Publications by authors named "Shunji Watanabe"

26 Publications

  • Page 1 of 1

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

Hepatol Res 2022 Aug 3. Epub 2022 Aug 3.

Division of Interventional Radiology, Shizuoka Cancer Center, Sunto-Gun, Japan.

Aim: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation.

Methods: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019).

Results: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111).

Conclusion: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.
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http://dx.doi.org/10.1111/hepr.13818DOI Listing
August 2022

Utility of FibroScan-based scoring systems to narrow the risk group of nonalcoholic fatty liver disease with comorbidities.

World J Gastrointest Pathophysiol 2022 May;13(3):96-106

Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan.

Background: Vibration-controlled transient elastography (VCTE) is proposed as a second step of examination to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) after triaging by the fibrosis-4 (FIB-4) index. Recently, VCTE-based scoring systems, including FibroScan-AST (FAST), Agile 3+, and Agile 4, emerged to determine the status of NAFLD. However, the significance of these scoring systems remains unknown in narrowing the high-risk group of NAFLD patients with comorbidities, including hepatocellular carcinoma (HCC) and esophagogastric varices (EGV).

Aim: To clarify the significance of VCTE-based scoring systems to narrow the high-risk group of NAFLD patients with comorbidities.

Methods: We performed a cross-sectional study to investigate the usefulness of VCTE-based scoring systems and other fibrosis markers to narrow the high-risk group of patients with NAFLD. FIB-4 index was used for the first triage. Risk groups of FAST, Agile 3+, and Agile 4 were stratified according to the published data. Among the 191 patients with NAFLD, there were 26 (14%) and 25 patients (13%) with HCC and EGV, respectively.

Results: When 1.3 was used as a cutoff value, the FIB-4 index narrowed the risk group to 120 patients, in which all patients with HCC and/or EGV were included. High risk group of Agile 3+ could subsequently narrow the risk group. The prevalence of HCC and EGV at this step were 33% (26/80) and 31% (25/80), respectively. In further narrowing of EGV, Agile 4 aggregated the patients with EGV into 43 patients, of whom 23 (53%) had EGV. FAST failed to narrow the risk group of patients with comorbidities. When 2.6 was used as a cutoff value of the FIB-4 index, three patients with HCC and two patients with EGV were missed at the first triage.

Conclusion: Agile 3+ and Agile 4 are useful to narrow the NAFLD patient group, in which patients may have HCC and/or EGV.
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http://dx.doi.org/10.4291/wjgp.v13.i3.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9157683PMC
May 2022

Evolution of Survival Impact of Molecular Target Agents in Patients with Advanced Hepatocellular Carcinoma.

Liver Cancer 2022 Jan 6;11(1):48-60. Epub 2021 Dec 6.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet.

Approach And Results: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, = 267; period 2: 2013-2016, = 352; period 3: 2017-2019, = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively ( = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC.

Conclusions: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.
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http://dx.doi.org/10.1159/000519868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8820147PMC
January 2022

Conventional Therapies Do Not Prolong the Prognosis of Hepatocellular Carcinoma Patients with Extrahepatic Metastases under Receiving of Tyrosine Kinase Inhibitors.

Cancers (Basel) 2022 Jan 31;14(3). Epub 2022 Jan 31.

Department of Medicine, Division of Gastroenterology, Jichi Medical University, 3311-1 Yakushiji Shimotsuke, Tochigi 329-0498, Japan.

Background: Conventional therapies, including chemoembolization and radiation therapy, have been expected to prolong the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases, which remains poor. However, little information is available on the efficacy of conventional therapies for such patients under tyrosine kinase inhibitor (TKI) treatment.

Methods: We retrospectively investigated 127 HCC patients with extrahepatic metastases, who were divided into the non-TKI (conventional therapies) and TKI groups and further subdivided into the TKI alone and TKI plus conventional therapies groups. Conventional therapies included transcatheter arterial chemoembolization, cisplatin-based chemotherapy, radiation, surgery, and UFT, an oral chemotherapeutic agent.

Results: The median of the overall survival (OS) of the 127 patients with extrahepatic metastases was 7.0 months. Meanwhile, the median OS of the TKI and non-TKI groups was 12.1 and 4.1 months, respectively. Imitating TKI after diagnosing metastases promoted a favorable increase in OS. Among the TKI group, the median OS in the TKI alone group was 8.9 months. TKI plus conventional therapies promoted no improvement in OS after adjusting for the patients' background data.

Conclusion: TKI promoted a better OS in HCC patients with extrahepatic metastases compared to conventional therapies. However, TKI plus conventional therapies promoted no improvement in the prognosis of such patients.
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http://dx.doi.org/10.3390/cancers14030752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8833467PMC
January 2022

Hepatitis C virus eradication prolongs overall survival in hepatocellular carcinoma patients receiving molecular-targeted agents.

J Gastroenterol 2022 02 15;57(2):90-98. Epub 2022 Jan 15.

Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan.

Background: The aim of this multicenter retrospective study was to evaluate the impact of the eradication of hepatitis C virus (HCV) on the clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with molecular-targeted agents (MTAs).

Methods: Among 877 patients who received any MTA as first-line systemic therapy for HCC between June 2009 and March 2019, 569 patients with HCV-related HCC were enrolled in this retrospective study. Of these, 109 patients achieved sustained virological response (SVR) before starting MTA. After propensity score matching, the clinical outcomes of 109 patients in the SVR group and 109 patients in the non-SVR group were compared.

Results: The median time to progression in the SVR group (7.8 months) was similar to that in the non-SVR group (5.6 months) (p = 0.212). The median time to treatment failure in the SVR group (5.3 months) was longer than that in the non-SVR group (2.8 months) (p = 0.059), and post-progression survival and overall survival in the SVR group were significantly longer than those in the non-SVR group (12.0 months vs 7.2 months; p = 0.039, and 18.1 months vs 11.3 months; p = 0.019). At the end of first-line MTA therapy, the albumin-bilirubin (ALBI) score in the SVR group ( - 2.25) was significantly lower than that in the non-SVR group ( - 2.10) (p = 0.008).

Conclusions: The eradication of HCV before MTA therapy maintained liver function and led to a prolonged treatment period and improved overall survival of HCV-related HCC patients. We should not overlook the benefits of HCV eradication in HCC patients.
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http://dx.doi.org/10.1007/s00535-021-01837-5DOI Listing
February 2022

Successful control of portal hypertension-related complications after two embolization procedures for multiple and large spontaneous portosystemic shunts in a patient with liver cirrhosis.

Clin J Gastroenterol 2021 Aug 16;14(4):1227-1232. Epub 2021 May 16.

Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan.

Liver cirrhosis is frequently complicated by spontaneous portosystemic shunt (SPSS) due to portal hypertension. Shunt embolization is considered when symptoms related to SPSSs are refractory to endoscopic and/or medical therapies. However, little information is available on the treatment of patients with multiple and large SPSS. We report a successfully managed case in which patient with such SPSS received two embolization procedures within 6 months. A 57-year-old man with alcoholic liver cirrhosis was transferred to our hospital due to a ruptured gastric varix. CT examination showed gastrorenal and splenorenal shunts of 8 mm and 11 mm in diameter, respectively. In addition, multiple hepatocellular carcinomas (HCCs) were noted. First, balloon-occluded retrograde transvenous obliteration (BRTO) was performed for the gastrorenal shunt, resulting in the disappearance of the varix, followed by transcatheter arterial chemoembolization (TACE) for HCCs. However, the hepatic encephalopathy worsened after the BRTO and TACE, and the splenorenal shunt enlarged to 18 mm in diameter. Although the shunt was tortuous and had another drainage vein, we completed the embolization for the shunt using metallic coils without any events. The patient's hepatic encephalopathy and hepatic function were ameliorated after embolization for the splenorenal shunt, and the patient was free from hepatic encephalopathy.
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http://dx.doi.org/10.1007/s12328-021-01441-3DOI Listing
August 2021

Oxidized High-Density Lipoprotein Shows a Stepwise Increase as Fibrosis Progresses in Patients with Nonalcoholic Fatty Liver Disease.

Antioxidants (Basel) 2021 Feb 4;10(2). Epub 2021 Feb 4.

Center for Community Medicine, Division of Community and Family Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.

Patients with nonalcoholic fatty liver disease (NAFLD) show dyslipidemia and a high risk for coronary heart disease (CHD). However, conventional atherosclerotic lipids are found at low levels in NAFLD patients with advanced fibrosis, in whom the risk for CHD is extremely high. The aim of the present study was to evaluate the levels of oxidized high-density lipoprotein (oxHDL), an emerging atherosclerotic biomarker, in patients with NAFLD. A total of 32 non-NAFLD subjects and 106 patients with NAFLD were enrolled. The fibrosis grades were stratified using non-invasive methods, including the Fibrosis-4 index and NAFLD fibrosis score. Total cholesterol and low-density lipoprotein (LDL)-cholesterol levels were significantly low in patients with advanced liver fibrosis. In contrast, oxHDL levels were high in NAFLD patients and showed a stepwise increase as fibrosis progressed. These oxHDL levels were independent of the HDL cholesterol levels, and statin use did not influence the oxHDL levels. Obese patients showed no increase in oxHDL levels, whereas patients with a low handgrip strength showed high oxHDL levels in NAFLD with advanced fibrosis. In conclusion, oxHDL is a potential biomarker for assessing the status of patients with NAFLD, including CHD and metabolic/nutritional disturbance, and particular cases with advanced liver fibrosis.
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http://dx.doi.org/10.3390/antiox10020239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914565PMC
February 2021

Lusutrombopag is effective and safe in patients with chronic liver disease and severe thrombocytopenia: a multicenter retrospective study.

BMC Gastroenterol 2020 Dec 14;20(1):427. Epub 2020 Dec 14.

Department of Medicine, Division of Gastroenterology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, 329-0498, Japan.

Background: Chronic liver disease (CLD) is often complicated by severe thrombocytopenia (platelet count < 50,000/µL). Platelet transfusion has been a gold standard for increasing the platelet count to prevent hemorrhagic events in such patients. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count in such patients when invasive procedures are scheduled. Former studies on lusutrombopag included patients with a platelet count of > 50,000/µL at baseline: the proportions of patients who did not require platelet transfusion were 84-96%, which might be overestimated.

Methods: The efficacy and safety of lusutrombopag were retrospectively investigated in CLD patients with platelet count of < 50,000/µL, a criterion for platelet transfusion, in real-world settings. We examined the proportion of patients who did not require platelet transfusion in 31 CLD patients, which exceeded a minimum required sample size (21 patients) calculated by 80% power at a significance level of 5%. Lusutrombopag, 3 mg once daily, was administered 8-18 days before scheduled invasive procedures.

Results: Among 31 patients who received lusutrombopag, 23 patients (74.2%) patients showed a platelet count of ≥ 50,000/µL (Group A) and did not require platelet transfusion. The remaining 8 patients (25.8%) did not reached platelet ≥ 50,000/µL (Group B). The means of platelet increase were 38,000/µL and 12,000/µL in groups A and B, respectively. A low platelet count at baseline was a characteristic of patients in group B. Among 13 patients who repeatedly used lusutrombopag, lusutrombopag significantly increased the platelet count as the initial treatment. When all repeated uses of lusutrombopag were counted among these 13 patients, platelet transfusion was not required in 82.1% (23/28) of treatments. Although one patient showed portal thrombosis after lusutrombopag treatment, the thrombosis was disappeared by anticoagulant treatment for 35 days. The degree of platelet increase with lusutrombopag was larger than that in their previous platelet transfusion.

Conclusions: The proportion of patients who did not require platelet transfusion was 74.2%, which is smaller than that in former studies which included CLD patients with a platelet count of > 50,000/µL. However, lusutrombopag is effective and safe for CLD patients with a platelet count of < 50,000/µL.
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http://dx.doi.org/10.1186/s12876-020-01573-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737263PMC
December 2020

Efficacy and safety of glecaprevir and pibrentasvir combination therapy in old-aged patients with chronic hepatitis C virus infection.

J Rural Med 2020 Oct 1;15(4):139-145. Epub 2020 Oct 1.

Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan.

Combination therapy with glecaprevir and pibrentasvir (G/P) has been shown to provide a sustained virologic response (SVR) rate of >97% in patients with chronic hepatitis C virus (HCV) infection in the first published real-world Japanese data. However, a recently published study showed that the treatment was often discontinued in patients ≥75 years old, resulting in low SVR in intention-to-treat (ITT) analysis. Thus, our aim was to evaluate real-world data for G/P therapy in patients ≥75 years of age, the population density of which is high in "rural" regions. We conducted a multicenter study to assess the efficacy and safety of G/P therapy for chronic HCV infection, in the North Kanto area in Japan. Of the 308 patients enrolled, 294 (95.5%) completed the treatment according to the protocol. In ITT and per-protocol analyses, the overall SVR12 rate was 97.1% and 99.7%, respectively. The old-aged patients group consisted of 59 participants, 56 of whom (94.9%) completed the scheduled protocol. Although old-aged patients tended to have non-SVR factors such as liver cirrhosis, history of HCC, and prior DAA therapies, the SVR12 rates in old-aged patients were 98.3% and 100% in the ITT and PP analyses, respectively. Of 308 patients enrolled, adverse events were observed in 74 patients (24.0%), with grade ≥3 events in 8 patients (2.6%). There was no significant difference in any grade and grade ≥3 adverse events between the old-aged group and the rest of the study participants. Only one patient discontinued the treatment because of adverse events. G/P therapy is effective and safe for old-aged patients.
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http://dx.doi.org/10.2185/jrm.2020-004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530586PMC
October 2020

Real-world efficacy and safety of 12-week sofosbuvir/velpatasvir treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus infection.

Hepatol Res 2021 Jan 20;51(1):51-61. Epub 2020 Oct 20.

Department of Medicine, Division of Gastroenterology, Jichi Medical University, Shimotsuke, Japan.

Aim: This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection.

Methods: A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function.

Results: All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P < 0.01); however, the serum bilirubin level and encephalopathy did not improve. Among patients who achieved SVR12, 75.0% showed an improvement in their CP score, while 5.9% showed a worsening. The presence of large portosystemic shunt (diameter ≥6 mm) and hyperbilirubinemia (≥2.0 mg/dL) were independent factors that interfered with the improvement in the CP score (P < 0.05). The most common AEs were encephalopathy (15.3%) and skin symptoms (7.9%). Two patients discontinued SOF/VEL due to AEs.

Conclusions: Treatment with SOF/VEL for 12 weeks was relatively safe and effective for patients with decompensated cirrhosis. An SVR provided an improvement of the liver function in the majority of patients. However, large portosystemic shunt and hyperbilirubinemia were independent factors that interfered with the improvement in the CP score.
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http://dx.doi.org/10.1111/hepr.13576DOI Listing
January 2021

Clinical and virologic features of hepatitis E virus infection at a university hospital in Japan between 2000 and 2019.

J Med Virol 2020 Jul 1. Epub 2020 Jul 1.

Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan.

The clinical and virologic features of hepatitis E virus (HEV) infection seem to vary among regions even in developed countries. However, we have little information on the diversity of HEV infection. Here, we investigated the characteristics of 26 patients in our hospital located in Tochigi prefecture, 90 km north of Tokyo, between 2000 and 2019. The reported number of patients with acute hepatitis E is increasing in Japan because measurement of IgA-class anti-HEV antibody was commercially available from 2011. In contrast, the numbers at our hospital were 1.5/y and 1.0/y in 2000 to 2011 and 2012 to 2019, respectively. This is attributed to the fact that we have been investigating HEV as a cause of unknown hepatitis before 2011. Among isolated HEV subgenotypes, including 3a, 3b, 4b, 4c, and 4d, all three patients with subgenotype 4c infection presented acute liver failure. Four HEV strains shared more than or equal to 99% identity within the 412-nucleotide partial sequence, in which the time and place of HEV infection varied, except for one intrafamilial infection. In addition, some strains were similar to HEV strains isolated far from Tochigi prefecture. In conclusion, the number of patients with acute hepatitis E was not increasing at Jichi Medical University Hospital and some strains were found to circulate in Japan.
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http://dx.doi.org/10.1002/jmv.26248DOI Listing
July 2020

Successful treatment of hepatocellular carcinoma by laparoscopic radiofrequency ablation in a patient with hemophilia A.

Clin J Gastroenterol 2020 Oct 26;13(5):907-913. Epub 2020 May 26.

Department of Biochemistry, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Percutaneous radiofrequency ablation (RFA) is a good indication for hepatocellular carcinoma (HCC) in cases involving ≦ 3 tumors of ≦ 30 mm in size, many hepatologists are hesitant to perform the procedure for patients with hemorrhagic disorders. We herein report the successful treatment of HCC by laparoscopic RFA in a patient with hemophilia A. A 48-year-old man with moderate form of hemophilia A had a single HCC at segment 8. To perform laparoscopic RFA safely, recombinant factor VIII (rFVIII) was administered to maintain factor VIII activity (FVIII:C) > 80% on the operation day and > 40% for 6 days after the operation in accordance with the guidelines. A total of 23,000 units of rFVIII was used. Laparoscopic RFA was completed with an operation time of 105 min and < 10 mL of blood loss. As a result, blood transfusion was not required. At 2 years after the initial treatment, HCC recurred at segment 7. Under rFVIII supplementation, we performed a second laparoscopic RFA without any events. Although partial hepatectomy is the main procedure used to treat HCC in patients with hemophilia, we could reduce in total use of rFVIII, blood and operation time by laparoscopic RFA compared with those in partial hepatectomy.
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http://dx.doi.org/10.1007/s12328-020-01133-4DOI Listing
October 2020

Acute Liver Failure Caused by the Transmission of Hepatitis B Virus from the Spouse after 38 Years of Marriage.

Intern Med 2019 Oct 27;58(20):2963-2968. Epub 2019 Jun 27.

Division of Gastroenterology, Department of Medicine, Jichi Medical University, Japan.

A 65-year-old man presented with acute liver failure and grade IV coma caused by hepatitis B virus (HBV) infection in 2017. The patient died on day 12 from the disease onset. The HBV isolated from the patient was genotype/subgenotype B/B1 and had multiple genomic mutations. The patient's wife was hepatitis B surface antigen (HBsAg)-positive when she delivered her first daughter in 1979. The HBV isolates of the patient and the wife shared 100% similarity over the entire genome. Because the patient's HBsAg value had been negative one year earlier, we considered the source of HBV transmission to be his wife.
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http://dx.doi.org/10.2169/internalmedicine.3028-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859391PMC
October 2019

Usefulness of Gd-EOB-DTPA-enhanced MRI for evaluating the potential for early development of hepatocellular carcinoma after HCV eradication by direct-acting antiviral treatment.

J Rural Med 2019 May 30;14(1):78-86. Epub 2019 May 30.

Department of Medicine, Division of Gastroenterology, Jichi Medical University, Japan.

The development of hepatocellular carcinoma (HCC) is not uncommon in patients who achieve eradication of the hepatitis C virus through direct-acting antiviral (DAA) treatment. The aim of this study was to identify the patients at high risk for novel HCC development after a sustained virologic response (SVR) by DAA treatment. A total of 518 patients with no history of HCC treatment and who achieved SVR by DAA treatment were evaluated retrospectively. The correlations between HCC development and the patients' characteristics were evaluated. For patients who underwent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) or dynamic contrast-enhanced computed tomography, the relationship between the imaging findings and subsequent HCC development was also assessed. HCC developed newly in 22 patients, and the 1-year and 3-year cumulative HCC rates were 2.0% and 8.5%, respectively. In multivariate analysis, a FIB-4 index >4.0 and a post-treatment α-fetoprotein >4.0 ng/ml were significant risk factors for HCC. In 26 of 118 patients who underwent an MRI before DAA treatment, a non-hypervascular hypo-intense nodule was seen in the hepatobiliary phase, and in 6 of 182 patients who underwent a CT, a non-hypervascular hypo-enhanced nodule was seen in the delayed phase. The sensitivity and specificity of the MRI-positive findings for the subsequent development of HCC were 0.92 and 0.87, respectively, and those of the CT were 0.40 and 0.99, respectively. In multivariate analysis of patients who underwent an MRI, a non-hypervascular hypo-intense nodule was the only factor that was significantly related to HCC development (HR 32.4, p = 0.001). Gd-EOB-DTPA-enhanced MRI was found to be reliable for risk evaluation of subsequent HCC development in patients after SVR by DAA treatment. Patients with a non-hypervascular hypo-intense nodule need more careful observation for incident HCC.
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http://dx.doi.org/10.2185/jrm.2993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545425PMC
May 2019

Full-genome characterization of the RIVM-HAV16-090-like hepatitis A virus strains recovered from Japanese men who have sex with men, with sporadic acute hepatitis A.

Hepatol Res 2019 May 20;49(5):521-530. Epub 2019 Feb 20.

Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan.

Aim: The major transmission mode of hepatitis A virus (HAV) in Japan is the fecal-oral route by contaminated foods. In contrast, HAV infection is well documented as a sexually transmitted disease in Europe and North America. The present study was undertaken to determine the full-genome sequence of HAV and trace the transmission route of HAV in Japanese men who have sex with men (MSM).

Methods: In 2018, we encountered three Japanese MSM with acute hepatitis A co-infected with HIV for 4-12 years. Serum samples obtained from these patients were used for HAV full-genome analyses.

Results: Isolated HAV strains were segregated into subgenotype IA. The three HAV strains shared 100% identity within the 481-nucleotide partial sequence. The entire nucleotide sequence showed that the three strains were 99.97% similar to each other with only two nucleotide substitutions. At the amino acid level, the three strains differed from each other by only one or two amino acids. All three strains obtained in the present study were >99.6% identical to the 66 reported strains isolated from Taiwan and European countries during 2015-2017. In addition, these 66 strains include the RIVM-HAV16-090 (EuroPride) strain, which has been involved in HAV outbreaks among MSM worldwide.

Conclusions: We determined for the first time the full-genome sequence of HAV isolated from Japanese MSM with acute hepatitis A and found that the strains were identical to those from MSM worldwide. Thus, these HAV strains were imported to Japan from foreign countries through MSM.
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http://dx.doi.org/10.1111/hepr.13313DOI Listing
May 2019

The successful treatment of hepatocellular carcinoma arising from congenital hepatic fibrosis using radiofrequency ablation under laparoscopy.

Clin J Gastroenterol 2019 Jun 7;12(3):223-230. Epub 2019 Jan 7.

Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

Congenital hepatic fibrosis (CHF), a fibropolycystic disease, is characterized by bile duct malformation, periportal fibrosis, and renal polycystic disease. Although cholangiocellular carcinoma is the primary tumor arising from fibropolycystic diseases, hepatocellular carcinoma (HCC) is extremely rare. In addition, no algorism for determining the optimum HCC treatment has yet been available in cases of fibropolycystic disease due to variations in the background liver and renal conditions. We herein report a patient with HCC arising from CHF that was successfully treated using radiofrequency ablation (RFA) under laparoscopic assistance. A 37-year-old man with CHF was admitted to our hospital for treatment of HCC in 2014. Imaging revealed HCC located in hepatic segments II and VIII with diameters of 28 and 24 mm, respectively. There had been no histories of recurrent cholangitis or renal failure after when CHF was diagnosed in 2003. In addition, esophageal varices were well controlled. We achieved sufficient ablation using a bipolar ablation system without any complications. The post-operative course was uneventful, and the patient was free from HCC for 4 years. Thus, locoregional therapy, including RFA, is acceptable for the treatment of HCC arising from CHF when the background liver and kidney are preserved.
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http://dx.doi.org/10.1007/s12328-018-00932-0DOI Listing
June 2019

Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet.

Cancer Sci 2019 Feb 9;110(2):771-783. Epub 2019 Jan 9.

Division of Gastroenterology, Department of Medicine, School of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan.

Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH-related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (Pten ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in Pten mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of Pten mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in Pten mice on the HF diet. Tumor cells were highly proliferative with HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in Pten mice with hypercholesterolemia.
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http://dx.doi.org/10.1111/cas.13902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361611PMC
February 2019

No Regional Disparities in Sofosbuvir Plus Ribavirin Therapy for HCV Genotype 2 Infection in Tochigi Prefecture and Its Vicinity.

Intern Med 2019 Feb 17;58(4):477-485. Epub 2018 Oct 17.

Division of Gastroenterology, Department of Medicine, Jichi Medical University, Japan.

Objective Regional disparities were observed in the outcomes of interferon (IFN)-based therapy for chronic hepatitis C virus (HCV) infection in a Japanese nationwide study. However, whether or not these regional disparities are observed in the outcomes of direct-acting antiviral drugs, including sofosbuvir (SOF) plus ribavirin (RBV) therapy, remains unclear. Methods We conducted a multicenter study to assess the efficacy of SOF plus RBV therapy for HCV genotype 2 infection in Tochigi Prefecture and its vicinity, in which IFN-based therapy yielded a low sustained virologic response (SVR) rate. In addition, we divided Tochigi Prefecture into six regions to examine regional disparities in the SVR. Patients We enrolled patients with chronic HCV genotype 2 infection. Results Of the 583 patients enrolled, 569 (97.6%) completed the treatment, and 566 (97.1%) also complied with post-treatment follow-up for 12 weeks. The overall SVR12 rate was 96.1% by per protocol and 93.7% by intention-to-treat analyses. No marked differences were observed in the SVR12 between subjects ≥65 and <65 years of age. Although large gaps were observed in the characteristics of patients and accessibility to medical resources, there was no significant difference in the SVR12 rate among the six regions in Tochigi Prefecture. Conclusion SOF plus RBV therapy was effective for HCV genotype 2 infection in an area where IFN-based therapy had previously shown unsatisfactory results. In addition, no regional disparities in the SVR12 were observed in Tochigi Prefecture.
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http://dx.doi.org/10.2169/internalmedicine.1194-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421161PMC
February 2019

A successful treatment for hepatocellular carcinoma with Osler-Rendu-Weber disease using radiofrequency ablation under laparoscopy.

Clin J Gastroenterol 2018 Dec 16;11(6):501-506. Epub 2018 Jun 16.

Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

Hepatocellular carcinoma (HCC) can be difficult to diagnose and treat in patients with Osler-Rendu-Weber disease due to vascular malformation and regenerative nodular hyperplasia. In addition, percutaneous liver puncture should be avoided for the diagnosis and treatment as the procedure carries a high risk of bleeding. We herein report the successful treatment of HCC in a patient with Osler-Rendu-Weber disease using radiofrequency ablation (RFA) under laparoscopy. A 71-year-old man with Osler-Rendu-Weber disease was admitted to our hospital for the treatment of HCC. He also had chronic hepatitis C virus infection. The arterioportal shunts in the liver were detected by computed tomography (CT) and angiography. A tumor 20 mm in size was detected as a defected-lesion in the hepatic segment IV during the portal phase by CT. RFA under laparoscopy was performed for the curative treatment for HCC, with sufficient ablation obtained. Although the blood gushed out from the needle tract at the end of the procedure, complete hemostasis was achieved promptly using coagulation forceps. The post-operative course was favorable. Thus, laparoscopic RFA is a useful treatment modality for HCC in patients with Osler-Rendu-Weber disease, as a hemostasis device can be used with direct visualization.
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http://dx.doi.org/10.1007/s12328-018-0877-xDOI Listing
December 2018

A 79-year-old Woman with Acute Hepatitis B Caused by the Infection of Subgenotype D1 Hepatitis B Virus in Japan: A Case Study.

Intern Med 2018 Nov 6;57(21):3099-3104. Epub 2018 Jun 6.

Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan.

A 79-year-old Japanese woman was diagnosed with acute hepatitis B based on laboratory tests showing positivity for IgM-class antibody against hepatitis B virus (HBV) core and hepatitis B surface antigen (HBsAg) as well as elevated transaminases. A phylogenetic analysis revealed that the HBV strain obtained from the patient belonged to genotype D/subgenotype D1, similar to strains circulating in foreign countries but different from those in Japan. The clinical course was favorable. HBsAg became negative within 10 weeks after the onset. To our knowledge, this is the first report of acute hepatitis B caused by subgenotype D1 HBV in Japan.
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http://dx.doi.org/10.2169/internalmedicine.0977-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262716PMC
November 2018

Short-Term Results of Laparoscopic Radiofrequency Ablation Using a Multipolar System for Localized Hepatocellular Carcinoma.

Liver Cancer 2017 Feb 17;6(2):137-145. Epub 2016 Dec 17.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan.

Background And Aim: Multipolar radiofrequency ablation (RFA) is feasible for the treatment of hepatocellular carcinoma (HCC) for which a large ablative area is planned, and it imposes a light physical burden on patients. Multipolar RFA via the percutaneous approach is performed in the majority of cases, but the efficacy of multipolar RFA with a laparoscopic approach has rarely been studied. This study aimed to evaluate the efficacy and safety of multipolar laparoscopic RFA (LRA) for localized HCC over the short term.

Methods: From January 2014 to January 2016, 77 consecutive patients with 130 HCCs treated by multipolar LRA were assessed. One to three bipolar needle applicators were inserted under laparoscopic ultrasonography guidance, regardless of tumor location. We intended to achieve parallel insertions and no-touch ablation as much as possible.

Results: The median size of the main tumor was 22 mm (range, 10-42 mm). The median follow-up time was 13.6 months (range, 3.1-24.8 months). In all cases, a sufficient ablative area was obtained as planned, without thermal injury of adjacent organs. During the follow-up period, all patients were alive with no local tumor progression, while intrahepatic recurrence distant from the primary site occurred in 7 patients. The 2-year local tumor progression-free survival rate and overall cancer-free survival rate were 100 and 81.6%, respectively. There were no procedural major complications caused prolonging the hospitalization, and all patients were discharged without subjective symptoms 4-7 days after LRA.

Conclusions: Multipolar LRA was efficacious in the treatment of localized HCCs by safely achieving a good ablative area.
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http://dx.doi.org/10.1159/000450925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340218PMC
February 2017

A case of small hepatocellular carcinoma treated with laparoscopic multipolar radiofrequency ablation with a no-touch ablation procedure.

Clin J Gastroenterol 2014 Dec 9;7(6):510-5. Epub 2014 Oct 9.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi, 329-0498, Japan,

A 77-year-old man with hepatocellular carcinoma was admitted to our institution. Computed tomography revealed two nodules, one at the surface and one within the liver, ≤3 cm in diameter. We performed laparoscopic radiofrequency ablation using a bipolar system with a "no-touch ablation" procedure using multiple applicators for insertion, not into the tumor directly, but to the perimeter of the tumor. A sufficient ablated area was obtained regardless of tumor location. No operative complications were encountered and adequate therapeutic effect was achieved safely. Laparoscopic multipolar radiofrequency ablation is a feasible procedure for treating hepatocellular carcinoma.
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http://dx.doi.org/10.1007/s12328-014-0531-1DOI Listing
December 2014

Full genome analysis of Philippine indigenous subgenotype IA hepatitis A virus strains from Japanese patients with imported acute hepatitis A.

Hepatol Res 2014 Mar 29;44(3):270-279. Epub 2013 Apr 29.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan.

Aim: Hepatitis A virus (HAV) is the most common cause of infectious hepatitis worldwide. Although hepatitis A cases imported from South-East Asian countries, including the Philippines, have been reported in Japan, the molecular epidemiological data have been limited for these HAV-endemic countries.

Methods: The full-length genomic sequences of HAV isolates were determined and subjected to the phylogenetic analyses.

Results: The HAV isolates (HA12-0796 and HA12-0938) obtained from two Japanese patients who developed acute hepatitis A in July 2012, 1 month after traveling to the Philippines, where they consumed undercooked shellfish, differed by only one nucleotide (nt) over the entire genome. These HAV isolates of genotype IA were 99.1-99.5% identical within 228-237 nt to those recovered from river water in the Philippines, suggesting that the HA12-0796 and HA12-0938 isolates represent HAV circulating in the Philippines. HAV isolates belonging to one of the two IA sublineages (IA-2) which were implicated in some of the mini-epidemics in 2010 in Japan are hypothesized to be connected with the Philippines. In support of this speculation, the present IA isolates (HA12-0796 and HA12-0938) shared 98.8% identity over the entire genome with one IA-2 isolate (HAJIH-Fukuo10) recovered from a Japanese female who developed a domestic HAV infection during the mini-epidemics. In the phylogenetic tree constructed based on the entire genome, these three isolates (HA12-0796, HA12-0938 and HAJIH-Fukuo10) segregated into a cluster with a bootstrap value of 100%.

Conclusion: These results indicate that HAV isolates belonging to the IA-2 lineage might have been imported from the Philippines.
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http://dx.doi.org/10.1111/hepr.12124DOI Listing
March 2014

Vernet's syndrome caused by large mycotic aneurysm of the extracranial internal carotid artery after acute otitis media--case report.

Neurol Med Chir (Tokyo) 2010 Jan;50(1):45-8

Department of General Medicine, Ibaraki Prefectural Central Hospital, Kasama, Ibaraki, Japan.

An 85-year-old man presented with a rare large aneurysm of the extracranial internal carotid artery (ICA) due to acute otitis media manifesting as Vernet's syndrome 2 weeks after the diagnosis of right acute otitis media. Angiography of the right extracranial ICA demonstrated an irregularly shaped large aneurysm with partial thrombosis. The aneurysm was treated by proximal ICA occlusion using endovascular coils. The ICA mycotic aneurysm was triggered by acute otitis media, and induced Vernet's syndrome as a result of direct compression to the jugular foramen. Extracranial ICA aneurysms due to focal infection should be considered in the differential diagnosis of lower cranial nerve palsy, although the incidence is thought to be very low.
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http://dx.doi.org/10.2176/nmc.50.45DOI Listing
January 2010

Postfluorination of fluoride films for vacuum-ultraviolet lithography to improve their optical properties.

Appl Opt 2006 Mar;45(7):1380-5

First Research and Development Section, Advanced Technology Department, Core Technology Center, Nikon Corporation, 10-1 Asamizodai 1-chome, Sagamihara, Kanagawa 228-0828, Japan.

Transmittance of fluoride films prepared by various kinds of deposition methods is not sufficient for a vacuum-ultraviolet (VUV) stepper application. Moreover, moisture penetrates into fluoride films because of porous structures. Then the moisture reacts with the fluoride chemically, and the photoabsorption of the films increases with elapsed time. Postfluorination treatment, in which F-poor areas of fluoride films are sufficiently fluorinated and the film structures are modified to be denser, has been developed. The postfluorination treatment was performed at 0.1 MPa of diluted F2 gas in a special apparatus made of nickel. This treatment reduces photoabsorption of fluoride films and prevents photoabsorption from increasing again with elapsed time. In a long-time F2 laser irradiation test, the transmittance of as-deposited fluoride films remarkably degraded with irradiation. On the other hand, there is no tendency of transmittance degradation in the case of postfluorinated fluoride films. The postfluorination is able to improve the optical performance of fluoride films, promising the highest coating level for VUV lithography.
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http://dx.doi.org/10.1364/ao.45.001380DOI Listing
March 2006

[Cytomegalovirus infection in a patient after splenectomy].

Nihon Naika Gakkai Zasshi 2003 Nov;92(11):2253-4

Department of Internal Medicine, Ibaraki Central Hospital, Ibaraki.

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http://dx.doi.org/10.2169/naika.92.2253DOI Listing
November 2003
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