Publications by authors named "Mitsuhiko Moriyama"

178 Publications

Large-volume cell-free and concentrated ascites reinfusion therapy improves venous flow in patients with liver cirrhosis.

J Med Ultrason (2001) 2021 Apr 9. Epub 2021 Apr 9.

Ascites Treatment Center, Kanamecho Hospital, 1-11-13 Kanamecho, Toshima-ku, Tokyo, 171-0043, Japan.

Purpose: Hemodynamic change after total paracentesis was investigated because it might lead to various complications. Although cell-free and concentrated ascites reinfusion therapy (CART) is safer and more effective than total paracentesis in theory, hemodynamic change after CART has been never reported. And previous studies did not mention hemodynamics of the venous system.

Methods: We investigated the hemodynamic change, including that of the venous system, before and after CART using color Doppler ultrasonography and fast Fourier transform analysis. Twenty-eight patients with tensive cirrhotic ascites underwent ultrasonography the day before and after total volume CART. The diameter and velocity of the main, right, and left portal vein; inferior vena cava (IVC); and right renal vein were measured using ultrasonography.

Results: A total of 11.8 ± 4.4 L of ascites (range 3.6-20.9 L) was filtered and concentrated to 0.85 ± 0.40 L (range 0.36-1.50 L). The diameter of the IVC increased from median 13.5 ± 5.4 mm (range 4-25 mm) to 18.5 ± 4.1 mm (range 7-29 mm) (p = 0.007). The diameter of the right segmental renal vein significantly increased after KM-CART [from 5.0 ± 1.0 (4-8) mm to 7.0 ± 2.0 (3-10) mm] (p = 0.011). Hemodynamic change of the portal venous system was not significant. The time to the next CART in patients with an IVC diameter ≥ 20 mm and < 20 mm was 86 days and 20.5 days (p = 0.035), respectively.

Conclusion: Tensive ascites results in venous congestion in patients with cirrhotic ascites. CART improved venous flow, but it did not change the hemodynamics of the portal venous system.
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http://dx.doi.org/10.1007/s10396-021-01094-2DOI Listing
April 2021

Renal vein measurement using ultrasonography in patients with cirrhotic ascites and congestive heart failure.

J Med Ultrason (2001) 2021 Apr 25;48(2):225-234. Epub 2021 Mar 25.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan.

Purpose: Ascites can cause compression of the inferior vena cava (IVC), leading to increased renal venous pressure and renal congestion. Previously, the left renal vein diameter in liver cirrhosis patients with ascites was measured using computed tomography, showing that enlargement of the left renal vein diameter affects the prognosis. Herein, the diameter and flow velocity of the renal veins were measured using ultrasonography.

Methods: Abdominal ultrasonography was performed on 186 patients. The patients were divided into four groups: normal liver (n = 102), liver cirrhosis (LC) without ascites (n = 37), LC with ascites (n = 30), and congestive liver (n = 17). Ultrasonographic measurements for diameter and flow velocity of the IVC, left renal vein main trunk, and segmental renal vein were performed.

Results: The left renal vein diameter increased in the following order: normal liver, LC, LC with ascites, and congestive liver groups (P < 0.001). IVC flow velocity was lower and left renal vein diameter was larger in the congestive liver and LC with ascites groups. These results suggest that the two groups have different pathological conditions, but the mechanism of renal congestion is similar. In patients with LC, IVC compression due to ascites might cause blood stagnation and renal congestion.

Conclusion: The left renal vein and IVC can be measured using ultrasonography. It might help in furthering our understanding of the pathophysiology of renal congestion in these patients.
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http://dx.doi.org/10.1007/s10396-021-01088-0DOI Listing
April 2021

Magnetic resonance elastography-based prediction of hepatocellular carcinoma recurrence after curative resection.

Surgery 2021 Mar 19. Epub 2021 Mar 19.

Departments of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.

Background: Liver stiffness measurement using magnetic resonance elastography can assess the severity of liver fibrosis, which is significantly associated with recurrence after curative resection for hepatocellular carcinoma. The aim of this prospective study was to investigate whether preoperative liver stiffness measurement by magnetic resonance elastograhy can predict recurrence after curative resection for hepatocellular carcinoma.

Methods: Patients who underwent preoperative liver stiffness measurement and curative resection for hepatocellular carcinoma were enrolled in this study. Potential associations between liver stiffness measurement, along with other clinical and pathologic variables, and intrahepatic hepatocellular carcinoma recurrence were analyzed.

Results: In total, 156 patients were included in this study. During a median follow-up period of 25.1 months (range, 6.0-60.5 months), 72 (46.1%) patients with hepatocellular carcinoma had an intrahepatic recurrence. The median disease-free period after resection was 17.9 months (range, 1.0-60.5 months). In the multivariate analysis, liver stiffness measurement (hazard ratio, 1.27; 95% confidence interval, 1.11-1.43; P <.001) and vascular invasion (hazard ratio, 1.96; 95% confidence interval, 1.15-3.25; P = .013) were identified as independent predictors of recurrence. When the optimal cutoff point was set at 4.53 kPa using the minimal P value approach, the disease-free period after curative resection in 71 patients with a liver stiffness measurement value ≥4.53 kPa (11.3 months [range, 2.0-60.5 months]) was significantly shorter than that of 85 patients with a liver stiffness measurement value <4.53 kPa (22.5 months [range, 1.1-60.5 months]; P <.001).

Conclusion: Liver stiffness measurement using magnetic resonance elastography is a useful preoperative predictor of intrahepatic recurrence after curative resection for hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.surg.2021.02.027DOI Listing
March 2021

Predictive value of combined computed tomography volumetry and magnetic resonance elastography for major complications after liver resection.

Abdom Radiol (NY) 2021 Mar 8. Epub 2021 Mar 8.

Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan.

Purpose: To retrospectively compare the predictive value of computed tomography volumetry (CTV), magnetic resonance elastography (MRE) of the liver, and their combination for major complications after liver resection.

Methods: We enrolled 108 consecutive patients who underwent anatomical liver resection for liver tumors and preoperative contrast-enhanced CT and MRE. The future liver remnant (FLR) ratio was calculated by CTV, while the liver stiffness measurement (LSM) was obtained by MRE. FLR ratio alone, LSM alone, and combined FLR ratio and LSM were evaluated to predict major complications (Clavien-Dindo grade ≥ IIIa). Univariate and multivariate analyses of hepatic biochemical parameters and imaging data were performed to identify predictors of major complications. Receiver operating characteristic analyses of FLR ratio, LSM, and their combination were performed, and the sensitivity and specificity were calculated.

Results: Twenty-two (20.4%) of the 108 patients experienced major complications. According to multiple regression analysis, the FLR ratio (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.91-0.99, p = 0.040) and LSM (OR 1.72, 95% CI 1.01-2.94, p = 0.047) were independent predictors of major complications. The combined FLR ratio and LSM were predictive of major complications, with an area under the curve (AUC) of 0.818, sensitivity of 68.2%, and specificity of 84.9%. The AUC and specificity for combined FLR ratio and LSM were larger than those for FLR ratio (AUC: 0.711, specificity: 80.2%) and LSM (AUC: 0.793, specificity: 80.2%).

Conclusion: Combined CTV and MRE analysis can improve the AUC and specificity for predicting major complications after anatomical liver resection.
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http://dx.doi.org/10.1007/s00261-021-02991-3DOI Listing
March 2021

Male-Dominant Hepatitis A Outbreak Observed among Non-HIV-Infected Persons in the Northern Part of Tokyo, Japan.

Viruses 2021 01 29;13(2). Epub 2021 Jan 29.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi, Tokyo 173-8610, Japan.

Recently, we experienced an outbreak of acute hepatitis A virus (HAV) infection between 2018 and 2020. Herein, we describe this male-dominant HAV infection outbreak observed among non-human immunodeficiency virus (HIV)-infected persons in the northern part of Tokyo, Japan. Clinical information was collected from patient interviews and from medical record descriptions. In the present study, 21 patients were retrospectively analyzed. A total of 90.4 and 33.3% of patients were males, and men who have sex with men (MSM), respectively. The total bilirubin levels and platelet counts tended to be lower in the MSM group than in the non-MSM group. C-reactive protein (CRP) levels tended to be higher in acute liver failure (ALF) patients than in non-ALF patients. Prolonged cholestasis was observed in one patient (4.8%). We also found that 18 HAV isolates belonged to HAV subgenotype IA/subgroup 13 (S13), which clustered with the HAV isolate (KX151459) that was derived from an outbreak of HAV infection among MSM in Taiwan in 2015. Our results suggest that the application of antivirals against HAV, as well as HAV vaccines, would be useful for the treatment and prevention of severe HAV infection.
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http://dx.doi.org/10.3390/v13020207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910831PMC
January 2021

Japanese Man with HCV Genotype 4 Infection and Cirrhosis Who was Successfully Treated by the Combination of Glecaprevir and Pibrentasvir.

Intern Med 2021 Feb 1. Epub 2021 Feb 1.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Japan.

A 74-year-old man with a history of transfusion at 35 years old in Egypt was referred to our hospital. He was infected with hepatitis C virus (HCV) genotype 4 (GT4), which is a rare HCV GT in Japan, and was also diagnosed with hepatic compensated cirrhosis. We safely treated the patient for 12 weeks with the combination of glecaprevir and pibrentasvir, and a sustained virologic response (SVR) was achieved. This is the first report of HCV GT4 infection in a treatment-naïve Japanese patient with cirrhosis in whom SVR was achieved with the combination treatment of glecaprevir and pibrentasvir.
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http://dx.doi.org/10.2169/internalmedicine.6728-20DOI Listing
February 2021

Hepatocellular adenoma, approximately half and predominantly inflammatory subtype, in 38 Japanese patients with several differences in age, gender, and clinical background factors from Western populations.

Hepatol Res 2021 Mar 22;51(3):336-342. Epub 2021 Feb 22.

Tokyo Central Pathology Laboratory, Tokyo, Japan.

Aim: Hepatocellular adenoma (HCA) has a lower prevalence in Japan than in Western countries and HCA subtypes have been reported for only a few Japanese patients. We analyzed HCA subtype data 38 patients from 23 hospitals in Japan in order to examine character and difference between Western countries.

Methods: To confirm HCA and to analyze subtypes, we performed immunohistochemical examinations.

Results: Thirty-eight cases were found to have HCA without cirrhosis. The male/female ratio was 18/20. Ages ranged from 15 to 79 (average, 43.2) years. Male and elder patients are not rare, furthermore, most of elder patients are male. Glycogen storage disease, past history of medicament use, hepatitis B virus surface antigen-positivity, antihepatitis C virus -positivity, diabetes mellitus, obesity, lipid metabolism disorder and alcoholism were present in of 6, 8, 1, 1, 6, 6, 4, and 6 cases, respectively. As to HCA subtypes, HNF1alpha-inactivated HCA, beta-catenin activated HCA (b-HCA), inflammatory HCA (IHCA) and unclassified HCA (U-HCA) accounted for nine (23.7%), four (10.5%), 17 (44.7%) and eight (21.1%) cases, respectively. Two cases showed coexistence of HCA and hepatocellular carcinoma (HCC) at surgery, and another had HCC which had been detected 23 years after HCA diagnosis. The HCA subtype of one of the former cases was U-HCA, while the remaining two had b-HCA and U-HCA.

Conclusions: In Japanese HCA cases, the proportions of U-HCA, male and elder cases were slightly higher than in Western countries, and most of elder patients were male. IHCA was however common regardless of race, and was assumed to be the predominant subtype of HCA.
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http://dx.doi.org/10.1111/hepr.13613DOI Listing
March 2021

[Use of EUS-FNA in the diagnosis of hilar schwannoma:a case report].

Nihon Shokakibyo Gakkai Zasshi 2020 ;117(11):1008-1017

Division of Oncologic Pathology, Department of Pathology and Microbiology, Nihon University School of Medicine.

Upon abdominal ultrasonography, a woman in her 36 years old was diagnosed with a hypoechoic tumor with a diameter of 60mm surrounding the bile duct in the hepatic portal region. Abdominal computed tomography and magnetic resonance cholangiopancreatography revealed a tumor-like mass in the bile duct. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) confirmed the diagnosis of schwannoma. Considering the lesion location, it appeared to rise from the hepatoduodenal ligament. She was unwilling to undergo tumor resection;however, a year after the diagnosis, no change was observed in the tumor. Here, we report a case of schwannoma in the hepatoduodenal ligament, wherein EUS-FNA was useful for establishing a diagnosis and determining a treatment strategy.
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http://dx.doi.org/10.11405/nisshoshi.117.1008DOI Listing
November 2020

Association of Genetic Polymorphisms With Hepatitis C Virus-related Liver Cirrhosis in Japan.

In Vivo 2020 Nov-Dec;34(6):3309-3313

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background/aim: Hepatitis C virus (HCV) infection is an important health problem in the direct-acting antivirals-era. HCV causes life-threatening diseases, such as cirrhosis and hepatocellular carcinoma. Our aim was to examine whether certain single-nucleotide polymorphisms (SNPs) are associated with the prevalence of HCV infections progressing to cirrhosis in the Japanese population by a genome-wide association study-based approach.

Materials And Methods: We used DNA extracted from blood specimens of Japanese subjects with the establishment of the BioBank Japan project.

Results: We observed statistically significant differences in the frequency of 4 SNPs (rs1989972, rs2293766, rs1877033 and rs4805439) between anti-HCV-positive cirrhotic patients and controls.

Conclusion: Four SNPs are associated with susceptibility to cirrhosis among HCV-infected Japanese subjects, while further studies with cohorts other than those sourced from BioBank Japan, must be conducted.
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http://dx.doi.org/10.21873/invivo.12169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811607PMC
June 2020

Additive Effects of Zinc Chloride on the Suppression of Hepatitis A Virus Replication by Interferon in Human Hepatoma Huh7 Cells.

In Vivo 2020 Nov-Dec;34(6):3301-3308

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background/aim: Hepatitis A virus (HAV) infection is still one of the serious health problems worldwide, despite the existence of effective vaccines for HAV. Zinc compounds have antiviral activities against various DNA and RNA viruses. Therefore, we investigated the effects of zinc compounds on the antiviral activity of interferon against HAV.

Materials And Methods: The effects of zinc compounds with or without interferon on HAV genotype IIIA HA11-1299 replication were examined in human hepatoma Huh7 cells. Cell viability was examined by the MTS assay. Inflammasome associated gene expression was examined by real-time reverse transcription-polymerase chain reaction.

Results: Both zinc sulfate and zinc chloride had an inhibitory effect on HAV replication. Zinc sulfate tended to enhance while zinc chloride significantly enhanced the anti-HAV effect induced by interferon-alpha-2a. Zinc chloride significantly up-regulated mitogen-activated protein kinase 12 (MAPK12) and down-regulated 6 related genes [baculoviral IAP repeat containing 3 (BIRC3), interleukin 1 beta (IL1B), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), prostaglandin-endoperoxide synthase 2 (PTGS2), PYD and CARD domain containing (PYCARD), and tumor necrosis factor (TNF)].

Conclusion: Zinc chloride inhibits HAV replication and has additive effects on the anti-HAV activities of interferon.
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http://dx.doi.org/10.21873/invivo.12168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811611PMC
September 2020

Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease.

Int J Mol Sci 2020 Sep 2;21(17). Epub 2020 Sep 2.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.
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http://dx.doi.org/10.3390/ijms21176384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504211PMC
September 2020

Quantitative Ultrasound Image Analysis Helps in the Differentiation of Hepatocellular Carcinoma (HCC) From Borderline Lesions and Predicting the Histologic Grade of HCC and Microvascular Invasion.

J Ultrasound Med 2021 Apr 25;40(4):689-698. Epub 2020 Aug 25.

Department of Pathology, Nihon University School of Medicine, Tokyo, Japan.

Objectives: Quantitative image analysis is one of the methods to overcome the lack of objectivity of ultrasound (US). The aim of this study was to clarify the correlation between the features from a US image analysis and the histologic grade and microvascular invasion (MVI) of hepatocellular carcinoma (HCC) and differentiation of HCC smaller than 2 cm from borderline lesions.

Methods: We retrospectively analyzed grayscale US images with histopathologic evidence of HCC or a precancerous lesion using ImageJ version 1.47 software (National Institutes of Health, Bethesda, MD).

Results: A total of 148 nodules were included (borderline lesion, n = 31; early HCC [eHCC], n = 3; well-differentiated HCC [wHCC], n = 16; moderately differentiated HCC [mHCC], n = 79; and poorly differentiated HCC [pHCC], n = 19). A multivariate analysis selected lower minimum gray values (odds ratio [OR], 0.431; P = .003) and a higher standard deviation (OR, 1.880; P = .019) as predictors of HCC smaller than 2 cm. Median (range) minimum gray values of borderline lesions, eHCC, wHCC, mHCC, and pHCC were 29 (0-103), 7 (0-47), 6 (0-60), 10 (0-53), and 2 (0-38), respectively, and gradually decreased from borderline lesions to pHCC (P < 0.001). The multivariate analysis showed a higher aspect ratio (OR, 2.170; P = .001) and lower minimum gray value (OR, 0.475; P = .043) as predictors of MVI. An anechoic area diagnosed by a subjective evaluation was correlated with the minimum gray value (P < .0001). The proportion of the anechoic area gradually increased from eHCC to pHCC (P = .031).

Conclusions: In a US image analysis, HCC smaller than 2 cm had features of greater heterogeneity and a lower minimum gray value than borderline lesions. Moderately differentiated HCC was smoother than borderline lesions, and the anechoic area correlated with histologic grading. Microvascular invasion was correlated with a slender shape and a lower minimum gray value.
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http://dx.doi.org/10.1002/jum.15439DOI Listing
April 2021

Involvement of the Interferon Signaling Pathways in Pancreatic Cancer Cells.

Anticancer Res 2020 Aug;40(8):4445-4455

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background/aim: To examine interferon (IFN) signaling pathways in human pancreatic cancer cells and their therapeutic application for pancreatic ductal adenocarcinoma (PDAC).

Materials And Methods: We examined the effects of IFNα on cytotoxicity, migration, as well as on the levels of toll-like receptor (TLR) signaling pathway-associated genes expression in pancreatic cancer cells. We also examined the additive effects of IFNα and poly(I-C) on tyrosine kinase inhibitor (TKI)-induced cytotoxicity. We performed transcriptome analysis (RNA-Seq) of clinical samples and compared the profile between pancreatic intraepithelial neoplasias (PanINs) and PDACs.

Results: IFNα suppressed cell viability and cell migration, and affected TLR signaling pathways, in pancreatic cancer cells. TLR3 is one of the potential genes involved in IFN-treated pancreatic cancer cells. Furthermore, similar to IFN, extracellular addition of poly(I-C) enhanced TKI-induced cytotoxicity in pancreatic cancer cells. RNA-Seq analysis demonstrated that IFN signaling is one of the potential pathways involved in the progression of PanIN to PDAC.

Conclusion: IFN signaling may be involved in the development of PDAC. Treatments that target the IFN and TLR3 signaling pathways may be therapeutic options against PDAC.
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http://dx.doi.org/10.21873/anticanres.14449DOI Listing
August 2020

High platelet count as a poor prognostic factor for liver cancer patients without cirrhosis.

Biosci Trends 2020 Nov 25;14(5):368-375. Epub 2020 Jul 25.

Department of Gastroenterology and Hepatology, Nihon University School of Medicine, Tokyo, Japan.

A low platelet count, one of parameters of portal hypertension, is clinically a predictor of postoperative mortality, while platelets induce tumor development during growth factor secretion. In this study, we retrospectively investigated whether high platelet count negatively affects the survival of patients with hepatocellular carcinoma (HCC). Patients undergoing initial and curative resection for HCC were included. Surgical outcomes were compared between the high platelet (platelet count ≥ 20 × 10/μL) and control (< 20 × 10/μL) groups in patients without cirrhosis and between the low platelet (< 10 × 10/μL) and control (≥ 10 × 10/μL) groups in patients with cirrhosis. Among patients without cirrhosis, tumor was larger (P < 0.001) and tumor thrombus was more frequent (P < 0.001) in the high-platelet group than in the control group. After a median follow-up period of 3.1 years (range 0.2-16.2), median overall survival was 6.3 years (95% confidence interval [CI], 5.3-7.8) and 7.6 years (6.6-10.9) in the high-platelet (n = 273) and control (n = 562) groups, respectively (P = 0.027). Among patients with cirrhosis, liver function was worse (P < 0.001) and varices were more frequent (P < 0.001) in the low-platelet group. The median overall survival of patients in the low-platelet group (n = 172) was significantly shorter than that of patients in the control group (n = 275) (4.5 years [95% CI, 3.7-6.0] vs. 5.9 years [4.5-7.5], P = 0.038). Taken together, thrombocytopenia indicates poor prognosis in HCC patients with cirrhosis, while thrombocytosis is a poor prognostic predictor for those without cirrhosis.
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http://dx.doi.org/10.5582/bst.2020.03230DOI Listing
November 2020

Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives.

Int J Mol Sci 2020 Jul 11;21(14). Epub 2020 Jul 11.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan.

Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.
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http://dx.doi.org/10.3390/ijms21144906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402287PMC
July 2020

Analysis of HBV Genomes Integrated into the Genomes of Human Hepatoma PLC/PRF/5 Cells by HBV Sequence Capture-Based Next-Generation Sequencing.

Genes (Basel) 2020 06 18;11(6). Epub 2020 Jun 18.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC) worldwide. The integration of HBV genomic DNA into the host genome occurs randomly, early after infection, and is associated with hepatocarcinogenesis in HBV-infected patients. Therefore, it is important to analyze HBV genome integration. We analyzed HBV genome integration in human hepatoma PLC/PRF/5 cells by HBV sequence capture-based next-generation sequencing (NGS) methods. We confirmed the results by using Sanger sequencing methods. We observed that HBV genotype A is integrated into the genome of PLC/PRF/5 cells. HBV sequence capture-based NGS is useful for the analysis of HBV genome integrants and their locations in the human genome. Among the HBV genome integrants, we performed functional analysis and demonstrated the automatic expression of some HBV proteins encoded by HBV integrants from chromosomes 3 and 11 in Huh7 cells transfected with these DNA sequences. HBV sequence capture-based NGS may be a useful tool for the assessment of HBV genome integration into the human genome in clinical samples and suggests new strategies for hepatocarcinogenesis in HBV infection.
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http://dx.doi.org/10.3390/genes11060661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348787PMC
June 2020

Remission of ulcerative colitis flare-up induced by nivolumab.

Int J Colorectal Dis 2020 Sep 26;35(9):1791-1795. Epub 2020 May 26.

Division of Urology, Department of Urology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.

Background: Immune checkpoint inhibitors (ICIs) have been used to treat many cancers, but ICIs are rarely administered for malignant tumours coexisting with inflammatory bowel disease.

Methods And Results: We report a 77-year-old man experiencing an ulcerative colitis (UC) flare-up after receiving nivolumab as third-line therapy for multiple metastases of renal cell carcinoma. Mild UC (proctitis form) had been diagnosed at age 59 years and remission was maintained for 17 years with only a low dose of 5-ASA. After nivolumab treatment, the patient developed diarrhoea, bloody stools and was hospitalised. Computed tomography revealed inflammation involving the entire colon and endoscopy revealed severe UC exacerbation. Histological analysis showed UC findings and also increased crypt apoptosis which is unusual for inflammatory bowel diseases, while being typical of ICI-induced colitis. As with ICI-induced colitis, this exacerbation was strongly suggested to have been caused by nivolumab, although remission was achieved by increasing the 5-ASA dose to 4000 mg without prednisolone.

Conclusion: The administration of ICI for UC is not as yet sufficiently safe and further research is required.
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http://dx.doi.org/10.1007/s00384-020-03638-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415029PMC
September 2020

Impact of a Novel Oblique-Tip Papillotome for Biliary Cannulation during ERCP: A Nonrandomized Coarsened Exact Matching Study.

Gastroenterol Res Pract 2020 7;2020:2417841. Epub 2020 May 7.

Department of Innovative Interventional Endoscopy Research, The Jikei University School of Medicine, Tokyo, Japan.

Background: We developed a novel oblique-tip papillotome (OT-papillotome) to facilitate biliary cannulation during endoscopic retrograde cholangiopancreatography (ERCP). This study was performed to evaluate the utility of the OT-papillotome for contrast-guided cannulation (CGC) and wire-guided cannulation (WGC) during ERCP, compared with standard cannulation by WGC using a standard-tip papillotome (ST-papillotome).

Methods: A prospective study was performed at two centers. CGC with the OT-papillotome (OT-CGC group) was performed at Jikei University Hospital, while WGC was done with the OT-papillotome and ST-papillotome (OT-WGC and ST-WGC groups, respectively) at the University of Malaya Medical Centre. The results of the OT-CGC and OT-WGC groups were compared with those of the ST-WGC group after performing coarsened exact matching (CEM) to reduce bias due to nonrandomized and center-based patient allocation.

Results: Eighty patients were enrolled in each of the OT-CGC, OT-WGC, and ST-WGC groups. After CEM, the successful biliary cannulation rate was significantly higher in the OT-CGC and OT-WGC groups than in the ST-WGC group, while rescue cannulation was reduced. The mean number of unintended pancreatic access events in the OT-WGC and OT-CGC groups was similar to the ST-WGC group. However, it was significantly lower in the OT-WGC group than in the OT-CGC group. Multivariate analysis revealed that the OT-papillotome was independently associated with less frequent rescue cannulation and a higher successful biliary cannulation rate.

Conclusions: Although use of the OT-papillotome in biliary cannulation did not reduce unintended pancreatic access events or PEP compared to the ST-papillotome, the OT-papillotome increased the successful biliary cannulation rate, while reducing the frequency of rescue cannulation procedures. Combining the OT-papillotome with WGC might be the best cannulation technique for minimizing unintended pancreatic access.
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http://dx.doi.org/10.1155/2020/2417841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229551PMC
May 2020

Cell Culture Systems and Drug Targets for Hepatitis A Virus Infection.

Viruses 2020 05 12;12(5). Epub 2020 May 12.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Hepatitis A virus (HAV) infection is one of the major causes of acute hepatitis, and this infection occasionally causes acute liver failure. HAV infection is associated with HAV-contaminated food and water as well as sexual transmission among men who have sex with men. Although an HAV vaccine has been developed, outbreaks of hepatitis A and life-threatening severe HAV infections are still observed worldwide. Therefore, an improved HAV vaccine and anti-HAV drugs for severe hepatitis A should be developed. Here, we reviewed cell culture systems for HAV infection, and other issues. This review may help with improving the HAV vaccine and developing anti-HAV drugs.
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http://dx.doi.org/10.3390/v12050533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291253PMC
May 2020

The influence of esophagogastroduodenoscopy using carbon dioxide insufflation on abdominal ultrasonographic imaging efficiency.

J Med Ultrason (2001) 2020 Jul 12;47(3):445-451. Epub 2020 May 12.

Department of Gastroenterology, Tokyo Metropolitan Cancer Detection Center, Tokyo, Japan.

Purpose: The ability to perform abdominal ultrasonography after esophagogastroduodenoscopy (EGD) is hypothesized to improve examination efficiency. Therefore, we performed abdominal ultrasonography before and after EGD to verify the effects of EGD on abdominal ultrasonographic imaging efficiency.

Methods: We performed abdominal ultrasonography before, immediately after, 30 min after, and 60 min after EGD with carbon dioxide (CO) insufflation in 23 consecutive patients who visited our center between July 2015 and December 2016. We examined the visualization status of the head, body, and tail of the pancreas; extrahepatic bile duct; and inferior pole of the right kidney.

Results: The visualization status of the pancreas decreased immediately after EGD in approximately 50% of patients; however, at 30 min and after, the status was almost the same as for imaging performed before endoscopy. Visualization of the extrahepatic bile duct decreased slightly immediately after the procedure; however, 30 min and later, it was almost the same as before endoscopy. The inferior pole of the right kidney was observable from the dorsal side and could be visualized at all examination points in all patients.

Conclusion: There was no difficulty in performing abdominal ultrasonography at 30 min or later following EGD with CO insufflation. Additionally, visualization of the head, body, and tail of the pancreas as well as the extrahepatic bile duct was improved in some patients.
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http://dx.doi.org/10.1007/s10396-020-01024-8DOI Listing
July 2020

Different Mechanisms of Action of Regorafenib and Lenvatinib on Toll-Like Receptor-Signaling Pathways in Human Hepatoma Cell Lines.

Int J Mol Sci 2020 May 9;21(9). Epub 2020 May 9.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Multiple kinase inhibitors are available for patients with advanced hepatocellular carcinoma (HCC). It is largely unknown whether regorafenib or lenvatinib modulates innate immunity including Toll-like receptor (TLR)-signaling pathways in HCC. We performed real-time RT-PCR to investigate 84 TLR-associated gene expression levels and compared these gene expression levels in each hepatoma cells treated with or without regorafenib or lenvatinib. In response to regorafenib, nine and 10 genes were upregulated in Huh7 and HepG2 cells, respectively, and only C-X-C motif chemokine ligand 10 was upregulated in both cell lines. A total of 14 and 12 genes were downregulated in Huh7 and HepG2 cells, respectively, and two genes (Fos proto-oncogene, AP-1 transcription factor subunit, and ubiquitin conjugating enzyme E2 N) were downregulated in both cell lines. In response to lenvatinib, four and 16 genes were upregulated in Huh7 and HepG2 cells, respectively, and two genes (interleukin 1 alpha and TLR4) were upregulated in both cells. Six and one genes were downregulated in Huh7 and HepG2, respectively, and no genes were downregulated in both cell lines. In summary, regorafenib and lenvatinib affect TLR signaling pathways in human hepatoma cell lines. Modulation of TLR signaling pathway may improve the treatment of HCC patients with refractory disease.
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http://dx.doi.org/10.3390/ijms21093349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246870PMC
May 2020

Japan's Practical Guidelines for Zinc Deficiency with a Particular Focus on Taste Disorders, Inflammatory Bowel Disease, and Liver Cirrhosis.

Int J Mol Sci 2020 Apr 22;21(8). Epub 2020 Apr 22.

Department of Internal Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610 Japan.

Zinc deficiency is common in Japan, yet awareness on this disorder is lacking. The Japanese Society of Clinical Nutrition recently issued the Japan's Practical Guideline for Zinc Deficiency 2018 setting forth criteria for diagnosing zinc deficiency, i.e., (a) one or more symptoms of zinc deficiency or low serum alkaline phosphatase, (b) ruling out other diseases, (c) low serum zinc, and (d) alleviation of symptoms upon zinc administration. Serum zinc <60 μg/dL and 60-80 μg/dL indicate zinc deficiency and marginal deficiency, respectively. Zinc deficiency symptoms vary and include dermatitis and taste disorders among others. Zinc administration improves taste in 50-82% of patients suffering from taste disorders (a common symptom of zinc deficiency). Effects of zinc administration do not appear immediately, and therapy should be continued for at least three months. Zinc deficiency often accompanies various diseases and conditions. Here, we focus on inflammatory bowel diseases and liver cirrhosis. As zinc deficiency enhances intestinal inflammation via macrophage activation, we discuss the pathological mechanism for inflammation and zinc deficiency in the context of IBD. Zinc deficiency can also lead to a nitrogen metabolic disorder in patients with liver cirrhosis. Zinc supplementation can improve not only the ammonia metabolism, but also the protein metabolism. We also discuss directions for future studies of zinc deficiency.
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http://dx.doi.org/10.3390/ijms21082941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215354PMC
April 2020

Molecular Mechanisms: Connections between Nonalcoholic Fatty Liver Disease, Steatohepatitis and Hepatocellular Carcinoma.

Int J Mol Sci 2020 Feb 23;21(4). Epub 2020 Feb 23.

Genome Analysis Center, Yamanashi Central Hospital, Yamanashi 400-8506, Japan.

Nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH), causes hepatic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The patatin-like phospholipase-3 (PNPLA3) I148M sequence variant is one of the strongest genetic determinants of NAFLD/NASH. PNPLA3 is an independent risk factor for HCC among patients with NASH. The obesity epidemic is closely associated with the rising prevalence and severity of NAFLD/NASH. Furthermore, metabolic syndrome exacerbates the course of NAFLD/NASH. These factors are able to induce apoptosis and activate immune and inflammatory pathways, resulting in the development of hepatic fibrosis and NASH, leading to progression toward HCC. Small intestinal bacterial overgrowth (SIBO), destruction of the intestinal mucosa barrier function and a high-fat diet all seem to exacerbate the development of hepatic fibrosis and NASH, leading to HCC in patients with NAFLD/NASH. Thus, the intestinal microbiota may play a role in the development of NAFLD/NASH. In this review, we describe recent advances in our knowledge of the molecular mechanisms contributing to the development of hepatic fibrosis and HCC in patients with NAFLD/NASH.
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http://dx.doi.org/10.3390/ijms21041525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073210PMC
February 2020

Gastric Neuroendocrine Carcinoma with Rapid Progression.

Intern Med 2020 May 19;59(10):1271-1276. Epub 2020 Feb 19.

Department of Pathology, Nihon University School of Medicine, Japan.

As gastric neuroendocrine carcinoma (NEC) is a rapidly growing cancer, most cases are diagnosed at advanced stages. We herein report a 74-year-old woman with an early-stage gastric NEC whose history included endoscopic submucosal dissection treatment for three early-stage gastric cancer lesions five years prior to the current presentation. We also describe the changes observed over time. An endoscopic examination during follow-up revealed an NEC (measuring 6 mm) in the gastric vestibule, for which distal gastrectomy was performed. Four months before surgery, the carcinoma exhibited specific morphological changes and lymphovascular invasion (despite the tumor being stage 1), suggesting a high-grade NEC.
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http://dx.doi.org/10.2169/internalmedicine.3961-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303455PMC
May 2020

Elderly-onset Crohn's disease remarkably responsive to ustekinumab: a case report.

Int J Colorectal Dis 2020 Feb 17;35(2):355-359. Epub 2019 Dec 17.

Department of Internal Medicine Division of Gastroenterology and Hepatology, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.

Background: Crohn's disease is intractable and is frequently diagnosed in younger people. No clear policies exist regarding medical treatment for seniors with this disease, and its diagnosis and treatment are often hindered by difficulties attributable to comorbidities, complex differential diagnoses, and polypharmacy. We describe an elderly-onset Crohn's disease patient showing a marked remission-maintaining effect with no adverse events after administration of ustekinumab.

Methods And Results: A 75-year-old patient with Crohn's disease and a history of pulmonary tuberculosis had first presented to our hospital at age 64 years and was hospitalized. Based on physical examinations, colonoscopy, and blood test results, Crohn's disease was diagnosed. The patient experienced secondary losses of responsiveness to two tumor necrosis factor (TNF)-alpha inhibitors, and after repeated hospital admissions, she was administered ustekinumab. The patient's symptoms, endoscopic findings, Crohn's Disease Activity Index, serum albumin, and physical activity levels improved markedly, and disease remission has been maintained for 2 years to date.

Conclusion: Ustekinumab is an effective treatment option for elderly patients with intractable Crohn's disease when TNF-alpha inhibitors are ineffective.
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http://dx.doi.org/10.1007/s00384-019-03476-yDOI Listing
February 2020

Spatial and temporal expansion of intrahepatic metastasis by molecularly-defined clonality in multiple liver cancers.

Cancer Sci 2020 Feb 11;111(2):601-609. Epub 2020 Jan 11.

Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan.

Multiple hepatocellular carcinoma (HCC) is divided into two categories: intrahepatic metastasis (IM), which is a true relapse of HCC, and multicentric origin (MO), which is a second primary tumor. Clinical diagnosis of multiple HCC is usually made based on tumor location and/or time to recurrence; however, it is often difficult to distinguish the two types of multiple HCC. Using 41 matched pairs of multiple HCC specimens, we confirmed the accuracy of clinical diagnoses using exome sequence data and investigated the importance of discriminating the type of multiple HCC. Genomic analysis revealed that 18 (43.9%) patients diagnosed as having genomic IM had common mutations in a pair of HCC tumors with the main tumor of these patients being more progressive compared to those with genomic MO. The accuracy of clinical diagnosis based on lobe (Definition 1) and segment (Definition 2) were 68.3% and 78.0%, respectively. Intriguingly, recurrence ≥2 years after initial surgery for 3 patients was IM. The survival of patients with clinical IM was significantly shorter than for those with clinical MO based on both Definition 1 (P = 0.045) and Definition 2 (P = 0.043). However, mean survival was not different between the patients with genomic IM and those with MO (P = 0.364). Taken together, genomic analysis elucidated that liver cancer may spread more extensively and more slowly than previously thought. In addition, distinguishing multiple HCC as IM or MC may have provided biological information but was not of clinical importance with respect to patient prognosis.
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http://dx.doi.org/10.1111/cas.14282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004543PMC
February 2020

Hepatic hemangioma supplied by abnormal portal vein: A case report.

J Clin Ultrasound 2020 May 13;48(4):231-234. Epub 2019 Nov 13.

Department of Pathology, Nihon University School of Medicine, Itabashi-ku, Tokyo, Japan.

Hepatic hemangioma is the most common hepatic tumor with a prevalence of approximately 3%. It is typically supplied by the hepatic artery as evident from findings of abdominal angiography, contrast-enhanced ultrasonography (CEUS), contrast-enhanced computed tomography (CT), and contrast-enhanced magnetic resonance imaging. However, few cases of hepatic hemangioma supplied by the portal vein have been reported. In this paper, we report a rare case of hepatic hemangioma supplied by the portal vein as shown on CEUS and CT arterioportography.
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http://dx.doi.org/10.1002/jcu.22790DOI Listing
May 2020

Superinfection of hepatitis A virus in hepatocytes infected with hepatitis B virus.

Int J Med Sci 2019 20;16(10):1366-1370. Epub 2019 Sep 20.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan; (T.K.).

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis including acute liver failure. Hepatitis B infection (HBV) occurs worldwide, with the highest rates in Asian and African countries, and there are several reports that HAV infection may have a more severe clinical course in patients with chronic HBV infection. We previously demonstrated that Japanese miso extracts have inhibitory effects on HAV replication. In the present study, we examined the replication of HAV and HBV in a hepatocyte superinfection model and the inhibitory effects of Japanese miso extracts on both viruses. According to the results, HAV infection inhibited HBV replication in superinfected hepatocytes, and Japanese rice-koji miso extracts had inhibitory effects on HAV replication. Our findings provide useful information for clinicians in managing HAV infection in patients with chronic HBV infection.
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http://dx.doi.org/10.7150/ijms.32795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818197PMC
April 2020

APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation.

Hepatol Int 2019 Nov 20;13(6):649-661. Epub 2019 Sep 20.

Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.

In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.
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http://dx.doi.org/10.1007/s12072-019-09988-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861433PMC
November 2019

Are direct-acting antivirals against hepatitis C virus infection not associated with the recurrence of hepatocellular carcinoma?

Hepatobiliary Surg Nutr 2019 Aug;8(4):423-425

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

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http://dx.doi.org/10.21037/hbsn.2019.03.19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700000PMC
August 2019