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While the preS1 region of the large hepatitis B surface protein plays an essential role in hepatitis B virus (HBV) infection, the effect of preS1 on liver fibrosis and hepatocarcinogenesis in chronic hepatitis B (CHB) patients is not well known. In this study, we measured serum preS1 levels by chemiluminescent immunoassay technology in 690 CHB patients and evaluated the correlation between serum preS1 levels and HBV, liver function markers and liver inflammation, fibrosis assessed by histological findings. Predictive factors for hepatocellular carcinoma (HCC) development in patients who had no previous history of HCC at the time of preS1 level measurement were also analysed. Median hepatitis B surface antigen (HBsAg) and preS1 levels were 3.08 log IU/mL and 98 ng/mL, respectively. PreS1 values were significantly correlated with serum HBsAg (p

Background and aim The aim of this study was to identify the factors that contribute to the maintenance of relative dose intensity (RDI) of lenvatinib in hepatocellular carcinoma (HCC) patients. Methods Thirty-two patients with advanced HCC treated with lenvatinib were enrolled. We evaluated the relationship between maintenance of RDI and various clinical data, parameters obtained by body composition measurements with bioelectrical impedance analysis (BIA) and grip strength at the start of lenvatinib treatment. Results Multivariate analysis showed that only the extracellular water to total body water ratio (ECW/TBW) ≤ 0.400 at initiation of treatment was associated with RDI ≥ 50% (odds ratio, 6.94; 95% confidence interval [CI], 1.00-48.00; P = 0.049). When the RDI was compared between ECW/TBW ≤ 0.400 group and ECW/TBW > 0.400 group, the RDI was significantly higher in the ECW/TBW ≤ 0.400 group at each of 0-4W, 4-6W, and 6-8W points. The P value at each point was 0.003, 0.003, and 0.005, respectively. On the other hand, multivariate analysis showed that only the ECW/TBW ≤ 0.400 at initiation of treatment was associated with the extension of duration until reduction or withdrawal of lenvatinib (hazard ratio, 4.86; 95% CI, 1.52-15.50; P = 0.007). Conclusion The extracellular water to total body water ratio, a parameter of body composition measurement by BIA, was significantly associated with the maintenance of RDI and the duration until reduction or withdrawal of lenvatinib in HCC patients. In addition to standard predictors such as Child-Pugh score and modified albumin-bilirubin grade that have been used to date, ECW/TBW might be a new predictor of RDI in HCC patients treated with lenvatinib.

AIM We analyzed the impact of hepatitis C virus eradication by direct-acting antiviral (DAA) therapy on the risk of development of hepatocellular carcinoma (HCC), prognosis, and portal hypertension in patients with liver cirrhosis. METHODS The rate of HCC development and overall survival after achievement of sustained virological response (SVR) in 173 DAA-treated compensated cirrhosis patients without HCC history were retrospectively compared with that of 125 cirrhosis patients who achieved SVR by interferon (IFN)-based therapy or that of 85 cirrhosis patients who failed to respond to anti-HCV therapy. Changes in esophagogastric varices (EGV) and incidence of portosystemic encephalopathy were analyzed in 87 consecutive cirrhosis patients. RESULTS The cumulative HCC development rates at 1, 3, and 5 years were 2%, 7%, and 7% for the DAA-SVR group, significantly lower than the 3%, 7%, and 18% for the non-SVR group (log-rank, P

Aim Pembrolizumab has been quickly approved in many countries for the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) solid tumors, which have progressed following previous treatment and who have no satisfactory alternative treatment options. We aimed to determine the incidence of MSI-H tumors in Japanese patients with advanced hepatocellular carcinoma (HCC). Methods We investigated the incidence of MSI-H tumors in 82 consecutive Japanese patients with unresectable HCC that had progressed after standard of care treatment. Using a companion diagnostic sequencing kit (polymerase chain reaction analysis of five microsatellite markers: BAT25, BAT26, NR21, NR24 and MONO27), we analyzed 49 biopsy specimens and 33 resection specimens. Responses to pembrolizumab were assessed with the modified Response Evaluation Criteria in Solid Tumors. Results MSI-H tumors were found in only two patients (2.4%), in whom all five markers showed slight shortening. One patient had a complete response to pembrolizumab for over 10 months, and the other was a non-responder. Conclusions MSI-H tumor status was found in only two of 82 (2.4%) Japanese patients with advanced HCC, one of whom had a complete response to pembrolizumab. Thus, MSI status should be assessed in patients with HCC who progress after standard of care treatment.

Aim The aim of this study is to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) between 5-fluorouracil (5-FU)-based continuous infusion chemotherapy and low-dose cisplatin (CDDP) monotherapy in patients with advanced hepatocellular carcinoma (HCC). Methods Patients were grouped according to HAIC regimen (5-FU group, n = 317/CDDP group, n = 66). A two-to-one match was created using propensity score analysis (5-FU group, n = 102/CDDP group, n = 51). After matching, response rate (RR) and adverse events as primary end-points, and survival and progression-free survival as secondary end-points, were analyzed. Results In the analysis of primary end-points, the RR in the 5-FU group was significantly higher than in the CDDP group (32.4% vs. 15.7%, P = 0.033). In patients with a Child-Pugh (CP) score of 5-7, the RR in the 5-FU group was significantly higher than that in the CDDP group (36.1% vs. 15.4%, P = 0.020). In those with a CP score of 8-9, there was no significant difference in RR between the two groups (15.8% vs. 16.6%, P = 1.000). The reservoir system-related complications were 9.8% in the 5-FU group, and there was no significant difference in the incidence of grade 3/4 adverse events between the two matched groups (P > 0.05). In terms of secondary end-points, the median survival time was 9.1 and 8.7 months for the 5-FU and CDDP groups, respectively (P = 0.4917). Progression-free survival was 3.9 months for the 5-FU group and 4.9 months for the CDDP group (P = 0.4). Conclusions 5-Fluorouracil-based continuous infusion chemotherapy could be suitable for advanced HCC patients with a CP score of 5-7 considering the treatment response.

Background Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. Methods Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. Results The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. Conclusion Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

Aim As second-line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second-line chemotherapy. Methods Patients (n = 160) with advanced HCC, Child-Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child-Pugh A liver function and ECOG PS 0-1 at progression as candidates for second-line chemotherapy and those who had tolerated sorafenib (≥400 mg/day for ≥20 of the last 28 days of treatment) as candidates eligible for regorafenib treatment. Results Among all 160 patients, median overall survival was 10 months, and median progression-free survival was 3.5 months. Among the 147 patients with PD, 74 (50.3%) were candidates for second-line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second-line chemotherapy (8.8 months) was statistically longer (P = 0.0002) than that of the non-candidates (3.6 months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin >3.5 g/dL (OR, 3.3; P = 0.005) at sorafenib initiation. Conclusion Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment.

Background and aim Sorafenib is the standard treatment for patients with advanced hepatocellular carcinoma (HCC) with distant metastasis, unresectable HCC, and HCC refractory to transcatheter arterial chemoembolization (TACE) or with macroscopic vascular invasion (MVI). Also, hepatic arterial infusion chemotherapy (HAIC) has been used for advanced HCC in Southeast and East Asian countries. However, clearer information is needed for choosing appropriately between these therapies. Methods The subjects were 391 HAIC and 431 sorafenibs administered at our hospital and related hospitals. In this case, cases that satisfy the following three conditions were targeted: (i) no extrahepatic metastasis, (ii) Child-Pugh A, and (ii) not having received treatment of both HAIC and sorafenib during the course. As a result, 150 cases of HAIC and 134 cases of sorafenib were analyzed this time. Results Univariate and multivariate analyses were performed for the HAIC and sorafenib groups. TACE refractory status and MVI were factors contributing to overall survival (OS). Therefore, this study divided all cases according to those variables. The median survival time of MVI-positive and non-TACE refractory cases was significantly better with HAIC (13 months) versus sorafenib (6 months). However, in MVI-negative and TACE refractory cases, the median survival time of HAIC (8 months) was significantly poorer than for sorafenib (20 months). Conclusion Transcatheter arterial chemoembolization refractory status with HAIC and MVI with sorafenib were factors for poor prognosis. In particular, HAIC was significantly better than sorafenib as primary treatment in MVI and non-TACE refractory cases. It is necessary to consider these factors in treatment selection.

Background/Aim To evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of hepatocellular carcinoma (HCC) in elderly patients. Methods From 2008 to 2015, 117 patients with HCC (≦3 nodules, ≦30 mm in diameter, Child-Pugh score ≦7, no vascular or extracellular metastasis) were treated with SBRT at our hospital. We evaluated overall survival (OS), disease-free survival (DFS), local control, and adverse events. Patients were stratified according to age 75 years and older (elderly group, n = 54) and age younger than 75 years (young group, n = 63). Results The median OS in the elderly group was not significantly different from that in the young group (52 months vs. not reached, P = 0.27). The 1, 2 and 3-year OS rates were 96.2%, 77.6% and 63.9%, respectively, in the elderly group, and 96.8%, 84.8% and 67.7%, respectively, in the young group. The median DFS in the elderly group was significantly shorter than that in the young group (13 vs. 25 months, respectively; P = 0.03). The 1, 2 and 3-year DFS rates were 50.6%, 30.4% and 26.6%, respectively, in the elderly group and 66.5%, 50.7% and 45.3%, respectively, in the young group. The 3-year local tumor control rate in the elderly group was 98.1%, and that in the young group was 98.4% (P = 0.83). There was no difference between groups in the incidence of any adverse events. Conclusions SBRT can be effective and safe for the treatment of HCC in elderly patients.

Aim Although interferon (IFN)-free antiviral therapy is expected to improve the treatment response for chronic hepatitis C, the effect on liver function and liver fibrosis is unknown. In this study, we analyzed the long-term follow up of liver function parameters and liver fibrosis markers in genotype 1b hepatitis C virus (HCV)-infected patients treated with daclatasvir and asunaprevir. Methods Thirty patients were treated with daclatasvir and asunaprevir for 24 weeks, and 26 patients achieved sustained virological response (SVR). We measured liver function parameters, serum alanine aminotransferase (ALT) and albumin levels and liver fibrosis markers, hyaluronic acid, type IV collagen and Mac-2-binding protein (M2BPGi) before and after (median, 27 months; range, 17–47) completion of the treatment in SVR and non-SVR patients. We also measured serum α-fetoprotein (AFP) levels during the therapy and follow-up period. Results Pretreatment serum ALT and albumin levels and liver fibrosis markers were similar between SVR and non-SVR patients. Twenty-seven months after treatment, serum ALT and albumin levels significantly improved only in SVR patients. Although there was no change in non-SVR patients, platelet count and serum liver fibrosis markers significantly improved in SVR patients. Serum AFP levels rapidly decreased during the treatment in both SVR and non-SVR patients, but the change was significant only in SVR patients. Conclusion Successful viral eradication by IFN-free daclatasvir and asunaprevir therapy could lead to improved liver function parameters and reduced liver fibrosis markers and AFP levels. This treatment has the potential to improve liver fibrosis and decrease the incidence of hepatocarcinogenesis.

Although interferon-free antiviral treatment is expected to improve treatment of hepatitis C, it is unclear to what extent pre-existing drug-resistant amino acid substitutions influence response to therapy. The impact of pre-existing drug-resistant substitutions on virological response to daclatasvir and asunaprevir combination therapy was studied in genotype 1b hepatitis C virus (HCV)-infected patients. Thirty-one patients were treated with daclatasvir and asunaprevir for 24 weeks. Twenty-six patients achieved sustained virological response (SVR), three patients experienced viral breakthrough, and two patients relapsed. Direct sequencing analysis of HCV showed the existence of daclatasvir-resistant NS5A-L31M or -Y93H/F variants in nine out of 30 patients (30%) prior to treatment, while asunaprevir-resistant NS3-D168 mutations were not detected in any patient. All 21 patients with wild-type NS5A-L31 and -Y93 achieved SVR, whereas only four out of nine patients (44%) with L31M or Y93F/H substitutions achieved SVR (P = 0.001). Ultra-deep sequencing analysis showed that treatment failure was associated with the emergence of both NS5A-L31/Y93 and NS3-D168 variants. NS5A-L31/Y93 variants remained at high frequency through post-treatment weeks 103 through 170, while NS3-D168 variants were replaced by wild-type in all patients. In conclusion, pre-existence of NS5A inhibitor-resistant substitutions compromised the response to daclatasvir and asunaprevir combination therapy, and treatment failure was associated with the emergence of both NS5A-L31/Y93 and NS3-D168 variants. While asunaprevir-resistant variants that emerged during therapy returned to wild-type, daclatasvir-resistant variants tended to persist in the absence of the drug. J. Med. Virol. 87:1913–1920, 2015. © 2015 Wiley Periodicals, Inc.

Background and Aim Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate and is used to reduce cancer-induced osteolysis. We reported previously that ZOL delayed both the growth and pain progression of bone metastases from hepatocellular carcinoma. The present study was designed to evaluate the effects of ZOL on hepatoma cell lines and the molecular mechanisms of such effects. Methods Cell viability assay, scratch assay, immunohistochemistry, Western blotting, and flow cytometry analysis were performed using Huh7 and HepG2 cells treated with and without ZOL. Results ZOL reduced cell growth in a dose-dependent manner and prevented cell migration when used at a concentration exceeding 10 μM. Immunohistochemistry showed that the inhibitory effects of ZOL on hepatoma cell progression was not due to the suppression of Ras and RhoA expression but due to inhibition of their translocation from the cytosol to the cell membrane, which terminates mevalonate pathway. Immunoblotting and flow cytometry showed that ZOL inhibited the mitogen-activated protein kinase pathway (MAPK) and induced apoptosis of hepatoma cells. Conclusions Our results indicated that ZOL prevented cell growth and metastasis based on direct antitumor effects in hepatoma cells. The use of ZOL could not only suppress the progression to bone metastatic lesions but also prevented growth of primary hepatocellular carcinoma.

Aim To assess the efficacy and safety of the anticoagulant drug, danaparoid sodium, in the treatment of portal vein thrombosis (PVT) in patients with liver cirrhosis. Methods A consecutive 26 cirrhotic patients with PVT were enrolled in this retrospective cohort study. The etiologies of cirrhosis were hepatitis B virus-related, hepatitis C virus-related, alcoholic and cryptogenic in five, 14, three and four patients, respectively. Child–Pugh grade A, B and C was noted in 13, eight and five patients, respectively. Patients were treated with 2 weeks' administration of danaparoid sodium followed by the evaluation of PVT reduction and adverse events. Results All patients experienced reduction of PVT through the treatment. The median volume of PVT before and after treatment was 2.40 cm3 (range, 0.18–16.63) and 0.37 cm3 (range, 0–5.74), respectively. The median reduction rate of PVT volume was 77.3% (range, 18–100%). According to the reduction rate, complete reduction (CR), partial reduction (PR, ≥50%) and stable disease (SD

Aim The predictive value of the recently identified interferon-λ (IFNL)4 polymorphism on the outcome of telaprevir (TVR), pegylated interferon (PEG IFN) plus ribavirin (RBV) combination therapy for chronic hepatitis C is unknown. Methods We assessed predictive factors for sustained virological response (SVR) for TVR, PEG IFN plus RBV combination therapy in 283 genotype 1 chronic hepatitis C patients. IFNL4 polymorphism ss469415590 was analyzed by Invader assay. Results SVR rates for patients with IFNL4 TT/TT genotype were significantly higher than for those with the IFNL4 TT/ΔG or ΔG/ΔG genotypes (93% and 59%, respectively, P

Aim Acoustic radiation force impulse (ARFI) technology, involving the shear wave velocity (SWV) with virtual touch tissue quantification (VTTQ), are currently available for the assessment of liver fibrosis, while there is no index derived from the combination of SWV and blood tests. The aim of this study was to develop a new index for assessment of liver fibrosis. Methods The subjects were 176 consecutive patients with hepatitis C (training set [n = 120] and validation set [n = 56]) who underwent liver biopsy in our institution. Results In the training set, SWV, international normalized ratio (INR) and alanine aminotransferase (ALT) correlated independently and significantly with fibrosis. According to this, we developed the VIA index = −1.282 + 0.965 × SWV + 1.785 INR + 0.00185 ALT. The areas under the receiver–operator curve (AUROC) of the VIA index were 0.838 for the diagnosis of significant fibrosis (≥F2), 0.904 for the severe fibrosis (≥F3) and 0.958 for the cirrhosis (F4) in the training set. While in the validation set, AUROC of the VIA index were 0.917 for F2 or higher, 0.906 for F3 or higher and 1.000 for F4, respectively. AUROC of the VIA index was improved compared to SWV alone, equivalent for VIA for the diagnosis of F2 or higher, and superior to that of FIB-4 index and aspartate aminotransferase-to-platelet ratio index for the diagnosis of F3 or higher and F4. Conclusion The VIA index is potentially more useful for assessment of liver fibrosis than SWV alone, and easily and accurately measures liver fibrosis stage.

Aim Steatosis is a common histological feature of chronic liver disease, especially alcoholic and non-alcoholic fatty liver disease, as well as chronic hepatitis C. A recent study showed that evaluating the controlled attenuation parameter (CAP) with transient elastography was an efficient way of non-invasively determining the severity of hepatic steatosis. The objective of this study was to prospectively evaluate the utility of CAP for diagnosing steatosis in patients with chronic liver disease. Methods One hundred and fifty-five consecutive patients with suspected chronic liver disease underwent steatosis diagnosis using CAP, blood sample analyses, computed tomography for assessing the liver/spleen ratio and liver biopsy. Steatosis was graded according to the percentage of fat-containing hepatocytes: S0, less than 5%; S1, 5–33%; S2, 34–66%; and S3: more than 66%. Results The CAP was significantly correlated with steatosis grade, and there were significant differences between the CAP value of the S0 patients and those of the patients with other grades of steatosis. S0 and S1–3 hepatic steatosis were considered to represent mild and significant steatosis, respectively. The CAP values of the patients with mild and significant steatosis were significantly different (P

Aim: We investigated the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) and systemic interferon (IFN)-α (HAIC-5-FU/IFN) for advanced hepatocellular carcinoma (HCC) with venous tumor thrombosis (VTT) in the hepatic vein trunk (Vv2) or inferior vena cava (Vv3). Methods: Thirty-three patients with HCC/Vv2/3 underwent HAIC with 5-FU (500 mg/body weight/day, into hepatic artery on days 1–5 on the first and second weeks) and IFN-α (recombinant IFN-α-2b 3 000 000 U or natural IFN-α 5 000 000 U, intramuscularly on days 1, 3 and 5 of each week). Three-dimensional conformal radiotherapy (3D-CRT) was used in combination with HAIC-5-FU/IFN in 14 of 33 patients to reduce VTT. Result: The median survival time (MST) was 7.9 months, and 1- and 2-year survival rates were 30% and 20%, respectively. Evaluation of intrahepatic response after two cycles of HAIC-5-FU/IFN showed complete response (CR) in three (9%) and partial response (PR) in seven (21%), with an objective response rate of 30%. Multivariate analysis identified reduction of VTT (P = 0.0006), size of largest tumor (P = 0.013) and intrahepatic response CR/PR (P = 0.030) as determinants of survival. CR/PR correlated significantly with tumor liver occupying rate (P = 0.016) and hepatitis C virus Ab (P = 0.010). Reduction of VTT correlated significantly with radiotherapy (P = 0.021) and platelet count (P = 0.015). Radiotherapy-related reduction in VTT significantly improved survival of 16 patients with Vv3 and non-CR/PR response of HAIC-5-FU/IFN (P = 0.028). Conclusion: As for advanced HCC with VTT of Vv2/3, HAIC-5-FU/IFN responsive patients could obtain favorable survival. Despite ineffective HAIC-5-FU/IFN, the combination with effective radiotherapy to VTT might improve patients' prognosis.

Aim: To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4). Methods: The study subjects were 45 consecutive patients who received HAIC for HCC with Vp3/4 between January 2005 and December 2009. HAIC comprised the combination therapy of intra-arterial 5-FU with interferon-α (5-FU/IFN) in 23 patients and low-dose cisplatin plus 5-FU (FP) in 22. Radiotherapy (RT) was also provided in 19 patients for portal vein tumor thrombosis. Aggravation rate for EV and overall survival rate were analyzed. Results: The aggravation rates for EV were 47% and 64% at 12 and 24 months, respectively. The survival rates were 47% and 33% at 12 and 24 months, respectively. The response rates to 5-FU/IFN and FP were 35% and 41%, while the disease control rates in these two groups were 57% and 50%, respectively. There were no significant differences in the objective response and disease control between 5-FU/IFN and FP. Multivariate analysis identified size of EV (F2/F3) (HR = 7.554, P = 0.006) and HCC disease control (HR = 5.948, P = 0.015) as significant and independent determinants of aggravation of EV, and HCC disease control (HR = 12.233, P