Phase I/IIa trial of 18F-prostate specific membrane antigen (PSMA) 1007 PET/CT in healthy volunteers and prostate cancer patients.

OBJECTIVE: 18F-PSMA 1007 is a promising PET tracer for prostate cancer. We aimed to examine the safety, biodistribution, radiation dosimetry, and clinical effectiveness in Japanese healthy volunteers and patients with prostate cancer. METHODS: Part A evaluated the pharmacokinetics and exposure doses in three healthy volunteers. Part B evaluated the diagnostic accuracy in patients with untreated preoperative prostate cancer (Cohort 1, n = 7) and patients with biochemical recurrence (Cohort 2, n = 3). All subjects received a single dose of 3.7 MBq/kg 18F-PSMA 1007. Results: 18F-PSMA 1007 was found to be safe and well tolerated in all subjects. No serous AEs or drug-related AEs were identified during the present study. The average blood radioactivity concentration reached a maximum of 47.87 ± 1.05 (percentage of injected dose [%ID]/ml) at 5 min and then decreased to 1.60 ± 0.78 in 6 h. The systemic radioactivity reached a maximum of 211.05 ± 6.77 (%ID$\times$103) at 5 min and decreased to 7.18 ± 3.91 in 6 h. The sensitivity and positive predictive value were 100% and 100% based on both pathologic and imaging confirmation as gold standard. In Cohort 1, 15 primary foci (11.9%) were >5 mm in the largest diameter and identified in 39 of 126 segments (30.1%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for 60 min uptake time acquisition were 80.0, 96.5, 91.4, 91.2 and 91.3%, respectively. CONCLUSIONS: Our study revealed that 18F-PSMA 1007 was safe, well tolerated and showed high accuracy in the diagnosis of prostate cancer.

Risk factors for hepatocellular carcinoma at baseline and 1 year after initiation of nucleos(t)ide analog therapy for chronic hepatitis B.

Nucleos(t)ide analogs (NAs) cannot completely suppress the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study aimed to identify the risk factors for HCC development in naïve CHB patients treated with current NA. Patients receiving NA (n = 905) were recruited retrospectively from the 17 hospitals of the Japanese Red Cross Liver Study Group. All treatment-naïve patients had been receiving current NA continuously for more than 1 year until the end of the follow-up. We analyzed the accuracy of predictive risk score using the area under receiver operating characteristic curve. The albumin-bilirubin (ALBI) score was significantly improved by NA therapy (-0.171 ± 0.396; p < 0.001 at Week 48). A total of 72 (8.0%) patients developed HCC over a median follow-up of 6.2 (1.03-15.7) years. An independent predictive factor of HCC development was older age, cirrhosis, lower platelet counts at baseline and ALBI score, and alpha-fetoprotein (AFP) at 1 year after NA therapy according to multivariate analysis. The accuracy was assessed using the PAGE-B, mPAGE-B, aMAP, APA-B, and REAL-B scores that included these factors. Discrimination was generally acceptable for these models. aMAP and REAL-B demonstrated high discrimination with 0.866/0.862 and 0.833/0.859 for 3- and 5-year prediction from the status of 1 year after NA therapy, respectively. Baseline age and platelet count, as well as ALBI and AFP one year after NA, were useful for stratifying carcinogenesis risk. The aMAP and REAL-B scores were validated with high accuracy in Japanese CHB patients.

General evaluation score for predicting the development of hepatocellular carcinoma in patients with advanced liver fibrosis associated with hepatitis C virus genotype 1 or 2 after direct-acting antiviral therapy.

Background and Aim: To validate a composite predictive model for hepatocellular carcinoma (HCC) development in patients with advanced liver fibrosis associated with chronic hepatitis C virus (HCV) who have received direct-acting antiviral (DAA) therapy and achieved sustained virologic response (SVR). Methods: This study included 1258 patients with advanced liver fibrosis associated with HCV genotype 1, 2, or both. General evaluation score (GES), which is based on sex, age, fibrosis stage, albumin, and α-fetoprotein, was used as a composite predictive model. Results: There were 645 (51.3%) patients in the low-risk group, 228 (18.1%) in the intermediate-risk group, and 385 (30.6%) in the high-risk group based on GES categories. The 12-, 36-, and 60-month cumulative incidence of HCC was 0.7%, 5.3%, and 13.0%, respectively. Multivariable analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 1.863; 95% confidence interval [CI], 1.204-2.883), F4 fibrosis stage (HR, 3.199; 95% CI, 1.696-6.036), and albumin (HR, 0.489; 95% CI, 0.288-0.828) are independently associated with HCC development. The incidence of HCC differed significantly by GES-based risk category (P < 0.001). Cox proportional hazards models showed that, with the low-risk group as the referent, the HR for HCC development was 1.875 (95% CI, 1.000-3.514) in the intermediate-risk group and 2.819 (95% CI, 1.716-4.630) in the high-risk group. GES had better predictive ability for HCC development than fibrosis-4 index according to time-dependent receiver operating characteristic analysis. Conclusion: GES is useful for predicting HCC development in patients with advanced liver fibrosis after SVR.

Real-World Data on Ramucirumab Therapy including Patients Who Experienced Two or More Systemic Treatments: A Multicenter Study.

BACKGROUND: The present study aimed to clarify the efficacy and safety of ramucirumab in a real-world setting, including patients who experienced two or more systemic treatments or whose hepatic reserve was deteriorated. METHODS: In total, 79 patients with hepatocellular carcinoma (HCC) from 14 institutes throughout Japan were retrospectively analyzed. The response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and AEs were recorded according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. RESULTS: Median overall survival (OS) in the total cohort was 7.5 months (m). Median OS was 8.8 m in patients who were administered ramucirumab as a second-line treatment, while it was 7.3 m in third- or later-line treatment. Progression-free survival rates in the second- and third- or later-line therapies were 3.2 m and 3.2 m, respectively. The disease control rate (DCR) in the study was 43%. There were no statistically significant differences in DCR between the treatment courses. Regarding adverse events (AEs), the development of ascites was observed significantly more frequently in modified albumin-bilirubin (mALBI) 2b/3 patients than in mALBI 1/2a patients (54.5% vs. 25.0%, p = 0.03). CONCLUSIONS: Ramucirumab is useful as a second-line therapy and feasible as a third- or later-line treatment for HCC.

Real-world long-term analysis of daclatasvir plus asunaprevir in patients with hepatitis C virus infection.

Background and Aim: This study aimed to evaluate the long-term clinical course of patients achieving a sustained virologic response (SVR) with daclatasvir plus asunaprevir (DCV/ASV) therapy. Methods: A total of 911 patients who achieved SVR with DCV/ASV were assessed. To evaluate pretreatment factors contributing to hepatocellular carcinoma (HCC) after SVR, univariate and multivariate analyses were performed in all patients, in those with preexisting HCC, and in those without preexisting HCC. We selected a low-risk group of HCC cases after SVR. Finally, we evaluated liver function after achieving SVR. Results: In multivariable analyses, male sex, older age, patients with a history of HCC treatment, excess alcohol use, lower albumin, and low platelet count remained significant in the overall group; male sex and low albumin remained significant in patients with a history of HCC treatment; and male sex, older age, excess alcohol use, low platelet count, high alpha-fetoprotein (AFP), and high des-γ-carboxy prothrombin (DCP) remained significant in those without a history of HCC treatment. Patients who had not received treatment for HCC, females, those under 70 years of age, and those with platelet count ≥13 (×104/µL), AFP <6 ng/mL, and DCP <23 mAU/mL were at low risk of HCC. The process of liver function improvement was different according to the factors. Conclusions: The incidence rate of HCC, risk factors associated with HCC, group with very low risk of developing HCC, and the clinical course in a real-world long-term study were evaluated.

Efficacy of hepatitis C virus eradication after curative treatment for hepatocellular carcinoma in patients with advanced hepatocellular carcinoma and decreased hepatic functional reserve: A nationwide, multicentre study by the Japanese Red Cross Liver Study Group.

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.

A validation study of after direct-acting antivirals recommendation for surveillance score for the development of hepatocellular carcinoma in patients with hepatitis C virus infection who had received direct-acting antiviral therapy and achieved sustained virological response.

BACKGROUND AND AIM: The pathogenic process underlying the development of hepatocellular carcinoma (HCC) is not yet clear in patients with hepatitis C virus (HCV) who have received direct-acting antiviral (DAA) therapy and achieved sustained virological response (SVR). This study validated a composite predictive model for HCC in these patients. METHODS: This study included 3058 patients in whom HCV was eradicated with DAA therapy. After DAAs recommendation for surveillance (ADRES) score, which is based on sex, FIB-4 index, and α-fetoprotein, was used as a composite predictive model for HCC development. RESULTS: The 1-, 3-, and 5-year cumulative incidence rates of HCC were 0.9, 4.5, and 15.2%, respectively. Multivariate analysis with Cox proportional hazards models showed that male sex (hazard ratio [HR], 2.646; 95% confidence interval [CI], 1.790-3.911), FIB-4 index >3.25 (HR, 2.891; 95% CI, 1.947-4.293), and α-fetoprotein >5 ng/mL (HR, 2.835; 95% CI, 1.914-4.200) are independently associated with HCC development. The incidence of HCC differed significantly by ADRES score (P < 0.001). Cox proportional hazards models showed that compared to the ADRES score 0 group, the HR for HCC development was 2.947 (95% CI, 1.367-6.354) in the ADRES score 1 group, 9.171 (95% CI, 4.339-19.380) in the ADRES score 2 group, and 20.630 (95% CI, 8.641-49.230) in the ADRES score 3 group. ADRES score had superior predictive power for HCC development compared with the FIB-4 index and α-fetoprotein according to time-dependent receiver operating characteristic analysis. CONCLUSION: The ADRES score is useful for predicting HCC development after SVR.

Hepatocellular Carcinoma Risk Assessment for Patients With Advanced Fibrosis After Eradication of Hepatitis C Virus.

The identification of patients with advanced fibrosis who do not need any further hepatocellular carcinoma (HCC) surveillance after the eradication of hepatitis C is pivotal. In this study, we developed a simple serum-based risk model that could identify patients with low-risk HCC. This was a nationwide multicenter study involving 16 Hospitals in Japan. Patients with advanced fibrosis (1,325 in a derivation cohort and 508 in a validation cohort) who achieved sustained virological responses at 24 weeks after treatment (SVR24) were enrolled. The HCC risk model at any point after SVR24 and its change were evaluated, and subsequent HCC development was analyzed. Based on the multivariable analysis, patients fulfilling all of the factors (GAF4 criteria: gamma-glutamyl transferase < 28 IU/L, alpha-fetoprotein < 4.0 ng/mL, and Fibrosis-4 Index < 4.28) were classified as low-risk and others were classified as high-risk. When patients were stratified at the SVR24, and 1 year, and 2 years after SVR24, subsequent HCC development was significantly lower in low-risk patients (0.5-1.1 per 100 person-years in the derivation cohort and 0.9-1.1 per 100 person-years in the validation cohort) than in high-risk patients at each point. HCC risk from 1 year after SVR24 decreased in patients whose risk improved from high-risk to low-risk (HCC incidence: 0.6 per 100 person-years [hazard ratio (HR) = 0.163 in the derivation cohort] and 1.3 per 100 person-years [HR = 0.239 in the validation cohort]) than in those with sustained high risk. Conclusion: The HCC risk model based on simple serum markers at any point after SVR and its change can identify patients with advanced fibrosis who are at low HCC risk, and these patients may be able to reduce HCC surveillance.

Image quality and quantification accuracy dependence on patient body mass in 89Zr PET/CT imaging.

BACKGROUND: This study was conducted to clarify how patient body mass affects the image quality and quantification accuracy of images obtained using 89Zr PET/CT. 89Zr PET/CT images from time-of-flight (TOF) PET/CT and semiconductor (SC) PET/CT were obtained using three types (M, L, LL; corresponding to increasing patient body weight) of custom-made body phantoms designed similarly to the National Electrical Manufacturers Association (NEMA) IEC body phantom. The phantom data were analyzed visually and quantitatively to derive image quality metrics, namely detectability of the 10-mm-diameter hot sphere, percent contrast for the 10-mm-diameter hot sphere (QH,10 mm), percent background variability (N10mm), contrast-to-noise ratio (QH,10 mm/N10mm), and coefficient of variation of the background area (CVBG). RESULTS: Visual assessment revealed that all the 10-mm-diameter hot spheres of the three types of phantoms were identifiable on both SC and TOF PET/CT images. The N10mm and CVBG values were within the proposed reference levels, and decreased with acquisition duration for both PET/CT types. At 10-min acquisition, the QH,10 mm/N10mm of SC PET/CT was greater than the proposed reference level in all phantoms. However, the QH,10 mm/N10mm of TOF PET/CT was greater than the proposed reference level in M-type phantom alone. All the SUVBG values were within 1.00 ± 0.05 for both PET/CT types. CONCLUSIONS: This study showed that the image quality and quantification accuracy depend on the patient's body mass, suggesting that acquisition time on 89Zr PET/CT should be changed according to the patient's body mass.

The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study.

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 < 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 > 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 < 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.

Real-world clinical outcomes of sofosbuvir and velpatasvir treatment in HCV genotype 1- and 2-infected patients with decompensated cirrhosis: A nationwide multicenter study by the Japanese Red Cross Liver Study Group.

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 < 0.001), and there were significant differences between baseline and end of treatment and between baseline and SVR12. Subgroup analyses showed no significant differences in SVR rates according to patient age, sex, HCV genotype (subtype), Child-Pugh classification, modified ALBI grade, presence of ascites, presence of hepatic coma, or history of hepatocellular carcinoma. In all subpopulations, the SVR rates were higher than 80%. There were no severe adverse events associated with the treatment. The SOF/VEL regimen showed good virological efficacy and acceptable safety even in patients with HCV-related decompensated cirrhosis.

Change in Fibrosis 4 Index as Predictor of High Risk of Incident Hepatocellular Carcinoma After Eradication of Hepatitis C Virus.

BACKGROUND: It is unclear whether the fibrosis 4 index (FIB-4), a marker of liver fibrosis, at baseline and change in FIB-4 after sustained virological response (SVR) is associated with incident hepatocellular carcinoma (HCC) risk. In this study, we examined the association of incident HCC risk with baseline FIB-4 and sustained high FIB-4 (>3.25) at any time point after SVR. METHODS: A total of 3823 patients who received direct-acting antiviral treatment and achieved SVR were enrolled. The FIB-4 was measured 24 weeks after the end of direct-acting antiviral treatment and achievement of SVR (SVR24), and 1, 2, and 3 years after SVR24, after which subsequent HCC development was investigated. RESULTS: In patients with an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years after SVR24, subsequent HCC development was significantly higher than in those with an FIB-4 ≤3.25 at each point. The rates of HCC development 1, 2, 3, and 4 years after SVR24 were significantly higher in patients with sustained FIB-4 >3.25 than in those whose FIB-4 decreased to ≤3.25 (5.4%, 9.2%, 11.7%, and 16.0%, respectively, vs 2.2%, 3.1%, 3.7%, and 4.4%; P < .001). The adjusted hazard ratios (95% confidence intervals) for an FIB-4 >3.25 at SVR24 and 1, 2, and 3 years later were 3.38 (2.4-4.8), 2.95 (1.9-4.7), 2.62 (1.3-5.1), and 3.37 (1.4-9.8), respectively. CONCLUSIONS: The FIB-4 could be used to assess HCC development risk at any time after SVR, and changes in FIB-4 were associated with changes in the HCC development risk. Repeated assessments of FIB-4 could serve as a prognostic indicator of a high-risk HCC cohort that may require more intensive HCC surveillance strategy.

Detectable HBV DNA during nucleos(t)ide analogues stratifies predictive hepatocellular carcinoma risk score.

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.

Changing clinical and molecular characteristics of hepatitis E virus infection in Mie Prefecture, Japan: Disappearance of indigenous subtype 3e strains.

AIM: To evaluate the clinical and molecular characteristics of hepatitis E virus (HEV) infection in Mie Prefecture, Japan, from 2004 through 2018. METHODS: The clinical information of hepatitis E cases was collected from 21 medical institutions in Mie Prefecture. The nucleotide sequences of infecting HEV strains were determined for cases with available serum samples. The origins or transmission routes were inferred from phylogenetic analyses of the nucleotide sequences. RESULTS: Fifty-three patients were diagnosed with HEV infection. The number of cases increased each year through 2012 and then decreased. Analyses of the clinical characteristics of the cases indicated that even mild cases were detected in the latter 10 years of the study. Nucleotide sequence analyses were undertaken on 38 of the 53 cases. The HEV subtype 3e (HEV-3e) strains identified for 13 cases were closely related to a swine HEV-3e strain that was isolated from the liver of a pig bred in Mie Prefecture. The number of cases infected with the indigenous Mie HEV-3e strains increased until 2012 but have not been reported since 2014. In the latter half of the study, cases involving various HEV strains of different genotypes and subtypes emerged. CONCLUSIONS: The disappearance of indigenous Mie HEV-3e strains appeared to be the primary cause for the decrease in hepatitis E cases in Mie Prefecture. The disappearance might have been associated with improved hygienic conditions on pig farms or the closure of contaminated farms. The results suggest that indigenous HEV strains can be eradicated by appropriate management.

Validity of Japanese version of SARC-F questionnaire in patients with chronic liver disease.

BACKGROUND AND AIM: We aimed to examine the validity of the Japanese version of SARC-F questionnaire (SARC-F-J) that employs the diagnostic criteria for sarcopenia established by the Japan Society of Hepatology in patients with chronic liver disease. METHODS: Subjects were outpatients at the Department of Hepatology at the Japanese Red Cross Ise Hospital, Japan. Evaluations were performed using the following self-administered questionnaires: SARC-F-J, Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC), the Japanese version of the Falls Efficacy Scale (FES), and Kaigo-Yobo Checklist (CL). Based on the diagnostic criteria of the Japan Society of Hepatology, we diagnosed sarcopenia from the skeletal muscle index calculated using the iliopsoas muscle area at the third lumbar vertebra on computed tomography and from grip strength. To evaluate construct validity, we calculated the sensitivity, specificity, and positive and negative predictive values of SARC-F-J that used the diagnostic criteria of the Japan Society of Hepatology as reference. Furthermore, to evaluate convergent validity, we calculated Pearson's correlation coefficients between SARC-F-J and TMIG-IC, FES, and CL. RESULTS: A total of 140 subjects were included in the analysis set. Sensitivity and specificity were 16.3% and 45.0% and 95.3% and 90.8% for men and women, respectively. The positive predictive value was 81.8% for both, whereas the negative predictive value was 47.1% and 64.5% for men and women, respectively. A significant correlation was seen between SARC-F-J and TMIG-IC, FES, and CL. CONCLUSIONS: We believe that the SARC-F-J is a valid tool for patients with chronic liver disease.

Real-world efficacy and safety of sofosbuvir + ribavirin for hepatitis C genotype 2: A nationwide multicenter study by the Japanese Red Cross Liver Study Group.

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-naïve 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 < 0.0001). Alpha-fetoprotein decreased significantly at end of treatment (P < 0.0001), and the degree of decrease was greater in patients with advanced fibrosis than in those without (21.7 ± 60.8 vs. 2.5 ± 15.5, P < 0.001). The most commonly reported adverse event was anemia (13.7%). CONCLUSIONS: Treatment with SOF + RBV was highly effective and safe in Japanese patients with HCV genotype 2 infection.

A 10-year Follow-up Study of a Japanese Family with Ferroportin Disease A: Mild Iron Overload with Mild Hyperferritinemia Co-occurring with Hyperhepcidinemia May Be Benign.

This is a 10-year follow-up study of a family with ferroportin disease A. The proband, a 59-year-old man showed no noteworthy findings with the exception of an abnormal iron level. The proband's 90-year-old father showed reduced abilities in gait and cognition; however, with the exception of his iron level, his biochemistry results were almost normal. Brain imaging showed age-matched atrophy and iron deposition. In both patients, the serum levels of ferritin and hepcidin25, and liver computed tomography scores declined over a 10-year period. These changes were mainly due to a habitual change to a low-iron diet. The iron disorder in this family was not associated with major organ damage.

Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC? A multicenter study by the Japanese Red Cross Hospital Liver Study Group.

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.

Real-world efficacy and safety of ledipasvir and sofosbuvir in patients with hepatitis C virus genotype 1 infection: a nationwide multicenter study by the Japanese Red Cross Liver Study Group.

BACKGROUND: 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. METHODS: 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). RESULTS: 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 < 0.0001; from 2.2 ± 4.9 to 1.5 ± 6.3%, p < 0.005; and from 3.6 ± 3.7 to 2.0 ± 3.5 cut-off index, p < 0.0001; respectively). Adverse events were rare and not associated with age. No decrease in estimated glomerular filtration rate was observed in patients with baseline chronic kidney disease stage 3. CONCLUSIONS: LDV/SOF therapy is highly effective and safe in elderly Japanese patients with HCV GT1, even in the presence of cirrhosis or NS5A RASs. Patients with SVR may have a lower risk of HCC.

Efficacy of daclatasvir plus asunaprevir in patients with hepatitis C virus infection undergoing and not undergoing hemodialysis.

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.