Okayama University Medical School Acta Medica Okayama 0386-300X 78 5 2024 Prognostic Efficacy of the Albumin Grade in Patients with Hepatocellular Carcinoma 377 386 EN Yuichi Hirano Department of Gastroenterology, Okayama City Hospital Kazuhiro Nouso Department of Gastroenterology, Okayama City Hospital Kazuya Kariyama Department of Gastroenterology, Okayama City Hospital Atsushi Hiraoka Gastroenterology Center, Ehime Prefectural Central Hospital Shohei Shiota Department of Gastroenterology, Okayama City Hospital Akiko Wakuta Department of Gastroenterology, Okayama City Hospital Satoshi Yasuda Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital Hidenori Toyoda Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital Kunihiko Tsuji Center of Gastroenterology, Teine Keijinkai Hospital Takeshi Hatanaka Department of Gastroenterology, Saiseikai Maebashi Hospital Satoru Kakizaki Department of Clinical Research, NHO Takasaki General Medical Center Atsushi Naganuma Department of Gastroenterology, NHO Takasaki General Medical Center Toshifumi Tada Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital Ei Itobayashi Department of Gastroenterology, Asahi General Hospital Toru Ishikawa Department of Gastroenterology, Saiseikai Niigata Hospital Noritomo Shimada Division of Gastroenterology and Hepatology, Otakanomori Hospital Koichi Takaguchi Department of Hepatology, Kagawa Prefectural Central Hospital Akemi Tsutsui Department of Hepatology, Kagawa Prefectural Central Hospital Takuya Nagano Department of Hepatology, Kagawa Prefectural Central Hospital Michitaka Imai Department of Gastroenterology, Niigata Cancer Center Hospital Shinichiro Nakamura Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital Takashi Kumada Department of Nursing, Gifu Kyoritsu University Real-Life Practice Experts for HCC (RELPEC) Study Group in Japan Original Article 10.18926/AMO/67662 We previously found that “albumin grade”, formerly called the “ALBS grade,” demonstrated significant capability for prognostic stratification in hepatocellular carcinoma (HCC) patients treated with lenvatinib. The purpose of the present study was to compare the performance of the albumin grade with that of the modified albumin-bilirubin (mALBI) grade in predicting overall survival of HCC patients with different BCLC stages and treatment types. We enrolled 7,645 Japanese patients newly diagnosed with HCC using the Akaike information criteria (AIC), likelihood ratio, and C-index in different Barcelona Clinic Liver Cancer (BCLC) stages and treatments. The albumin grade showed similar and slightly better performance than the mALBI grade for BCLC stage 0 and A and especially for patients who underwent curative surgery and ablation. In patients treated with transcatheter arterial chemoembolization, molecular targeted agents, and the best supportive care, the mALBI grade had better performance than the albumin grade. However, the differences of the indices were very small in all scenarios. Overall, the albumin grade was comparable in efficacy to the mALBI grade, showing particular benefit for patients with early-stage HCC. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 2692-4609 2 1 2021 Fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection for patients with immunosuppressants and steroids e83 EN Shumpei Yamamoto Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Hideaki Kinugasa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Yasushi Yamasaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Mami Hirai Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Soichiro Ako Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Kensuke Takei Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Shoko Igawa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Eriko Yasutomi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Shohei Oka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Masayasu Ohmori Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Toshihiro Inokuchi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Keita Harada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Sakiko Hiraoka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Kazuhiro Nouso Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University Objectives: Transient fever and electrocoagulation syndrome after colorectal endoscopic submucosal dissection (ESD) remain a challenge. The aim of this study was to assess the risk factors of post-ESD fever and post-ESD coagulation syndrome (PECS), focusing on the involvement of immunosuppressive drugs and steroids (IM). Methods: This retrospective analysis included 510 patients who underwent colorectal ESD at Okayama University Hospital from 2015 to 2020. The incidence rate, clinical outcome, and factors associated with post-ESD fever and PECS were investigated. Results: Post-ESD fever and PECS occurred in 63 patients (12.4%) and 43 patients (8.4%), respectively. In multivariate analysis, the American Society of Anesthesiologists Physical Status ≥3, the use of immunosuppressants or prednisolone ≥5mg (IM group), and injury to muscle layer/perforation were significantly associated with post-ESD fever. In PECS, IM group, tumors located on the right side, treatment time ≥60 min, injury to the muscle layer, and multiple lesions were independent risk factors. Both post-ESD fever and PECS improved conservatively in the IM group, and no serious complication was observed. Conclusions: The use of IM was a risk factor for both post-ESD fever and PECS. However, there were no serious complications in colorectal ESD for patients taking IM. No potential conflict of interest relevant to this article was reported.

Baishideng Publishing Group Inc Acta Medica Okayama 1007-9327 27 41 2021 Circulating tumor DNA dynamics analysis in a xenograft mouse model with esophageal squamous cell carcinoma 7134 7143 EN Hiroyuki Terasawa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hideaki Kinugasa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Kazuhiro Nouso Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Shumpei Yamamoto Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Mami Hirai Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Akinobu Takaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences BACKGROUND It remains unclear which factors, such as tumor volume and tumor invasion, influence circulating tumor DNA (ctDNA), and the origin of ctDNA in liquid biopsy is always problematic. To use liquid biopsies clinically, it will be very important to address these questions. AIM To assess the origin of ctDNA, clarify the dynamics of ctDNA levels, assess ctDNA levels by using a xenograft mouse after treatment, and to determine whether tumor volume and invasion are related to ctDNA levels. METHODS Tumor xenotransplants were established by inoculating BALB/c-nu/nu mice with the TE11 cell line. Groups of mice were injected with xenografts at two or four sites and sacrificed at the appropriate time point after xenotransplantation for ctDNA analysis. Analysis of ctDNA was performed by droplet digital PCR, using the human telomerase reverse transcriptase (hTERT) gene. RESULTS Mice given two-site xenografts were sacrificed for ctDNA at week 4 and week 8. No hTERT was detected at week 4, but it was detected at week 8. However, in four-site xenograft mice, hTERT was detected both at week 4 and week 6. These experiments revealed that both tumor invasion and tumor volume were associated with the detection of ctDNA. In resection experiments, hTERT was detected at resection, but had decreased by 6 h, and was no longer detected 1 and 3 d after resection.CONCLUSIONWe clarified the origin and dynamics of ctDNA, showing that tumor volume is an important factor. We also found that when the tumor was completely resected, ctDNA was absent after one or more days. No potential conflict of interest relevant to this article was reported.

Lippincott Williams & Wilkins Acta Medica Okayama 2155-384X 12 11 2021 The Impact of KRAS Mutation in Patients With Sporadic Nonampullary Duodenal Epithelial Tumors e00424 EN Hideaki Kinugasa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiromitsu Kanzaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shumpei Yamamoto Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasushi Yamasaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuhiro Nouso Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kouichi Ichimura Department of Pathology, Hiroshima City Hiroshima Citizens Hospital Masahiro Nakagawa Department of Endoscopy, Hiroshima City Hiroshima Citizens Hospital Toshiharu Mitsuhashi Center for Innovative Clinical Medicine, OkayamaUniversity Hospital Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences INTRODUCTION: The genomic characterization of primary nonampullary duodenal adenocarcinoma indicates a genetic resemblance to gastric and colorectal cancers. However, a correlation between the clinical and molecular characteristics of these cancers has not been established. This study aimed to elucidate the clinicopathological features of sporadic nonampullary duodenal epithelial tumors, including their molecular characteristics and prognostic factors. METHODS: One hundred forty-eight patients with sporadic nonampullary duodenal epithelial tumors were examined in this study. Patient sex, age, TNM stage, tumor location, treatment methods, histology, KRAS mutation, BRAF mutation, Fusobacterium nucleatum, mucin phenotype, and programmed death-ligand 1 (PD-L1) status were evaluated. KRAS and BRAF mutations, Fusobacterium nucleatum, mucin phenotype, and PD-L1 status were analyzed by direct sequencing, quantitative polymerase chain reaction, and immunochemical staining. RESULTS: The median follow-up duration was 119.4 months. There were no deaths from duodenal adenoma (the primary disease). Kaplan-Meier analysis for duodenal adenocarcinoma showed a significant effect of TNM stage (P < 0.01). In univariate analysis of primary deaths from duodenal adenocarcinoma, TNM stage II or higher, undifferentiated, KRAS mutations, gastric phenotype, intestinal phenotype, and PD-L1 status were significant factors. In multivariate analysis, TNM stage II or higher (hazard ratio: 1.63 x 10(10), 95% confidence interval: 18.66-6.69 x 10(36)) and KRAS mutation (hazard ratio: 3.49, confidence interval: 1.52-7.91) were significant factors. DISCUSSION: Only KRAS mutation was a significant prognostic factor in primary sporadic nonampullary duodenal adenocarcinoma in cases in which TNM stage was considered. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1471-2407 20 1 2020 Liquid biopsy for patients with IBD-associated neoplasia 1188 EN Hideaki Kinugasa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Sakiko Hiraoka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Kazuhiro Nouso Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shumpei Yamamoto Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Mami Hirai Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroyuki Terasawa Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Eriko Yasutomi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Shohei Oka Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masayasu Ohmori Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Yasushi Yamasaki Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Toshihiro Inokuchi Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Masahiro Takahara Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Keita Harada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Takehiro Tanaka Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Hiroyuki Okada Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Background It is often difficult to diagnose inflammatory bowel disease (IBD)-associated neoplasia endoscopically due to background inflammation. In addition, due to the absence of sensitive tumor biomarkers, countermeasures against IBD-associated neoplasia are crucial. The purpose of this study is to develop a new diagnostic method through the application of liquid biopsy. Methods Ten patients with IBD-associated cancers and high-grade dysplasia (HGD) with preserved tumor tissue and blood were included. Tumor and non-tumor tissues were analyzed for 48 cancer-related genes using next-generation sequencing. Simultaneously, circulating tumor DNA (ctDNA) was analyzed for mutations in the target genes using digital PCR. Results Out of 10 patients, seven had IBD-related cancer and three had IBD-related HGD. Two patients had carcinoma in situ; moreover, three had stageII and two had stage III. To avoid false positives, the mutation rate cutoff was set at 5% based on the control results; seven of 10 (70%) tumor tissue samples were mutation-positive. Mutation frequencies for each gene were as follows: TP53 (20.9%; R136H), TP53 (25.0%; C110W), TP53 (8.5%; H140Q), TP53 (31.1%; R150W), TP53 (12.8%; R141H), KRAS (40.0%; G12V), and PIK3CA (34.1%; R 88Q). The same mutations were detected in the blood of these seven patients. However, no mutations were detected in the blood of the remaining three patients with no tumor tissue mutations. The concordance rate between tumor tissue DNA and blood ctDNA was 100%. Conclusion Blood liquid biopsy has the potential to be a new method for non-invasive diagnosis of IBD-associated neoplasia. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 69 3 2015 Aberrant Expression of Keratin 7 in Hepatocytes as a Predictive Marker of Rapid Progression to Hepatic Failure in Asymptomatic Primary Biliary Cirrhosis 137 144 EN 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 Original Article 10.18926/AMO/53520 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 patientsʼ 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. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0815-9319 29 5 2014 Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer 973 983 EN Daisuke Uchida Hidenori Shiraha Hironari Kato Teruya Nagahara Masaya Iwamuro Junro Kataoka Shigeru Horiguchi Masami Watanabe Akinobu Takaki Kazuhiro Nouso Yasutomo Nasu Takahito Yagi Hiromi Kumon Kazuhide Yamamoto Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer. MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine. ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling. ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 5 2014 Nursing Support Increases the Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C 263 268 EN Shihoko Namba Kayoko Miyake Fusao Ikeda Tomoko Hazama Yu Hitobe Noriko Yamasaki Hidenori Shiraha Akinobu Takaki Kazuhiro Nouso Yoshiaki Iwasaki Kazuhide Yamamoto Original Article 10.18926/AMO/52894 Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p＝0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0815-9319 29 2 2014 Assessment of health-related quality of life and how it predicts the outcome of pegylated interferon and ribavirin therapy for chronic hepatitis C 337 343 EN 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 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. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0012-2823 86 2 2012 Serum Levels of Soluble Adhesion Molecules as Prognostic Factors for Acute Liver Failure 122 128 EN Atsuyuki Ohnishi Yasuhiro Miyake Hiroshi Matsushita Kazuyuki Matsumoto Akinobu Takaki Tetsuya Yasunaka Kazuko Koike Fusao Ikeda Hidenori Shiraha Kazuhiro Nouso Kazuhide Yamamoto Background/Aims: In patients with septic shock, the degree of liver dysfunction is correlated with serum levels of soluble intercellular adhesion molecule (sICAM)-1. We aimed to assess the usefulness of serum levels of soluble adhesion molecules as prognostic factors for acute liver failure (ALF). Methods: Serum levels of soluble platelet endothelial cell adhesion molecule (sPECAM)-1, sICAM-3, soluble endothelial (sE) selectin, sICAM-1, soluble platelet selectin, and soluble vascular cell adhesion molecule-1 on admission were measured in 37 ALF patients and 34 healthy controls. Results: Twenty-two ALF patients (59%) reached to fatal outcomes. Serum levels of sPECAM-1, sICAM-3, sE-selectin and sICAM-1 were higher in ALF patients than healthy controls. In 37 ALF patients, by the multivariate logistic regression analysis, ratio of direct to total bilirubin (per 0.1 increase; OR 0.11, 95% CI 0.01-0.99), serum sPECAM-1 level (per 100 ng/ml increase; OR 4.37, 95% CI 1.23-15.5) and serum sICAM-1 level (per 100 ng/ml increase; OR 0.49, 95% CI 0.27-0.89) were associated with fatal outcomes. Using receiver operating characteristics curve, each area under the curve of serum sPECAM-1 and sICMA-1 levels as prognostic factors was 0.71 and 0.74, respectively. Conclusion: Serum sPECAM-1 and sICAM-1 levels may be useful for predicting the prognosis of ALF. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0815-9319 26 1 2011 Serum levels of platelet-derived growth factor-BB and vascular endothelial growth factor as prognostic factors for patients with fulminant hepatic failure 116 121 EN Hiroki Takayama Yasuhiro Miyake Kazuhiro Nouso Fusao Ikeda Hidenori Shiraha Akinobu Takaki Haruhiko Kobashi Kazuhide Yamamoto Background and Aims: In animal models for acute liver injury, the administration of some angiogenic factors such as vascular endothelial growth factor (VEGF) and granulocyte-colony stimulating factor (G-CSF) are shown to reduce liver injury and improve liver proliferative capacity. The aim of the present study was to assess the role of angiogenic factors in fulminant hepatic failure (FHF). Methods: Serum levels of nine angiogenic factors (angiopoietin-2, follistatin, G-CSF, hepatocyte growth factor [HGF], interleukin-8, leptin, platelet-derived growth factor [PDGF]-BB, platelet endothelial cell adhesion molecule-1 and VEGF) were measured using the Bio-Plex Protein Array System in 30 patients, 17 of whom were diagnosed with FHF, 13 with acute hepatitis (AH), and 20 controls. Results: Serum levels of PDGF-BB and VEGF were lower in FHF patients than AH patients and controls (PDGF-BB; 2050 +/- 1572 pg/mL vs 4521 +/- 2419 pg/mL vs 8506 +/- 5500 pg/mL, VEGF; 39 +/- 38 pg/mL vs 144 +/- 122 pg/mL vs 205 +/- 121 pg/mL). By using univariate logistic regression models, serum levels of PDGF-BB and VEGF were associated with poor outcomes. Serum PDGF-BB levels were strongly correlated with serum VEGF levels (r = 0.70). Furthermore, serum PDGF-BB levels were significantly correlated with platelet counts (r = 0.79), PT activity (r = 0.37) and D.Bil/T.Bil ratio (r = 0.50), while serum VEGF levels were significantly correlated with platelet counts (r = 0.68) and PT activity (r = 0.38). Conclusions: We consider that serum levels of PDGF-BB and VEGF are worth investigating as biomarkers for predicting outcomes of FHF patients. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 68 1 2014 Impact of Comorbid Hepatic Steatosis on Treatment of Chronic Hepatitis C in Japanese Patients and the Relationship with Genetic Polymorphism of IL28B, PNPLA3 and LDL Receptor 17 22 EN Yuki Moritou Fusao Ikeda Yoshiaki Iwasaki Nobuyuki Baba Kouichi Takaguchi Tomonori Senoh Takuya Nagano Yasuto Takeuchi Tetsuya Yasunaka Hideki Ohnishi Yasuhiro Miyake Akinobu Takaki Kazuhiro Nouso Kazuhide Yamamoto Original Article 10.18926/AMO/52139 The impact of hepatic steatosis on interferon therapy for patients with chronic hepatitis C (CHC) has been associated with single-nucleotide polymorphisms (SNP) of IL28B, patatin-like phospholipase domain-containing protein 3 (PNPLA3), and low-density lipoprotein (LDL) receptor. Whether this holds true for Japanese patients, however, remains unresolved. The present study prospectively enrolled 226 Japanese patients with CHC, and investigated the impact of hepatic steatosis and its related SNPs, including rs8099917 of IL28B, rs738409 of PNPLA3, and rs14158 of LDL receptor, on outcomes of peg-interferon and ribavirin therapy. In multivariate logistic regression analysis, significant factors affecting the severity of hepatic steatosis were high body mass index and the minor alleles of IL28B SNP (p＝0.020 and 0.039, respectively). The risk alleles of PNPLA3 SNP also showed weak association (p＝0.059). Severe steatosis and the minor alleles of IL28B SNP were significantly associated with null or partial virological response in patients with HCV genotype 1, as were female gender, and low LDL cholesterol (p＝0.049, and ＜0.001, respectively). The SNP genotype of PNPLA3 and LDL receptor did not have a significant impact on therapeutic outcomes. With respect to the SNP sites examined, the SNP of PNPLA3 has a weak association with severe hepatic steatosis, but not with the outcome of interferon therapy. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0944-1174 47 4 2012 Risk factors for recurrence after transarterial chemoembolization for early-stage hepatocellular carcinoma 421 426 EN Hideaki Kinugasa Kazuhiro Nouso Yasuto Takeuchi Tetsuya Yasunaka Hideki Onishi Shin-ichiro Nakamura Hidenori Shiraha Kenji Kuwaki Hiroaki Hagihara Fusao Ikeda Yasuhiro Miyake Akinobu Takaki Kazuhide Yamamoto Radiofrequency ablation (RFA) is a standard therapy for the treatment of hepatocellular carcinoma (HCC) with 3 or fewer tumors of up to 3 cm (early-stage HCC); when RFA is unsuccessful or unfeasible, transcatheter arterial chemoembolization (TACE) has often been performed. However, little information about the outcome of TACE for early-stage HCC has been reported and it is hard to decide whether to perform additional treatment following TACE in these difficult conditions. The aim of this study was to determine the risk factors for local or intrahepatic distant recurrence after TACE in early-stage HCC. Among 1,560 newly diagnosed HCC patients who were admitted to Okayama University Hospital, 43 patients with early-stage HCC who received only TACE in at least one nodule were enrolled in this study. We analyzed the risk factors for local and distant recurrence by the Cox proportional hazard model. The local recurrence rates and intrahepatic distant recurrence rates at 3 months, 6 months, and 1 year were 18.6, 33.4, and 61.8%, and 2.8, 2.8, and 10.2%, respectively. Among 12 parameters examined as possible risk factors for recurrence, heterogeneous Lipiodol uptake (risk ratio 3.38; 95% confidence interval 1.14-10.60) and high serum des-gamma-carboxy prothrombin (DCP) (2.58; 1.03-7.14) were significantly correlated with local recurrence, and the presence of multiple tumors (10.64; 1.76-93.75) was significantly correlated with intrahepatic distant recurrence. Heterogeneous Lipiodol uptake, high serum DCP, and multiple tumors are risk factors for recurrence in patients with early-stage HCC who have undergone palliative TACE. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0815-9319 27 10 2012 Des-gamma-carboxyl prothrombin is associated with tumor angiogenesis in hepatocellular carcinoma 1602 1608 EN Minoru Matsubara Hidenori Shiraha Jyunro Kataoka Masaya Iwamuro Shigeru Horiguchi Shin-ichi Nishina Nobuyuki Takaoka Masayuki Uemura Akinobu Takaki Shinichiro Nakamura Yoshiyuki Kobayashi Kazuhiro Nouso Kazuhide Yamamoto Background and Aim: Hepatocellular carcinoma (HCC) is a hypervascular tumor, and angiogenesis plays an important role in its development. Previously, we demonstrated that des-gamma-carboxyl prothrombin (DCP) promotes both cell proliferation and migration of human umbilical vein endothelial cells (HUVECs) by inducing the autophosphorylation of kinase insert domain receptor (KDR). In the present study, DCP-associated tumor angiogenesis was assessed by comparing hypovascular and common hypervascular HCC. Methods: The solitary HCCs of 827 patients were classified into two groups according to the tumor density at the arterial phase of a dynamic computed tomography scan; the initial clinical data of patients with the hyper- and hypovascular types were compared. The HCC tissues from 95 tumors were analyzed by immunohistochemical staining for DCP and phosphorylated KDR, and intratumoral microvessel density (MVD) was analyzed to evaluate microvessel angiogenesis. Results: The serum DCP levels (320 +/- 3532 mAU/mL) and tumor size (18.4 +/- 9.0 mm) of patients with hypervascular HCC were significantly greater than those with hypovascular HCC (38.7 +/- 80 mAU/mL and 14.6 +/- 5.2 mm, P < 0.001). Immunohistochemical analysis revealed that the expressions of DCP and phospho-KDR were significantly greater in hypervascular HCC (71.4% and 31.0%, respectively) than in hypovascular HCC (7.6% and 5.7%, respectively). Intratumoral MVD was significantly correlated with DCP (r = 0.48, P < 0.0001). Conclusions: des-gamma-carboxyl prothrombin production is associated with tumor angiogenesis in HCC. No potential conflict of interest relevant to this article was reported.

Wiley-Blackwell Acta Medica Okayama 1386-6346 43 10 2013 Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma 1078 1092 EN Mamoru Nishimura Akinobu Takaki Naofumi Tamaki Takayuki Maruyama Hideki Onishi Sayo Kobayashi Kazuhiro Nouso Tetsuya Yasunaka Kazuko Koike Hiroaki Hagihara Kenji Kuwaki Shinichiro Nakamura Fusao Ikeda Yoshiaki Iwasaki Takaaki Tomofuji Manabu Morita Kazuhide Yamamoto Aim Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. Methods We recruited a study population of 208 patients, including healthy volunteers (HV; n = 15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Results Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. Conclusion HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. No potential conflict of interest relevant to this article was reported.

Karger Acta Medica Okayama 1424-3903 12 5 2012 Monitoring of CA19-9 and SPan-1 can facilitate the earlier confirmation of progressing pancreatic cancer during chemotherapy 409 416 EN Koichiro Tsutsumi Hirofumi Kawamoto Ken Hirao Ichiro Sakakihara Naoki Yamamoto Yasuhiro Noma Masakuni Fujii Hironari Kato Tsuneyoshi Ogawa Etsuji Ishida Kenji Kuwaki Kazuhiro Nouso Hiroyuki Okada Kazuhide Yamamoto Background: Measurement of objective response to chemotherapy using imaging modalities is sometimes difficult in pancreatic cancer (PC). We aimed to verify whether monitoring of serum tumor markers (TMs), namely carcinoembryonic antigen, CA19-9, DUPAN-2, SPan-1, can facilitate earlier confirmation of treatment failure. Methods: Monitoring of serum TMs and computed tomography were performed every 4 weeks until progression of disease in 90 patients with PC undergoing gemcitabine therapy. In Group A (January 2006 October 2007), we analyzed the fluctuation rates of TMs with high pretreatment positive rates, and defined the criteria of progressive disease under TM monitoring (TM-PD). In Group B (November 2007 October 2008), we calculated the time to progression (TTP) under this TM-PD criteria, which was compared with the UP under the RECIST criteria. Results: CA19-9 and SPan-1 had the highest pretreatment positive rates: 83% and 90%, respectively. In Group A (CA19-9, n = 38; SPan-1, n = 36), TM-PD criteria were defined as follows: fluctuation rates were >25% for a month or >= 10% for 2 consecutive months in CA19-9, and >= 10% for a month in SPan-1. In Group B (CA19-9, n = 18; SPan-1, n = 17), under these criteria, one-month earlier confirmation of treatment failure was feasible in 61% by CA19-9 and 59% by SPan-1. Furthermore, the combination could facilitate this determination in 72% (35/49), significantly better than CA19-9 alone (P = 0.004). Conclusion: Monitoring of serum CA19-9 and Span-1 is helpful for earlier confirmation of treatment failure during gemcitabine therapy in PC. No potential conflict of interest relevant to this article was reported.

Wiley-Blackwell Acta Medica Okayama 1386-6346 42 12 2012 Clinical utility of serum fucosylated hemopexin in Japanese patients with hepatocellular carcinoma 1187 1195 EN Sayo Kobayashi Kazuhiro Nouso Hideaki Kinugasa Yasuto Takeuchi Takeshi Tomoda Koji Miyahara Hiroaki Hagihara Kenji Kuwaki Hideki Onishi Shinichiro Nakamura Fusao Ikeda Yasuhiro Miyake Hidenori Shiraha Akinobu Takaki Kazuhide Yamamoto Aim: Hepatocellular carcinoma (HCC) is a common clinical problem all over the world. Fucosylated hemopexin (Fuc-Hpx) is a newly reported glycoprotein for the diagnosis of HCC, however, its clinical implications are unclear. The aim of this study was to elucidate the clinical utility of Fuc-Hpx in Japanese patients with HCC. Methods: The sera from 331 HCC patients, 45 with liver cirrhosis (LC), 85 with chronic hepatitis (CH) and 22 healthy people were examined for the expression of Fuc-Hpx; the level was compared with clinical parameters as well as hemopexin (Hpx) expression. The expressions of Fuc-Hpx in 12 HCC tissues and corresponding adjacent non-cancerous liver tissues were also examined. Results: No correlation was observed between Hpx and Fuc-Hpx level. The median Fuc-Hpx levels in healthy people and CH, LC and HCC patients were 3.8, 3.7, 6.1 and 7.6 AU/mL, respectively (CH vs LC, P = 0.002; CH vs HCC, P < 0.001; LC vs HCC, P = 0.02). Multivariate analysis revealed that low albumin, low prothrombin time and the presence of HCC were significantly correlated with high Fuc-Hpx (P = 0.013, =0.001 and <0.001, respectively). Among the HCC patients, albumin was correlated with high Fuc-Hpx; however, none of the tumor factors, such as tumor size, tumor number and tumor stage, was correlated with Fuc-Hpx level. The expression of Fuc-Hpx in cancer tissue was not different from that in non-cancerous tissue. Conclusion: Fuc-Hpx is a valuable biomarker for HCC but it might be a marker for hypercarcinogenic liver rather than a marker for tumor-bearing liver. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0020-7136 131 11 2012 Runt-related transcription factor 3 reverses epithelial-mesenchymal transition in hepatocellular carcinoma 2537 2546 EN Shigetomi Tanaka Hidenori Shiraha Yutaka Nakanishi Shin-Ichi Nishina Minoru Matsubara Shigeru Horiguchi Nobuyuki Takaoka Masaya Iwamuro Junro Kataoka Kenji Kuwaki Hiroaki Hagihara Junichi Toshimori Hideki Ohnishi Akinobu Takaki Shinichiro Nakamura Kazuhiro Nouso Takahito Yagi Kazuhide Yamamoto Loss or decreased expression of runt-related transcription factor 3 (RUNX3), a tumor suppressor gene involved in gastric and other cancers, has been frequently observed in hepatocellular carcinoma (HCC). The objective of this study was to identify the regulatory mechanism of the epithelialmesenchymal transition (EMT) by RUNX3 in HCC. Human HCC cell lines, Hep3B, Huh7, HLF and SK-Hep1, were divided into low- and high-EMT lines, based on their expression of TWIST1 and SNAI2, and were used in this in vitro study. Ectopic RUNX3 expression had an anti-EMT effect in low-EMT HCC cell lines characterized by increased E-cadherin expression and decreased N-cadherin and vimentin expression. RUNX3 expression has previously been reported to reduce jagged-1 (JAG1) expression; therefore, JAG1 ligand peptide was used to reinduce EMT in RUNX3-expressing low-EMT HCC cells. Immunohistochemical analyses were performed for RUNX3, E-cadherin, N-cadherin and TWIST1 in 33 human HCC tissues, also divided into low- and high-EMT HCC, based on TWIST1 expression. E-cadherin expression was correlated positively and N-cadherin expression was correlated negatively with RUNX3 expression in low-EMT HCC tissues. Correlations between EMT markers and RUNX3 mRNA expression were analyzed using Oncomine datasets. Similarly, mRNA expression of E-cadherin was also significantly correlated with that of RUNX3 in low-EMT HCC, while mRNA expression of JAG1 was negatively correlated with that of RUNX3. These results suggest a novel mechanism by which loss or decreased expression of RUNX3 induces EMT via induction of JAG1 expression in low-EMT HCC. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 0143-3334 14 7 1993 32P-Postlabeling analysis of IQ, MelQx and PhIP adducts formed in vitro in DNA and polynucleotides and found in vivo in hepatic DNA from IQ-, MelQx- and PhIP-treated monkeys 1389 1395 EN Elizabeth G. Snyderwine Cindy D. Davis Kazuhiro Nouso Peter P. RoIler Herman A.J. Schut The P-32-postlabeling method was used to examine the adducts in DNA, polynucleotides, and mononucleotides reacted in vitro with the N-hydroxy and N-acetoxy derivatives of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) or 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Adduct profiles were compared to those found in vivo in liver of cynomolgus monkeys fed IQ, MeIQx or PhIP. The N-acetoxy derivatives of IQ, MeIQx and PhIP (generated in situ from the corresponding N-hydroxylamine in the presence of acetic anhydride) each formed three principal adducts in DNA. Adduct 1 of IQ, MeIQx and PhIP was chromatographically identical to the P-32-labeled bis(phosphate) derivative of N-(deoxyguanosin-8-yl)-IQ, N-(deoxyguanosin-8-yl)-MeIQx, and N-(deoxyguanosin-8-yl)-PhIP respectively, and this adduct comprised approximately 65% of total adduct levels found in DNA in vitro. The C8-guanine adduct and the two minor adducts were also found in poly(dG-dC).poly(dG-dC), suggesting that the two minor adducts of IQ, MeIQx and PhIP are also formed on the guanine base. The N-acetoxy derivatives of IQ, MeIQx, and to a much lesser extent PhIP, also formed adducts with adenine-containing polynucleotides including poly(dA), poly(dA).poly(dT) and poly(dA-dT).poly(dA-dT), but these adenine adducts were chromatographically different from those found in DNA. The three guanine adducts of N-acetoxy-IQ, -MeIQx and -PhIP found in vitro in DNA and in guanine-containing polynucleotides were also found in the liver of monkeys fed IQ, MeIQx or PhIP respectively, indicating that metabolic activation via N-hydroxylation and esterification occurred in vivo in monkeys. With each compound, the C8-guanine adduct was the predominant adduct found in vivo. The results indicate similarities among IQ, MeIQx and PhIP in the DNA adducts formed in vitro and in vivo and substantiate the use of the P-32-postlabeling method for comparative adduct studies. No potential conflict of interest relevant to this article was reported.

Cases Network Ltd. Acta Medica Okayama 2 2009 A case of hepatocellular carcinoma with skin injury of the upper abdominal wall after transcatheter arterial chemoembolization: a case report EN Hiromitsu Kanzaki Kazuhiro Nouso Koji Miyahara Naoko Kajikawa Sayo Kobayashi Ichiro Sakakihara Shota Iwadow Shuji Uematsu Ryoichi Okamoto Kunihiro Shiraga Motowo Mizuno Yasuyuki Araki Introduction Transcatheter arterial chemoembolization has been widely used to treat advanced hepatocellular carcinoma that cannot be treated by local ablation therapies or surgical resection. The effectiveness of transcatheter arterial chemoembolization in prolonging survival has been well established, and approximately one third of newly discovered hepatocellular carcinoma patients were repeatedly treated by transcatheter arterial chemoembolization in Japan. Various kinds of complications have been reported, and many of which are general complications such as hepatic coma, jaundice, fever-up, ascites, and bile duct injury. The hepatic falciform artery is found frequently during postmortem anatomic dissection and the incidence of hepatic falciform artery is reported to be over 60%. Hepatic falciform artery is known to be the responsible artery for supraumbilical skin rash development after arterial chemo infusion therapy; however, skin complications after transcatheter arterial chemoembolization are rare. Case presentation A 70-year-old female with chronic hepatitis C infection was diagnosed as having hepatocellular carcinoma (S4, 20 mm in diameter). Transcatheter arterial chemoembolization was performed via the left hepatic artery, which was a feeding artery of the hepatocellular carcinoma. Two days after that, supraumbilical skin rash with local tenderness and redness appeared. Retrospective analysis revealed that occlusion of the hepatic falciform artery branching from the left hepatic artery with micromaterials caused the skin lesion. Conclusion We should keep in mind that anticancer drugs or embolic materials can flow into the HFA and may cause abdominal wall injury after transcatheter arterial chemoembolization. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1007-9327 16 12 2010 Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: Our case series and literature review 1436 1441 EN Yoshitaka Takuma Kazuhiro Nouso Recently, nonalcoholic steatohepatitis (NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma (HCC). The natural history and prognosis of NASH are controversial. Accordingly, we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC. We experienced 11 patients with NASH-associated HCC (6 male, 5 female; mean age 73.8 +/- 4.9 years) who received curative treatments. Most (91%) patients had been diagnosed with obesity, diabetes, hypertension, or dyslipidemia. Seven patients (64%) also had a non-cirrhotic liver. The recurrence-free survival rates at 1, 3 and 5 years were 72%, 60%, and 60%. We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature (64 male; mean age 66 years). The majority of patients (68%) were obese, 66% of patients had diabetes, and 24% had dyslipidemia. Furthermore, 26% of the HCCs arose from the non-cirrhotic liver. In conclusion, patients with non-cirrhotic NASH may be a high-risk group for HCC, and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1471-2407 11 2011 Loss of runt-related transcription factor 3 expression leads hepatocellular carcinoma cells to escape apoptosis EN Yutaka Nakanishi Hidenori Shiraha Shin-ichi Nishina Shigetomi Tanaka Minoru Matsubara Shigeru Horiguchi Masaya Iwamuro Nobuyuki Takaoka Masayuki Uemura Kenji Kuwaki Hiroaki Hagihara Junichi Toshimori Hideki Ohnishi Akinobu Takaki Shinichiro Nakamura Yoshiyuki Kobayashi Kazuhiro Nouso Takahito Yagi Kazuhide Yamamoto Background: Runt-related transcription factor 3 (RUNX3) is known as a tumor suppressor gene for gastric cancer and other cancers, this gene may be involved in the development of hepatocellular carcinoma (HCC). Methods: RUNX3 expression was analyzed by immunoblot and immunohistochemistry in HCC cells and tissues, respectively. Hep3B cells, lacking endogenous RUNX3, were introduced with RUNX3 constructs. Cell proliferation was measured using the MTT assay and apoptosis was evaluated using DAPI staining. Apoptosis signaling was assessed by immunoblot analysis. Results: RUNX3 protein expression was frequently inactivated in the HCC cell lines (91%) and tissues (90%). RUNX3 expression inhibited 90 +/- 8% of cell growth at 72 h in serum starved Hep3B cells. Forty-eight hour serum starvation-induced apoptosis and the percentage of apoptotic cells reached 31 +/- 4% and 4 +/- 1% in RUNX3-expressing Hep3B and control cells, respectively. Apoptotic activity was increased by Bim expression and caspase-3 and caspase-9 activation. Conclusion: RUNX3 expression enhanced serum starvation-induced apoptosis in HCC cell lines. RUNX3 is deleted or weakly expressed in HCC, which leads to tumorigenesis by escaping apoptosis. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1471-2407 9 2009 Twist expression promotes migration and invasion in hepatocellular carcinoma EN Noriyuki Matsuo Hidenori Shiraha Tatsuya Fujikawa Nobuyuki Takaoka Naoki Ueda Shigetomi Tanaka Shinichi Nishina Yutaka Nakanishi Masayuki Uemura Akinobu Takaki Shinichiro Nakamura Yoshiyuki Kobayashi Kazuhiro Nouso Takahito Yagi Kazuhide Yamamoto Background: Twist, a transcription factor of the basic helix-loop-helix class, is reported to regulate cancer metastasis. It is known to induce epithelial-mesenchymal transition (EMT). In this study, we evaluated the expression of twist and its effect on cell migration in hepatocellular carcinoma (HCC). Methods: We examined twist expression using immunohistochemistry in 20 tissue samples of hepatocellular carcinoma, and assessed twist expression in HCC cell lines by RT-PCR and Western blot analysis. Ectopic twist expression was created by introducing a twist construct in the twist-negative HCC cell lines. Endogenous twist expression was blocked by twist siRNA in the twist-positive HCC cell lines. We studied EMT related markers, E-cadherin, Vimentin, and N-cadherin by Western blot analysis. Cell proliferation was measured by MTT assay, and cell migration was measured by in vitro wound healing assay. We used immunofluorescent vinculin staining to visualize focal adhesion. Results: We detected strong and intermediate twist expression in 7 of 20 tumor samples, and no significant twist expression was found in the tumor-free resection margins. In addition, we detected twist expression in HLE, HLF, and SK-Hep1 cells, but not in PLC/RPF/5, HepG2, and Huh7 cells. Ectopic twist-expressing cells demonstrated enhanced cell motility, but twist expression did not affect cell proliferation. Twist expression induced epithelial-mesenchymal transition together with related morphologic changes. Focal adhesion contact was reduced significantly in ectopic twist-expressing cells. Twist-siRNA-treated HLE, HLF, and SK-Hep1 cells demonstrated a reduction in cell migration by 50, 40 and 18%, respectively. Conclusion: Twist induces migratory effect on hepatocellular carcinoma by causing epithelial-mesenchymal transition. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 66 3 2012 Safety and Efficacy of Radiofrequency Ablation with Artificial Ascites for Hepatocellular Carcinoma 279 284 EN Mamoru Nishimura Kazuhiro Nouso Kazuya Kariyama Akiko Wakuta Masayuki Kishida Nozomu Wada Toshihiro Higashi Kazuhide Yamamoto Original Article 10.18926/AMO/48568 The artificial ascites technique is often used during radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) treatment because it prevents visceral damage and improves visualization by minimizing interference of the lungs and mesentery. This study determined the efficacy and safety of RFA using the artificial ascites technique in HCC patients. We examined 188 HCC patients who were treated by RFA and fulfilled the Milan criteria. Treatment outcomes (complete ablation rate, local recurrence rate, complication rate, liver function including total bilirubin level, alanine aminotransferase level, albumin level, and prothrombin time) were compared among patients divided into 3 groups based on the volume of artificial ascites injected:GroupⅠ (n＝86), no artificial ascites injected;GroupⅡ (n＝35), ＜1,000ml artificial ascites injected;and Group Ⅲ (n＝67), ＞1,000ml artificial ascites injected. No significant difference was observed in complete ablation or local recurrence rates among the 3 groups, or in the extent of liver function damage after RFA. Artificial ascites disappeared within 7 days; additional diuretics were needed only in 5 (all from Group Ⅲ) of 102 patients. No serious complications such as intestinal perforation or intraperitoneal bleeding were observed. Thus, we found that artificial ascites injection during RFA is effective and safe, and can be used to prevent major procedural complications. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 65 1 2011 Prognostic Model for Hepatocellular Carcinoma with Time-Dependent Factors 11 19 EN Kenji Kuwaki Kazuhiro Nouso Yoshiyuki Kobayashi Shinichiro Nakamura Yoichi M. Ito Shouta Iwadou Hiroaki Hagihara Tetsuya Yasunaka Junichi Toshimori Hirokazu Miyatake Kenji Miyoshi Hideki Onishi Yasuhiro Miyake Bon Shoji Akinobu Takaki Hidenori Shiraha Yoshiaki Iwasaki Haruhiko Kobashi Kazuhide Yamamoto Original Article 10.18926/AMO/43825 The purpose of this study was to build a prognostic model of hepatocellular carcinoma (HCC) using time-dependent covariates to re-evaluate the prognosis at any stage of the disease. The subjects were consecutive HCC patients who were treated at our institute between 1995 and 2007. We constructed time-fixed and time-dependent prognostic models with a training group (n＝336) and compared the prognostic abilities between conventional Cancer of the Liver Italian Program (CLIP) scores, Japan Integrated Staging (JIS) scores, an Okuda classification, and our prognostic models in the testing group (n＝227) with the c-index. The time-dependent prognostic model consisted of main tumor size, tumor number, portal vein invasion, distant metastasis, alpha-fetoprotein, des-gamma-carboxy prothrombin (DCP), bilirubin, and albumin and the weighted scores were set for each factor depending on the hazard ratio for the prognosis. The prognostic index was determined by summing the scores. The c-index values for the CLIP scores, JIS scores, Okuda classification, and our time-dependent model were 0.741, 0.727, 0.609, and 0.870, respectively. These results indicate that our time-dependent model can estimate the prognosis of HCC more precisely than traditional time-fixed models and can be used to re-predict the prognosis of HCC. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 122 3 2010 中四国における肝細胞癌ラジオ波焼灼療法の現状 215 217 EN Kazuhiro Nouso The state of radiofrequency ablation for the treatment of hepatocellular carcinoma in Japan's Chugoku-Shikoku district was assessed by a questionnaire completed by 18 participating hospitals. Inclusion criteria of the therapy and the methods of evaluating ablated areas were similar among the 18 hospitals. However, large differences were observed in some questionnaires, in matters such as ablation protocols. These factors may need to be standardized. No potential conflict of interest relevant to this article was reported.

BioMed Central Acta Medica Okayama 3 2004 Elevated levels of tissue inhibitor of metalloproteinases (TIMPS) in human hepatocellular carcinomas EN Eiji Matsumoto Harushige Nakatsuka Kazuhiｒo Nouso Shin-ichiro Nakamura Mayumi Suzuki Yoshiyuki Kobayashi Masayuki Uemura Syuichiro Sato Ei-ichiro Sato Junko Yokoyama Sou Tsuboi Hironori Tanaka Yoshitake Takuma Tatsuya Fujikawa Yasushi Shiratori No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 55 6 2001 Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. 349 355 EN Yasuhiro Yoshida Toshihiro Higashi Kazuhiro Nouso Harushige Nakatsukasa Shin-ichiro Nakamura Akiharu Watanabe Takao Tsuji Article 10.18926/AMO/32003 Hepatic encephalopathy is one of the major complications in decompensated liver cirrhosis. The current study was conducted to clarify the mechanisms of zinc deficiency in liver cirrhosis and its involvement in hepatic encephalopathy via ammonia metabolism. Ten patients each with compensated or decompensated liver cirrhosis and 11 healthy volunteers were enrolled in the study. Serum zinc levels and its daily urinary excretion were measured, an oral zinc-tolerance test was performed to examine zinc malabsorption, and the effects of diuretics on zinc excretion and of zinc supplementation on ammonia metabolism in the skeletal muscle were studied. The mean serum zinc levels in patients with decompensated liver cirrhosis were found to be significantly lower than the levels in controls and patients with compensated liver cirrhosis. The serum zinc levels were inversely correlated with blood ammonia in the fasting state. In the oral zinc-tolerance test, the percent increase in serum zinc levels 120 and 180 min after ingestion was less in cirrhotic patients than in controls. A diuretic administration resulted in a significant reduction in serum zinc levels. An increased uptake of ammonia by and an increased release of glutamine from leg skeletal muscle after oral supplementation of zinc sulfate were evident. Taken together, zinc deficiency in decompensated cirrhotic patients appears to be due to low absorption and to high urinary excretion, for which excessive diuretic administration is, in part, responsible, and zinc supplementation might play an important role in the prevention of hepatic encephalopathy by activating glutamine synthetase. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 56 3 2002 Hepatitis C virus quasispecies in cancerous and noncancerous hepatic lesions: the core protein-encoding region. 141 147 EN Shahjalal S. Alam Takashi Nakamura Atsushi Naganuma Akito Nozaki Kazuhiro Nouso Hiroyuki Shimomura Nobuyuki Kato Article 10.18926/AMO/31716 We have shown that highly proofreading DNA polymerase is required for the polymerase chain reaction in the genetic analysis of hepatitis C virus (HCV). To clarify the status of HCV quasispecies in hepatic tissue using proofreading DNA polymerase, we performed a genetic analysis of the HCV core protein-encoding region in cancerous and noncancerous lesions derived from 4 patients with hepatocellular carcinoma. In contrast to the previously published data, we observed neither deletions nor stop codons in the analyzed region and no significant difference in the complexity of HCV quasispecies between cancerous and noncancerous lesions. This result suggests that the HCV core gene is never structurally defective in hepatic tissues, including cancerous lesions. However, in 3 of the patients, the consensus HCV species differed between cancerous and noncancerous lesions, suggesting that the predominant replicating HCV species differs between these 2 types of lesions. Moreover, during the course of the study, we obtained several interesting variants possessing a substitution at codon 9 of the core gene, whose substitution has been shown to induce the production of the F protein synthesized by a - 2/+1 ribosomal frameshift. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 47 6 1993 Recombinant mouse cytochromes P1-450 and P3-450: enzymatic characterization of the hemoprotein expressed in human cells infected with recombinant vaccinia virus. 377 382 EN Kazuhiro Nouso Narayama Battula Snorri S Thorgeirsson Toshihiro Higashi Takao Tsuji Article 10.18926/AMO/31563 We expressed mouse cytochrome P1-450 and P3-450 using recombinant vaccinia virus gene expression system in HeLa cells that were devoid of significant basal levels of P-450. HeLa cells were infected with the recombinant vaccinia virus containing either mouse cytochrome P1-450 or P3-450 cDNA, and the cell lysates were analyzed for the kinetics of P-450 enzyme activity and protein expression at the same time. 7-Ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase activities were measured as an expression of the cytochrome P-450 enzyme activities. Both cell lines began to express these enzyme activities as early as 12h after infection. The activities increased linearly up to the 24 h time point, and were kept for 36 h. Western immunoblot analysis showed that these cytochrome P-450 proteins were detected at 16 h and reached maximum quantity at 24 h after infection. These data showed a good correlation between cytochrome P-450 enzyme activity and protein concentration throughout the process of P-450 gene expression by vaccinia virus vector, suggesting a complete formation of cytochrome P-450 holoenzyme from the early stage of the protein expression. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 42 3 1988 Ultrasonographic characteristics of small hepatocellular carcinoma. 151 157 EN Toshihiro Higashi Kazuo Tobe Ken-ichiro Asano Hiroshi Ikeda Toshiya Ohsawa Yoshiaki Iwasaki Kazuhiro Nouso Noriyuki Shinji Yohichi Morimoto Yasumasa Satoh Masaharu Andoh Yasuyuki Araki Osamu Tomita Hirofumi Morishita Keiji Kita Takahiro Tsuchiya Shigeru Morichika Takahiro Tanabe Hideo Nagashima Takao Tsuji Article 10.18926/AMO/31032 The ultrasonographic characteristics of hepatocellular carcinomas (HCC) were investigated. Four typical features of HCCs, "mosaic internal echo pattern", "halo", "lateral shadow" and "posterior echo enhancement", were not recognized in minute HCCs smaller than 2 cm in diameter. These characteristics developed as the tumors grew. Only hypoechoic space-occupying lesions can be considered as small HCCs. In differentiating small HCCs from hypoechoic non-malignant space-occupying lesions in the cirrhotic liver, the ratios of short to long dimensions of the lesions seemed to be important since the ratios of HCCs were significantly larger than those of non-malignant lesions. The fact that 3 hyperechoic small HCCs could not be diagnosed even by celiac arteriography has suggested to us that ultrasonically guided biopsies should be performed in order to differentiate from small hemangiomas. Serum alpha-fetoprotein (AFP) levels of 1/3 of the patients with HCCs were below 100 ng/ml, indicating that it is impossible to detect small HCCs only by measuring serum AFP. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 50 5 1996 Usefulness of indocyanine green injection during ultrasound-guided liver biopsy for the diagnosis of small hepatocellular carcinoma. 255 259 EN Yoshihiro Kimura Toshihiro Higashi Naoaki Kuwahara Kazuhiro Nouso Shouhei Ohguchi Naoki Hino Masato Tanimizu Harushige Nakatsukasa Kazuo Tobe Takao Tsuji Article 10.18926/AMO/30498 To diagnose hepatocellular carcinoma (HCC) functionally and immediately, we examined the usefulness of indocyanine green (ICG) injection during ultrasound-guided liver biopsy. Liver specimens were obtained after intravenous ICG injection by ultrasound-guided biopsy from 251 space-occupying lesions (SOL) in 136 patients. The tissues were immediately examined for ICG uptake using an infrared Vidicon camera and were also subjected to histopathological examinations. Of the 112 ICG-negative biopsy specimens, 105 were histologically diagnosed as HCC, 6 as dysplastic nodules (DN) and 1 as a regenerative nodule (RN). Of the 139 ICG-positive specimens, 18 were diagnosed as HCC, 1 as DN and 120 as RN. The sensitivity of the absence of ICG uptake (SEAIU), the specificity of the absence of ICG uptake (SPAIU), and the positive predictive value of the absence of ICG uptake (PPAIU) for the diagnosis of HCC were 85.3%, 94.5% and 93.8%, respectively. Of the 251 SOLs, 184 were less than 2 cm. SEAIU, SPAIU and PPAIU for the diagnosis of these small HCC were 85.3%, 94.5% and 91.4%, respectively. These results support the reliability of ICG injection during ultrasound-guided liver biopsy to diagnose even small HCC. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 50 6 1996 Cathepsin B in the Growth of Colorectal Cancer: Increased Activity of Cathepsin B in Human Colorectal Cancer 305 311 EN Yasumasa Satoh Toshihiro Higashi Kazuhiro Nouso Tetsuya Shiota Nobuyuki Kinugasa Keigo Yoshida Shuji Uematsu Harushige Nakatsukasa Yukio Nishimura Takao Tsuji Article 10.18926/AMO/30482 Cathepsin B, a thiol protease, is involved in cancer metastasis. To clarify the role of cathepsin B in tumor progression in human colorectal cancer, the relationship between its activity, immunohistochemical staining, and clinical tumor progression was investigated. Cathepsin B activity in adenocarcinomas was significantly elevated compared with that in the tumor-bearing tissue. Furthermore, the tumor/tumor-bearing tissue (T/Tb) ratio of the activity was significantly higher than that of colorectal adenoma. Immunohistochemical studies demonstrated intense staining in the cancerous tissue. With respect to the clinical stage of tumors, the activity tended to be higher in tumors that had invaded the serosa or subserosa than in those that invaded the proper muscle. The results suggest that cathepsin B participates in the progression of human colorectal cancer, and its increased expression is a sensitive marker of the differentiation between colorectal adenoma and adenocarcinoma. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 50 6 1996 Cathepsin B in the Growth of Colorectal Cancer: Suppressive Effect of Leupeptin on the Growth of DMH-Induced Rat Colon Neoplasm 305 311 EN Yasumasa Satoh Toshihiro Higashi Kazuhiro Nouso Tetsuya Shiota Nobuyuki Kinugasa Keigo Yoshida Shuji Uematsu Harushige Nakatsukasa Yukio Nishimura Takao Tsuji Article 10.18926/AMO/30480 Cathepsin B, a thiol protease, has been reported to be involved in cancer progression and metastasis. The suppressive effects of two kinds of protease inhibitors, leupeptin and dietary camostate (FOY-305), on tumorigenesis and progression in 1, 2-dimethylhydrazine (DMH)-induced rat colon neoplasm were examined in relation to tissue cathepsin B activity. Male Donryu rats were treated with leupeptin or FOY-305 during or after the administration of DMH. There were no significant differences in average tumor numbers among all DMH-treated groups. However, the percentage of small tumors was significantly higher in the group in which leupeptin was supplied during DMH administration. This trend was not recognized in the FOY-305-treated groups. The ratio of cathepsin B activity in the tumors to that in the tumor-bearing tissue (T/Tb) was significantly increased with increasing tumor size (P = 0.009). The cathepsin B activity levels in the tumor-bearing mucosa in the groups which received leupeptin or FOY-305 following DMH treatment were both significantly lower than that in the group which received neither protease inhibitor (P = 0.046 and P = 0.0067, respectively). The results obtained indicate that leupeptin may have suppressed tumor growth by lowering the tissue cathepsin B activity. No potential conflict of interest relevant to this article was reported.

Okayama University Medical School Acta Medica Okayama 0386-300X 49 1 1995 Immunohistochemical studies of PIVKA-II in hepatocellular carcinoma by indirect immunofluorescence 19 24 EN Naoaki Kuwahara Toshihiro Higashi Kazuhiro Nouso Toshio Ito Takao Tsuji Article 10.18926/AMO/30416 Tissue PIVKA-II was examined in 32 hepatocellular carcinomas and 2 metastatic liver tumors using indirect immunofluorescence, and the results were compared with the size, histological grading and serum PIVKA-II level. The specificity of this method was confirmed by the disappearance of reactivity in PLC/PRF/5 cells after the addition of vitamin K to the culture medium. Positive PIVKA-II staining was observed as a clustered or a single cell pattern only in the HCC nodules, but not in the surrounding cirrhotic tissue. PIVKA-II staining was observed in all HCC groups regardless of histological grade. There was no relationship between PIVKA-II staining and the size of HCC. PIVKA-II was detected immunohistochemically even in small HCC of patients whose plasma PIVKA-II levels were below the detection limit. These results suggest that PIVKA-II production is a specific phenotype of HCC regardless of its histological grading and demonstrate that this immunofluorescent PIVKA-II staining is more sensitive and useful than plasma PIVKA-II assay for the diagnosis of HCC. No potential conflict of interest relevant to this article was reported.

BioMed Central Acta Medica Okayama 1471-2407 5 2005 Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation EN Tadashi Hanafusa Toshiyuki Shinji Hidenori Shiraha Kazuhiro Nouso Yoshiaki Iwasaki Eichiro Yumoto Toshiro Ono Norio Koide Background: Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulinlike growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered. Methods: In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity. Results: Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated. Conclusion: From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 121 1 2009 肝癌診療ガイドライン 41 45 EN Yoshiyuki Kobayashi Shinichiro Nakamura Hideki Ohnishi Junichi Toshimori Kenji Kuwaki Hiroaki Hagihara Yasuhiro Miyake Hidenori Shiraha Kazuhiro Nouso Takahito Yagi Noriaki Tanaka Kazuhide Yamamoto No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 113 2 2001 多発性肝嚢胞の1例 159 164 EN Yutaka Nakanishi Kohsaku Sakaguchi Yoshiaki Iwasaki Kazuhiro Nouso Hiroyuki Shimomura Hiroaki Matsuda Takahito Yagi Noriaki Tanaka Takao Tsuji A 45-year-old female was admitted to our hospital with sever abdominal fullness, and was diagnosed as polycystic liver disease with ultrasonography, abdominal CT and abdominal angiography. Almost all part of the right lobe of the liver was replaced with a lot of cysts. The liver obviously swelled up. We thought her symptom came from oppression of the digestive tract by the liver. Liver function is good. Right lobe resection, deroofing and fenestration were performed, and after operation the volume of the liver was reduced and the symptom got better. We report a case of polycystic liver disease improved with surgical therapy, adding some study with reference. No potential conflict of interest relevant to this article was reported.

岡山医学会 Acta Medica Okayama 0030-1558 113 3 2001 肝細胞癌の超音波ガイド下ラジオ波焼灼療法による治療 289 294 EN Kazuhiro Nouso Yoshiyuki Kobayashi Shinichiro Nakamura Eiichiro Yumoto Takahiro Suzuki Tomomi Hakoda Yoshitaka Takuma Hironori Tanaka Eiji Matsumoto Hideaki Taniguchi Tatsuya Fujikawa Mayumi Suzuki Akio Moriya Kousaku Sakaguchi Takao Tsuji Hapatocellular carcinoma (HCC) is one of the most prevalent malignancies in Japan. Percutaneous ethanol injection therapy (PEIT) of microwave coagulation therapy (MCT) have been used to treat small HCC. These two methods are effective methods to treat HCC; however, they have weak points. A period of admission is long to treat patients with PEIT because it requires several sessions to kill HCC completely. The risk of complications of MCT is high because the needle is thick, although it can coagulate HCC completely in one session. Radio frequecy ablation (RFA) is a new method to treat HCC. RFA compensates these weak points and is thought to become a main modality to treat HCC. In this paper, we demonstrated two patients with HCC who were treated with RFA. The effect of the treatment was examined with helical computed tomography and contrast harmonic power doppler, and the results were satisfactory. We also mentioned the merits and demerits of RAF in Discussion. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 1993 Recombinant Mouse Cytochromes P1-450 and P3-450: Enzymatic Characterization of the Hemoprotein Expressed in Human Cells Infected with Recombinant Vaccinia Virus EN No potential conflict of interest relevant to this article was reported.