Hideki Onishi, Shinichiro Nakamura, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

Oncology reports 34 ( 3 ) 1169 - 77 2015.9

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

Microenvironment plays an important role in epithelial-mesenchymal transition (EMT) and stemness of cells in hepatocellular carcinoma (HCC). Epithelial cell adhesion molecule (EpCAM) is known as a tumor stemness marker of HCC. To investigate the relationship between microenvironment and stemness, we performed an in vitro co-culture assay. Four HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) were co-cultured with the TWNT-1 immortalized hepatic stellate cells (HSCs), which create a microenvironment with HCC. Cell proliferation ability was analyzed by flow cytometry (FCM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while migration ability was assessed by a wound healing assay. Expression of EpCAM was analyzed by immunoblotting and FCM. HCC cell lines were co-cultured with TWNT-1 treated with small interfering RNA (siRNA) for TGF-β and HB-EGF; we then analyzed proliferation, migration ability and protein expression using the methods described above. Proliferation ability was unchanged in HCC cell lines co-cultured with TWNT-1. Migration ability was increased in HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) directly (216.2±67.0, 61.0±22.0, 124.0±66.2 and 51.5±40.3%) and indirectly (102.5±22.0, 84.6±30.9, 86.1±25.7 and 73.9±29.7%) co-cultured with TWNT-1 compared with the HCC uni-culture. Immunoblot analysis revealed increased EpCAM expression in the HCC cell lines co-cultured with TWNT-1. Flow cytometry revealed that the population of E-cadherin-/N-cadherin+ and EpCAM-positive cells increased and accordingly, EMT and stemness in the HCC cell line were activated. These results were similar in the directly and indirectly co-cultured samples, indicating that humoral factors were at play. Conversely, HCC cell lines co-cultured with siRNA‑treated TWNT-1 showed decreased migration ability, a decreased population of EpCAM-positive and E-cadherin-/N-cadherin+ cells. Taken together, humoral factors secreted from TWNT-1 promote upregulation of EpCAM and EMT in hepatic cancer cells.

DOI： 10.3892/or.2015.4126

Serum N-glycan profiles in patients with intraductal papillary mucinous neoplasms of the pancreas. Reviewed

Akimoto Y, Nouso K, Kato H, Miyahara K, Dohi C, Morimoto Y, Kinugasa H, Tomoda T, Yamamoto N, Tsutsumi K, Kuwaki K, Onishi H, Ikeda F, Nakamura S, Shiraha H, Takaki A, Okada H, Amano M, Nishimura S, Yamamoto K

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 15 ( 4 ) 432 - 438 2015.7

Prognostic value of altered N-glycosylation of circulating glycoproteins in patients with unresectable pancreatic cancer treated with gemcitabine. Reviewed International journal

Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Hideaki Kinugasa, Hironari Kato, Naoki Yamamoto, Koichiro Tsutsumi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Taku Nakahara, Yoshiaki Miura, Hidehisa Asada, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

Pancreas 44 ( 4 ) 551 - 6 2015.5

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

OBJECTIVES: The objectives of this study were to examine the whole-serum N-glycan profile of patients with unresectable pancreatic cancer and to evaluate the ability of glycans to predict gemcitabine treatment efficacy and patient survival. METHODS: We collected serum from 52 patients with advanced pancreatic cancer before they began gemcitabine monotherapy. The serum glycan profile was measured through comprehensive quantitative high-throughput glycome analysis and compared with the treatment efficacy and patient survival. RESULTS: Of the 61 glycans detected, the serum levels of glycan 4310 (molecular weight [m/z] 1549.566), 6301 (m/z 2032.724), and 9200 (m/z 2010.692) were high in patients with a short time to tumor progression (TTP). Multivariate analysis revealed that a high glycan 9200 concentration was an independent risk factor for shorter TTP (hazard ratio, 2.11; 95% confidence interval, 1.07-4.17) and poor overall survival (hazard ratio, 2.56; 95% confidence interval, 1.08-6.19). The median TTP of patients with up-regulation of 9200 after gemcitabine treatment was shorter than for the remaining patients (91 vs 301 days; P = 0.0005). A similar relationship was observed for overall survival (median, 181 vs 561 days; P = 0.001). CONCLUSIONS: Glycan 9200 is a possible biomarker predicting gemcitabine efficacy survival in patients with unresectable pancreatic cancer.

DOI： 10.1097/MPA.0000000000000321

Use of non-invasive serum glycan markers to distinguish non-alcoholic steatohepatitis from simple steatosis. Reviewed International journal

Yasushi Yamasaki, Kazuhiro Nouso, Koji Miyahara, Nozomu Wada, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Yasuto Takeuchi, Tetsuya Yasunaka, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

Journal of gastroenterology and hepatology 30 ( 3 ) 528 - 34 2015.3

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

BACKGROUND AND AIMS: Serum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). METHODS: We collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined. RESULTS: Among the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis. CONCLUSION: We clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

DOI： 10.1111/jgh.12726

Efficacy of hepatic arterial infusion chemotherapy in combination with irradiation for advanced hepatocellular carcinoma with portal vein invasion. Reviewed International journal

Hideki Onishi, Kazuhiro Nouso, Shinichiro Nakamura, Kuniaki Katsui, Nozomu Wada, Yuki Morimoto, Koji Miyahara, Yasuto Takeuchi, Kenji Kuwaki, Tetsuya Yasunaka, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Yoshiyuki Kobayashi, Kohsaku Sakaguchi, Susumu Kanazawa, Kazuhide Yamamoto

Hepatology international 9 ( 1 ) 105 - 12 2015.1

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

BACKGROUND: The presence of portal vein tumor thrombosis (PVTT) is a poor prognostic factor for patients with hepatocellular carcinomas (HCC). The purpose of this study was to determine the treatment effect of irradiation in combination with hepatic arterial infusion chemotherapy (HAIC) for these patients. METHODS: We retrospectively examined the outcome of 67 HCC patients with PVTT of the main trunk or first branch who received HAIC alone or with concurrent irradiation for PVTT (CCRT). RESULTS: Thirty-four patients received HAIC, and 33 patients received CCRT. The time to progression (TTP) of PVTT in the CCRT group was significantly longer than in the HAIC group (p < 0.01), and the TTP of intrahepatic nodules in the CCRT group tended to be longer than in the HAIC group (p = 0.06). The objective response rates of intrahepatic nodules (52 vs. 18%, p < 0.01) and PVTT (45 vs. 18%, p = 0.01) were both significantly higher in the CCRT group than in the HAIC group, respectively. No significant difference in overall survival was found between the two groups (p = 0.14); however, the median survival time in the CCRT group was longer than that in the HAIC group (12.4 vs. 5.7 months, respectively). CONCLUSIONS: CCRT might be a promising treatment for advanced-stage HCC with PVTT. CCRT prolonged the TTP of intrahepatic nodules and PVTT, and it improved the objective response rate of intrahepatic nodules and PVTT.

DOI： 10.1007/s12072-014-9592-y

Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis. Reviewed

Hiroyuki Seki, Fusao Ikeda, Shintaro Nanba, Yuki Moritou, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Minoru Nakamura, Kazuhide Yamamoto

Acta medica Okayama 69 ( 3 ) 137 - 44 2015

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

A predictive marker of the rapid progression to hepatic failure is desired for patients with asymptomatic primary biliary cirrhosis (aPBC). We performed a systematic cohort analysis of 101 patients diagnosed as having aPBC and the rapid progression to liver failure in some, by focusing on cholestasis. Cholestasis was assessed by aberrant keratin7 (K-7) expressions in the patients' hepatocytes. Intralobular expressions of K-7 were found in 9 of the 101 patients. The grades of K-7 expression were significantly associated with the levels of alanine aminotransferase, alkaline phosphatase, and total bilirubin at the time of diagnosis, but not with bile duct loss or cholestasis. Stepwise logistic regression analysis revealed that high grades of K-7 expression correlated positively with high levels of total bilirubin. During the follow-up period, 8 patients developed jaundice, and the mean period until the development of jaundice was 5.2 years. The proportional hazards models for the risk of developing jaundice identified a high grade of aberrant K-7 expression in hepatocytes as the only significant risk factor. Aberrant K-7 expression in hepatocytes can be used as an additional marker to predict rapid progression to liver failure in patients with aPBC at the time of diagnosis.

Local recurrence and complications after percutaneous radiofrequency ablation of hepatocellular carcinoma: a retrospective cohort study focused on tumor location. Reviewed

Junichi Toshimori, Kazuhiro Nouso, Shinichiro Nakamura, Nozomu Wada, Yuki Morimoto, Yasuto Takeuchi, Tetsuya Yasunaka, Kenji Kuwaki, Hideki Ohnishi, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

Acta medica Okayama 69 ( 4 ) 219 - 26 2015

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

We conducted a retrospective cohort study to investigate the predisposing factors for local recurrence and complications after percutaneous radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). HCC patients (n＝397) consecutively treated with RFA (256 males, 141 females, median age 69 years) were enrolled. In these patients, 1,455 nodules (median size 17mm) were ablated. Predisposing factors for overall recurrence and local recurrence in the context of tumor location and complications were examined. Local recurrence was observed for 113 of the 1,455 nodules. The 1-, 3- and 5-year local recurrence rates were 2.2%, 7.4% and 9.5%, respectively. A multivariate Cox proportional hazard analysis revealed that large tumor size (＞2cm), tumor location (adjacent to the major portal branch or hepatic vein), and small ablated margin (＜3mm) were independent predisposing factors for local recurrence after RFA (HR＝1.70-2.81). Tumor location (adjacent to the major portal branch, hepatic vein, or diaphragm) was also revealed as a risk factor for liver damage due to RFA. HCC adjacent to the major portal vein or hepatic vein was associated with a higher risk for local recurrence and for complications;therefore, special precautions are necessary when applying RFA to HCC near vessels even when the tumors are located at an easy-to-puncture site.

Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma. Reviewed International journal

Yuki Morimoto, Kazuhiro Nouso, Nozomu Wada, Yasuto Takeuchi, Hideaki Kinugasa, Koji Miyahara, Tetsuya Yasunaka, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

Hepatology research : the official journal of the Japan Society of Hepatology 44 ( 14 ) E353-9 2014.12

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

AIM: Recently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC). METHODS: We examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case-control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC. RESULTS: In the case-control study, multivariate analysis revealed that high platelet counts (odds ratio [OR] = 4.84; 95% confidence interval [CI] = 1.29-29.54; P = 0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time = 23.3 months). On multivariate analysis, high tumor number, high des-γ-carboxyprothrombin (DCP) and Child-Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR = 1.73; 95% CI = 0.99-3.14; P = 0.055). CONCLUSION: HCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

DOI： 10.1111/hepr.12315

Prevention of vagotonia and pain during radiofrequency ablation of liver tumors. Reviewed International journal

Shinichiro Nakamura, Kazuhiro Nouso, Hideki Onishi, Kenji Kuwaki, Hiroaki Hagihara, Yasuto Takeuchi, Nozomu Wada, Yuki Morimoto, Koji Miyahara, Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Yoshiyuki Kobayashi, Hidenori Shiraha, Shinichi Ishikawa, Akinobu Takaki, Kazuhide Yamamoto

Hepatology research : the official journal of the Japan Society of Hepatology 44 ( 13 ) 1367 - 70 2014.12

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

Radiofrequency ablation (RFA) is frequently used to treat early stage hepatocellular carcinoma. Two of the most cumbersome side-effects of the ablation procedure are intractable pain and vagotonia when deep sedation is not used. We describe local injection of anesthetic into Glisson's sheath as a new technique for overcoming these problems. Lidocaine was injected into Glisson's sheath when radiofrequency ablation of hepatocellular carcinomas, which were located adjacent to Glisson's sheath, could not be continued due to severe pain (n = 8) or bradycardia (n = 3). In all three patients who showed vagotonia with bradycardia during the ablations, injection of lidocaine prevented bradycardia, allowing completion of the radiofrequency ablation. Pain was reduced in all eight patients who experienced pain during ablation. No side-effects were observed during the procedures. Injection of anesthetic into Glisson's sheath is simple and effective for reducing intractable pain and vagotonia associated with RFA.

DOI： 10.1111/hepr.12321

Efficacy of sorafenib beyond first progression in patients with metastatic hepatocellular carcinoma. Reviewed International journal

Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Shouta Iwadou, Yoshiyuki Kobayashi, Koichi Takaguchi, Yoshitaka Takuma, Hiroyuki Takabatake, Kohsaku Sakaguchi, Kazuhide Yamamoto

Hepatology research : the official journal of the Japan Society of Hepatology 44 ( 3 ) 296 - 301 2014.3

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

AIM: We investigated whether continuous sorafenib administration keeps suppressing the growth of hepatocellular carcinoma (HCC) after first progressive disease (PD), and whether it prolongs patients' survival. METHODS: The size of metastatic lesions was measured in 36 patients with advanced HCC treated with sorafenib. The tumor growth rates before and after radiological PD as well as survival were compared between the patients who continued (n = 23) and stopped (n = 13) sorafenib at first radiological PD. RESULTS: The growth rate did not differ between before and after PD in patients who continued sorafenib, while it increased after PD in patients who stopped sorafenib at PD (P = 0.002). Survival beyond first progression was longer in patients who continued sorafenib than in those who stopped it at PD (P = 0.012), and this tendency was observed even when the analysis was limited to Child-Pugh class A patients (P = 0.085). CONCLUSION: Sorafenib administration beyond first radiological PD could continuously suppress HCC growth and may have survival benefit.

DOI： 10.1111/hepr.12123

Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C. Reviewed International journal

Hiroshi Matsushita, Fusao Ikeda, Yoshiaki Iwasaki, Hiroyuki Seki, Shintaro Nanba, Yasuto Takeuchi, Yuki Moritou, Tetsuya Yasunaka, Hideki Onishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Kazuhide Yamamoto

Journal of gastroenterology and hepatology 29 ( 2 ) 337 - 43 2014.2

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

BACKGROUND AND AIM: Chronic infection with hepatitis C virus (HCV) decreases health-related quality of life (HRQOL). The present study was planned to investigate the impact of HRQOL of patients with chronic hepatitis C (CHC) on the outcomes of therapy with pegylated interferon and ribavirin (RBV), in addition to IL28B polymorphisms. METHODS: The present study enrolled 228 CHC patients and assessed their HRQOLs prospectively with the 36-item short-form health survey. RESULTS: The patients with CHC have lower physical HRQOL status than the general population (P = 0.037, the Z-test). The patients with advanced liver diseases exhibited further decreases in HRQOL (P = 0.036, Spearman's rank correlation coefficient). The score of total HRQOL was significantly lower in the group with sustained virological response (SVR) to the therapy with pegylated interferon and RBV than the non-SVR group (P = 0.031, the Mann-Whitney U-test), with significantly lower scores of mental component and its comprising subscales in the SVR group. Stepwise multivariate logistic regression analysis showed that low HRQOL score ≤ 400 points was significantly associated with SVR (odds ratio = 2.4, P = 0.013), independently from high platelet counts, low HCV RNA, favorable single-nucleotide polymorphism type of IL28B, and HCV serotype 2. The patients with low HRQOL score will have significantly less decrease in HRQOL score by 4 weeks of the treatment than those with high HRQOL score at baseline (P = 0.0045). CONCLUSION: HRQOL is one of the significant predictor of the outcomes of therapy with pegylated interferon and RBV independently from IL28B polymorphism.

DOI： 10.1111/jgh.12337

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