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Cholangiocarcinoma (CC) has a poor prognosis and different driver genes depending on the site of onset. Intrahepatic CC is the second‐most common liver cancer after hepatocellular carcinoma, and novel therapeutic targets are urgently needed. The present study was conducted to identify novel therapeutic targets by exploring differentially regulated genes in human CC. MicroRNA (miRNA) and mRNA microarrays were performed using tissue and serum samples obtained from 24 surgically resected hepatobiliary tumor cases, including 10 CC cases. We conducted principal component analysis to identify differentially expressed miRNA, leading to the identification of miRNA‐3648 as a differentially expressed miRNA. We used an in silico screening approach to identify its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). SKI protein expression was decreased in human CC cells overexpressing miRNA‐3648, endogenous SKI protein expression was decreased in human CC tumor tissues, and endogenous SKI mRNA expression was suppressed in human CC cells characterized by rapid growth. SKI‐overexpressing OZ cells (human intrahepatic CC cells) showed upregulation of cyclin‐dependent kinase inhibitor p21 mRNA and protein expression and suppressed cell proliferation. Nuclear expression of CDT1 (chromatin licensing and DNA replication factor 1), which is required for the G1/S transition, was suppressed in SKI‐overexpressing OZ cells. SKI knockdown resulted in the opposite effects. Transgenic p21‐luciferase was activated in SKI‐overexpressing OZ cells. These data indicate SKI involvement in p21 transcription and that SKI–p21 signaling causes cell cycle arrest in G1, suppressing intrahepatic CC cell growth. Therefore, SKI may be a potential therapeutic target for intrahepatic CC.

Abstract Background and Aim We evaluated the efficacy of rechallenge transcatheter arterial chemoembolization (TACE) after lenvatinib (LEN) treatment in patients with previous TACE failure/refractoriness. Methods We enrolled 63 consecutive patients with a history of TACE failure/refractoriness prior to LEN treatment as a first‐line systemic therapy. We reviewed the clinical backgrounds and courses of the patients. Results In total, 25 patients underwent rechallenge TACE after LEN due to LEN‐refractoriness (17 cases) or intolerance (8 cases). A complete or partial response was obtained for 13 (65.0%) of the 20 patients whose therapeutic effects were determined. The survival rate of patients who underwent rechallenge TACE was significantly higher than that of patients who did not undergo rechallenge TACE (median survival time, not reached vs 403 days, P = 0.015). Rechallenge TACE significantly reduced the risk of death in univariate (hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.08–0.69, P = 0.008) and multivariate analyses (HR 0.26, 95% CI 0.08–0.80, P = 0.019). If complete or partial response was obtained by rechallenge TACE, the median survival time of these patients was significantly longer than those of the progressive disease (PD) group (P = 0.05), and the median survival time of the PD group after rechallenge TACE was not different from that of the group who did not undergo rechallenge TACE (P = 0.36). We did not observe a decrease in the ALBI score after TACE. Conclusion Rechallenge TACE after LEN is an effective treatment that may result in a favorable prognosis.

Abstract Soluble immune checkpoint molecules are emerging novel mediators of immune regulation. However, it is unclear whether soluble immune checkpoint proteins affect the development of hepatocellular carcinoma (HCC) during nucleos(t)ide analogue (NA) treatment in patients with chronic hepatitis B virus infection. This study included 122 NA-naïve patients who received NA therapy. We assessed the associations of clinical factors, including soluble immune checkpoint proteins, with HCC development during NA treatment. The baseline serum concentrations of 16 soluble immune checkpoint proteins were measured using multiplexed fluorescent bead-based immunoassay. In total, 13 patients developed HCC during the follow-up period (median duration, 4.3 years). Of the 16 proteins, soluble inducible T-cell co-stimulator (≥ 164.71 pg/mL; p = 0.014), soluble programmed cell death-1 (sPD-1) (≤ 447.27 pg/mL; p = 0.031), soluble CD40 (≤ 493.68 pg/mL; p = 0.032), and soluble herpes virus entry mediator (≤ 2470.83 pg/mL; p = 0.038) were significantly associated with HCC development (log-rank test). In multivariate analysis, an sPD-1 level ≤ 447.27 pg/mL (p = 0.014; hazard ratio [HR], 4.537) and α-fetoprotein level ≥ 6.4 ng/mL (p = 0.040; HR, 5.524) were independently and significantly associated with HCC development. Pre-treatment sPD-1 is a novel predictive biomarker for HCC development during NA treatment.

It is not fully clear as to which dietary patterns are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD) in Asia. We conducted a cross-sectional study of 136 consecutively recruited patients with NAFLD (49% female, median age 60 years). Severity of liver fibrosis was assessed using the Agile 3+ score, a recently proposed system based on vibration-controlled transient elastography. Dietary status was assessed using the 12-component modified Japanese diet pattern index (mJDI12). Skeletal muscle mass was assessed by bioelectrical impedance. Factors associated with intermediate–high-risk Agile 3+ scores and skeletal muscle mass (75th percentile or higher) were analyzed by multivariable logistic regression. After adjustment for confounders, such as age and sex, the mJDI12 (OR: 0.77; 95% CI: 0.61, 0.99) and skeletal muscle mass (75th percentile or higher) (OR: 0.23; 95% CI: 0.07, 0.77) were significantly associated with intermediate–high-risk Agile 3+ scores. Soybeans and soybean foods were significantly associated with skeletal muscle mass (75th percentile or higher) (OR: 1.02; 95% CI: 1.00, 1.04). In conclusion, the Japanese diet pattern was associated with the severity of liver fibrosis in Japanese patients with NAFLD. Skeletal muscle mass was also associated with the severity of liver fibrosis, and intake of soybeans and soybean foods.

Abstract Background and Aim We assessed direct‐acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV) and a history of injection drug use (IDU) in Japan. Method This retrospective observational study was based on clinical records. Overall, 804 DAA‐naïve HCV‐infected patients were enrolled, treated with a 12‐week regimen of DAAs, and had available information about a history of IDU. Anti‐HCV efficacy was defined as a sustained viral response 12 weeks post‐treatment (SVR12) only in patients who were assessed after 12 weeks [modified intention‐to‐treat (ITT) analyses]. We compared the antiviral effect between patients with (past‐IDU) and without a history of IDU (non‐IDU). We also evaluated the characteristics of each group, including the overall dropout rate and economic background. Results Overall, 78 (9.7%) patients had a history of IDU. Compared to the non‐IDU group at baseline, the past‐IDU group consisted of predominantly male and younger patients infected with HCV genotype 2. Overall, 3% (3/78) and 16% (116/726) of the patients had cirrhosis in the past‐IDU and non‐IDU group, respectively. There was a significantly higher rate of welfare recipients in the past‐IDU group. SVR rate was 97% (59/61) in the past‐IDU group and 99% (689/699) in the non‐IDU group. The cumulative rate of dropout from an aftercare program was high in the past‐IDU group (P

Background: The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). Material and methods: A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). Results: The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cir-rhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). Conclusion: RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.

Hepatocellular carcinoma (HCC) develops in some patients who achieve sustained virological response (SVR) against hepatitis C virus (HCV) infection via anti-HCV therapy. To examine the pathogenesis of HCC development after HCV eradication, histopathological changes and clinical markers were evaluated in SVR patients.Of 654 SVR patients treated with interferon (IFN)-based therapies, 34 patients who had undergone liver biopsy before initiating IFN therapy and after SVR achievement were enrolled: 11 patients with HCC and 23 patients without HCC (male/female, 9/2 and 8/15, respectively: age, 58 ± 5 and 54 ± 11 years, respectively). We compared the clinical and histopathological factors between the two groups. Immunohistochemistry for Cytoglobin (CYGB) and α smooth muscle actin (α-SMA) was also performed.At baseline, prior to initiating the IFN-based therapy, there were significant differences between the SVR-non-HCC and SVR-HCC groups in the male gender, HBc antibody positivity, prothrombin activity, and histological inflammatory grade. Histopathological evaluation, using the new Inuyama classification system, revealed an improvement in the inflammatory grade, from 2.1 ± 0.6 to 1.0 ± 0.6 (p < 0.0001), whereas the fibrosis stage remained unchanged, from 2.3 ± 0.9 to 2.0 ± 1.2 (p = 0.2749), during the 97 ± 72-month observation period in the SVR-HCC group. Both the grade and stage scores were significantly improved in the SVR-non-HCC group. The area of collagen deposition, evaluated using Sirius red staining, showed a marked decrease, from 18.6 ± 7.6% to 7.7 ± 4.6%, in the SVR-non-HCC group, with no change in the SVR-HCC group. CYGB- and α-SMA-positive hepatic stellate cells (HSCs), indicative of the HSC activated phenotype, remained in the fibrotic tissue of livers among patients in the SVR-HCC group.Stagnation of fibrosis regression is associated with a high risk for HCC after SVR. HSC activation may inhibit improvement in fibrosis after SVR and potentially contribute to hepatocarcinogenesis.

[This corrects the article DOI: 10.1371/journal.pone.0194163.].

Aim. Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (sVR) during combination therapy.Material and methods. This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups.Results. No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR-standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant).Conclusions. TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.

We evaluated the transition of dominant resistance-associated substitutions (RASs) in hepatitis C virus during long-term follow-up after the failure of DAAs (direct acting antivirals)-based therapy. RASs in non-structure (NS)3/4A, NS5A, NS5B, and deletions in NS5A from 20 patients who failed simeprevir/pegylated-interferon/ribavirin (SMV/PEG-IFN/RBV) and 25 patients who failed daclatasvir/asunaprevir (DCV/ASV) treatment were examined by direct sequencing. With respect to SMV/PEG-IFN/RBV treatment, RAS was detected at D168 in NS3/4A but not detected in NS5A and NS5B at treatment failure in 16 of 20 patients. During the median follow-up period of 64 weeks, the RAS at D168 became less dominant in 9 of 16 patients. Among 25 DCV/ASV failures, RASs at D168, L31, and Y93 were found in 57.1%, 72.2%, and 76.9%, respectively. NS5A deletions were detected in 3 of 10 patients treated previously with SMV/PEG-IFN/RBV. The number of RASs in the breakthrough patients exceeded that in relapsers (mean 3.9 vs. 2.7, p < 0.05). RAS at D168 in NS3/4A became less dominant in 6 of 15 patients within 80 weeks. Y93H emerged at the time of relapse, then decreased gradually by 99% at 130 weeks post-treatment. Emerged RASs were associated with the clinical course of treatment and could not be detected during longer follow-up.