Publications by authors named "Osamu Yokosuka"

620 Publications

Analysis of non-severe acute onset autoimmune hepatitis according to the presence of radiological heterogeneity.

Hepatol Res 2022 May 31. Epub 2022 May 31.

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

Aim: Diagnosis of acute onset autoimmune hepatitis (A-AIH) has been difficult in that patients may not have typical clinicopathological features of AIH. In our previous reports of severe and fulminant AIH, two-thirds of them showed radiological heterogeneity: hepatic heterogeneous hypoattenuation on unenhanced computed tomography (CT) reflecting heterogeneous distribution of massive hepatic necrosis (severe centrilobular necrosis), which would be beneficial for the diagnosis. In the present study, we analyzed non-severe A-AIH patients with or without radiological heterogeneity and tried to find novel clinical features for supporting the early diagnosis.

Methods: Clinical, biochemical, immunological, radiological and histological features of 42 patients with non-severe A-AIH at community hospitals between 2010 and 2020 were analyzed.

Results: Of 42, 28 patients on whom CT scans were performed and who could be fully analyzed were enrolled. Five patients showed hepatic heterogeneous hypoattenuation on unenhanced CT. There was no significant difference in clinical, biochemical, immunological and histological features at diagnosis between the two groups according to the presence of radiological heterogeneity, although mean minimum prothrombin time activity during the course was lower in patients with heterogeneity without statistical significance (p = 0.080). All responded to treatment well and achieved initial remission within 3 months.

Conclusions: It is possible that patients with non-severe A-AIH show radiological heterogeneity reflecting centrilobular necrosis which is one of important diagnostic features of A-AIH. Accordingly, radiological heterogeneity might be beneficial for the diagnosis of A-AIH in combination with conventional clinicopathological features if it is detected in the absence of features suggestive of other liver diseases.
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http://dx.doi.org/10.1111/hepr.13799DOI Listing
May 2022

Histological re-evaluation of autoimmune hepatitis with acute presentation.

Liver Int 2022 08 27;42(8):1916-1917. Epub 2022 May 27.

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

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http://dx.doi.org/10.1111/liv.15317DOI Listing
August 2022

Impact of compensated cirrhosis on survival in patients with acute-on-chronic liver failure.

Hepatol Int 2022 Feb 25;16(1):171-182. Epub 2021 Nov 25.

Department of Hepatology, Institute of Liver and Biliary Sciences, D-1, Acharya Shree Tulsi Marg, Vasant Kunj, New Delhi, 110070, India.

Background And Aims: Acute-on-chronic liver failure (ACLF) is considered a main prognostic event in patients with chronic liver disease (CLD). We analyzed the 28-day and 90-day mortality in ACLF patients with or without underlying cirrhosis enrolled in the ACLF Research Consortium (AARC) database.

Methods: A total of 1,621 patients were prospectively enrolled and 637 (39.3%) of these patients had cirrhosis. Baseline characteristics, complications and mortality were compared between patients with and without cirrhosis.

Results: Alcohol consumption was more common in cirrhosis than non-cirrhosis (66.4% vs. 44.2%, p < 0.0001), while non-alcoholic fatty liver disease/cryptogenic CLD (10.9% vs 5.8%, p < 0.0001) and chronic HBV reactivation (18.8% vs 11.8%, p < 0.0001) were more common in non-cirrhosis. Only 0.8% of patients underwent liver transplantation. Overall, 28-day and 90-day mortality rates were 39.3% and 49.9%, respectively. Patients with cirrhosis had a greater chance of survival compared to those without cirrhosis both at 28-day (HR = 0.48; 95% CI 0.36-0.63, p < 0.0001) and 90-day (HR = 0.56; 95% CI 0.43-0.72, p < 0.0001), respectively. In alcohol CLD, non-cirrhosis patients had a higher 28-day (49.9% vs. 23.6%, p < 0.001) and 90-day (58.4% vs. 35.2%, p < 0.001) mortality rate than cirrhosis patients. ACLF patients with cirrhosis had longer mean survival than non-cirrhosis patients (25.5 vs. 18.8 days at 28-day and 65.2 vs. 41.2 days at 90-day). Exaggerated systemic inflammation might be the reason why non-cirrhosis patients had a poorer prognosis than those with cirrhosis after ACLF had occurred.

Conclusions: The 28-day and 90-day mortality rates of ACLF patients without cirrhosis were significantly higher than those with cirrhosis in alcoholic CLD. The presence of cirrhosis and its stage should be evaluated at baseline to guide for management. Thai Clinical Trials Registry, TCTR20191226002.
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http://dx.doi.org/10.1007/s12072-021-10266-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844167PMC
February 2022

Comparative accuracy of prognostic models for short-term mortality in acute-on-chronic liver failure patients: CAP-ACLF.

Hepatol Int 2021 Jun 25;15(3):753-765. Epub 2021 Jun 25.

Department of Medicine, Ankara University School of Medicine, Ankara, Turkey.

Background: Multiple predictive models of mortality exist for acute-on-chronic liver failure (ACLF) patients that often create confusion during decision-making. We studied the natural history and evaluated the performance of prognostic models in ACLF patients.

Methods: Prospectively collected data of ACLF patients from APASL-ACLF Research Consortium (AARC) was analyzed for 30-day outcomes. The models evaluated at days 0, 4, and 7 of presentation for 30-day mortality were: AARC (model and score), CLIF-C (ACLF score, and OF score), NACSELD-ACLF (model and binary), SOFA, APACHE-II, MELD, MELD-Lactate, and CTP. Evaluation parameters were discrimination (c-indices), calibration [accuracy, sensitivity, specificity, and positive/negative predictive values (PPV/NPV)], Akaike/Bayesian Information Criteria (AIC/BIC), Nagelkerke-R, relative prediction errors, and odds ratios.

Results: Thirty-day survival of the cohort (n = 2864) was 64.9% and was lowest for final-AARC-grade-III (32.8%) ACLF. Performance parameters of all models were best at day 7 than at day 4 or day 0 (p < 0.05 for C-indices of all models except NACSELD-ACLF). On comparison, day-7 AARC model had the numerically highest c-index 0.872, best accuracy 84.0%, PPV 87.8%, R 0.609 and lower prediction errors by 10-50%. Day-7 NACSELD-ACLF-binary was the simple model (minimum AIC/BIC 12/17) with the highest odds (8.859) and sensitivity (100%) but with a lower PPV (70%) for mortality. Patients with day-7 AARC score > 12 had the lowest 30-day survival (5.7%).

Conclusions: APASL-ACLF is often a progressive disease, and models assessed up to day 7 of presentation reliably predict 30-day mortality. Day-7 AARC model is a statistically robust tool for classifying risk of death and accurately predicting 30-day outcomes with relatively lower prediction errors. Day-7 AARC score > 12 may be used as a futility criterion in APASL-ACLF patients.
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http://dx.doi.org/10.1007/s12072-021-10175-wDOI Listing
June 2021

Comprehensive mutational analysis of background mucosa in patients with Lugol-voiding lesions.

Cancer Med 2021 06 2;10(11):3545-3555. Epub 2021 May 2.

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

Somatic mutations including the background mucosa in patients with Lugol-voiding lesions (LVLs) are still not well known. The aim of this study was to evaluate the somatic mutations of the background mucosa in patients with LVLs (Squamous cell carcinoma (SCC), intraepithelial neoplasia (IN), and hyperplasia). Twenty-five patients with LVLs (9 with SCC, 6 with IN, and 10 with hyperplasia) were included. A targeted sequence was performed for LVLs and background mucosa using an esophageal cancer panel. Each mutation was checked whether it was oncogenic or not concerning OncoKB. In LVLs, TP53 was the most dominant mutation (80%). Furthermore, 72% of TP53 mutations was putative drivers. In background mucosa, NOTCH1 was the most dominant mutation (88%) and TP53 was the second most dominant mutation (48%). Furthermore, 73% of TP53 mutations and 8% of NOTCH1 mutations were putative drivers. Putative driver mutations of TP53 had significantly higher allele frequency (AF) in SCC than in IN and hyperplasia. Conversely, putative driver mutations of NOTCH1 did not have a significant accumulation of AF in the progression of carcinogenesis. Furthermore, in SCC, AF of TP53 mutations was significantly higher in LVLs than in background mucosa, but not in IN and hyperplasia. Regarding NOTCH1, a significant difference was not observed between LVLs and background mucosa in each group. The background mucosa in patients with LVLs already had putative driver mutations such as TP53 and NOTCH1. Of these two genes, TP53 mutation could be the main target gene of carcinogenesis in esophageal SCC. Clinical Trials registry: UMIN000034247.
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http://dx.doi.org/10.1002/cam4.3905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178505PMC
June 2021

Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines.

Sci Rep 2021 03 2;11(1):3703. Epub 2021 Mar 2.

Genome Medical Science Project, National Center for Global Health and Medicine, Ichikawa, 272-8516, Japan.

Hepatitis B (HB) vaccines (Heptavax-II and Bimmugen) designed based on HBV genotypes A and C are mainly used for vaccination against HB in Japan. To determine whether there are differences in the genetic background associated with vaccine responsiveness, genome-wide association studies were performed on 555 Heptavax-II and 1193 Bimmugen recipients. Further HLA imputation and detailed analysis of the association with HLA genes showed that two haplotypes, DRB1*13:02-DQB1*06:04 and DRB1*04:05-DQB1*04:01, were significantly associated in comparison with high-responders (HBsAb > 100 mIU/mL) for the two HB vaccines. In particular, HLA-DRB1*13:02-DQB1*06:04 haplotype is of great interest in the sense that it could only be detected by direct analysis of the high-responders in vaccination with Heptavax-II or Bimmugen. Compared with healthy controls, DRB1*13:02-DQB1*06:04 was significantly less frequent in high-responders when vaccinated with Heptavax-II, indicating that high antibody titers were less likely to be obtained with Heptavax-II. As Bimmugen and Heptavax-II tended to have high and low vaccine responses to DRB1*13:02, 15 residues were found in the Heptavax-II-derived antigenic peptide predicted to have the most unstable HLA-peptide binding. Further functional analysis of selected hepatitis B patients with HLA haplotypes identified in this study is expected to lead to an understanding of the mechanisms underlying liver disease.
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http://dx.doi.org/10.1038/s41598-021-82986-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925550PMC
March 2021

Propofol midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

JGH Open 2021 Feb 22;5(2):273-279. Epub 2020 Dec 22.

Departmetn of Anesthesiology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single-blind, investigator-initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

Methods: Few- and small-nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100-mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.

Results: Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.

Conclusion: Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.
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http://dx.doi.org/10.1002/jgh3.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857294PMC
February 2021

APASL practical recommendations for the management of hepatocellular carcinoma in the era of COVID-19.

Hepatol Int 2020 Dec 11;14(6):920-929. Epub 2020 Nov 11.

Department of Gastroenterology, Yamanashi Prefectural Central Hospital, Kofu-city, Yamanashi, Japan.

Background: COVID-19 has been giving the devastating impact on the current medical care system. There are quite many guidelines on COVID-19, but only a few on the management of hepatocellular carcinoma (HCC) during COVID-19 pandemic.

Aims: We develop these recommendations to preserve adequate clinical practice for the management of HCC.

Methods: Experts of HCC in the Asia-Pacific region exchanged opinions via webinar, and these recommendations were formed.

Results: Close contact should be minimized to reduce possible exposure of both medical staff and patients to the novel coronavirus. To prevent transmission of the virus, meticulous hygiene measures are important. With the decrease in regular medical service, the medical staff may be mobilized to provide COVID-19-related patient care. However, diagnosis and treatment of HCC should not be delayed because of COVID-19 pandemic. The management of HCC should be the same as in non-pandemic circumstances. HCC is highly malignant, thus it is recommended not to delay curative treatment such as surgery and ablation. However, a kind of triage is necessary even among patients with HCC when resources are insufficient for all to be treated. Curative treatments should be periodized and cytoreductive or non-curative treatment such as vascular interventions and systemic therapy may be postponed until it can be performed safely with sufficient resources. For patients with confirmed or suspected to be infected with the novel coronavirus, diagnosis and treatment should be postponed until the virus is eliminated or they are confirmed as not being infected with it.

Conclusions: These are collection of measures implemented by front-line medical professionals. We would evolve these recommendations over time as more real-world data becomes available.
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http://dx.doi.org/10.1007/s12072-020-10103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655459PMC
December 2020

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

Liver Cancer 2020 Sep 22;9(5):596-612. Epub 2020 Jul 22.

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

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden.

Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs.

Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC.

Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC.

Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.
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http://dx.doi.org/10.1159/000508809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548915PMC
September 2020

Role of Autoimmunity in Patients Transplanted for Acute Liver Failure of Unknown Origin: A Clinical and Graft Biopsy Analysis.

Liver Transpl 2021 02 22;27(2):309-310. Epub 2020 Nov 22.

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

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http://dx.doi.org/10.1002/lt.25917DOI Listing
February 2021

Comprehensive Analysis of Barrett's Esophagus: Focused on Carcinogenic Potential for Barrett's Cancer in Japanese Patients.

Dig Dis Sci 2021 08 25;66(8):2674-2681. Epub 2020 Aug 25.

Department of Gastroenterology, Graduate School of Medicine, Chiba University Hospital, Inohana 1-8-1, Chiba-City, 260-8670, Japan.

Background/aim: Barrett's esophagus (BE) is a precursor of esophageal adenocarcinoma (EAC). Therefore, an accurate diagnosis of BE is important for the subsequent follow-up and early detection of EAC. However, the definitions of BE have not been standardized worldwide; columnar-lined epithelium (CLE) without intestinal metaplasia (IM) and/or < 1 cm is not diagnosed as BE in most countries. This study aimed to clarify the malignant potential of CLE without IM and/or < 1 cm genetically.

Method: A total of 96 consecutive patients (including nine patients with EAC) who had CLE were examined. Biopsies for CLE were conducted, and patients were divided into those with IM and > 1 cm (Group A) and those without IM and/or < 1 cm (Group B). Malignant potential was assessed using immunochemical staining for p53. Moreover, causative genes were examined using next-generation sequencing (NGS) on ten patients without Helicobacter pylori infection and without atrophic gastritis.

Result: Of the 96 patients, 66 were in Group B. The proportion of carcinoma/dysplasia in Group A was significantly higher than that in Group B (26.7% in Group A and 1.5% in Group B; p < 0.01). However, one EAC patient was found in Group B. In the immunostaining study for non-EAC patients, an abnormal expression of p53 was not observed in Group A, whereas p53 loss was observed in three patients (4.6%) in Group B. In the NGS study, a TP53 mutation was found in Group B.

Conclusion: CLE without IM and/or < 1 cm has malignant potential. This result suggests that patients with CLE as well as BE need follow-up.
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http://dx.doi.org/10.1007/s10620-020-06563-1DOI Listing
August 2021

Pre-existing liver disease is associated with poor outcome in patients with SARS CoV2 infection; The APCOLIS Study (APASL COVID-19 Liver Injury Spectrum Study).

Hepatol Int 2020 Sep 4;14(5):690-700. Epub 2020 Jul 4.

Division of Hepatobiliary, Cipto Mangunkusuamo Hospital, University of Indonesia, Jakarta, Indonesia.

Background And Aims: COVID-19 is a dominant pulmonary disease, with multisystem involvement, depending upon comorbidities. Its profile in patients with pre-existing chronic liver disease (CLD) is largely unknown. We studied the liver injury patterns of SARS-Cov-2 in CLD patients, with or without cirrhosis.

Methods: Data was collected from 13 Asian countries on patients with CLD, known or newly diagnosed, with confirmed COVID-19.

Results: Altogether, 228 patients [185 CLD without cirrhosis and 43 with cirrhosis] were enrolled, with comorbidities in nearly 80%. Metabolism associated fatty liver disease (113, 61%) and viral etiology (26, 60%) were common. In CLD without cirrhosis, diabetes [57.7% vs 39.7%, OR = 2.1 (1.1-3.7), p = 0.01] and in cirrhotics, obesity, [64.3% vs. 17.2%, OR = 8.1 (1.9-38.8), p = 0.002] predisposed more to liver injury than those without these. Forty three percent of CLD without cirrhosis presented as acute liver injury and 20% cirrhotics presented with either acute-on-chronic liver failure [5 (11.6%)] or acute decompensation [4 (9%)]. Liver related complications increased (p < 0.05) with stage of liver disease; a Child-Turcotte Pugh score of 9 or more at presentation predicted high mortality [AUROC 0.94, HR = 19.2 (95 CI 2.3-163.3), p < 0.001, sensitivity 85.7% and specificity 94.4%). In decompensated cirrhotics, the liver injury was progressive in 57% patients, with 43% mortality. Rising bilirubin and AST/ALT ratio predicted mortality among cirrhosis patients.

Conclusions: SARS-Cov-2 infection causes significant liver injury in CLD patients, decompensating one fifth of cirrhosis, and worsening the clinical status of the already decompensated. The CLD patients with diabetes and obesity are more vulnerable and should be closely monitored.
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http://dx.doi.org/10.1007/s12072-020-10072-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334898PMC
September 2020

Infectious complications and timing for liver transplantation in autoimmune acute liver failure in Japan: a subanalysis based on nationwide surveys between 2010 and 2015.

J Gastroenterol 2020 Sep 17;55(9):888-898. Epub 2020 Jun 17.

Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.

Background: The prognosis of autoimmune acute liver failure (ALF) without liver transplantation (LT) is poor worldwide. We subanalyzed infectious complications of autoimmune ALF using data of nationwide surveys between 2010 and 2015 retrospectively and tried to determine when to evaluate the efficacy of corticosteroid (CS) treatment or abandon it for LT based on objective data.

Methods: One hundred and forty-four patients with autoimmune ALF, comprising 79 ALF with coma ≤ I, 52 ALF with coma ≥ II and 13 late onset hepatic failure (LOHF), were analyzed.

Results: CS was administered to 140 (97%) patients. Thirty-seven (26%) patients had infectious complications. Patients with infection revealed more advanced disease type (p < 0.001) and poorer spontaneous survival (p < 0.001) than those without infection. Median (interquartile range) duration between diagnosis of ALF and onset of infection was 18.5 (11-36) days, and that between introduction of CS and onset of infection was 17 (10.5-36) days. Seventy-nine (55%) recovered without LT, 14 (10%) received LT and 51 (35%) died without LT. Dead or transplanted patients were older (p = 0.0057), and revealed more advanced liver failure (p < 0.001) and more occurrence of infection (p < 0.001).

Conclusions: A critical point for evaluating the efficacy of CS treatment and switching to LT is at most 2-week after diagnosis of ALF and introduction of CS. More important, we should accelerate the point and prepare for LT in cases of ALF with coma ≥ II and LOHF, and we should have performed LT by then at the latest in case of failure to improve.
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http://dx.doi.org/10.1007/s00535-020-01699-3DOI Listing
September 2020

Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial.

Gut 2020 08 4;69(8):1492-1501. Epub 2019 Dec 4.

Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.

Objective: This trial compared the efficacy and safety of transarterial chemoembolisation (TACE) plus sorafenib with TACE alone using a newly established TACE-specific endpoint and pre-treatment of sorafenib before initial TACE.

Design: Patients with unresectable hepatocellular carcinoma (HCC) were randomised to TACE plus sorafenib (n=80) or TACE alone (n=76). Patients in the combination group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable (unTACEable) progression (TTUP), defined as untreatable tumour progression, transient deterioration to Child-Pugh C or appearance of vascular invasion/extrahepatic spread. Co-primary endpoints were progression-free survival (PFS), which is not a conventional one but defined as TTUP, or time to any cause of death plus overall survival (OS). Multiplicity was adjusted by gatekeeping hierarchical testing.

Results: Median PFS was significantly longer in the TACE plus sorafenib than in the TACE alone group (25.2 vs 13.5 months; p=0.006). OS was not analysed because only 73.6% of OS events were reached. Median TTUP (26.7 vs 20.6 months; p=0.02) was also significantly longer in the TACE plus sorafenib group. OS at 1 year and 2 years in TACE plus sorafenib group and TACE alone group were 96.2% and 82.7% and 77.2% and 64.6%, respectively. There were no unexpected toxicities.

Conclusion: TACE plus sorafenib significantly improved PFS over TACE alone in patients with unresectable HCC. Adverse events were consistent with those of previous TACE combination trials.

Trial Registration Number: NCT01217034.
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http://dx.doi.org/10.1136/gutjnl-2019-318934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398460PMC
August 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

Correction to: Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

Hepatol Int 2019 11 9;13(6):826-828. Epub 2019 Oct 9.

Department of Gastroenterology, DMC, Ludhiana, India.

The article Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update, written by [Shiv Sarin], was originally published electronically on the publisher's internet portal (currently SpringerLink) on June 06, 2019 without open access.
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http://dx.doi.org/10.1007/s12072-019-09980-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861344PMC
November 2019

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

Prognostic four-gene signature for overall survival in patients with hepatocellular carcinoma.

Hepatol Int 2019 09 16;13(5):519-520. Epub 2019 Aug 16.

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

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http://dx.doi.org/10.1007/s12072-019-09976-xDOI Listing
September 2019

Acute Severe Autoimmune Hepatitis: Corticosteroids or Liver Transplantation?

Liver Transpl 2019 09 19;25(9):1455-1456. Epub 2019 Jul 19.

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

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http://dx.doi.org/10.1002/lt.25590DOI Listing
September 2019

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific association for the study of the liver (APASL): an update.

Hepatol Int 2019 Jul 6;13(4):353-390. Epub 2019 Jun 6.

Department of Gastroenterology, DMC, Ludhiana, India.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the "APASL ACLF Research Consortium (AARC)" was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the 'Golden Therapeutic Window', extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.
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http://dx.doi.org/10.1007/s12072-019-09946-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728300PMC
July 2019

Japanese patient preferences regarding intermediate to advanced hepatocellular carcinoma treatments.

Patient Prefer Adherence 2019 30;13:637-647. Epub 2019 Apr 30.

Japan Community Health care Organization Funabashi Central Hospital, Funabashi, Chiba Prefecture, Japan.

This study aimed to evaluate Japanese patient preferences regarding features of intermediate or advanced (Progressed) hepatocellular carcinoma (HCC) treatments: transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and oral anti-cancer therapy. Patients with HCC, recruited from clinical sites and a patient panel in Japan, completed a cross-sectional web-based survey. Preferences were quantified using best-worst scaling, where patients identified the best and worst among 13 treatment features. Direct elicitation was used to identify preference for TACE, HAIC, or oral therapy, including the likelihood of trying each. Additional items asked for the willingness to try an oral medication that delays progression by six months but has an 8% or 21% risk of severe hand-foot skin reaction (HFSR). The sample (N=119; 29 early stage; 90 Progressed) most preferred "oral medication", "artery branches plugged", and "prevents formation of new blood vessels", and least preferred "risk of liver damage" and "risk of catheter-related complications". Overall, 51%, 40%, and 8% preferred oral therapy, TACE, and HAIC, respectively (<0.05), and the mean likelihood of trying each were 59%, 52%, and 35%, respectively (<0.001). Patients with sorafenib or TACE experience most preferred what they had received; however, both groups were equally willing to try the other treatment. Patients preferring oral therapy favored "oral medication" over "artery branches plugged", "surgery is repeated as required when the cancer grows again", and "risk of liver damage", compared to those preferring TACE (<0.05). Sixty-eight percent would probably try therapy with an 8% risk of severe HFSR, compared to 50% with a 21% risk. Treatment type, mode of action, and risks may drive HCC patient preferences. Such features likely should be incorporated into physician-patient interactions regarding treatment decision-making.
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http://dx.doi.org/10.2147/PPA.S198363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503324PMC
April 2019

Subgroup analysis of efficacy and safety of orantinib in combination with TACE in Japanese HCC patients in a randomized phase III trial (ORIENTAL).

Med Oncol 2019 May 3;36(6):52. Epub 2019 May 3.

Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan.

A randomized, phase III trial of orantinib in combination with transcatheter arterial chemoembolization (TACE) did not prolong overall survival (OS) over placebo (ORIENTAL study). A subgroup analysis was conducted to evaluate the efficacy and safety of orantinib in Japanese patients enrolled in the ORIENTAL study. The data of Japanese patients from this study were analyzed. The overall survival (OS), time to progression (TTP), and time to TACE failure (TTTF) were compared between orantinib and placebo arms using stratified log-rank test. Since TTTF in patients with Barcelona Clinic Liver Cancer stage B (BCLC-B) showed favor outcome in this study, the OS and TTTF according to BCLC staging system were also analyzed. The subgroup analysis consisted of 219 and 213 patients in the orantinib and placebo arms. Median OS was 32.5 vs 33.0 months (p = 0.906), median TTP was 4.7 vs 3.1 months (p = 0.011), and median TTTF was 25.3 vs 18.2 months (p = 0.160) in the orantinib and placebo groups, respectively. Patients with BCLC-B in the orantinib and placebo groups showed a median OS of 33.7 and 30.1 months, respectively (p = 0.260), while the corresponding median TTTF were 25.3 and 14.0 months (p = 0.125). The Japanese population safety profile was similar to all over population in the ORIENTAL study. No significant differences were observed in the OS and TTTF though the TTP was significantly improved in the orantinib arm. The OS and TTTF showed a tendency to be prolonged following orantinib treatment of Japanese HCC patients with BCLC-B in the ORIENTAL study.
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http://dx.doi.org/10.1007/s12032-019-1272-2DOI Listing
May 2019

Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

Am J Gastroenterol 2019 06;114(6):929-937

Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore.

Objectives: Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF.

Methods: We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation.

Results: Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality.

Discussion: Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.
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http://dx.doi.org/10.14309/ajg.0000000000000201DOI Listing
June 2019

Letter to the Editor: Ductular Reaction in Acute Onset Autoimmune Hepatitis.

Hepatology 2019 08;70(2):756-757

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

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http://dx.doi.org/10.1002/hep.30621DOI Listing
August 2019

Exosomes and Hepatocellular Carcinoma: From Bench to Bedside.

Int J Mol Sci 2019 Mar 20;20(6). Epub 2019 Mar 20.

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

As hepatocellular carcinoma (HCC) usually occurs in the background of cirrhosis, which is an end-stage form of liver diseases, treatment options for advanced HCC are limited, due to poor liver function. The exosome is a nanometer-sized membrane vesicle structure that originates from the endosome. Exosome-mediated transfer of proteins, DNAs and various forms of RNA, such as microRNA (miRNA), long noncoding RNA (lncRNA) and messenger RNA (mRNA), contributes to the development of HCC. Exosomes mediate communication between both HCC and non-HCC cells involved in tumor-associated cells, and several molecules are implicated in exosome biogenesis. Exosomes may be potential diagnostic biomarkers for early-stage HCC. Exosomal proteins, miRNAs and lncRNAs could provide new biomarker information for HCC. Exosomes are also potential targets for the treatment of HCC. Notably, further efforts are required in this field. We reviewed recent literature and demonstrated how useful exosomes are for diagnosing patients with HCC, treating patients with HCC and predicting the prognosis of HCC patients.
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http://dx.doi.org/10.3390/ijms20061406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471845PMC
March 2019

POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33.

Sci Rep 2019 01 14;9(1):102. Epub 2019 Jan 14.

Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan.

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.
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http://dx.doi.org/10.1038/s41598-018-36490-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331557PMC
January 2019

Hepatitis C virus-associated hepatocellular carcinoma after sustained virologic response.

World J Hepatol 2018 Dec;10(12):898-906

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

The introduction of a direct-acting antiviral (DAA) for patients with hepatitis C virus (HCV) infection, could lead to higher sustained virologic response (SVR) rates with fewer adverse events, and it could shorten the treatment duration relative to the interferon era. Although most recent clinical studies have demonstrated that the occurrence rates of hepatocellular carcinoma (HCC) are decreased by SVR with both interferon-based and interferon-free-regimens, there are several reports about the unexpected observation of high rates of early tumor occurrence and recurrence in patients with HCV-related HCC undergoing interferon-free therapy despite SVR. Several mechanisms of HCC occurrence and rapid immunological changes, including cytokines and chemokines during and after DAA treatment, have also been reported. We focused on the possibilities that HCC occurs or recurs during and after DAA treatment, based on the reported clinical and basic studies. Further studies and observations will be needed to determine the short-term and long-term effects on hepatocarcinogenesis caused by the eradication of HCV with DAAs. New serum biomarkers and a follow-up system for HCV-patients with SVR should be established.
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http://dx.doi.org/10.4254/wjh.v10.i12.898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323517PMC
December 2018

APASL clinical practice recommendation: how to treat HCV-infected patients with renal impairment?

Hepatol Int 2019 Mar 11;13(2):103-109. Epub 2018 Dec 11.

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

Chronic hepatitis C virus (HCV) infection is common among patients with chronic kidney disease (CKD) and those on hemodialysis due to nosocomial infections and past blood transfusions. While a majority of HCV-infected patients with end-stage renal disease are asymptomatic, some may ultimately experience decompensated liver diseases and hepatocellular carcinoma. Administration of a combination of elbasvir/grazoprevir for 12 weeks leads to high sustained virologic response (SVR) rates in patients with HCV genotypes (GTs) 1a, 1b or 4 and stage 4 or 5 CKD. Furthermore, a combination of glecaprevir/pibrentasvir for 8-16 weeks also results in high SVR rates in patients with all HCV GTs and stage 4 or 5 CKD. However, these regimens are contraindicated in the presence of advanced decompensated cirrhosis. Although sofosbuvir and/or ribavirin are not generally recommended for HCV-infected patients with severe renal impairment, sofosbuvir-based regimens may be appropriate for those with mild renal impairment. To eliminate HCV worldwide, HCV-infected patients with renal impairment should be treated with interferon-free therapies.
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http://dx.doi.org/10.1007/s12072-018-9915-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418053PMC
March 2019

Letter: acute liver failure of indeterminate aetiology.

Aliment Pharmacol Ther 2018 11;48(9):1024-1025

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

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http://dx.doi.org/10.1111/apt.14931DOI Listing
November 2018
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