Publications by authors named "Eiichi Tomita"

74 Publications

[Non-surgical management using pancreatic duct drainage for a traumatic pancreatic injury with main pancreatic rupture: a case report].

Nihon Shokakibyo Gakkai Zasshi 2022 ;119(5):466-475

Department of Gastroenterology, Gifu Municipal Hospital.

After an abdominal injury, a woman in her 20s presented to our hospital with abdominal pain. Pancreatic trauma was discovered on computed tomography, along with a pancreatic duct injury and pancreatic juice leakage. Endoscopic retrograde pancreatography revealed a 10-mm rupture of the pancreatic body's main pancreatic duct (MPD) and intraperitoneal leakage of contrast enzyme from the MPD. The pancreatic injury was treated with the placement of a 5-Fr endoscopic nasopancreatic drainage tube in the ruptured distal side of the pancreatic duct;however, 3 months later, the MPD stenosis occurred. The MPD stenosis was improved using a 7-Fr pancreatic stent, and finally, placement of the pancreatic stent was not required for MPD drainage.
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http://dx.doi.org/10.11405/nisshoshi.119.466DOI Listing
May 2022

Combined Use of Calcium-channel Blockers With Ombitasvir/Paritaprevir/Ritonavir Exacerbates Peripheral Edema in Elderly Japanese Patients.

Anticancer Res 2022 04;42(4):2087-2093

Laboratory of Pharmaceutics, Department of Biomedical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan;

Background/aim: The antiviral agent ritonavir is a substrate for cytochrome P450 3A4 (CYP3A4); therefore, concomitant use of CYP3A4-metabolising drugs might cause adverse reactions to this drug. We investigated the plasma level of calcium channel blockers (CCBs) as CYP3A4 substrates and peripheral edema as a potential adverse drug reaction possibly caused by the anti-hepatitis C virus (HCV) regimen of ombitasvir/paritaprevir/ritonavir (OPR) and CCBs.

Patients And Methods: We enrolled Japanese patients prescribed OPR for HCV infection. Peripheral edema was graded according to the Common Terminology Criteria for Adverse Events ver. 4. Plasma samples were collected on days 0, 7, 14, 28, and 42 after antiviral treatment, at the trough level.

Results: Out of 52 patients, 64% experienced grade 1 or grade 2 peripheral edema, but not grade 3. Concomitant use of CCBs significantly increased the emergence of grade 2 edema (62%), compared with patients treated solely with OPR (48%). The use of OPR significantly increased the plasma concentration of amlodipine.

Conclusion: Peripheral edema in patients treated with OPR and CCBs, although tolerable, should be closely monitored.
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http://dx.doi.org/10.21873/anticanres.15690DOI Listing
April 2022

Clinical Outcomes in Biopsy-Proven Nonalcoholic Fatty Liver Disease Patients: A Multicenter Registry-based Cohort Study.

Clin Gastroenterol Hepatol 2022 Jan 17. Epub 2022 Jan 17.

Department of Clinical Pharmacology and Therapeutics, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage.

Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients.

Results: The median follow-up period was 4.6 years (range, 0.3-21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52-3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02-7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02-5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality.

Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.
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http://dx.doi.org/10.1016/j.cgh.2022.01.002DOI Listing
January 2022

Electrohydraulic lithotripsy under the mother-baby cholangioscope system using a colonoscope for large common bile duct stones in a patient with Roux-en-Y reconstruction.

VideoGIE 2021 Aug 26;6(8):358-361. Epub 2021 May 26.

Department of Gastroenterology, Gifu Municipal Hospital, Gifu, Japan.

Video 1After insertion of the cholangioscope into the common bile duct, electrohydraulic lithotripsy was performed. All common bile duct stones were shattered and successfully removed using a basket and balloon catheter.
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http://dx.doi.org/10.1016/j.vgie.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351126PMC
August 2021

Serum GP88 as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after direct-acting antiviral agents.

Ann Clin Biochem 2021 11 11;58(6):605-613. Epub 2021 Aug 11.

Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Toyoake, Japan.

Background: Progranulin (GP88) is an 88-kDa glycoprotein growth factor with important biological effects in tumorigenesis and tumour survival. We investigated the usefulness of measuring serum GP88 concentrations as a predictive biomarker for hepatocellular carcinoma in patients with viral hepatitis C after treatment with direct-acting antiviral agents.

Methods: We measured the serum GP88 concentrations by using a sandwich enzyme-linked immunoassay from 67 healthy control subjects and 29 patients (20 patients who did not develop hepatocellular carcinoma and 9 patients who developed hepatocellular carcinoma after treatment) with viral hepatitis C after treatment with asunaprevir and daclatasvir.

Results: The serum GP88 concentrations of patients with chronic hepatitis C prior to antiviral treatment were significantly higher than those of healthy control subjects. After antiviral treatment, the serum GP88 concentrations of patients who eventually developed hepatocellular carcinoma were significantly higher than those who did not develop hepatocellular carcinoma. The changes in the serum GP88 concentrations before and after treatment in patients who developed hepatocellular carcinoma were significantly lower than those in patients who did not develop hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma was significantly higher in either patients with high serum GP88 concentrations after treatment or those with small changes of serum GP88 concentrations pre- and post-treatment.

Conclusions: Sustained high concentrations of serum GP88 in patients treated with direct-acting antiviral agents are correlated with the risk of developing hepatocellular carcinoma.
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http://dx.doi.org/10.1177/00045632211036723DOI Listing
November 2021

Preoperative perihilar cholangiocarcinoma assessment using virtual endoscopic imaging magnetic resonance cholangioscopy.

Endosc Int Open 2021 Jul 21;9(7):E1158-E1163. Epub 2021 Jun 21.

First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan.

Preoperative assessment of the superficial ductal spread (SDS) of perihilar cholangiocarcinoma (PCCA) is important for determining its resectability. A virtual endoscopic imaging method, magnetic resonance cholangioscopy (MRCS), wherein a three-dimensional image is created from magnetic resonance imaging (MRI) data, can evaluate all aspects of arbitrary bile ducts. Overall, 15 patients with PCCA who underwent preoperative MRI were enrolled. All patients underwent surgical treatment. MRCS could be performed based on preoperative MRI data in all patients. MRCS could not be used in one patient due to debris in the obstructed bile duct. The remaining 14 patients (93 %) were diagnosed with obstructed bile duct or irregular surface of the bile duct, signifying tumor invasion. The accuracy rate of diagnosing the SDS was 93 % (14/15). Seven patients underwent preoperative peroral cholangioscopy; the scope could not pass through the tumor in three patients. In these three patients, MRCS was able to be use dtoevaluate the obstructed side of the bile duct and faciliated accurate diagnosis of SDS. MRCS can be used to noninvasively evaluate the bile duct in all directions. This novel method makes it easy to create virtual images and can be useful for diagnosing the preoperative SDS of PCCA.
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http://dx.doi.org/10.1055/a-1401-9962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218596PMC
July 2021

Surveillance of Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease.

Diagnostics (Basel) 2020 Aug 10;10(8). Epub 2020 Aug 10.

Japan Strategic Medical Administration Research Center (J-SMARC), Nagoya, Aichi 460-0011, Japan.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is sufficient epidemiological cohort data to recommend the surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommends that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) consider HCC surveillance. NITs include the fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US), which is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US, or if an US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, the lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and the protein induced by the absence of vitamin K or antagonist-II (PIVKA-II), can help identify a high risk of HCC in NAFLD patients. Innovative parameters, including a Mac-2 binding protein glycated isomer, type IV collagen 7S, free apoptosis inhibitor of the macrophage, and a combination of single nucleoside polymorphisms, are expected to be established. Considering the large size of the NAFLD population, optimal screening tests must meet several criteria, including high sensitivity, cost effectiveness, and availability.
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http://dx.doi.org/10.3390/diagnostics10080579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459689PMC
August 2020

Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Int J Mol Sci 2020 Jul 13;21(14). Epub 2020 Jul 13.

Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan.

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.
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http://dx.doi.org/10.3390/ijms21144939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404115PMC
July 2020

Evaluation of endoscopic reintervention for self-expandable metallic stent obstruction after stent-in-stent placement for malignant hilar biliary obstruction.

J Hepatobiliary Pancreat Sci 2019 Jun 11;26(6):211-218. Epub 2019 May 11.

First Department of Internal Medicine, Gifu University Hospital, Gifu, Japan.

Background: Bilateral self-expandable metallic stent (SEMS) placement is effective for long-term management of unresectable malignant hilar biliary obstruction (UMHBO). However, endoscopic reintervention (ERI) for bilateral SEMSs is not well-studied. This study aimed to evaluate ERI efficacy after stent-in-stent placement.

Methods: Data of 31 patients who underwent ERI from May 2000 to July 2018 were analyzed.

Results: The technical success rate was 80.7% (25/31) and no adverse events occurred. The functional success rate was 100% (25/25). In a multivariate logistic regression analysis, the angle between the bilateral SEMSs (ABBS) >104° (odds ratio 50.49, 95% CI 3.370-2131, P = 0.0039) and overgrowth (odds ratio 25.70, 95% CI 1.121-1234, P = 0.0423) were risk factors for ERI failure. Multiple liver metastases, which sometimes cause overgrowth, were also risk factors. After ERI, some patients underwent additional SEMS (n = 4), plastic stent (n = 14) placement, or internal cleaning of the initial SEMS alone (n = 7). There were no significant intergroup differences in the 50% time to recurrent biliary obstruction.

Conclusions: ABBS >104° and overgrowth were risk factors for ERI failure after stent-in-stent placement. In the decision-making process for initial SEMS placement for UMHBO, patient condition should be considered, including the angle between bilateral bile ducts and multiple liver metastases.
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http://dx.doi.org/10.1002/jhbp.626DOI Listing
June 2019

Potent viral suppression and improvements in alpha-fetoprotein and measures of fibrosis in Japanese patients receiving a daclatasvir/asunaprevir/beclabuvir fixed-dose combination for the treatment of HCV genotype-1 infection.

J Gastroenterol 2018 Sep 2;53(9):1089-1097. Epub 2018 Mar 2.

Toranomon Hospital, Tokyo, Japan.

Background: In the UNITY-3 study, 96% sustained virologic response (SVR12) rate was observed in Japanese patients with hepatitis C virus (HCV) genotype (GT)-1 infection treated for 12 weeks with fixed-dose daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO). As HCV clearance may improve liver outcomes, we assessed hepatic fibrosis and alpha-fetoprotein (AFP), a hepatocellular carcinoma risk marker, pre- and post-treatment in UNITY-3.

Methods: Treatment-naive or interferon-experienced UNITY-3 patients with HCV GT-1 who received twice-daily DCV-TRIO were assessed for fibrosis [FibroTest; FibroScan; fibrosis-4 index (FIB-4), aspartate-aminotransferase-to-platelet-ratio index] and AFP at baseline and Weeks 4 (FIB-4 only), 12 or 24 post-treatment.

Results: Of 217 patients, 99% had GT-1b infection, 46% were aged > 65 years, 21% had compensated cirrhosis, and 26% baseline HCV-RNA > 10 IU/mL. All GT-1b patients treated ≥ 4 weeks achieved SVR12 with (n = 54) or without (n = 144) baseline NS5A polymorphisms associated with DCV resistance (positions 28/30/31/93). Statistically significant post-treatment reductions from baseline were observed for all fibrosis measures and AFP, with numerically greater reductions in cirrhotic patients. FibroTest category improved in 44%, remained stable in 50%, and worsened in 6% of patients; 98% with baseline AFP < 6 μg/L remained < 6 μg/L and 51% with baseline AFP ≥ 6 μg/L were < 6 μg/L post-treatment.

Conclusions: DCV-TRIO administered for 12 weeks to Japanese patients with primarily GT-1b infection achieved a high SVR12 rate and resulted in improved measures of hepatic fibrosis and serum AFP that may reduce the risk of future liver disease progression and hepatocellular carcinoma, particularly in those with compensated cirrhosis.
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http://dx.doi.org/10.1007/s00535-018-1445-3DOI Listing
September 2018

Hepatitis E virus subtype 3f strains isolated from Japanese hepatitis patients with no history of travel to endemic areas - The origin analyzed by molecular evolution.

Virology 2018 01 24;513:146-152. Epub 2017 Oct 24.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498, Japan.

Hepatitis E virus subtype 3f (HEV-3f) strains are usually isolated in Europe and Thailand. Recently, HEV-3f strains were detected from six acute hepatitis E patients in Japan, none of whom had a history of travel to endemic areas. We inferred the origin and transmission route of the six HEV-3f strains. A time-scaled phylogenetic tree of the six strains with reference strains was constructed using a Bayesian statistical inference framework. The time-scaled tree indicated that the six strains independently derived from similar European strains between 2008 and 2014. The pattern suggested recent inflow of multiple HEV-3f strains from Europe to Japan. Japan imports a substantial amount of pork from European countries every year. The emergence of acute hepatitis cases caused by HEV-3f strains in Japan, in patients with no history of travel abroad, might be influenced by the increased opportunities to consume pork products imported from European countries.
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http://dx.doi.org/10.1016/j.virol.2017.08.008DOI Listing
January 2018

Hemostatic Radiotherapy Used Twice for Inoperable Progressive Gastric Cancer with Bleeding.

J Gastrointest Cancer 2019 Mar;50(1):151-155

Department of Radiation Oncology, Gifu University School of Medicine, 1-1, Yanagido, Gifu City, Gifu, 501-1194, Japan.

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http://dx.doi.org/10.1007/s12029-017-9994-xDOI Listing
March 2019

The advantage of iron-containing fiducial markers placed with a thin needle for radiotherapy of liver cancer in terms of visualization on MRI: an initial experience of Gold Anchor.

Radiol Case Rep 2017 Jun 12;12(2):416-421. Epub 2017 Apr 12.

Department of Hepatology, Gifu Municipal Hospital, Gifu City, Gifu, Japan.

Radiotherapy for liver malignancy is increasing due to advances in radiotherapy technique. Visualization of the tumor as well as fiducial markers is essential. To see if improved visibility exists on computed tomography (CT) and magnetic resonance imaging (MRI), we evaluated an iron-containing fiducial marker. A patient with hepatocellular carcinoma and a patient with cholangiocarcinoma were enrolled. Pain caused by placement of marker and the best MRI sequence for visualization of both the fiducial marker as well as the liver tumor on MRI was evaluated. CT was obtained in 2.5-mm thickness, and MRIs were obtained in eight sequences (ie, T2-weighted image). 22G preloaded needles were used for marker placement in both patients; this caused little pain during placement under local anesthesia with xylocaine. No complication occurred in either patient. Both markers and tumors were well visualized by the same MRI sequence. The iron-containing fiducial marker is safe and useful for detecting fiducial markers in the liver and for registration using CT and MRI.
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http://dx.doi.org/10.1016/j.radcr.2017.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417757PMC
June 2017

Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection.

Gastroenterology 2017 05 3;152(6):1383-1394. Epub 2017 Feb 3.

Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan.

Background & Aims: There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection.

Methods: We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls).

Results: We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene (TLL1) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT.

Conclusions: In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1, and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.
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http://dx.doi.org/10.1053/j.gastro.2017.01.041DOI Listing
May 2017

Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection.

J Gastroenterol 2017 Mar 9;52(3):385-395. Epub 2016 Aug 9.

Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, Japan.

Background: DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.

Methods: In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b).

Results: SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred.

Conclusion: SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.
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http://dx.doi.org/10.1007/s00535-016-1245-6DOI Listing
March 2017

Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1.

Sci Rep 2016 07 20;6:29920. Epub 2016 Jul 20.

Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.

Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites' levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.
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http://dx.doi.org/10.1038/srep29920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951771PMC
July 2016

Usefulness of early vascular phase images from contrast-enhanced ultrasonography using Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma.

Hepatol Res 2016 May 22;46(6):497-504. Epub 2015 Sep 22.

Laboratory Center, Gifu Municipal Hospital, Gifu, Japan.

Aim: This study aimed to evaluate the usefulness of early vascular phase images produced by contrast-enhanced ultrasonography (CE-US) with Sonazoid for the diagnosis of hypovascular hepatocellular carcinoma (HCC).

Methods: Four hundred and seventeen patients with 674 hepatic nodules were evaluated using CE-US with Sonazoid between January 2007 and March 2010. Retrospective analysis was conducted on 49 histologically confirmed nodules showing hypovascularity relative to the surrounding liver tissue in the early vascular phase and no enhancement defect in the Kupffer phase of CE-US with Sonazoid. These nodules were classified according to early vascular phase image enhancement patterns as types I (largest avascular; avascular as a whole), II (second avascular; partially avascular), III (smallest avascular; not avascular, but faintly hypovascular relative to the surrounding liver) and IV (hypovascular as a whole with vessel-like structures passing inside nodules).

Results: Among the 49 nodules, types I, II, III and IV were identified in 19 (38.8%), nine (18.4%), 15 (30.6%) and six (12.2%) cases, respectively. The proportion of tumorous nodules (well-differentiated HCC and high-grade dysplastic nodules) significantly decreased with a reduction of the avascular area (68.4% in the type I, 55.6% in the type II and 33.3% in the type III nodules; P < 0.05). All nodules demonstrating the type IV enhancement pattern were non-tumorous.

Conclusion: Based on the size of avascular area in the early vascular phase of CE-US with Sonazoid, we can predict the malignant potential of the nodules. CE-US with Sonazoid is very useful for evaluation of hypovascular hepatic nodules.
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http://dx.doi.org/10.1111/hepr.12580DOI Listing
May 2016

Investigating the origin and global dispersal history of hepatitis E virus genotype 4 using phylogeographical analysis.

Liver Int 2016 Jan 26;36(1):31-41. Epub 2015 Jun 26.

Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan.

Background & Aims: Hepatitis E virus (HEV) genotype 4 has mainly been isolated from sporadic hepatitis cases and swine in Asian countries. We analysed the origin and global dispersal history of genotype 4 using a Bayesian phylogeographical approach.

Methods: The 412-nucleotide sequences of open reading frame 2 of genotype 4 (47 Japanese, 40 Chinese, 1 Indian, 8 Indonesian, 1 Korean, 1 Taiwanese, 2 Danish and 2 Italian), of which sampling date and location were known, were collected. Evolutionary rate, divergence time, demographic growth and phylogeography were co-estimated in the Bayesian statistical inference framework implemented in the BEAST package to model spatial dispersal on a time-scaled genealogy.

Results: The most probable origin of genotype 4 was Japan and the time of origin was 1909 (95% highest posterior density, 1871-1940). Seven lineages of genotype 4 migrated from Japan to China. The analysis also showed the migration of genotype 4 from Japan or China to India and Indonesia and from China to Indonesia, Taiwan, Korea and a few European countries.

Conclusions: Swine trade between countries coincided with the migration time and direction of genotype 4 in some cases and was considered the primary cause of dispersal. However, there was no clear cause of dispersal for some cases, for which no records of pig trade were found. Future research should analyse additional nucleotide sequences paired with epidemiological data from various countries to improve our understanding of HEV dispersal.
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http://dx.doi.org/10.1111/liv.12880DOI Listing
January 2016

Impact of serum chemerin levels on liver functional reserves and platelet counts in patients with hepatocellular carcinoma.

Int J Mol Sci 2014 Jun 25;15(7):11294-306. Epub 2014 Jun 25.

Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.

Obesity-related metabolic abnormalities, including adipokine imbalance and chronic inflammation, are involved in liver carcinogenesis. Chemerin, a novel adipokine, plays a critical role in adipogenesis, energy metabolism, and inflammation. We evaluated the impact of serum chemerin levels on liver functional reserves in hepatocellular carcinoma (HCC) patients and on the recurrence and prognosis of HCC. This study included 44 patients with any stage of HCC who underwent curative treatment at Gifu Municipal Hospital (Gifu, Japan) between 2006 and 2007. Recurrence-free survival and overall survival were estimated using the Kaplan-Meier method. Serum albumin levels (Pearson's correlation coefficient; r = 0.3110, p = 0.0399), platelet counts (r = 0.4159, p = 0.0050), and prothrombin times (r = 0.3775, p = 0.0115) were significantly correlated with serum chemerin levels in patients with HCC, and they were inversely correlated with Child-Pugh scores (r = -0.3732, p = 0.0126), serum alanine aminotransferase levels (r = -0.3864, p = 0.0105), and total bilirubin levels (r = -0.4023, p = 0.0068). Among these variables, a multiple comparison test identified that platelet counts and total bilirubin levels were associated with serum chemerin levels (p < 0.0083). No significant correlation was found between serum chemerin levels and recurrence-free survival (p = 0.3691) or overall survival (p = 0.7916). In HCC patients, serum chemerin concentrations were correlated with liver functional reserves and platelet counts, but not with recurrence or prognosis.
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http://dx.doi.org/10.3390/ijms150711294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4139783PMC
June 2014

Efficacy and safety of cisplatin versus miriplatin in transcatheter arterial chemoembolization and transarterial infusion chemotherapy for hepatocellular carcinoma: A randomized controlled trial.

Hepatol Res 2015 May 24;45(5):514-22. Epub 2014 Jul 24.

Department of Gastroenterology and Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.

Aim: Transcatheter arterial chemoembolization (TACE) and transarterial infusion chemotherapy (TAI) are the main therapeutic strategies for treatment of advanced hepatocellular carcinoma (HCC). We conducted a randomized controlled trial to compare the efficacy and safety of cisplatin and miriplatin in TACE and TAI.

Methods: Patients with HCC of indication for TACE or TAI were randomly assigned to receive either cisplatin or miriplatin (49 patients per group) between April 2010 and May 2013. The primary end-point was the therapeutic effect (TE) 3 months after initial treatment, and the secondary end-point was overall survival.

Results: TE could be evaluated in 26 patients of the cisplatin group and 20 patients of the miriplatin group. In the cisplatin group, 11 (42.3%) and 15 (57.7%) patients were classified as showing TE3 + 4 and TE1 + 2, respectively, while in the miriplatin group, each number was nine (45.0%) and 11 (55.0%) (P = 0.8551). Furthermore, no significant difference in overall survival was found between two groups for all patients (P = 0.905) or those treated only with TAI (10 in the cisplatin group and eight in the miriplatin group; P = 0.695). TE3 + 4 group showed better overall survival than TE1 + 2 group (P = 0.0263). Grade 4 or higher adverse event did not occur in either group. Creatinine levels in the cisplatin group rose 3 days after TACE or TAI (P = 0.0397).

Conclusion: Cisplatin and miriplatin had equal efficacy for TACE and TAI, but cisplatin should be avoided for patients with renal dysfunction or inadequate hydration. Good TE improved overall survival.
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http://dx.doi.org/10.1111/hepr.12376DOI Listing
May 2015

Usefulness of contrast-enhanced ultrasonography using Sonazoid for the assessment of therapeutic response to percutaneous radiofrequency ablation for hepatocellular carcinoma.

Hepatol Res 2015 Apr 27;45(4):432-40. Epub 2014 Jun 27.

Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan.

Aim: Accurate assessment of the coagulated area is imperative to achieve an excellent outcome from percutaneous radiofrequency ablation (PRFA) for the treatment of hepatocellular carcinoma (HCC). We evaluated the efficacy of contrast-enhanced ultrasonography (CEUS) with the contrast-enhancing agent Sonazoid for precisely assessing the therapeutic effect of PRFA for HCC.

Methods: We enrolled 87 consecutive patients with solitary naïve HCC of less than 3 cm in diameter. PRFA treatment was performed with a 17-G cool-tip needle, and CEUS was performed to assess the ablative margin 3 h after the procedure, when the coagulated tumor outline was easiest to discern. The treatment was repeated until an ablative margin greater than 5 mm was confirmed. After CEUS assessment of the therapeutic response, the patients were followed to investigate local tumor recurrence.

Results: In 78 patients (89.7%), the outline of the coagulated tumors could be recognized by ultrasonography, and CEUS assessment of the ablative margin was successful. The remaining nine patients were assessed by computed tomography. The 5-year cumulative survival rate after the assessment of the treatment response with CEUS was 58.4%, and the 4-year cumulative total recurrence rate was 72.3%. The 5-year cumulative local tumor recurrence rate was very low (2.3%).

Conclusion: The assessment with CEUS at 3 h after the PRFA procedure was successful in the majority of the patients, and it yielded a very low rate of local recurrence.
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http://dx.doi.org/10.1111/hepr.12370DOI Listing
April 2015

Effects of pioglitazone on nonalcoholic steatohepatitis in a patient with anorexia nervosa: A case report.

Exp Ther Med 2014 Apr 28;7(4):811-815. Epub 2014 Jan 28.

Department of Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.

Diseases associated with metabolic syndromes are of major concern in developed countries. Nonalcoholic steatohepatitis (NASH) is one of the manifestations of metabolic syndrome in the liver. Previous studies have shown that NASH is also caused by malnutrition. In the present study, a case of malnutrition-associated NASH in a 66-year-old female with anorexia nervosa is reported. The patient had a body mass index (BMI) of only 11.1 kg/m and serum alanine aminotransferase levels of 1,495 IU/l. Steatohepatitis with fibrosis was confirmed by percutaneous liver needle biopsy. Total parenteral nutrition was conducted at first, followed by the administration of Stronger Neo-Minophagen C (a glycyrrhizin-containing preparation), ursodeoxycholic acid and prednisolone. The abnormal elevation of aminotransferase levels of the patient was prolonged and total bilirubin levels increased. Pioglitazone (15 mg/day), which has been identified to be effective for nonalcoholic steatohepatitis, was then administered. This resulted in marked reductions in aminotransferase and bilirubin levels within three months. Histological improvement of the liver was also confirmed by percutaneous liver needle biopsy after one year. The observations in the present case suggest that pioglitazone may be useful for the treatment of malnutrition-associated NASH.
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http://dx.doi.org/10.3892/etm.2014.1509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961108PMC
April 2014

[Clinical significance of the measurement of serum cytokeratin-18 in patients with non-alcoholic steatohepatitis].

Rinsho Byori 2013 Jan;61(1):19-24

Section of Clinical Laboratory, Gifu University Hospital, Gifu, Japan.

Epidemiologic data suggest that non-alcoholic fatty liver disease (NAFLD) have an increased tendency to occur in patients who are associated with metabolic conditions such as obesity, type 2 diabetes mellitus, and dyslipidemia. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, no-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end stage liver disease. However, currently the diagnosis of NASH requires an invasive liver biopsy. The aim of this study is to evaluate whether Cytokeratin 18 (CK-18) has potential non-invasive diagnostic capability for the NASH. Serum levels of alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, adiponectin, leptin, and CK-18 were measured in 27 patients (8 patients with simple fatty liver, 6 fatty liver with fibrosis patients, 13 patients with NASH) and 23 healthy controls. Regarding gender difference in the control group, although both adiponectin and leptin significantly increased in the female compared with the male (p < 0.002 and p < 0.01, respectively), there were no significant gender differences in CK-18. For the conventional liver function tests, there were no significant differences in 4 groups. Serum levels of adiponectin was significantly lower in patients with NASH compared with the control group(p < 0.001), and both leptin and CK-18 were markedly higher in patients with NASH compared with control group (p < 0.001). These results suggested that measurement of serum CK-18 is useful for assessing the NASH.
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January 2013

Hepatocellular carcinoma patients with increased oxidative stress levels are prone to recurrence after curative treatment: a prospective case series study using the d-ROM test.

J Cancer Res Clin Oncol 2013 May 15;139(5):845-52. Epub 2013 Feb 15.

Department of Gastroenterology, Gifu Municipal Hospital, Gifu, Japan.

Purpose: Oxidative stress plays an important role in liver carcinogenesis. To determine the impact of oxidative stress on the recurrence of stage I/II hepatocellular carcinoma (HCC) after curative treatment, we conducted a prospective case series analysis.

Methods: This study included 45 consecutive patients with stage I/II HCC, who underwent curative treatment by surgical resection or radiofrequency ablation at Gifu Municipal Hospital from 2006 to 2007. In these 45 cases, recurrence-free survival was estimated using the Kaplan-Meier method. The factors contributing to HCC recurrence, including the serum levels of derivatives of reactive oxygen metabolites (d-ROM) as an index of oxidative stress, were subjected to univariate and multivariate analyses using the Cox proportional hazards model.

Results: The serum levels of d-ROM (P = 0.0231), α-fetoprotein (AFP, P = 0.0274), and fasting plasma glucose (P = 0.0400) were significantly associated with HCC recurrence in the univariate analysis. Multivariate analysis showed that the serum levels of d-ROM (hazard ratio [HR] 1.0038, 95 % confidence interval [CI] 1.0002-1.0071, P = 0.0392) and AFP (HR 1.0002, 95 % CI 1.0000-1.0003, P = 0.0316) were independent predictors of HCC recurrence. Kaplan-Meier analysis showed that recurrence-free survival was low in patients with high serum d-ROM (≥570 Carr U, P = 0.0036) and serum AFP (≥40 ng/dL, P = 0.0185) levels.

Conclusions: The serum levels of d-ROM and AFP can be used for screening patients with a high risk for HCC recurrence. Patients who show increased levels of these factors require careful surveillance.
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http://dx.doi.org/10.1007/s00432-013-1389-1DOI Listing
May 2013

Combination of proton pump inhibitor and rebamipide, a free radical scavenger, promotes artificial ulcer healing after endoscopic submucosal dissection with dissection size >40 mm.

J Clin Biochem Nutr 2012 Nov 8;51(3):185-8. Epub 2012 Jun 8.

Department of Gastroenterology, Gifu University Hospital, Gifu 501-1194, Japan.

In our previous study, the healing effect of proton pump inhibitor plus rebamipide for endoscopic submucosal dissection-related artificial ulcer smaller than 40 mm showed statistical significance. However, such effect of the combination was not yet clear for ulcers with dissected diameter more than 40 mm. The aim of this present study was to resolve this problem under sufficient statistical power, with adequate sample size. We conducted a randomized controlled study. Either the proton pump inhibitor mono-therapy or the combination therapy was prescribed for 28 days after endoscopic submucosal dissection. Eighty-seven patients were eligible for outcome evaluation. Combination therapy was significantly superior to mono-therapy, 27.8% vs 0% reached healing stage (scar stage) in cases with ulcers of dissection diameter more than 40 mm. In conclusion, the combination therapy with rebamipide was favorable regimen in patients with larger artificial ulcer after endoscopic submucosal dissection.
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http://dx.doi.org/10.3164/jcbn.12-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3491242PMC
November 2012

Comparison of long-term outcomes after endoscopic sphincterotomy versus endoscopic papillary balloon dilation: a propensity score-based cohort analysis.

J Gastroenterol 2013 Sep 10;48(9):1090-6. Epub 2012 Nov 10.

First Department of Internal Medicine, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan.

Background: Endoscopic sphincterotomy (ES) is widely performed in patients with common bile duct stones (CBDS). However, the long-term outcomes of patients following ES have not been sufficiently elucidated. Impaired papillary function following ES may result in additional late complications. In contrast, endoscopic papillary balloon dilation (EPBD)-another option for treating CBDS-is expected to preserve papillary function. This study aimed to compare the long-term outcomes of patients with CBDS treated with ES to those treated with EPBD in a large cohort. In addition, a subgroup analysis was performed, according to gallbladder (GB) status.

Methods: A cohort study was performed using propensity score matching to reduce treatment selection bias. This involved the analysis of follow-up data for 1086 patients who underwent EPBD or ES for CBDS.

Results: Propensity score matching extracted 246 pairs of patients. The median (interquartile range) follow-up period after EPBD or ES was 93.5 (46.8-129.2) months and 90 (42-139.3) months, respectively. The incidence of CBDS recurrence after EPBD and ES were 8.5 and 15.0 %, respectively. The hazard ratio (95 % CI) was 0.577 (0.338-0.986) (P = 0.044). Based on the status of the GB, the incidence of CBDS recurrence was significantly different between post-EPBD and post-ES in the group with cholecystectomy after EPBD/ES (P = 0.013).

Conclusions: The incidence of biliary complications was significantly lower in patients after EPBD than in those after ES, and this outcome appeared most markedly in patients who also underwent cholecystectomy.
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http://dx.doi.org/10.1007/s00535-012-0707-8DOI Listing
September 2013
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