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We investigated pretreatment neutrophil-to-lymphocyte ratio (NLR) for predicting survival outcomes of atezolizumab plus bevacizumab therapy for hepatocellular carcinoma (HCC) and determined the predictive ability of combined liver reserve-NLR.This retrospective, multicenter study enrolled 242 patients receiving atezolizumab plus bevacizumab for unresectable HCC. Pretreatment NLR2.56 was designated as the "low group" and NLR ≥2.56 as the "high group" (120 and 122 patients, respectively). Propensity score-matched analysis was undertaken between the low and high groups.In this cohort, the objective response and disease control rates were 20% and 72.5%, respectively, in the low group and 19.6% and 72.9%, respectively, in the high group. After matching, median progression-free survival (PFS) time was 283 and 167 days in the low and high groups, respectively (p = 0.022). Neutrophil-to-lymphocyte ratio ≥2.56 (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.05-2.28; p = 0.028), modified albumin-bilirubin index (mALBI) grade 2b or 3 (HR 1.55; 95% CI, 1.05-2.29; p = 0.025), and protein induced by vitamin K absence or antagonist-II ≥ 400 (HR 2.03; 95% CI, 1.36-3.02; p = 0.001) were significantly associated with PFS in univariate analysis using the Cox proportional hazards model. In cases involving mALBI grade 1 or 2a (n = 131), the median PFS time was not reached in the low group, whereas it was 210 days in the high group (p = 0.037).Pretreatment NLR is a simple tool for routine measurement in clinical practice. It can predict PFS in patients with unresectable HCC treated with atezolizumab plus bevacizumab, especially mALBI grade 1 or 2a.

We retrospectively investigated patients with administration of nucleos(t)ide analogs (NAs) for prevention of or against hepatitis B virus (HBV) reactivation, and their clinical outcomes after cessation of the NA.We enrolled 180 patients who were positive for HBsAg when they started immunosuppressive therapy or chemotherapy and an NA was administered to prevent HBV reactivation (HBV carrier group), and 82 patients with resolved HBV infection who started administration of an NA after HBV reactivation (de novo HBV group). Cessation of the NA depended on each physician's judgment without definite criteria.A total of 27 patients in the HBV carrier group and 22 in the de novo HBV group stopped NA therapy. In the HBV carrier group, 16 patients experienced virological relapse, which was defined as HBV DNA levels ≥20 IU/ml, and one with hematological disease had an alanine aminotransferase flare after cessation of NA. Of the 16 patients, the NA was reintroduced in three, whereas, the remaining 13 had low levels of HBV DNA and no alanine aminotransferase flare. In the de novo HBV group, virological relapse occurred in six patients, and one with hematological disease had an alanine aminotransferase flare after cessation of the NA. The NA was reintroduced in four of the six patients.We may be able to consider to cease NA therapy proactively in HBV carriers and resolved patients with non-hematological disease, if their primary diseases are under remission after completion of immunosuppressive therapy or chemotherapy. However, careful follow up is necessary after stopping NA therapy.

The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with sofosbuvir (SOF) and velpatasvir (VEL) were assessed in hepatitis C virus (HCV) genotype 1- and 2-infected patients with decompensated cirrhosis. A total of 65 patients with HCV-related decompensated cirrhosis (Child-Pugh score of 7 points or more) who were treated with the SOF/VEL regimen were enrolled. The sustained virological response (SVR) rate and safety profile were analyzed. SVR was defined as undetectable serum HCV RNA at 12 weeks after the end of treatment (SVR12). The percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 81.2% (95% confidence interval [CI], 69.5-89.9) (52/64), 98.4% (95% CI, 91.2-100.0) (60/61), and 98.5% (95% CI, 91.7-100.0) (64/65), respectively. The overall SVR rate was 92.3% (95% CI, 83.0-97.5) (60/65). Albumin-bilirubin (ALBI) scores decreased during and after treatment (p

Alpha-fetoprotein (AFP) response (relative decline in AFP) is associated with imaging response evaluated by response evaluation criteria in solid tumors ver1.1 (RECIST) and survival in treatment for hepatocellular carcinoma (HCC). However, the optimal threshold of AFP response is still unknown, especially in atezolizumab and bevacizumab (Atez/Bev) treatment. In this prospective multicenter study, we aimed to investigate an optimal threshold of AFP response in Atez/Bev treatment. Out of 284 patients with unresectable HCC who were treated with Atez/Bev, 91 patients with AFP ≥ 10 ng/ml were enrolled in the multicenter study. We investigated the relationship between various AFP response thresholds (relative decline ≥ 20%, ≥ 50%, and ≥ 75%) and treatment response and progression-free survival (PFS). An AFP relative decrease of ≥ 50% was associated with an overall response rate (ORR) with an odds ratio (95% confidence interval [CI]) of 5.7 (1.9-17). Disease control rate (DCR) was associated with an AFP relative decrease of ≥ 20%, with a 100% positive predictive value and a 52.0% sensitivity. AFP relative decreases of ≥ 50% and ≥ 20% were significantly associated with PFS with a hazard ratio (HR) of 5.60 (95% CI: 1.6-19, p = 0.006) and a HR of 4.44 (95% CI: 1.9-10, p 0.001), respectively. AFP response of ≥ 50% and ≥ 20% were related to ORR and DCR, respectively, and both of these responses were also associated with PFS. AFP can be used as a real-time monitor during Atez/Bev treatment and is helpful for treatment optimization.

Improvements in the hepatocellular carcinoma (HCC) recurrence rate and survival have been frequently reported following virus eradication after hepatitis C virus (HCV)-related HCC cure. However, the efficacy of direct-acting antiviral (DAA) therapy in patients who included those with advanced HCC and decreased hepatic functional reserve is unknown. A comparative examination was retrospectively conducted of 141 patients with hepatitis C who started DAA therapy within 1 year after undergoing curative HCC treatment and showed a sustained viral response (SVR) and 327 patients who underwent curative treatment for HCV-related HCC and did not subsequently receive antiviral therapy. Whether DAA therapy was given was identified as an independent factor related to both HCC recurrence and survival. Both the recurrence and survival rates improved significantly with DAA therapy in Child-Pugh (CP)-A, whereas no difference in the recurrence rate was seen with DAA therapy in CP-B. However, the survival rate was significantly higher in the DAA group in this class. Similarly, dividing the patients by the Milan criteria showed significant improvements in the recurrence rate and survival with DAA therapy in patients within the Milan criteria. Patients with HCC beyond the Milan criteria showed no difference in recurrence rates, but the DAA group tended to have higher survival rates. Thus, DAA after curative therapy for HCC can be expected to improve survival in patients with advanced HCC or decreased hepatic functional reserve. HCV should be aggressively eradicated in all patients eligible for curative treatment of HCC.

We herein report a 49-year-old woman with a perivascular epithelial cell tumor (PEComa) of the pancreas. Imaging studies demonstrated a relatively well-demarcated mass, measuring approximately 40 mm in diameter, located in the pancreatic tail. It was heterogeneously enhanced almost to the same degree as the surrounding pancreatic tissue in both the arterial and portal venous phases. We performed endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) using the AcquireⓇ 22-gauge needle and preoperatively obtained a definitive diagnosis with a sufficient sample. Clinicians should consider pancreatic PEComa in their differential diagnosis of patients with a pancreatic mass.

Aim Rescue therapy for patients with genotype 2 (GT2) chronic hepatitis C who failed prior sofosbuvir (SOF) plus ribavirin (RBV) awaits establishment. This study aims to investigate the efficacy and safety of the fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) (GLE/PIB) for patients with GT2 chronic hepatitis C. Methods In this nationwide observational study undertaken by the Japanese Red Cross Liver Study Group, 28 GT2 patients with prior failure of SOF + RBV were retreated with GLE/PIB for 12 weeks. We evaluated the rate of sustained virologic response (SVR) and adverse events. Results After 4 weeks of therapy, serum hepatitis C virus RNA was below the limit of quantification in all patients. The SVR after 4 and 12 weeks of the end of treatment was validated in 100% (28/28) and 100% (28/28), respectively. The adverse events comprised pruritus (eight patients), fatigue (four patients), and appetite loss (four patients), all of which were mild in severity. Conclusions This study establishes the efficacy of GLE/PIB as retreatment in Japanese patients with GT2 chronic hepatitis C not responding to SOF + RBV.

Background: Lenvatinib (LEN) has been approved for patients with unresectable hepatocellular carcinoma (u-HCC) since March 2018 in Japan. We performed a retrospective nationwide multicenter study to clarify the clinical characteristics of LEN in real-world practice. Methods: A total of 343 u-HCC patients who received LEN from March 2018 to May 2020 at 23 sites in Japan were registered. Results: During the median observation period of 10.5 months, 143 patients died. In Child-Pugh A (n = 276) and Child-Pugh B (n = 67) patients, the median overall survival (OS) was 21.0 and 9.0 months. The median progression-free survival (PFS) was 8.8 months in Child-Pugh A patients. The objective response rate (ORR) and disease control rate (DCR) according to modified response evaluation criteria in solid tumors (RECIST criteria) were 42.1% and 82.1%. The independent pretreatment factors associated with mortality in all patients were AFP ≥ 400 ng/mL (hazard ratio (HR) 2.00, 95% confidential interval (95% CI) 1.08–2.09, p &lt, 0.0001), modified albumin-bilirubin (ALBI) grade 2b or 3 (HR 1.56, 95% CI 1.09–2.17, p = 0.012), major vascular invasion (HR 1.91, 95% CI 1.26–2.89, p = 0.0022), PS &gt, 0 (HR 1.50, 95% CI 1.09–2.08, p = 0.014), and MTT (molecular targeted therapy) experience (HR 2.22, 95% CI 1.56–3.13, p = 0.00038). In the MTT naïve patients with ALBI grade 1 or modified ALBI 2a and BCLC stage B (n = 68), median OS and PFS were 25.3 and 12.3 months. Liver-related adverse events during LEN were the only significant adverse event associated with OS (HR 2.74, 95% CI 1.93–3.88, p &lt, 0.0001). Among the Child-Pugh A patients with extrahepatic metastasis and no major vascular invasion, median PFS in the patients with bone metastasis was significantly shorter than those with lung or adrenal grand metastasis (6.3 vs. 12.5 months, p = 0.0025). Conclusion: LEN showed a high response rate in real-world practice. Pretreatment factors, including ALBI score, AFP, and major vascular invasion are important in making a treatment strategy for patients with u-HCC. The patients with bone metastasis would be candidates for new therapeutic approaches.

Nucleos(t)ide analogs (NA) suppress hepatitis B virus (HBV) replication and reduce the risk of hepatocellular carcinoma (HCC). However, NA cannot suppress carcinogenesis completely in patients with chronic hepatitis B. The aims of this study were to identify risk factors for HCC and develop a refined carcinogenesis prediction model. Patients receiving NA therapy (n = 1,183) were recruited retrospectively from the 16 hospitals. All patients had been receiving NA continuously for more than 1 year until the end of the follow-up. During a median follow-up of 4.9 (1.0–12.9) years, 52 (4.4%) patients developed HCC. A multivariate analysis revealed that male gender, older age, lower platelet counts at the baseline, and detectable HBV DNA during NA therapy were independent predictive factors of HCC development. The PAGE-B score was calculated by using these factors. 240 (20.3%), 661 (55.9%), and 282 (23.8%) patients were classified into low-, intermediate-, and high-risk groups, respectively. In the intermediate- and high-risk group, detectable HBV DNA was significantly associated with a higher risk of HCC development compared with continuously undetectable HBV DNA, respectively (HR 3.338; 95% CI 1.045–10.66/HR 3.191; 95% CI 1.543–6.597). PAGE-B–DNA, which is the combined PAGE-B and HBV DNA status, was valuable for a more refined stratification of PAGE-B.

The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC). A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1 year from the end of treatment (EOT) (median 104 weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1 year from the EOT. Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6 ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively). The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.

Aim To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV). Methods A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken. Results The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared. Conclusions For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.

Aim This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy. Methods Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing. Results Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P

We report a case of a 70-year-old man with acute acalculous cholecystitis caused by Giardia lamblia. Contrast-enhanced computed tomography (CT) showed distention of the gallbladder due to a pericholecystic abscess without gallstones. Magnetic resonance cholangiopancreatography and drip infusion cholecystocholangiography-CT demonstrated a stricture of the hilar bile duct and cystic duct obstruction. We conducted transpapillary bile duct brush cytology and a biopsy of the hilar bile duct stricture; numerous active trophozoites of Giardia lamblia were observed without malignant findings. We considered this bile duct lesion to be biliary giardiasis. Biliary giardiasis should be taken into consideration when diagnosing acute acalculous cholecystitis.

AIM The present study aimed to determine the real-world efficacy and safety of the non-structural protein (NS)5A inhibitor elbasvir (EBR) combined with the NS3/4A protease inhibitor grazoprevir (GZR) in patients with hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS This study retrospectively evaluated the rate of sustained virologic response at 12 weeks post-treatment (SVR12) and the safety of EBR/GZR treatment in 159 men and 194 women with a median age of 72 years, and it assessed factors associated with the SVR12 rate. The attending physicians were responsible for selecting candidate patients for EBR/GZR in this retrospective study. RESULTS Treatment outcomes for EBR/GZR were good in direct-acting antiviral (DAA)-naive patients, of whom 99.4% achieved SVR. Of 353 patients, 10 (2.9%) had treatment failure. Of these patients, eight previously underwent DAA therapy, and the remaining two had NS5A-L31/Y93 double mutation. The SVR rate was 50% (8/16 patients) in patients who previously underwent DAA therapy, and 18.2% (2/11 patients) in patients with NS5A-L31/Y93 double mutation. On multivariate logistic regression analysis, NS5A-Y31/Y93 double mutation (odds ratio 356.3; 95% confidence interval, 23.91-16 940; P

The present study explored the treatment outcome of daclatasvir (DCV) and asunaprevir (ASV) therapy combining oral direct-acting antiviral agents (DAAs) for chronic hepatitis C (HCV) including liver cirrhosis according to resistance-associated variants (RAVs) in NS3/NS5A region. Overall, 641 patients enrolled in Japan with HCV-1b received DCV and ASV for 24 weeks. Baseline drug-resistant mutations L31F/I/M/V, Q54H, P58S, A92K, and Y93H in the HCV NS5A region and V36A, T54A/S, Q80K/L/R, R155K/T/Q, A156S/V/T, and D168A/E/H/T/V in the HCV NS3/4A region were assessed by direct sequencing. Overall, 86.9 % (543/625) of patients had SVR12, which was significantly higher in NS5A 93Y (wild) (88.3 %) compared with NS5A 93H at baseline (48.0 %), indicating the SVR12 rate was significantly lower in patients with 93H mutations. Additionally, 66.7 % (18/27) of patients with prior triple therapy including simeprevir (SMV) failure had virological failure. The virological failure rate of DCV/ASV therapy after SMV failure was significantly higher in those with preexisting NS3/4A 168 substitutions compared with without substitutions at baseline [84.2 % (16/19) vs. 28.6 % (2/7), p = 0.014]. The number of patients with multiple RAVs or deletions in NS5A increased from 0 to 85 % in failed patients. Alanine aminotransferase elevation was a frequent adverse event causing discontinuation of DCV/ASV therapy, although 87.5 % (14/16) patients achieved SVR12, subsequently. History of SMV therapy and pre-existing NS5A Y93H were associated with virological failure of DCV/ASV therapy, resulting in the emergence of multiple RAVs. Patients with RAVs at baseline should be assessed to optimize future DAA therapies.

548 Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. We conducted a nationwide multicenter study and especially focused on the efficacy and safety in the patients with intermediate-stage u-HCC. Methods: A total of 240 patients received LEN from March 2018 at 15 sites in Japan was enrolled. Tumour assessments in accordance with modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Results: In this study, 88 of 240 (36.7%) patients were BCLC stage B. Among them 76 (86.3%) patients received TACE before LEN and the median number of TACE was 2 (1-10). Only 4 patients were TKI experienced and other 84 (95.5%) patients received LEN as a 1st line therapy. The median pretreatment ALBI score was -2.35 and 75 (85.2%) patients were Child-Pugh A. In this cohort, 73 (83.0%) patients were beyond up-to-seven criteria and the median pretreatment AFP was 38.2 (2-12870) ng/mL. The median observation time was 8.5 months and 16 patients died. The median progression free survival was 8.7 months, and the median overall survival (OS) was not reached. Objective response rate (ORR) and disease control rate (DCR) were 48.5% and 80.3%. AFP decrease ( > 20%) after 1 month was observed in 52 (59.0%) patients. Child-Pugh B patients (n = 13) had significantly shorter OS than Child-Pugh A (p = 0.02) and median OS in Child-Pugh B patients was 8.8 months. The patients received > 6 times TACE before LEN had significantly shorter OS than patients received ≤ 6 times TACE (p = 0.02). Additional TACE was performed in 8 patients and The median time of restarting LEN was 19 days. The median ALBI score before additional TACE, Day 1 after TACE and Day 28 after TACE were -2.38, -2.07, and -2.36.There was no severe adverse event associated with additional TACE. The median duration of LEN in patients treated with LEN and additional TACE was 8.5 months. Conclusions: The ORR and DCR of LEN in Child-Pugh A patients with intermediate-stage HCC were 46.6% and 79.3%. The therapeutic strategies for intermediate-stage HCC should be discussed based on the liver function, tumor states, and treatment course about TACE.

AIM This study aimed to describe the real-world efficacy and safety of sofosbuvir (SOF) + ribavirin (RBV) for chronic hepatitis C, genotype 2. METHODS This was a retrospective analysis of a nationwide, multicenter registry including 914 hepatitis C genotype 2 Japanese patients treated with SOF + RBV for 12 weeks. The rate of sustained virologic response at 12 weeks after treatment (SVR12), incidence of adverse events, and changes in serological parameters were analyzed. RESULTS Treatment was completed in 98.9% of patients. Ribavirin dose reduction was required in 29.7% of patients. The SVR12 rate was 96.8% in the intention-to-treat population and 97.6% in the per-protocol population. Factors associated with SVR12 were absence of advanced fibrosis (odds ratio, 5.76, P = 0.003) and interferon-treatment-naive status (odds ratio, 4.79, P = 0.017). Dose reduction or total adherence of RBV was not associated with SVR. The resistance-associated substitution S282 T in NS5B was not detected in any patient at virologic failure. Serum albumin levels significantly increased, and the degree of increase was greater in patients with advanced fibrosis than in those without (0.21 ± 0.32 vs. 0.05 ± 0.29, P

We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection. This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC). Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP-L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 ± 37.6 to 6.0 ± 10.6 ng/mL, p

Background and aim This study aimed to elucidate whether interferon (IFN)-free direct-acting antiviral (DAA) therapy for hepatitis C after curative treatment of hepatocellular carcinoma (HCC) promotes HCC recurrence in a real-world large-scale cohort. Methods This multicenter study was conducted by the Japanese Red Cross Hospital Liver Study Group. This retrospective study analyzed 516 patients who underwent antiviral treatment for hepatitis C with either IFN (n = 148) or IFN-free DAA (n = 368) after curative HCC treatment; 78 IFN-treated patients and 347 IFN-free DAA-treated patients achieved sustained virological response (SVR). The recurrence rate of HCC was compared between the antiviral therapies. Logistic analysis and Cox proportional hazards analysis identified factors associated with early recurrence of HCC within 24 weeks of antiviral therapy and recurrence throughout the observation period, respectively. Results AFP at the completion of antiviral therapy, clinical stage of HCC, and non-SVR were independent factors associated with early recurrence of HCC. Among patients who had achieved SVR, the clinical stage of HCC and the level of AFP at completion of antiviral therapy were independent factors associated with early recurrence of HCC. For recurrence throughout the observation period in SVR patients, AFP at completion of antiviral therapy, duration between last HCC treatment to antiviral therapy, and the number of treatments were independent factors. There was no significant difference in the rate of early recurrence of HCC or recurrence throughout the observation period between IFN and IFN-free DAA treated patients. Conclusions There were no differences in the early recurrence rate of HCC between patients who underwent IFN and those who underwent IFN-free DAA as antiviral therapies.

To evaluate the virologic responses and clinical course of daclatasvir plus asunaprevir treatment in non-hemodialysis (non-HD) and hemodialysis (HD) patients infected with genotype 1 hepatitis C virus (HCV).A total of 1113 non-HD patients and 67 HD patients were assessed. To evaluate pretreatment factors contributing to sustained virological response at 12 weeks (SVR12), univariate and multivariate analyses were carried out. To adjust for differences in patient background, propensity score matching was undertaken.The overall SVR12 rates were 91.6% in non-HD patients and 95.5% in HD patients. Compared with non-HD patients, HD patients were younger, were more likely to be male, were less likely to have received interferon-based pretreatment, had a lower viral load, and had lower levels of alanine transaminase, hemoglobin, and α-fetoprotein. Multivariate analysis revealed that viral load, α-fetoprotein, L31 substitution negative, and Y93 substitution negative were independent predictive factors for SVR12 in non-HD patients. The proportion of patients with undetectable HCV-RNA during the initial 4 weeks was significantly higher in HD patients than in non-HD patients. The SVR12 rate was clearly higher in HD patients than in non-HD patients, although the difference was not statistically significant. After propensity score matching to adjust for viral load, α-fetoprotein, L31 substitution, and Y93 substitution, these trends disappeared.For treatment of HCV genotype 1 infection, daclatasvir plus asunaprevir is useful not only in non-HD patients but also in HD patients. Viral load, α-fetoprotein levels, L31 substitution, and Y93 substitution influence treatment course and outcome.

We report a case of a 70-year-old man with acute acalculous cholecystitis caused by Giardia lamblia. Contrast-enhanced computed tomography (CT) showed distention of the gallbladder due to a pericholecystic abscess without gallstones. Magnetic resonance cholangiopancreatography and drip infusion cholecystocholangiography-CT demonstrated a stricture of the hilar bile duct and cystic duct obstruction. We conducted transpapillary bile duct brush cytology and a biopsy of the hilar bile duct stricture; numerous active trophozoites of Giardia lamblia were observed without malignant findings. We considered this bile duct lesion to be biliary giardiasis. Biliary giardiasis should be taken into consideration when diagnosing acute acalculous cholecystitis.

This study explored treatment outcomes of sofosbuvir (SOF)/ledipasvir (LDV) therapy for chronic hepatitis C patients with and without prior daclatasvir (DCV)/asunaprevir (ASV) therapy.Overall, 530 Japanese patients who were infected with hepatitis C virus genotype 1 received SOF/LDV therapy for 12 weeks, and resistance-associated variants (RAVs) in the hepatitis C virus non-structural protein (NS)5A and NS5B regions were assessed at baseline and virological relapse by direct sequencing.Sustained virological response (SVR) rates did not significantly differ between patients with and without NS5A Y93H/N (94.2% [113/120] vs. 97.7% [345/353]), but the SVR rate was significantly lower in patients with prior DCV/ASV therapy compared to those without (69.2% [18/26] vs. 98.4% [496/504], P 0.001). Among 26 patients with prior DCV/ASV therapy, the prevalence of NS5A multi-RAVs (≥2) was similar between responders and non-responders (61% [11/18] vs. 75% [5/8]), but all patients without RAVs achieved SVR. Multivariate analysis showed that prior DCV/ASV therapy and history of hepatocellular carcinoma were independently associated with treatment failure (odds ratio, 37.55; 95% confidence interval, 10.78-130.76; P 0.001 for prior DCV/ASV therapy; odds ratio, 4.42; 95% confidence interval, 1.09-18.04; P = 0.03 for the history of HCC). All SOF/LDV failure patients (n = 8) with prior DCV/ASV treatment had two or more factors of cirrhosis, IL28B unfavorable genotype, and baseline NS5A multi-RAVs. The multiple NS5A RAVs had increased but NS5B substitutions, C316N/A207T/A218S or L159F, had not changed at the time of relapse.Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.

Aim Some patients develop hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy even if alanine aminotransferase (ALT) or hepatitis B virus (HBV) DNA levels are sufficiently reduced. The aim of this study is to identify the risk factors of development of HCC during NA therapy. Methods Six hundred and two patients were analyzed who were continuously receiving NA for chronic HBV infection. The patients who developed HCC previously or within 1 year of therapy were excluded. In the patients studied, the median duration of therapy was 90 months. A total of 492 patients had chronic hepatitis (CH) and 110 had liver cirrhosis (LC). Results In 602 patients, the rate of normalization of ALT, loss of serum HBV DNA and development of HCC were 90.4%, 55.4%, and 6.1%, respectively. The significant risk factors of development of HCC were LC status and duration of therapy. The annual incidence of HCC in LC patients was 2.53%/year, compared with 0.34%/year in CH patients. When the relation between the incidence of HCC and the response to therapy was evaluated, in patients with normalization of ALT level, loss of HBV DNA by real-time polymerase chain reaction or hepatitis B e-antigen seroconversion, the incidences of HCC was reduced to some extent. However, none of the patients who achieved hepatitis B surface antigen (HBsAg) seroclearance during NA therapy developed HCC. Conclusion LC status was the significant risk factor of development of HCC during NA therapy. However, none of the patients who showed HBsAg seroclearance developed HCC. The ultimate goal of therapy for reduced risk of HCC may be HBsAg seroclearance.

AIM Several studies have shown that high pretreatment concentrations of serum interferon-γ-inducible protein-10 (IP-10) are correlated with non-response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC). However, there are few reports on their effect on the Asian population. METHODS We enrolled 104 Japanese genotype 1 CHC individuals treated with PEG-IFN/RBV and 45 with PEG-IFN/RBV/telaprevir, and evaluated the impact of pretreatment serum IP-10 concentrations on their virological responses. RESULTS The pretreatment serum IP-10 concentrations were not correlated with IL28B genotype. The receiver-operator curve analysis determined the cut-off value of IP-10 for predicting a sustained virological response (SVR) as 300 pg/mL. In multivariate analysis, the IL28B favorable genotype and IP-10 concentration of less than 300 pg/mL were independent factors for predicting SVR. In a subgroup of patients with the IL28B favorable genotype, the SVR rate was higher in the patients with IP-10 of less than 300 than in those with 300 pg/mL or more, whereas no patient with the IL28B unfavorable genotype and IP-10 of 300 pg/mL or more achieved SVR. Among the patients treated with PEG-IFN/RBV/telaprevir, low pretreatment concentrations of serum IP-10 were associated with a very rapid virological response, defined as undetectable HCV RNA at week 2 after the start of therapy. CONCLUSION Pretreatment serum IP-10 concentrations are associated with treatment efficacy in PEG-IFN/RBV and with early viral kinetics of hepatitis C virus in PEG-IFN/RBV/telaprevir therapy.

364 Background: Lenvatinib(LEN) has been approved as a single agent for patients with unresectable hepatocellular carcinoma (u-HCC) since Mar 2018 in Japan. A few results from a large sample size cohort of LEN therapy in real world practice has been reported. Therefore, we performed a retrospective nationwide multicenter study. Methods: A total of 116 u-HCC patients received LEN from March 2018 at 14 sites in Japan were registered. Tumour assessments in accordance with RECICT ver1.1 and modified RECIST were done using dynamic CT or MRI within 4-8 weeks and every 6-8 weeks thereafter. Adverse events (AEs) were graded according to the CTCAE ver4.0. Results: Median age was 72 (46-91)years, 88 (75.9%) patients were male, and median body weight was 60 (30-94) kg. The baseline liver function was Child-Pugh class A in 106 (91.4%) patients. Seventy-three (62.9%) patients were BCLC stage C. As the 2nd-line therapy (after sorafenib), 28 (24.1%) patients received LEN and 17 (14.7%) patients did as the 3rd-line (after regorafenib). Median observation time was 2.5 months and one patient died from HCC progression. The imaging findings of 49 (42.2%) patients were evaluated at 4-8weeks. Based on mRECIST, CR was shown in 3 (6.1%), PR in 14 (28.6%), SD in 23 (46.9%), and PD in 6 (12.2%). In the 3 patients, target lesions of liver showed PR, however bone metastases had progressed. [overall response rate (ORR) 34.7%, disease control rate (DCR) 81.6%]. ORR and DCR of tyrosine kinase inhibitor (TKI) naïve patients (n = 26) were 34.6% and 80.8%, while those of TKI experienced (n = 23) were 34.8% and 82.6%. The most common any-grade AEs were hypertension (52.0%), diarrhoea (32.1%), decreased appetite (63.5%) and fatigue (49.4%). Hand-food skin reaction (HFSR) was observed in 28% of patients. Conclusions: The efficacy of LEN therapy in real world practice in Japan was similar to the phase 3 clinical trial, even though elderly patients with lower body weight were included in this study. The incidence of HFSR during LEN in real world practice was lower than that of the sorafenib group in the phase 3 trial of LEN. Decrease appetite and fatigue must be carefully monitored and managed during LEN therapy.

Summary Inosine triphosphatase (ITPA) genetic variants are strongly associated with ribavirin (RBV)-induced anaemia during pegylated interferon (PEG-IFN) plus RBV therapy. However, the treatment efficacy of ITPA genetic variants has not been fully explored. We enrolled 309 individuals infected with hepatitis C virus genotype 1, who were treated with PEG-IFN plus RBV for 48 weeks. The ITPA SNP: rs1127354 and IL28B SNP: rs8099917 were genotyped. We examined the risk factors for severe anaemia up to week 12 after the start of treatment and treatment efficacy. The incidence of severe anaemia, ≥3 g/dL reduction or

Background and Aims Liver biopsy is the gold standard test to determine the grade of fibrosis, but there are associated problems. Because gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid is secreted partially in hepatocytes and bile, it is possible that ethoxybenzyl-magnetic resonance imaging (EOB-MRI) correlates with liver function and liver fibrosis. The aim of this study was to compare the fibrosis seen in liver biopsy samples to the signal intensity of the hepatobiliary phase measured on EOB-MRI in hepatitis C virus (HCV)-infected patients. Methods Two hundred twenty-four (estimation 149, validation 75) HCV-infected patients with histologically proven liver tissue who underwent EOB-MRI were studied. Overall, fibrosis staging was 15/24/19/46/45 for F0/F1/F2/F3/F4, respectively. A 1.5-Tesla magnetic resonance system was used, and the regions of interest of the liver were measured. Four methods were used: (i) relative enhancement: (post-enhanced signal intensity [SI] − pre-enhanced intensity)/pre-enhanced intensity; (ii) liver-to-intervertebral disk ratio (LI): post-enhanced (liver SI/interdisc SI)/pre-enhanced (liver SI/inter disc SI); (iii) liver-to-muscle ratio: post-enhanced (liver SI/muscle SI)/pre-enhanced (liver SI/muscle SI); and (iv) liver-to-spleen ratio: post-enhanced (liver SI/spleen SI)/pre-enhanced (liver SI/spleen SI). Results To discriminate F0-1 versus F2-4 or F0-2 versus F3-4 or F0-3 versus F4, LI at 25 min (LI25) had the highest area under receiver operating characteristic (0.88, 0.87, and 0.87, respectively) in these four methods and also in the validation set. Conclusion LI at 25 min seems to be a useful method to determine the staging of fibrosis as a non-invasive method in HCV-infected hepatitis or cirrhosis patients.

Background Patients with active upper gastrointestinal bleeding (UGIB) require urgent endoscopy, but appropriate criteria for urgent endoscopy in these patients have not yet been established.

Summary Hepatitis B surface antigen (HBsAg) reduction during nucleoside/nucleotide analogue (NA) therapy is slow and an alternative strategy for patients receiving ongoing NA to facilitate HBsAg reduction is required. We investigated whether switching to pegylated interferon (PEG-IFN) after long-term NA administration enhances HBsAg reduction. Forty-nine patients who switched from long-term NA to 48 weeks of PEG-IFN alfa-2a were studied. The mean duration of previous NA was 48 months (sequential group). A total of 147 patients who continued NA and matched for baseline characteristics were analysed for comparison (NA continuation group). The treatment response was defined as HBsAg reduction ≥1.0 logIU/mL at the end of PEG-IFN. HBsAg reduction at week 48 was 0.81±1.1 logIU/mL in the sequential group, which was significantly higher than that in the NA continuation group (0.11±0.3 logIU/mL, P

Background & Aims There is still a risk for hepatocellular carcinoma (HCC) development after eradication of hepatitis C virus (HCV) infection with antiviral agents. We investigated genetic factors associated with the development of HCC in patients with a sustained virologic response (SVR) to treatment for chronic HCV infection. Methods We obtained genomic DNA from 457 patients in Japan with a SVR to interferon-based treatment for chronic HCV infection from 2007 through 2015. We conducted a genome-wide association study (GWAS), followed by a replication analysis of 79 candidate single nucleotide polymorphisms (SNPs) in an independent set of 486 patients in Japan. The study end point was HCC diagnosis or confirmation of lack of HCC (at follow-up examinations until December 2014 in the GWAS cohort, and until January 2016 in the replication cohort). We collected clinical and laboratory data from all patients. We analyzed expression levels of candidate gene variants in human hepatic stellate cells, rats with steatohepatitis caused by a choline-deficient L-amino acid-defined diet, and a mouse model of liver injury caused by administration of carbon tetrachloride. We also analyzed expression levels in liver tissues of patients with chronic HCV infection with different stages of fibrosis or tumors vs patients without HCV infection (controls). Results We found a strong association between the SNP rs17047200, located within the intron of the tolloid like 1 gene ( TLL1 ) on chromosome 4, and development of HCC; there was a genome-wide level of significance when the results of the GWAS and replication study were combined (odds ratio, 2.37; P = 2.66 × 10 −8 ). Multivariate analysis showed rs17047200 AT/TT to be an independent risk factor for HCC (hazard ratio, 1.78; P = .008), along with male sex, older age, lower level of albumin, advanced stage of hepatic fibrosis, presence of diabetes, and higher post-treatment level of α-fetoprotein. Combining the rs17047200 genotype with other factors, we developed prediction models for HCC development in patients with mild or advanced hepatic fibrosis. Levels of TLL1 messenger RNA (mRNA) in human hepatic stellate cells increased with activation. Levels of Tll1 mRNA increased in liver tissues of rodents with hepatic fibrogenesis compared with controls. Levels of TLL1 mRNA increased in liver tissues of patients with progression of fibrosis. Gene expression levels of TLL1 short variants, including isoform 2, were higher in patients with rs17047200 AT/TT. Conclusions In a GWAS, we identified the association between the SNP rs17047200, within the intron of TLL1 , and development of HCC in patients who achieved an SVR to treatment for chronic HCV infection. We found levels of Tll1/TLL1 mRNA to be increased in rodent models of liver injury and liver tissues of patients with fibrosis, compared with controls. We propose that this SNP might affect splicing of TLL1 mRNA, yielding short variants with high catalytic activity that accelerates hepatic fibrogenesis and carcinogenesis. Further studies are needed to determine how rs17047200 affects TLL1 mRNA levels, splicing, and translation, as well as the prevalence of this variant among other patients with HCC. Tests for the TLL1 SNP might be used to identify patients at risk for HCC after an SVR to treatment of HCV infection.

症例は33歳男性．B型肝炎無症候性キャリアの経過観察中に悪性リンパ腫を発症し，2001年よりラミブジン（LVD）投与が開始された．2005年にbreakthrough hepatitisを発症し，アデフォビル（ADV）追加併用療法に移行した．2007年にはエンテカビル（ETV）単独治療へ変更された．2008年，2回目のbreakthrough hepatitisと悪性リンパ腫の再発を認め，再度LVD+ADV併用療法に変更した．しかし，ALT上昇とウイルス量高値が持続したため，耐性検査が実施された．L80I，L180M，A181T，T184I，M204I/Vの変異を確認し，多剤耐性変異と判断した．倫理委員会承認のもと，テノフォビル（TDF）+LVD併用療法を開始し，ウイルス量の低下と肝炎の改善が得られた．合併する悪性リンパ腫に対して，化学療法後にB型肝炎キャリアである実兄から同種骨髄移植を施行した．移植後ドナー由来の野生株によるウイルス血症を呈したが，治療継続により改善した．今回，多剤耐性変異株，かつドナー由来の野生株ウイルスに対し，TDFが著効した症例を経験したため報告する．

Aim: In the 2007–2008 guidelines of the study group (Ministry of Health, Labor and Welfare of Japan), lamivudine (LAM)-continuous treatment was recommended in patients treated with LAM for more than 3 years who maintained hepatitis B virus (HBV) DNA less than 2.6 log copies/mL, because in these patients LAM resistance might exist and switching treatment to entecavir (ETV) might cause ETV resistance. However, there was no evidence on whether switching treatment to ETV- or LAM-continuous treatment was better in those patients. In the present study, we performed a randomized controlled trial of LAM-to-ETV switching treatment. Methods: Twenty-seven patients treated with LAM for more than 3 years whose HBV DNA levels were less than 2.6 log copies/mL were enrolled and randomly divided into two groups, LAM-continued group or switching to ETV group. Then, we examined incidence of virological breakthrough (VBT) and breakthrough hepatitis (BTH) in each group. Results: There was no BTH in any of the patients. VBT was observed in six patients of the LAM group (6/15, 40%), and no patient of the ETV group (0/11, 0%) (P = 0.02). The differences of the proportion of cumulated VBT using a log–rank test with Kaplan–Meier analysis were significant between the LAM and ETV groups (P = 0.025). Conclusion: In patients treated with LAM for more than 3 years maintaining HBV DNA less than 2.6 log copies/mL, switching treatment to ETV is recommended at least during the 2 years' follow-up period.

Aim: Non-alcoholic steatohepatitis (NASH) may progress to liver cirrhosis, and NASH patients with liver cirrhosis are at risk of developing hepatocellular carcinoma. Statins, 3-hydroxy-3-methyglutaryl-coenzyme A reductase inhibitors, are well known to reduce low-density lipoprotein cholesterol and reduce the incidence of coronary heart disease and other major vascular events by anti-inflammatory and antifibrotic effects, and antiproliferative properties in colorectal cancers have also been reported. Recently, statins have been reported to improve hepatic steatosis; however, the effect on fibrosis is controversial. Methods: The effects of pitavastatin (one of the strongest statins) were examined using a choline-deficient L-amino acid-defined (CDAA) diet liver fibrosis model. Results: Pitavastatin significantly attenuated increases in serum aspartate aminotransferase, alanine aminotransferase, hepatic steatosis, oxidative stress, pre-neoplastic lesions (glutathione S-transferase placental form-positive lesions), expression of cytokines, such as tumor necrosis factor-α and transforming growth factor-β1, and the expression of tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2 and type I procollagen genes followed by attenuating fibrosis of the liver of CDAA-fed rats. Conclusion: These results indicate that pitavastatin may inhibit steatosis, hepatic fibrosis and carcinogenesis in rat model of NASH.

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

Biochemical responders maintain normal alanine aminotransferase levels after interferon (IFN) therapy despite persistent presence of hepatitis C virus (HCV) RNA in their sera. There have been few reports on predictive factors for biochemical response. A region associated with sensitivity to IFN was identified in the nonstructural protein 5 A of genotype 1b [aa 2209-2248; IFN sensitivity-determining region (ISDR)]. The substitutions in ISDR correlate with sustained response to IFN. In this report, we assessed the association of ISDR with biochemical response. The sequences of ISDR were determined in 62 patients with HCV genotype 1b treated by IFN in two randomized controlled trials. 30 patients had wild ISDR (identical to HCV-J), 20 intermediate ISDR (1-3 amino acid substitutions compared with HCV-J), and 12 mutant ISDR (four or more amino acid substitutions). All 12 patients with mutant ISDR had a sustained response, while only one of those with wild or intermediate ISDR had a sustained response (P < 0.0001). In the 49 patients other than sustained responders, the patients with intermediate ISDR obtained biochemical response significantly more frequently (52.6%, 10/19) than those with wild-type ISDR (20.0%, 6/30) (P < 0.05). Multivariate analysis indicated the number of substitutions in ISDR as the most important predictor for biochemical response (discriminant coefficient=1.08, P < 0.05) and sustained response (discriminant coefficient=6.13, P < 0.0001). In phylogenetic analysis, clustering of sustained responders and biochemical responders was observed. These results demonstrate that the substitutions in ISDR are the most important predictor for biochemical response to IFN in patients infected with genotype 1b as well as for sustained response.

Several studies have shown that high pretreatment concentrations of serum interferon-γ-inducible protein-10 (IP-10) are correlated with non-response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC). However, there are few reports on their effect on the Asian population.We enrolled 104 Japanese genotype 1 CHC individuals treated with PEG-IFN/RBV and 45 with PEG-IFN/RBV/telaprevir, and evaluated the impact of pretreatment serum IP-10 concentrations on their virological responses.The pretreatment serum IP-10 concentrations were not correlated with IL28B genotype. The receiver-operator curve analysis determined the cut-off value of IP-10 for predicting a sustained virological response (SVR) as 300 pg/mL. In multivariate analysis, the IL28B favorable genotype and IP-10 concentration of less than 300 pg/mL were independent factors for predicting SVR. In a subgroup of patients with the IL28B favorable genotype, the SVR rate was higher in the patients with IP-10 of less than 300 than in those with 300 pg/mL or more, whereas no patient with the IL28B unfavorable genotype and IP-10 of 300 pg/mL or more achieved SVR. Among the patients treated with PEG-IFN/RBV/telaprevir, low pretreatment concentrations of serum IP-10 were associated with a very rapid virological response, defined as undetectable HCV RNA at week 2 after the start of therapy.Pretreatment serum IP-10 concentrations are associated with treatment efficacy in PEG-IFN/RBV and with early viral kinetics of hepatitis C virus in PEG-IFN/RBV/telaprevir therapy.

Shunsuke Nojiri,1 Atsunori Kusakabe,1 Kei Fujiwara,1 Noboru Shinkai,1 Kentaro Matsuura,1 Etsuko Iio,1 Tomokatsu Miyaki,1 Tomoyuki Nomura,2 Satoshi Sobue,3 Hitoshi Sano,4 Izumi Hasegawa,5 Tomoyoshi Ohno,5 Yoshitsugu Takahashi,6 Etsuro Orito,7 Takashi Joh11Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, 2Inabe General Hospital, Inabe, 3Kasugai Municipal Hospital, Kasugai, 4Tajimi Prefectural Hospital, Tajimi, 5Social Chukyo Insurance Hospital, Nagoya, 6Chita Kousei Hospital, Aichi-ken, 7Nagoya Daini Red Cross Hospital, Showa-ku, JapanBackground: Sorafenib has been approved in the indication of unresectable hepatocellular carcinoma, but there are many cases in which administration of the drug is discontinued due to severe side effects. In this study, we compared the characteristics of patients who continued and discontinued sorafenib.Methods: Ninety-six patients (75 men and 21 women) were initiated on sorafenib from July 2009 through September 2011. The patient characteristics of interest included gender, age, etiology, Child-Pugh classification, treatment history and frequency, and levels of α-fetoprotein, des-gamma-carboxy prothrombin, aspartate amino acid transferase, and alanine aminotransferase. Duration of administration of sorafenib and reasons for its discontinuation were compared.Results: Median overall survival was 11.8 months. Discontinuation of sorafenib within 90 days was identified as an independent prognostic factor for overall survival on multivariate analysis (P < 0.0001). Transarterial chemoembolization performed six times or more (P = 0.013) was also identified as an independent factor contributing to discontinuation of sorafenib within 90 days in multivariate analysis. Patients who received sorafenib for ≥90 days had significantly longer overall survival than those who discontinued it (P < 0.0001).Conclusion: Prolonged treatment with sorafenib is an important factor in achieving extended overall survival. We recommend starting sorafenib before latent liver damage has occurred as a result of too many transarterial chemoembolization procedures.Keywords: sorafenib, hepatocellular continuation, discontinuation, efficacy