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

AIM: This study aimed to evaluate the real-world efficacy and safety of 12-week sofosbuvir/velpatasvir (SOF/VEL) treatment for patients with decompensated liver cirrhosis caused by hepatitis C virus (HCV) infection. METHODS: A total 72 of patients with Child-Pugh (CP) class B or C were enrolled. We evaluated the sustained virologic response at 12 weeks after the end of treatment (SVR12), adverse events (AEs), and changes in the liver function. RESULTS: All participants had genotype 1 or 2 HCV infection. At baseline, the numbers of patients with CP class B and C were 59 and 13, respectively. The overall SVR12 rate was 95.8% (69/72); 94.9% (56/59) in CP class B and 100% (13/13) in CP class C. The serum albumin level, prothrombin time and ascites were significantly improved (P < 0.01); however, the serum bilirubin level and encephalopathy did not improve. Among patients who achieved SVR12, 75.0% showed an improvement in their CP score, while 5.9% showed a worsening. The presence of large portosystemic shunt (diameter ≥6 mm) and hyperbilirubinemia (≥2.0 mg/dL) were independent factors that interfered with the improvement in the CP score (P < 0.05). The most common AEs were encephalopathy (15.3%) and skin symptoms (7.9%). Two patients discontinued SOF/VEL due to AEs. CONCLUSIONS: Treatment with SOF/VEL for 12 weeks was relatively safe and effective for patients with decompensated cirrhosis. An SVR provided an improvement of the liver function in the majority of patients. However, large portosystemic shunt and hyperbilirubinemia were independent factors that interfered with the improvement in the CP score.

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

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.

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

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

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

BACKGROUND: Chronic liver disease (CLD) is often complicated by severe thrombocytopenia (platelet count < 50,000/µL). Platelet transfusion has been a gold standard for increasing the platelet count to prevent hemorrhagic events in such patients. Lusutrombopag, a thrombopoietin receptor agonist, can increase the platelet count in such patients when invasive procedures are scheduled. Former studies on lusutrombopag included patients with a platelet count of > 50,000/µL at baseline: the proportions of patients who did not require platelet transfusion were 84-96%, which might be overestimated. METHODS: The efficacy and safety of lusutrombopag were retrospectively investigated in CLD patients with platelet count of < 50,000/µL, a criterion for platelet transfusion, in real-world settings. We examined the proportion of patients who did not require platelet transfusion in 31 CLD patients, which exceeded a minimum required sample size (21 patients) calculated by 80% power at a significance level of 5%. Lusutrombopag, 3 mg once daily, was administered 8-18 days before scheduled invasive procedures. RESULTS: Among 31 patients who received lusutrombopag, 23 patients (74.2%) patients showed a platelet count of ≥ 50,000/µL (Group A) and did not require platelet transfusion. The remaining 8 patients (25.8%) did not reached platelet ≥ 50,000/µL (Group B). The means of platelet increase were 38,000/µL and 12,000/µL in groups A and B, respectively. A low platelet count at baseline was a characteristic of patients in group B. Among 13 patients who repeatedly used lusutrombopag, lusutrombopag significantly increased the platelet count as the initial treatment. When all repeated uses of lusutrombopag were counted among these 13 patients, platelet transfusion was not required in 82.1% (23/28) of treatments. Although one patient showed portal thrombosis after lusutrombopag treatment, the thrombosis was disappeared by anticoagulant treatment for 35 days. The degree of platelet increase with lusutrombopag was larger than that in their previous platelet transfusion. CONCLUSIONS: The proportion of patients who did not require platelet transfusion was 74.2%, which is smaller than that in former studies which included CLD patients with a platelet count of > 50,000/µL. However, lusutrombopag is effective and safe for CLD patients with a platelet count of < 50,000/µL.

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

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

Homocysteine supplementation ameliorates steatohepatitis induced by a choline-deficient diet in mice.

AIM: High concentrations of homocysteine are believed to induce lipid synthesis and cell injury through endoplasmic reticulum (ER) stress in metabolic syndrome. However, homocysteine could be used to improve steatohepatitis induced by choline deficiency, in which methyl donors are decreased. The aim of the present study was to clarify the role of the physiological concentration of homocysteine in the development of steatohepatitis induced by choline deficiency. METHODS: Wild-type mice were fed a choline-deficient amino acid-defined (CDAA) diet with or without homocysteine supplementation for 24 weeks. Liver cells isolated from mice were exposed to homocysteine under choline-deficient conditions. RESULTS: Wild-type mice fed the CDAA diet developed steatohepatitis with increased ER stress and decreased S-adenosylmethionine (SAM), a methyl donor. Homocysteine supplementation reduced ER stress and restored hepatic SAM, leading to the improvement of steatohepatitis. In in vitro experiments using primary cultured hepatocytes, the physiological concentration of homocysteine decreased the lipid accumulation and ER stress induced by the choline-deficient conditions. However, hepatocyte death was not induced by a physiological concentration of homocysteine or in choline-deficient medium. Interestingly, tumor necrosis factor (TNF)α promoted hepatocyte death under choline-deficient conditions, which was suppressed by homocysteine supplementation. Hepatic macrophages increased the production of TNFα under choline-deficient conditions whereas supplementation of SAM reduced the TNFα production. CONCLUSIONS: Homocysteine supplementation ameliorates steatohepatitis by reducing ER stress and increasing SAM in mice fed a CDAA diet. These results were opposite to those of previous reports, which showed that homocysteine induced cell injury.

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

AIM: The major transmission mode of hepatitis A virus (HAV) in Japan is the fecal-oral route by contaminated foods. In contrast, HAV infection is well documented as a sexually transmitted disease in Europe and North America. The present study was undertaken to determine the full-genome sequence of HAV and trace the transmission route of HAV in Japanese men who have sex with men (MSM). METHODS: In 2018, we encountered three Japanese MSM with acute hepatitis A co-infected with HIV for 4-12 years. Serum samples obtained from these patients were used for HAV full-genome analyses. RESULTS: Isolated HAV strains were segregated into subgenotype IA. The three HAV strains shared 100% identity within the 481-nucleotide partial sequence. The entire nucleotide sequence showed that the three strains were 99.97% similar to each other with only two nucleotide substitutions. At the amino acid level, the three strains differed from each other by only one or two amino acids. All three strains obtained in the present study were >99.6% identical to the 66 reported strains isolated from Taiwan and European countries during 2015-2017. In addition, these 66 strains include the RIVM-HAV16-090 (EuroPride) strain, which has been involved in HAV outbreaks among MSM worldwide. CONCLUSIONS: We determined for the first time the full-genome sequence of HAV isolated from Japanese MSM with acute hepatitis A and found that the strains were identical to those from MSM worldwide. Thus, these HAV strains were imported to Japan from foreign countries through MSM.

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

AIM: Hepatitis A virus (HAV) is the most common cause of infectious hepatitis worldwide. Although hepatitis A cases imported from South-East Asian countries, including the Philippines, have been reported in Japan, the molecular epidemiological data have been limited for these HAV-endemic countries. METHODS: The full-length genomic sequences of HAV isolates were determined and subjected to the phylogenetic analyses. RESULTS: The HAV isolates (HA12-0796 and HA12-0938) obtained from two Japanese patients who developed acute hepatitis A in July 2012, 1 month after traveling to the Philippines, where they consumed undercooked shellfish, differed by only one nucleotide (nt) over the entire genome. These HAV isolates of genotype IA were 99.1-99.5% identical within 228-237 nt to those recovered from river water in the Philippines, suggesting that the HA12-0796 and HA12-0938 isolates represent HAV circulating in the Philippines. HAV isolates belonging to one of the two IA sublineages (IA-2) which were implicated in some of the mini-epidemics in 2010 in Japan are hypothesized to be connected with the Philippines. In support of this speculation, the present IA isolates (HA12-0796 and HA12-0938) shared 98.8% identity over the entire genome with one IA-2 isolate (HAJIH-Fukuo10) recovered from a Japanese female who developed a domestic HAV infection during the mini-epidemics. In the phylogenetic tree constructed based on the entire genome, these three isolates (HA12-0796, HA12-0938 and HAJIH-Fukuo10) segregated into a cluster with a bootstrap value of 100%. CONCLUSION: These results indicate that HAV isolates belonging to the IA-2 lineage might have been imported from the Philippines.

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

BACKGROUND: Conventional therapies, including chemoembolization and radiation therapy, have been expected to prolong the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases, which remains poor. However, little information is available on the efficacy of conventional therapies for such patients under tyrosine kinase inhibitor (TKI) treatment. METHODS: We retrospectively investigated 127 HCC patients with extrahepatic metastases, who were divided into the non-TKI (conventional therapies) and TKI groups and further subdivided into the TKI alone and TKI plus conventional therapies groups. Conventional therapies included transcatheter arterial chemoembolization, cisplatin-based chemotherapy, radiation, surgery, and UFT, an oral chemotherapeutic agent. RESULTS: The median of the overall survival (OS) of the 127 patients with extrahepatic metastases was 7.0 months. Meanwhile, the median OS of the TKI and non-TKI groups was 12.1 and 4.1 months, respectively. Imitating TKI after diagnosing metastases promoted a favorable increase in OS. Among the TKI group, the median OS in the TKI alone group was 8.9 months. TKI plus conventional therapies promoted no improvement in OS after adjusting for the patients' background data. CONCLUSION: TKI promoted a better OS in HCC patients with extrahepatic metastases compared to conventional therapies. However, TKI plus conventional therapies promoted no improvement in the prognosis of such patients.

Final Results of TACTICS: A Randomized, Prospective Trial Comparing Transarterial Chemoembolization Plus Sorafenib to Transarterial Chemoembolization Alone in Patients with Unresectable Hepatocellular Carcinoma.

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment 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 progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

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

BACKGROUND AND AIMS: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

Steroid treatment in patients with membranous nephropathy and hepatitis B virus surface antigenemia: a report of two cases.

Although the clinical benefits of antiviral treatment in the management of membranous nephropathy (MN) in patients with chronic hepatitis B virus (HBV) infection have been suggested, it should be evaluated more carefully. In this report, we present two cases with quiescent HBV who were administered lamivudine for either the initial treatment of MN or to control the reactivation of HBV during treatment with corticosteroids. No clinical benefit of lamivudine as an initial treatment was observed in one patient, which obliged us to commence administration of prednisolone (PSL). On the other hand, lamivudine seemed to play a pivotal role in the remission of an acute exacerbation of hepatitis B during treatment with PSL and mizoribine in the other patient. These two patients seemed to tolerate administration of PSL with or without an immunosuppressive agent well, since gradual and prompt improvements of nephrotic status were confirmed within a few months, thus suggesting the potential benefit of steroid treatment. There is little consensus regarding the optimal choice of steroids and immunosuppressants for the treatment of MN with chronic HBV infection, due to the potential for stimulation of viral replication and precipitation of hepatic flares. Our observations, however, suggest that treatment with PSL still should be reserved for quiescent HBV carriers with MN. Further studies will be required to determine the optimal timing and appropriate duration of antiviral treatment in such patients requiring long-term immunosuppression.

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

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

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

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

Hepatitis E Virus (HEV) strains in serum samples can replicate efficiently in cultured cells despite the coexistence of HEV antibodies: characterization of HEV virions in blood circulation.

We recently developed a cell culture system for hepatitis E virus (HEV) in PLC/PRF/5 and A549 cells, using fecal specimens from HEV-infected patients. Since transfusion-associated hepatitis E has been reported, we examined PLC/PRF/5 and A549 cells for the ability to support replication of HEV in various serum samples obtained from 23 patients with genotype 1, 3, or 4 HEV. HEV progenies emerged in culture media of PLC/PRF/5 cells, regardless of the coexistence of HEV antibodies in serum but dependent on the load of HEV inoculated (31% at 2.0 x 10(4) copies per well and 100% at >or=3.5 x 10(4) copies per well), and were successfully passaged in A549 cells. HEV particles in serum, with or without HEV antibodies, banded at a sucrose density of 1.15 to 1.16 g/ml, which was markedly lower than that for HEV particles in feces, at 1.27 to 1.28 g/ml, and were nonneutralizable by immune sera in this cell culture system. An immuno-capture PCR assay of HEV virions treated with or without detergent indicated that HEV particles in serum are associated with lipids and HEV ORF3 protein, similar to those in culture supernatant. By immunoprecipitation, it was found that >90% of HEV particles in the circulation exist as free virions not complexed with immunoglobulins, despite the coexistence of HEV antibodies. These results suggest that our in vitro cell culture system can be used for propagation of a wide variety of HEV strains in sera from various infected patients, allowing extended studies on viral replication specific to different HEV strains.

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

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

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

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

Endoscopic thermal ablation therapies for hepatocellular carcinoma: a multi-center study.

AIM: The differing efficacies of radiofrequency ablation and microwave coagulation for hepatocellular carcinoma (HCC) are unknown. Therefore, we performed a multi-center study to assess the factors contributing to survival and local recurrences of HCC among patients with solitary tumors who underwent endoscopic thermal ablation as their primary treatment. METHODS: From six institutions, 391 patients with solitary HCC who were first treated by endoscopic thermal ablation were enrolled in this study and assessed retrospectively. We investigated age, gender, location of tumor, longest diameter of tumor, method of anesthesia, type of endoscope, method of thermal ablation, Child-Pugh classification, the Japan Integrated Staging score and the Cancer of the Liver Italian Program score. Statistical analyses were performed using univariate analysis with log-rank test and multivariate analysis with the Cox proportional hazards model. RESULTS: On univariate analysis, advanced Child-Pugh score, advanced Italian Program score and local recurrences were significant predictors of poor survival. Young age (30 mm) and the use of the thoracoscopic approach were significant predictors for the development of local recurrence. On multivariate analysis, local anesthesia and advanced Child-Pugh score were independent predictors of poor survival. Young age, large tumor, local anesthesia and the use of the thoracoscopic approach were independent predictors for the development of local recurrence. The method of thermal ablation did not influence survival or local recurrence. CONCLUSIONS: Differences in the effect on survival and local recurrence between microwave and radiofrequency were not observed in this retrospective, multi-center study of endoscopic thermal ablation for HCC.

Case-control study for the identification of virological factors associated with fulminant hepatitis B.

BACKGROUND: Host and viral factors can promote the development of fulminant hepatitis B (FHB), but there have been no case-control studies for figuring out virological parameters that can distinguish FHB. METHODS: In a case-control study, virological factors associated with the development of FHB were sought in 50 patients with FH developed by transient hepatitis B virus (HBV) infection (FH-T) and 50 with acute self-limited hepatitis B (AHB) who were matched for sex and age. In addition, 12 patients with FH developed by acute exacerbation (AE) of asymptomatic HBV carrier (ASC) (FH-C) were also compared with 12 patients without FH by AE of chronic hepatitis B (AE-C). RESULTS: Higher HBV DNA levels, subgenotype B1/Bj, A1762T/G1764A, G1896A, G1899A and A2339G mutation were significantly more frequent (P < 0.05), while hepatitis B e-antigen was less frequent in the FH-T patients than AHB. In multivariate analysis, G1896A mutation (odds ratio [OR], 13.53; 95% confidence interval [CI], 2.75-66.64), serum HBV DNA more than 5.23 log copies/mL (OR, 5.14; 95% CI, 1.10-24.15) and total bilirubin more than 10.35 mg/mL (OR, 7.81; 95% CI, 1.77-34.51) were independently associated with a fulminant outcome by transient HBV infection. On the other hand, in comparison with the patients between FH-C and AE-C groups, there was no significant difference of virological factors associated with the development of FHB. CONCLUSION: A number of virological factors have been defined that may distinguish FH-T from AHB in a case-control study. The pathogenic mechanism of FHB between transient HBV infection and AE of ASC would be different.

Clinical efficacy of superfine dispersed lentinan (beta-1,3-glucan) in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: Recently, complementary alternative medicine is actively performed for cancer therapy. We investigated the effectiveness of supplementary food containing superfine dispersed lentinan (beta-1,3-glucan) in patients with unresectable or recurrent hepatocellular carcinoma in a multi-center study. METHODOLOGY: Peripheral blood was collected prior to the test food ingestion and was incubated with fluorescein-labeled lentinan. The rates of lentinan-binding CD14+ monocytes were determined by flow cytometry. Patient survival times were followed up for 3 years. RESULTS: Thirty-six patients were eligible among 40 enrolled patients. Median survival time of eligible patients was 13.6 months (95% confidence interval, 8.7-18.9 months). Survival times of patients who ingested test food for a mean period of 47 weeks (range, 26 to 145 weeks) were significantly longer than that of patients who ingested for 7 to 12 weeks (p < 0.05). The rates of lentinan-binding cells in CD14+ monocytes showed individual variations (0.1-19.7%; Median, 1.6%). Survival times (median survival time, 16.3 months) of lentinan-high-binding group were significantly longer than those (median survival time, 12.5 months) of lentinan-low-binding group (p < 0.05). CONCLUSIONS: A superfine dispersed lentinan-containing supplementary food is effective for hepatocellular carcinoma patients' survival. Long-time ingestion is preferable. Assessment of lentinan-binding CD14+ monocytes is a promising prognostic predictor.