記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma. METHODS: We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity-score-matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed-effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow-up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups. RESULTS: Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were -2.41 ± 0.40 and -2.44 ± 0.42 at baseline, and -2.17 ± 0.56 and -2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN-treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev. CONCLUSIONS: Using a nonlinear mixed-effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN-treated patients with BCLC advanced stage or those receiving the full dose of LEN.

DOI： 10.1002/cam4.6726

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Elderly patients are believed to have a reduced immune capacity, which may make immunotherapy less effective. The aim of this study was to compare the therapeutic outcome of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) for advanced hepatocellular carcinoma (HCC) in patients aged 80 years and older. METHODS: From March 2018 to July 2022, 170 and 92 elderly patients who received LEN and Atez/Bev as first-line treatment, respectively, were retrospectively analyzed. RESULTS: The median ages of the Atez/Bev and LEN groups were 83.0 (8.01-86.0) and 83.0 (82.0-86.0) years (p=0.3), respectively. Males accounted for approximately 70% of the patients in both groups. The objective response rate was 35.9% in the LEN group and 33.7% in the Atez/Bev group (p=0.8), whereas the disease control rates in the LEN and Atez/Bev groups were 62.9% and 63.0%, respectively (p=1.0). The median PFS in the LEN and Atez/Bev groups was 6.3 months and 7.2 months, respectively, which were not significantly different (p=0.2). The median OS was 17.9 months in the LEN group and 14.0 months in the Atez/Bev group. This difference was not statistically significant (p=0.7). In multivariate analyses, the choice of treatment (LEN vs. Atez/Bev) showed no association with PFS or OS. The Atez/Bev group had a significantly higher rate of post-progression treatment (59.0% vs. 35.7%, p=0.01) and a lower rate of discontinuation due to adverse events (69 [40.6%] vs. 19 [20.7%], p<0.001) compared to the LEN group. CONCLUSIONS: Atez/Bev showed comparable effectiveness to LEN in HCC patients aged 80 years and older. Given the results of post-progression treatment and discontinuation due to adverse events, Atez/Bev could serve as a first-line treatment even for elderly HCC patients. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13991

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Elevated serum gamma-glutamyl transferase (GGT) levels are associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma. However, their role in predicting mortality in patients with CHB treated with nucleotide/nucleoside analogs (NAs) remains elusive. Altogether, 2843 patients with CHB treated with NAs were recruited from a multinational cohort. Serum GGT levels before and 6 months (Month-6) after initiating NAs were measured to explore their association with all-cause, liver-related, and non-liver-related mortality. The annual incidence of all-cause mortality was 0.9/100 person-years over a follow-up period of 17,436.3 person-years. Compared with patients who survived, those who died had a significantly higher pretreatment (89.3 vs. 67.4 U/L, p = 0.002) and Month-6-GGT levels (62.1 vs. 38.4 U/L, p < 0.001). The factors associated with all-cause mortality included cirrhosis (hazard ratio [HR]/95% confidence interval [CI]: 2.66/1.92-3.70, p < 0.001), pretreatment GGT levels (HR/CI: 1.004/1.003-1.006, p < 0.001), alanine aminotransferase level (HR/CI: 0.996/0.994-0.998, p = 0.001), and age (HR/CI: 1.06/1.04-1.07, p < 0.001). Regarding liver-related mortality, the independent factors included cirrhosis (HR/CI: 4.36/2.79-6.89, p < 0.001), pretreatment GGT levels (HR/CI: 1.006/1.004-1.008, p < 0.001), alanine aminotransferase level (HR/CI: 0.993/0.990-0.997, p = 0.001), age (HR/CI: 1.03/1.01-1.05, p < 0.001), and fatty liver disease (HR/CI: 0.30/0.15-0.59, p = 0.001). Pretreatment GGT levels were also independently predictive of non-liver-related mortality (HR/CI: 1.003/1.000-1.005, p = 0.03). The results remained consistent after excluding the patients with a history of alcohol use. A dose-dependent manner of <25, 25-75, and >75 percentile of pretreatment GGT levels was observed with respect to the all-cause mortality (trend p < 0.001). Pretreatment serum GGT levels predicted all-cause, liver-related, and non-liver-related mortality in patients with CHB treated with NAs.

DOI： 10.1002/kjm2.12771

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: This study aimed to investigate the safety and efficacy of lenvatinib in real-world settings, including patients excluded from the REFLECT trial. METHODS: This multicenter, nonrandomized, open-label prospective study was conducted at 10 medical facilities in Japan (jRCTs031190017). Eligible patients had advanced HCC and were suitable for lenvatinib therapy. The study included patients with high tumor burden (with >50% intrahepatic tumor volume, main portal vein invasion, or bile duct invasion), Child-Pugh B status, and receiving lenvatinib as second-line therapy following atezolizumab plus bevacizumab. RESULTS: From Dec 2019 to Sep 2021, 59 patients were analyzed (47 and 12 patients with Child-Pugh A and B, respectively). In patients with Child-Pugh A, the frequency of aspartate aminotransferase elevation was high (72.7%) in high-burden group. No other significant adverse events (AEs) were observed even in second-line treatment. However, patients with Child-Pugh B had high incidence of grade ≥3 AEs (100.0%) and high discontinuation rates caused by AEs (33.3%) compared to patients with Child-Pugh A (80.9% and 17.0%, respectively). Median PFS was 6.4 and 2.5 months and median OS was 19.7 and 4.1 months in Child-Pugh A and B, respectively. Lenvatinib plasma concentration was higher in Child-Pugh B patients on days 8 and 15 and correlated with dose modifications and lower relative dose intensity. CONCLUSION: Lenvatinib is safe and effective for advanced HCC in patients with Child-Pugh A, even with high tumor burden. However, it carries a higher risk of AEs and may not provide adequate efficacy for patients with Child-Pugh B.

DOI： 10.1158/1078-0432.CCR-23-1462

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: The study goal was to compare the outcomes of patients with intermediate-stage (Barcelona Clinic Liver Cancer [BCLC]-B) hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic therapy. METHODS: A total of 358 patients with BCLC-B HCC treated with Atezo/Bev (n = 177) or LEN (n = 181) as first-line systemic therapy were included. RESULTS: The median progression-free survival (PFS) times in the Atezo/Bev and LEN groups were 10.8 months (95% confidence interval [CI], 7.8-12.6) and 7.3 months (95% CI, 6.3-8.5), respectively (p = .019). In the propensity score-matched cohort, the median PFS times in the Atezo/Bev (n = 151) and LEN (n = 151) groups were 10.2 months (95% CI, 7.0-12.3) and 6.9 months (95% CI, 5.9-8.1), respectively (p = .020). Restricted mean survival times of PFS were significantly higher in the Atezo/Bev group than in the LEN group at landmarks of 12 and 18 months (p = .031 and .012, respectively). In a subgroup analysis of patients with HCC beyond the up-to-seven criteria, the median PFS times in the Atezo/Bev (n = 134) and LEN (n = 117) groups were 10.5 months (95% CI, 7.0-11.8) and 6.3 months (95% CI, 5.5-7.3), respectively (p = .044). CONCLUSIONS: The use of Atezo/Bev as first-line systemic therapy in patients with BCLC-B HCC is expected to result in good PFS.

DOI： 10.1111/liv.15753

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to evaluate the ability of a previously reported tumor marker (TM) score involving alpha-fetoprotein (AFP), fucosylated AFP (AFP-L3), and des gamma-carboxy prothrombin (DCP) as TMs in predicting the prognosis and therapeutic efficacy in hepatocellular carcinoma (HCC) patients administered atezolizumab plus bevacizumab (Atez/Bev) as first-line treatment. MATERIALS/METHODS: The study period covered September 2020 to December 2022 and involved 371 HCC patients treated with Atez/Bev. The values of the TMs AFP, AFP-L3, and DCP were measured upon introducing Atez/Bev. Elevations in the values of AFP (≥100 ng/mL), AFP-L3 (≥10%), and DCP (≥100 mAU/mL) were considered to indicate a positive TM. The number of positive TMs was summed up and used as the TM score, as previously proposed. Hepatic reserve function was assessed using the modified albumin-bilirubin grade (mALBI). Predictive values for prognosis were evaluated retrospectively. RESULTS: A TM score of 0 was shown in 81 HCC patients (21.8%), 1 in 110 (29.6%), 2 in 112 (29.9%), and 3 in 68 (18.3%). The median overall survival (OS) times for TM scores 0, 1, 2, and 3 were not applicable [NA] (95% CI NA-NA), 24.0 months (95% CI 17.8-NA), 16.7 months (95% CI 17.8-NA), and NA (95% CI 8.3-NA), respectively (p < 0.001). The median progression-free survival (PFS) times for TM scores 0, 1, 2, and 3 were 16.5 months (95% CI 8.0-not applicable [NA]), 13.8 months (95% CI 10.6-21.3), 7.7 months (95% CI 5.3-8.9), and 5.8 months (95% CI 3.0-7.6), respectively (p < 0.001). OS was well stratified in mALBI 1/2a and mALBI 2a/2b. PFS was well stratified in mALBI 2a/2b, but not in mALBI 1/2a. CONCLUSIONS: The TM score involving AFP, AFP-L3, and DCP as TMs was useful in predicting the prognosis and therapeutic efficacy in terms of OS and PFS in HCC patients administered Atez/Bev as first-line treatment.

DOI： 10.3390/cancers15174348

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. METHODS: From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score -1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. RESULTS: There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4-7] vs. 5.5 [95% CI: 3.4-7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3-11] vs. 8.8 [95% CI: 6.1-12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). DISCUSSION: This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC.

DOI： 10.1159/000530028

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bevacizumab inhibits vascular endothelial growth factor-A (VEGF-A), though is known to increase bleeding risk as an adverse event (AE). This study examined whether atezolizumab/bevacizumab (Atez/Bev) for unresectable hepatocellular carcinoma (uHCC) can be used for patients with esophageal-gastric varices (EGV). METHODS: From October 2020 to December 2022, 506 uHCC patients (median 74 years) underwent an upper gastrointestinal endoscopy examination were enrolled, after exclusion of those with portal vein tumor thrombus (PVTT). Patients with EGV (≧ F1) were defined as EGV positive, and the cohort was divided into non-EGV (n = 355) and EGV (n = 151). Before introducing Atez/Bev, endoscopic treatment was performed, when necessary. Prognosis was evaluated, retrospectively. RESULTS: The EGV group had significantly worse hepatic function, lower platelet count, elevated alpha-fetoprotein, and lower rate of extrahepatic metastasis, and lower rate of first-line use (each P < 0.05) than the other. However, progression-free survival (PFS) was also not a significantly difference between the EGV and non-EGV groups in analyses with (PFS rate at 6/12/18 months: 60%/38%/30% vs. 65%/46%/34%, P = 0.29) or without inverse probability weighting adjustment [median: 10.6 months (95% CI 8.3-14.0) vs. 10.5 months (95% CI 7.8-13.7), P = 0.79]. As for AEs, diarrhea was more frequent in the EGV group (≧ G3: 2.0% vs. 0.3%, P = 0.036), while no significant difference was noted for EGV hemorrhage (≧ G3: 1.3% vs. 0.6%, P = 0.345). Of 28 patients who underwent endoscopic treatments before introducing Atez/Bev, none showed EGV-associated hemorrhage. CONCLUSIONS: Atez/Bev might be an effective therapeutic option in patients with EGV, when appropriate endoscopic treatment for EGV is performed.

DOI： 10.1007/s00535-023-02026-2

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The aim of this retrospective proof-of-concept study was to compare different second-line treatments for patients with hepatocellular carcinoma and progressive disease (PD) after first-line lenvatinib or atezolizumab plus bevacizumab. MATERIALS AND METHODS: A total of 1381 patients had PD at first-line therapy. 917 patients received lenvatinib as first-line treatment, and 464 patients atezolizumab plus bevacizumab as first-line. RESULTS: 49.6% of PD patients received a second-line therapy without any statistical difference in overall survival (OS) between lenvatinib (20.6months) and atezolizumab plus bevacizumab first-line (15.7months; p = 0.12; hazard ratio [HR]= 0.80). After lenvatinib first-line, there wasn't any statistical difference between second-line therapy subgroups (p = 0.27; sorafenib HR: 1; immunotherapy HR: 0.69; other therapies HR: 0.85). Patients who underwent trans-arterial chemo-embolization (TACE) had a significative longer OS than patients who received sorafenib (24.7 versus 15.8months, p < 0.01; HR=0.64). After atezolizumab plus bevacizumab first-line, there was a statistical difference between second-line therapy subgroups (p < 0.01; sorafenib HR: 1; lenvatinib HR: 0.50; cabozantinib HR: 1.29; other therapies HR: 0.54). Patients who received lenvatinib (17.0months) and those who underwent TACE (15.9months) had a significative longer OS than patients treated with sorafenib (14.2months; respectively, p = 0.01; HR=0.45, and p < 0.05; HR=0.46). CONCLUSION: Approximately half of patients receiving first-line lenvatinib or atezolizumab plus bevacizumab access second-line treatment. Our data suggest that in patients progressed to atezolizumab plus bevacizumab, the systemic therapy able to achieve the longest survival is lenvatinib, while in patients progressed to lenvatinib, the systemic therapy able to achieve the longest survival is immunotherapy.

DOI： 10.1016/j.ejca.2023.05.021

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: There is no known report regarding the relationship of atezolizumab plus bevacizumab (Atez/Bev) treatment with muscle volume loss (MVL) in unresectable hepatocellular carcinoma (u-HCC) patients. This study aimed to elucidate the clinical relationship between MVL and Atez/Bev. MATERIALS/METHODS: From September 2020 to December 2021, 229 u-HCC patients treated with Atez/Bev and with muscle volume data obtained by computed tomography at the baseline available were analyzed (median age, 74 years; males, 186 (81.2%); ECOG PS 0/1, 221 (96.5%); HCV:HBV:alcohol:others = 81:33:40:75; Child-Pugh A, 212 (92.6%); modified albumin-bilirubin (mALBI) grade 1:2a:2b = 79:60:90; BCLC 0:A:B:C = 1:24:87:117; median observation period, 6.8 months). Japan Society of Hepatology criteria were used for definition of MVL and prognostic factors were retrospectively evaluated. RESULTS: Multivariate Cox-hazard analysis of prognostic factors for progression-free survival (PFS) showed elevated alpha-fetoprotein (AFP) (≥100 ng/mL) (HR 1.848, 95% CI 1.264-2.702, p = 0.002), mALBI grade (≥2a) (HR 1.563, 95% CI 1.035-2.359, p = 0.034), and MVL (HR 1.479, 95% CI 1.020-2.144, p = 0.039) as significant factors. For overall survival (OS), significant factors included elevated AFP (≥100 ng/mL) (HR 3.564, 95% CI 1.856-6.844, p < 0.001), mALBI grade (≥2a) (HR 3.451, 95% CI 1.580-7.538, p = 0.002), and MVL (HR 2.119, 95% CI 1.150-3.904, p = 0.016). Patients with MVL (MVL group, n = 91) showed worse PFS than those without (non-MVL group, n = 138) (median PFS 5.3 vs. 7.6 months, p = 0.025), while the MVL group showed worse OS (p = 0.038), though neither reached the median survival time. CONCLUSION: MVL may be a clinical factor related to poor prognosis in patients receiving Atez/Bev treatment for u-HCC.

DOI： 10.1159/000527402

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/jgh3.12949

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cabozantinib was found to be effective as a second- or third-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) in the phase 3 CELESTIAL trial. So far, as immunotherapy has substituted molecular target agents as the primary systemic therapy for advanced HCC, cabozantinib is extensively used in the latest real-world clinical practice in a greatly different position than that shown by the CELESTIAL trial. In the current analysis, we examined the safety and effectiveness of cabozantinib administration in real-life settings for patients with advanced HCC. METHODS: We retrospectively obtained data from patients with advanced HCC who received cabozantinib in three institutions in Japan between 14 September 2018 and 30 November 2021. RESULTS: During the study period, 23 patients with advanced HCC received cabozantinib. Our cohort included 21.7% of patients with Child-Pugh class B, and 52.2% of patients in fourth line or later. The median progression-free survival of patients given cabozantinib was 3.7 months. Regarding patients with Child-Pugh class B or administration in fourth line or later, the discontinuation rate due to adverse events in patients who initialized at 40 or 20 mg was lower than those who initialized at 60 mg (42.9% versus 75.0%). Patients who were able to continue treatment with cabozantinib for more than 3 months were more likely to undergo dose reduction than those who did not (85.7% versus 25.0%). CONCLUSIONS: Cabozantinib has recently been administered to a diverse range of patients, including those who were not enrolled in the CELESTIAL trial. Deliberate dose reduction could potentially offer clinical benefits to patients with impaired liver function. Furthermore, managing adverse events by reducing the dose could play a crucial role in extending the duration of treatment with cabozantinib. The preprint version of this work is available on https://www.researchsquare.com/article/rs-2655181/v1 .

DOI： 10.1007/s40801-023-00379-x

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.cgh.2023.06.026

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: The present study focused on geriatric nutritional risk index (GNRI), which is based on body weight and serum albumin, and known as an easy-to-use nutritional assessment tool in clinical settings, to elucidate the prognostic predictive ability of GNRI in patients treated with atezolizumab plus bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC). MATERIALS/METHODS: Five hundred twenty-five HCC patients treated with Atez/Bev, based on their classification of unsuitable status for curative treatments and/or transarterial catheter chemoembolization, were enrolled [Child-Pugh A:B:C=484:40:1, BCLC 0:A:B:C:D=7:25:192:283:18]. Prognosis was evaluated retrospectively using GNRI. RESULTS: Atez/Bev was used in 338 of the present cohort as first-line systemic chemotherapy (64.4%). Median progression-free survival (PFS) based on GNRI indicating normal, mild-decline, moderate-decline, and severe-decline was 8.3, 6.7, 5.3 and 2.4 months, respectively, while median overall survival (OS) was 21.4, 17.0, 11.5 and 7.3 months, respectively (both P<0.001). The concordance index (c-index) values of GNRI for predicting prognosis (PFS/OS) were superior to those of Child-Pugh class and albumin-bilirubin grade (0.574/0.632 vs. 0.527/0.570 vs. 0.565/0.629). As a sub-analysis, muscle volume loss (MVL) was observed in 37.5% in 256 patients with CT data available. Along with GNRI decline, frequency of MVL became progressively larger (normal vs. mild vs. moderate vs. severe=17.6% vs. 29.2% vs. 41.2% vs. 57.9%, P<0.001), and a GNRI value of 97.8 was predictive of its occurrence (AUC 0.715, 95%CI 0.649-0.781) (specificity/sensitivity=0.644/0.688). CONCLUSION: These findings indicate that GNRI is an effective nutritional prognostic tool for predicting prognosis and MVL complication in HCC patients treated with Atez/Bev. This article is protected by copyright. All rights reserved.

DOI： 10.1111/hepr.13934

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Lack of an established methodology for post-progression systemic treatment following atezolizumab plus bevacizumab (Atez/Bev) administration is an important clinical issue. The present study aimed to elucidate the potential of lenvatinib as a second-line treatment option after Atez/Bev failure. MATERIALS/METHODS: From 2020 to 2022, 101 patients who received lenvatinib as second-line treatment were enrolled (median 72 years, males 77, Child-Pugh A 82, BCLC-A:B:C:D=1:35:61:4), while 29 treated with another molecular targeting agent (MTA) during the period as second-line treatment were enrolled as controls. The therapeutic efficacy of lenvatinib given as second-line treatment was retrospectively evaluated. RESULTS: Median progression-free survival/median overall survival for all patients was 4.4/15.7 months and for those with Child-Pugh A was 4.7 months/not-reached. When prognosis was compared with patients who received another MTA, there was no significant difference for PFS (3.5 months, P=0.557) or OS (13.6 months, P=0.992), and also no significant differences regarding clinical background factors. mRECIST findings showed that objective response and disease control rates in patients treated with lenvatinib were 23.9% and 70.4%, respectively (CR:PR:SD:PD=3:14:33:21), while those shown by RECIST, ver. 1.1, were 15.4% and 66.2%, respectively (CR:PR:SD:PD=1:10:36:24). Adverse events (any grade ≥10%) were appetite loss (26.7%) (grade 1:2:3=2:15:10), general fatigue (21.8%) (grade 1:2:3=3:13:6), protein in urine (16.8%) (grade 1:2:3=0:4:13), and hypertension (13.9%) (grade 1:2:3=1:8:5). CONCLUSION: Although lenvatinib treatment might not provide a pseudo-combination immunotherapy effect following Atez/Bev failure, lenvatinib when used as second-line treatment after Atez/Bev failure might be expected to be comparable as compared to its use as first-line treatment.

DOI： 10.1159/000531316

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population. METHODS: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment. RESULTS: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77). CONCLUSION: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data.

DOI： 10.1007/s12072-023-10547-4

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy. METHODS: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n = 268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n = 162). RESULTS: The median progression-free survival times in the first- and later-line groups were 7.7 months (95% confidence interval [CI], 6.7-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006-1.690; P = 0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5 months (95% CI, 6.8-13.8) and 6.8 months (95% CI, 5.0-9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7 months (95% CI, 6.3-9.2) and 6.2 months (95% CI, 5.0-7.7) (P = 0.022). CONCLUSION: The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.

DOI： 10.1111/jgh.16225

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/hep.0000000000000459

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This retrospective study aimed to investigate the impact of proton pump inhibitor treatment (PPI) and antibiotic treatment on the therapeutic outcomes of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). METHODS: The present study included a total of 441 HCC patients who were treated with Atez/Bev in 20 Japanese institutions from September 2020 to April 2022. We adopted the inverse probability of treatment weight to adjust for imbalance in the baseline characteristics of patients with and without PPI treatment as well as patients with and without antibiotic treatment. RESULTS: The progression-free survival (PFS) and overall survival (OS) of patients with and without PPI treatment did not differ to a statistically significant extent. In the weighted cohort, the difference in PFS and OS between the patients with and without PPI did not reach statistical significance (median PFS, 7.0 vs. 6.5 months, p = 0.07; 1-year survival rate 66.3% and 73.8%, p = 0.9). The PFS and OS in patients with antibiotic treatment were worse in comparison to patients without antibiotic treatment (median PFS, 3.8 vs. 7.0 months, p = 0.007; 1-year survival rate 58.8% and 70.3%, p = 0.01). In the weighted cohort, the PFS and OS of the two groups did not differ to a statistically significant extent (median PFS, 3.8 vs. 6.7 months, p = 0.2; 1-year survival rate, 61.8% and 71.0%, p = 0.6). CONCLUSIONS: The therapeutic outcomes of Atez/Bev in HCC patients did not differ between patients with and without PPI treatment or between patients with and without antibiotic treatment.

DOI： 10.1111/hepr.13905

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本内科学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The prognostic nutritional index (PNI) is a multiparametric score introduced by Onodera based on the blood levels of lymphocytes and albumin in patients with gastrointestinal neoplasms. Regarding hepatocellular carcinoma (HCC), its prognostic role has been demonstrated in patients treated with sorafenib and lenvatinib. The aim of this real-world study is to investigate the association between clinical outcomes and PNI in patients being treated with atezolizumab plus bevacizumab. METHODS: The overall cohort of this multicentric study included 871 consecutive HCC patients from 4 countries treated with atezolizumab plus bevacizumab in first-line therapy. The PNI was calculated as follows: 10 × serum albumin concentration (g/dL) + 0.005 × peripheral lymphocyte count (number/mm3). RESULTS: For only 773 patients, data regarding lymphocyte counts and albumin levels were available, so only these patients were included in the final analysis. The cut-off point of the PNI was determined to be 41 by receiver operating characteristic (ROC) analysis. 268 patients (34.7%) were categorized as the PNI-low group, while the remaining 505 (65.3%) patients as the PNI-high group. At the univariate analysis, high PNI was associated with longer overall survival (OS) (22.5 vs. 10.1 months, HR 0.34, p < 0.01) and progression-free survival (PFS) (8.7 vs. 5.8 months, HR 0.63, p < 0.01) compared to patients with low PNI. At the multivariate analysis, high versus low PNI resulted as an independent prognostic factor for OS (HR 0.49 , p < 0.01) and PFS (HR 0.82, p = 0.01). There was no difference in objective response rate (ORR) between the two groups (high 26.1% vs. low 19.8%, p = 0.09), while disease control rate (DCR) was significantly higher in the PNI-high group (76.8% vs. 66.4%, p = 0.01). CONCLUSION: PNI is an independent prognostic factor for OS and PFS in HCC patients on first-line treatment with atezolizumab plus bevacizumab.

DOI： 10.1159/000528818

PubMed

researchmap

掲載種別：研究論文（学術雑誌）  

Background and Aim: The study goal was to compare the outcomes of patients with unresectable hepatocellular carcinoma (HCC) who received atezolizumab plus bevacizumab (Atezo/Bev) as either first- or later-line systemic therapy. Methods: A total of 430 patients with HCC treated with Atezo/Bev at 22 institutions in Japan were included. Patients treated with Atezo/Bev as first-line therapy for HCC were defined as the first-line group (n = 268) while those treated with Atezo/Bev as second- or later-line therapy were defined as the later-line group (n = 162). Results: The median progression-free survival times in the first- and later-line groups were 7.7 months (95% confidence interval [CI], 6.7–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.021). Regarding treatment-related adverse events, hypertension of any grade was more common in the first-line group than in the later-line group (P = 0.025). Analysis adjusted by inverse probability weighting, including patient and HCC characteristics, showed that the later-line group (hazard ratio, 1.304; 95% CI, 1.006–1.690; P = 0.045) was significantly associated with progression-free survival. In patients with Barcelona Clinic Liver Cancer stage B, the median progression-free survival times in the first- and later-line groups were 10.5 months (95% CI, 6.8–13.8) and 6.8 months (95% CI, 5.0–9.4) (P = 0.021). Among patients with a history of lenvatinib therapy, the median progression-free survival times in the first- and later-line groups were 7.7 months (95% CI, 6.3–9.2) and 6.2 months (95% CI, 5.0–7.7) (P = 0.022). Conclusion: The use of Atezo/Bev as first-line systemic therapy in patients with HCC is expected to prolong survival.

DOI： 10.1111/jgh.16225

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although eliminating HCV can prevent hepatocellular carcinoma (HCC), some patients develop HCC even after obtaining sustained virologic response (SVR). Previously, we developed a new formula to predict advanced liver fibrosis. This study aimed to clarify the usefulness of this formula for predicting HCC after achieving SVR. Among 351 consecutive patients who had been treated with direct-acting antivirals, 299 were included in this study. New formula scores were used as a marker for predicting liver fibrosis and as a predictive model for HCC incidence. The participants were 172 men and 127 women with a median age of 68 years. The median new formula score was -1.291. The cumulative HCC incidence rates were 4.3%, 9.7%, and 12.5% at 1, 3, and 5 years, respectively. The cumulative incidence of HCC was significantly higher in patients with a history of HCC than in those without treatment history of HCC (P = 2.52×10-26). Multivariate analysis revealed that male (HR = 6.584, 95% CI = 1.291-33.573, P = 0.023) and new formula score (HR = 1.741, 95% CI = 1.041-2.911, P = 0.035) were independent factors associated with the development of HCC in patients without a treatment history of HCC. The optimal cutoff value for predicting the development of HCC was -0.214. The cumulative incidence rates of HCC in patients with new formula scores ≥-0.214 were 5.4%, 15.3%, and 15.3% at 1, 3, and 5 years, respectively, whereas the incidence rates of HCC in patients with new formula scores <-0.214 were 0.0%, 0.6%, and 4.8%, respectively (P = 2.12×10-4). In conclusion, this study demonstrated the usefulness of new formula scores as a predictor of HCC after achieving SVR, especially in patients without past treatment history of treatment for HCC.

DOI： 10.1371/journal.pone.0292019

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To investigate the possible correlation between the development of adverse events (AEs) and prognosis in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). METHODS: A total of 286 patients with unresectable HCC treated with Atez/Bev as first-line systematic therapy were included. RESULTS: Regarding treatment-related AEs, decreased appetite of any grade, proteinuria of any grade, and fatigue of any grade were found with a frequency of ≥20%. Multivariate analysis adjusted for immune-related liver injury, immune-related endocrine dysfunction, proteinuria, fatigue, decreased appetite, hypertension, sex, age, Eastern Cooperative Oncology Group performance status, HCC etiology, HCC stage, Child-Pugh score, and α-fetoprotein showed that hypertension of any grade (hazard ratio [HR], 0.527; 95% confidence interval [CI], 0.326-0.854; p = 0.009) and α-fetoprotein ≥100 ng/ml (HR, 1.642; 95% CI, 1.111-2.427; p = 0.013) were independently associated with progression-free survival. Multivariate analysis adjusted for the same AEs showed that fatigue (HR, 2.354; 95% CI, 1.299-4.510; p = 0.010) was independently associated with overall survival. Median progression-free survival was 6.5 months (95% CI, 5.2-8.1) in patients without hypertension of any grade and 12.6 months (95% CI, 6.7-not available) in patients with hypertension of any grade (p = 0.035). The overall survival was significantly shorter in patients in whom treatment-related fatigue of any grade was observed (p < 0.001). Regarding response rates, the disease control rate of patients who developed treatment-related hypertension (94.2%) was significantly higher than those who did not (79.1%) (p = 0.009). CONCLUSIONS: Treatment-related hypertension is associated with good outcomes in patients with HCC treated with Atez/Bev.

DOI： 10.1002/cam4.5535

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting. METHODS: Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea). RESULTS: 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab. Objective response rate (ORR) was 38.6% for patients receiving lenvatinib, and 27.3% for patients receiving atezolizumab plus bevacizumab (p < 0.01; odds ratio 0.60). For patients who achieved complete response (CR), overall survival (OS) was not reached in both arms, but the result from univariate Cox regression model showed 62% reduction of death risk for patients treated with atezolizumab plus bevacizumab (p = 0.05). In all multivariate analyses, treatment arm was not found to be an independent factor conditioning OS. Comparing ORR achieved in the two arms, there was a statistically significant difference in favor of lenvatinib compared to atezolizumab plus bevacizumab in all subgroups except for Eastern patients, Child-Pugh B patients, presence of portal vein thrombosis, α-feto-protein ≥ 400 ng/mL, presence of extrahepatic disease, albumin-bilirubin (ALBI) grade 2, and no previous locoregional procedures. CONCLUSION: Lenvatinib achieves higher ORR in all patient subgroups. Patients who achieve CR with atezolizumab plus bevacizumab can achieve OS so far never recorded in HCC patients. This study did not highlight any factors that could identify patient subgroups capable of obtaining CR.

DOI： 10.1007/s00432-022-04512-1

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Recently, the neo-Glasgow prognostic score (GPS), a composite biomarker determined by the C-reactive protein level and albumin-bilirubin grade, was developed to predict outcomes in hepatocellular carcinoma (HCC) patients who undergo hepatic resection. The present research investigated whether the neo-GPS could predict prognosis in HCC patients treated with atezolizumab plus bevacizumab (Atez/Bev). METHODS: A total of 421 patients with HCC who were treated with Atez/Bev were investigated. RESULTS: Multivariate Cox hazards analysis showed that a GPS of 1 (hazard ratio (HR), 1.711; 95% confidence interval (CI), 1.106-2.646) and a GPS of 2 (HR, 4.643; 95% CI, 2.778-7.762) were independently associated with overall survival. Conversely, multivariate Cox hazards analysis showed that a neo-GPS of 1 (HR, 3.038; 95% CI, 1.715-5.383) and a neo-GPS of 2 (HR, 5.312; 95% CI, 2.853-9.890) were also independently associated with overall survival in this cohort. Additionally, cumulative overall survival rates differed significantly by GPS and neo-GPS (p < 0.001). The neo-GPS, compared with the GPS, had a lower Akaike information criterion (1207 vs. 1,211, respectively) and a higher c-index (0.677 vs. 0.652, respectively) regarding to overall survival. In a subgroup analysis of patients considered to have a good prognosis as confirmed using a Child-Pugh score of 5 (p = 0.001), a neutrophil-to-lymphocyte ratio <3 (p = 0.001), or an α-fetoprotein level < 100 ng/mL (p < 0.001), those with a high neo-GPS (≥1) had a statistically poorer overall survival than those with a low neo-GPS. CONCLUSIONS: The neo-GPS can predict prognosis in advanced unresectable HCC patients treated with Atez/Bev.

DOI： 10.1002/cam4.5495

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tricuspid regurgitation pressure gradient (TRPG) measurement by echocardiography is recommended as the most objective examination to detect portopulmonary hypertension (PoPH). This study aimed to identify factors associated with a high TRPG in patients with cirrhosis and develop a scoring model for identifying patients who are most likely to benefit from echocardiography investigations. RESULTS: A total of 486 patients who underwent echocardiography were randomly allocated to the derivation and validation sets at a ratio of 2:1. Of the patients, 51 (10.5%) had TRPG ≥ 35 mmHg. The median brain natriuretic peptide (BNP) was 39.5 pg/mL. Shortness of breath (SOB) was reported by 91 (18.7%) patients. In the derivation set, multivariate analysis identified female gender, shortness of breath, and BNP ≥ 48.9 pg/mL as independent factors for TRPG ≥ 35 mmHg. The risk score for predicting TRPG ≥ 35 mmHg was calculated as follows: - 3.596 + 1.250 × gender (female: 1, male: 0) + 1.093 × SOB (presence: 1, absence: 0) + 0.953 × BNP (≥ 48.9 pg/mL: 1, < 48.9 pg/mL: 0). The risk score yielded sensitivity of 66.7%, specificity of 75.3%, positive predictive value of 25.5%, negative predict value of 94.3%, and predictive accuracy of 74.4% for predicting TRPG ≥ 35 mmHg. These results were almost similar in the validation set, indicating the reproducibility and validity of the risk score. CONCLUSIONS: This study clarified the characteristics of patients with suspected PoPH and developed a scoring model for identifying patients at high risk of PoPH, which may be used in selecting patients that may benefit from echocardiography.

DOI： 10.1007/s12072-022-10456-y

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction This study investigated the relationship between nutritional status, as determined by the prognostic nutritional index (PNI), and outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). Methods The study analyzed 485 HCC patients treated with Atez/Bev. Results There were 342 patients with a low PNI (<47) and 143 with a high PNI (≥47). The median follow-up duration was 9.4 (6.0-14.3) months. Multivariate Cox hazards analysis showed that an α-fetoprotein level ≥100 ng/mL (hazard ratio (HR), 2.217; 95% confidence interval (CI), 1.588-3.095; p<0.001) and PNI ≥47 (HR, 0.333; 95% CI, 0.212-0.525; p<0.001) were independently associated with overall survival. Multivariate analysis showed that an α-fetoprotein level ≥100 ng/mL (HR, 1.690; 95% CI, 1.316-2.170; p<0.001) and PNI ≥47 (HR, 0.696; 95% CI, 0.528-0.918; p=0.010) were independently associated with progression-free survival. Cumulative overall and progression-free survival rates differed significantly by PNI (p<0.001 and p<0.002, respectively). In a subgroup analysis using inverse probability weighting (IPW) adjustment in patients with albumin-bilirubin grade 1 (n=173), univariate Cox hazards analysis showed that a PNI ≥47 (HR, 0.502; 95% CI, 0.260-0.991; p=0.047) was significantly associated with overall survival. Spline curve analysis revealed that a PNI of approximately 34-48 is an appropriate cutoff for predicting good overall and progression-free survival. Discussion/Conclusion The PNI, a biomarker of nutritional status, can predict prognosis in patients with HCC treated with Atez/Bev, even those who are considered to have a good prognosis due to good liver function.

DOI： 10.1159/000527676

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima’s pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima’s pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.

DOI： 10.1038/s41598-022-11431-1

researchmap

その他リンク： https://www.nature.com/articles/s41598-022-11431-1

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. METHODS: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. RESULTS: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). CONCLUSIONS: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

DOI： 10.1159/000525145

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Atezolizumab plus bevacizumab and lenvatinib have not been compared in a randomised controlled trial. We conducted a retrospective multi-centre study to compare the clinical efficacy and safety of lenvatinib and atezolizumab with bevacizumab as a first-line treatment for patients with unresectable HCC in the real-world scenario. METHODS: Clinical features of lenvatinib and atezolizumab plus bevacizumab patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival (OS) was the primary end-point. RESULTS: The analysis included 1341 patients who received lenvatinib, and 864 patients who received atezolizumab plus bevacizumab. After IPTW adjustment, atezolizumab plus bevacizumab did not show a survival advantage over lenvatinib HR 0.97 (p = 0.739). OS was prolonged by atezolizumab plus bevacizumab over lenvatinib in viral patients (HR: 0.76; p = 0.024). Conversely, OS was prolonged by lenvatinib in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease (HR: 1.88; p = 0.014). In the IPTW-adjusted population, atezolizumab plus bevacizumab provided better safety profile for most of the recorded adverse events. CONCLUSION: Our study did not identify any meaningful difference in OS between atezolizumab plus bevacizumab and lenvatinib. Although some hints are provided suggesting that patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease might benefit more from lenvatinib therapy and patients with viral aetiology more from atezolizumab plus bevacizumab.

DOI： 10.1016/j.ejca.2022.11.017

PubMed

researchmap

記述言語：英語  

DOI： 10.1007/s12072-022-10446-0

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aim of this retrospective multicenter study was to clarify the antifibrotic effect and long-term outcome of sodium glucose cotransporter 2 inhibitors (SGLT2-Is) in patients with nonalcoholic fatty liver disease (NAFLD) complicated by type 2 diabetes mellitus (T2DM). Of the 1262 consecutive patients with T2DM who recently received SGLT2-Is, 202 patients with NAFLD had been receiving SGLT2-Is for more than 48 weeks and were subjected to this analysis. Furthermore, 109 patients who had been on SGLT2-I therapy for more than 3 years at the time of analysis were assessed for the long-term effects of SGLT2-Is. Significant decreases in body weight, liver transaminases, plasma glucose, hemoglobin A1c, and Fibrosis-4 (FIB-4) index were found at week 48. Overall, the median value of FIB-4 index decreased from 1.42 at baseline to 1.25 at week 48 (p < 0.001). In the low-risk group (FIB-4 index < 1.3), there was no significant change in the FIB-4 index. In the intermediate-risk (≥1.3 and <2.67) and high-risk (≥2.67) groups, the median levels significantly decreased from 1.77 and 3.33 at baseline to 1.58 and 2.75 at week 48, respectively (p < 0.001 for both). Improvements in body weight, glucose control, liver transaminases, and FIB-4 index were found at 3 years of SGLT2-I treatment. In the intermediate-risk and high-risk groups (≥1.3 FIB-4 index), the FIB-4 index maintained a significant reduction from baseline throughout the 3 years of treatment. Conclusion: This study showed that SGLT2-Is offered a favorable effect on improvement in FIB-4 index as a surrogate marker of liver fibrosis in patient with NAFLD complicated by T2DM, especially those with intermediate and high risks of advanced fibrosis, and this antifibrotic effect is sustained for the long term.

DOI： 10.1002/hep4.2069

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study compared the efficacy and safety of atezolizumab and bevacizumab (Atez/Bev) in patients with viral and non-viral infection in clinical settings. METHODS: We conducted the retrospective cohort study of 323 BCLC stage B or C hepatocellular carcinoma (HCC) patients with Child-Pugh class A, and a performance status of 0 or 1 who started Atez/Bev from September 2020 to December 2021 at 22 institutions in Japan. Patients with viral infection was defined as those who were either serum anti-HCV- Ab or HBs-Ag-positive, while patients with non-viral infection was defined as those who were both serum anti-HCV Ab- and HBs-Ag-negative. We constructed a propensity-score-matched cohort to minimize the risk of observable potential confounders. RESULTS: Propensity score matching produced 126 matched pairs for patients with viral versus non-viral infection. After matching, the significant differences in baseline demographic features did not exist between the two groups. The objective response rate was 20.6% and 24.6% in viral- and non-viral-related HCC patients, respectively, without a significant difference (p = 0.55). The disease control rate was not also significantly different (68.3% vs 69.0%, p = 1.00). The median progression-free survival was 7.0 months (95% confidence interval [CI] 6.0-9.6) and 6.2 months (95% CI 5.1-7.8) in patients with viral and non-viral infection, and the 12-month survival rates were 65.5% (95% CI 50.8-76.8) and 71.7% (95% CI 57.3-81.9) in those with viral and non-viral infection, respectively, which were not significantly different (p = 0.33, p = 0.38). No significant difference in treatment-related adverse events was found between the two groups. CONCLUSIONS: Our etiology-based study demonstrated that Atez/Bev showed good efficacy and safety for HCC patient with non-viral infection as well as those with viral infection.

DOI： 10.1002/cam4.5337

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study investigated whether or not the hepatocellular carcinoma modified Gustave Roussy Immune Score (HCC-GRIm-Score) serves as a prognostic indicator for HCC patients treated with atezolizumab and bevacizumab (Atez/Bev). METHODS: A total of 405 HCC patients who received Atez/Bev from September 2020 to January 2022 at 22 different institutions were included in this retrospective study. The HCC-GRIm score was based on the combination of the albumin level (<3.5 g/L = 1 point), lactate dehydrogenase (≥245 U/L = 1 point), neutrophil-to-lymphocyte ratio (≥4.8 = 1 point), aspartate aminotransferase-to-alanine aminotransferase ratio (≥1.44 = 1 point), and total bilirubin level (≥1.3 mg/dl = 1 point). Patients were divided into the low-score group (0, 1, or 2 points) and the high-score group (3, 4, or 5 points). RESULTS: There were 89 (22.0%), 141 (34.8%), 106 (26.2%), 49 (12.1%), 16 (4.0%), and 4 (1.0%) patients with scores of 0, 1, 2, 3, 4, 5, respectively. The progression-free survival (PFS) in the low-score group was significantly longer than that in the high-score group (median 7.8 vs. 3.5 months, p < 0.001). The median overall survival (OS) of the low-score group was not reached at the time cutoff, with a 1-year survival rate of 75.5%, whereas the median OS of the high-score group was 8.5 months, showing a significant difference (p < 0.001). A high HCC-GRIm score was a significant unfavorable factor associated with the PFS and OS in multivariate analyses (p = 0.002 and p < 0.001, respectively). CONCLUSIONS: The HCC-GRIm score serves as a novel prognostic score for HCC patients treated with Atez/Bev.

DOI： 10.1002/cam4.5294

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The association between thrombolytic therapy and the outcome in patients with portal vein thrombosis (PVT) remains controversial. This study aimed to evaluate the outcome in patients with PVT who received antithrombin III-based therapy. METHODS: This study was a retrospective, multicenter study to investigate the liver-related events and the survival rates in 240 patients with PVT who received the therapy. RESULTS: The patients comprised 151 men and 89 women, with a median age of 69 years. The rate of favorable response, defined as maximum area of PVT changed to ≤75%, was 67.5% (162/240). The cumulative rates of liver-related events at 1, 2, and 3 years were 38.2%, 53.9%, and 68.5%, respectively. The multivariate analysis showed that viable hepatocellular carcinoma, absence of maintenance therapy, non-responder, and PVT progression were significantly associated with liver-related events. The PVT progression was observed in 23.3% (56/240). The multivariate analysis identified older age, absence of maintenance therapy, and non-responder as independent factors associated with PVT progression. The multivariate analysis revealed that younger age, no hepatocellular carcinoma, presence of maintenance therapy, and lower Model for End-stage Liver Disease-Sodium score significantly contributed to 3-year survival. Of the 240 patients, 13 (8.9%) prematurely discontinued treatment due to any adverse events. CONCLUSIONS: This study suggests that maintenance therapy, favorable response, and absence of PVT progression may suppress or control liver-related events in antithrombin III-based therapy for patients with PVT. Specifically, maintenance therapy could suppress not only liver-related events, but also PVT progression and improve the prognosis.

DOI： 10.1111/hepr.13840

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Adverse events (AEs) of urinary protein from monoclonal antibodies against vascular endothelial growth factor (VEGF) are factors that often inhibit systemic therapy for unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate risk factors of urinary protein in the early period (<12 weeks) of atezolizumab plus bevacizumab treatment (Atez/Bev). MATERIALS/METHODS: From 2020 to June 2022, 193 uHCC patients treated with Atez/Bev at our affiliated hospitals were enrolled (median 73 years, 158 males, 183 Child-Pugh A, BCLC-0: A: B: C=1: 7: 73: 112). AEs related to urinary protein (≥G2) within 12 weeks were defined as significant and related clinical features were analyzed retrospectively. RESULTS: In analyses of risk factors of urinary protein-related AEs during the first 12 weeks after starting Atez/Bev using a logistic regression method, univariate analysis showed positive for hypertension [odds ratio (OR) 3.54, 95%CI: 1.28-9.80, P=0.015] and baseline urinary protein urine creatinine ratio (UPC: ≥0.16) (OR 2.52, 95%CI: 1.09-5.83, P=0.031) as pre-treatment clinical factors, while elevation of urinary protein in the early period (baseline to three weeks) with delta UPC per three weeks (ΔUPC/3W) (≥0.23) (OR 15.80, 95%CI: 6.15-40.50, P<0.001) was a clinical factor after starting treatment. Multivariate analysis of only baseline clinical factors revealed positive for history of hypertension as the only predictive factor (OR 3.20, 95%CI: 1.14-8.95, P=0.027), while only ΔUPC/3W (≥0.23) (OR 14.40, 95%CI: 4.91-42.00, P<0.001) were noted in multivariate analysis including ΔUPC/3W. Predictive factors for ΔUPC/3W (≥0.23) (OR 3.50, 95%CI: 1.23-99.90, P=0.019) were hypertension and UPC (≥0.16) (OR 6.12, 95%CI 2.61-14.30, P<0.001) in multiple analysis. CONCLUSION: Urinary protein-related AEs are frequently observed during Atez/Bev treatment in uHCC patients with elevated ΔUPC/3W (≥0.23), and ΔUPC/3W (≥0.23) is often seen in patients with hypertension and/or UPC (≥0.16).

DOI： 10.1159/000526521

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Predicting the survival of hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/bev) remains a challenge. This study aims to validate the modified albumin-bilirubin grade and α-fetoprotein score (mALF score). METHODS: This retrospective, multicenter study included 426 HCC patients receiving Atez/Bev. Each patient was randomized 3:2 to a training set (n = 255) and a validation set (n = 171). We investigated prognostic factors in the training set and developed an easily applicable mALF score, which was evaluated in the validation set. RESULTS: We built the mALF score using baseline mALBI grade 2b or 3 (HR 2.36, 95% CI 1.37-4.05, p = 0.002) and α-fetoprotein ≥ 100 ng/ml (HR 2.61, 95% CI 1.49-4.55, p < 0.001), which were identified as unfavorable prognostic factors in a multivariate analysis. The 1-year OS rates were 82.7% (95% CI 68.9-90.8) in patients who meet neither of the criteria (mALF 0 points, n = 101), 61.7% (95% CI 44.5-74.9) in patients who meet either of the two criteria (mALF 1 point, n = 109), and 24.6% (95% CI 9.0-44.3) in patients who meet both criteria (mALF 2 points, n = 45); the difference was statistically significant (p < 0.001). The median PFS in patients with mALF 0, 1, and 2 points was 9.5 months (95% CI 4.3-NA), 6.6 months (95% CI 6.0-8.0), and 3.8 months (95% CI 3.0-5.2), respectively, which amounted to a significant difference (p < 0.001). These results were confirmed in the validation set (1-year OS rates, 0/1/2 points = 94.2%/62.1%/46.3%, p < 0.001; median PFS, 0/1/2 points = 9.3/6.7/4.7 months, p = 0.018). CONCLUSION: The mALF score can reliably predict the prognosis of HCC patients receiving Atez/Bev.

DOI： 10.1007/s12072-022-10406-8

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/jvh.13717

researchmap

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/jvh.13717

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: The use of Glasgow prognostic score (GPS), calculated using the serum C-reactive protein and albumin levels, to predict the outcomes of patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib was investigated in this study. METHODS: A total of 508 patients with Child-Pugh class A HCC treated with lenvatinib were included in this study. RESULTS: The median overall and progression-free survivals were 20.4 months [95% confidence interval (CI), 17.7-23.2 months] and 7.5 months (95% CI, 6.8-8.5 months), respectively. The median overall survivals of patients with a GPS of 0, 1, and 2 were 28.5, 16.0, and 9.1 months, respectively (P < 0.001). When adjusted for age, sex, performance status, etiology, α-fetoprotein, macroscopic vascular invasion, extrahepatic spread, history of sorafenib therapy, and GPS, a GPS of 1 [hazard ratio (HR), 1.664; 95% CI, 1.258-2.201; P < 0.001] and a GPS of 2 (HR, 2.664; 95% CI, 1.861-3.813; P < 0.001) were found to be independently associated with overall survival. The median progression-free survivals of patients with a GPS of 0, 1, and 2 were 8.8, 6.8, and 3.8 months, respectively (P < 0.001). When adjusted for the same factors of overall survival, a GPS of 2 (HR, 2.010; 95% CI, 1.452-2.784; P < 0.001) was found to be independently associated with progression-free survival. As the albumin-bilirubin with tumor node metastasis score increased, the proportion of patients with a GPS of 1 or 2 increased (P < 0.001). CONCLUSIONS: GPS can be used to predict survival in patients with unresectable HCC who were treated with lenvatinib.

DOI： 10.1097/MEG.0000000000002398

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本アルコール・アディクション医学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to investigate the utility of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score in hepatocellular carcinoma (HCC) patients receiving atezolizumab and bevacizumab (Atez/Bev). METHODS: This retrospective cohort study included a total of 297 patients receiving Atez/Bev from September 2020 to November 2021 at 21 different institutions and hospital groups in Japan. Patients with AFP ≥ 100 ng/mL and those with CRP ≥ 1 mg/dL were assigned a CRAFITY score of 1 point. RESULTS: The patients were assigned CRAFITY scores of 0 points (n = 147 [49.5%]), 1 point (n = 111 [37.4%]), and 2 points (n = 39 [13.1%]). AFP ≥ 100 ng/mL and CRP ≥ 1.0 mg/dL were significantly associated with progression-free survival (PFS) and overall survival (OS). The median PFS in the CRAFITY score 0, 1, and 2 groups was 11.8 months (95% confidence interval [CI] 6.4-not applicable [NA]), 6.5 months (95% CI 4.6-8.0), and 3.2 months (95% CI 1.9-5.0), respectively (p < 0.001). The median OS in patients with CRAFITY score 0, 1 and 2 was not reached, 14.3 months (95% CI 10.5-NA), and 11.6 months (95% CI 4.9-NA), respectively. The percentage of patients with grade ≥ 3 liver injury, any grade of decreased appetite, any grade of proteinuria, any grade of fever, and any grade of fatigue was lowest in patients with a CRAFITY score of 0, followed by patients with CRAFITY scores of 1 and 2. CONCLUSIONS: The CRAFITY score is simple and could be useful for predicting therapeutic outcomes and treatment-related adverse events.

DOI： 10.1007/s12072-022-10358-z

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/jgh3.12780

researchmap

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jgh3.12780

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: A comparison of therapeutic efficacy between atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib treatment given as first-line therapy for unresectable hepatocellular carcinoma (u-HCC) in regard to progression-free survival (PFS) overall survival (OS) has not been reported. We aimed to elucidate which of those given as initial treatment for u-HCC has greater prognostic impact on PFS and OS of affected patients, retrospectively. MATERIALS/METHODS: From 2020 to January 2022, 251 u-HCC (Child-Pugh A, ECOG PS 0/1, BCLC-B/C) treated were enrolled (Atez/Bev-group, n = 194; lenvatinib-group, n = 57). PFS and OS were analyzed following adjustment based on inverse probability weighting (IPW). RESULTS: There was a greater number of patients with macro-vascular invasion in Atez/Bev-group (22.7% vs. 8.8%, p = 0.022). In lenvatinib-group, the frequencies of appetite loss (38.6% vs. 19.6%, p = 0.002), hypothyroidism (21.1% vs. 6.7%, p = 0.004), hand foot skin reaction (19.3% vs. 1.0%, p < 0.001), and diarrhea (10.5% vs. 4.6%, p = 0.012) were greater, while that of general fatigue was lower (22.8% vs. 26.3%, p = 0.008). Comparisons of therapeutic best response using modified response evaluation criteria in solid tumors (mRECIST) did not show significant differences between the present groups (Atez/Bev vs. lenvatinib: CR/PR/SD/PD = 6.1%/39.1%/39.1%/15.6% vs. 0%/48.0%/38.0%/14.0%, p = 0.285). In patients of discontinuation of treatments, 48.2% switched to lenvatinib, 10.6% continued beyond PD, 8.2% received another systemic treatment, 5.9% underwent transcatheter arterial chemoembolization (TACE), 3.5% received hepatic arterial infusion chemotherapy (HAIC), and 1.2% underwent surgical resection in Atez/Bev-group, while 42.2% switched to Atez/Bev, 4.4% continued beyond PD, 4.4% received another systemic treatment, 2.2% nivolumab, 6.7% received TACE, and 2.2% received HAIC in lenvatinib-group. Following adjustment with inverse probability weighting (IPW), Atez/Bev-group showed better PFS (0.5-/1-/1.5-years: 56.6%/31.6%/non-estimable vs. 48.6%/20.4%/11.2%, p < 0.0001) and OS rates (0.5-/1-/1.5-years: 89.6%/67.2%/58.1% vs. 77.8%/66.2%/52.7%, p = 0.002). CONCLUSION: The present study showed that u-HCC patients who received Atez/Bev as a first-line treatment may have a better prognosis than those who received lenvatinib.

DOI： 10.1002/cam4.4854

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The role of serum type III procollagen peptide (P3P) level in the acute phase of acute heart failure (AHF) requires clarification. We hypothesized that serum P3P level is temporarily higher during the acute phase, reflecting liver dysfunction due to congestion. METHODS AND RESULTS: A total of 800 AHF patients were screened, and data from 643 patients were analysed. Heart failure was diagnosed by the treating physician according to the European Society of Cardiology (ESC) guidelines, and included patients being treated with high-concentration oxygen inhalation (including mechanical support) for orthopnea, inotrope administration, or mechanical support for low blood pressure, and various types of diuretics for peripheral or pulmonary oedema. In all cases, diuretics or vasodilators were administered to treat AHF. The patients were divided into three groups according to their quartile (Q) serum P3P level: low-P3P (Q1, P3P ≤ 0.6 U/mL), mid-P3P (Q2/Q3, 0.6 < P3P <1.2 U/mL), and high-P3P (Q4, P3P ≥ 1.2 U/mL). The plasma volume status (PVS) was calculated using the following formula: ([actual PV - ideal PV]/ideal PV) × 100 (%). The primary endpoint was 365 day mortality. A Kaplan-Meier curve analysis showed that prognoses, including all-cause mortality and heart failure events within 365 days, were significantly (P < 0.001) worse in the high-P3P group when compared with the mid-P3P and low-P3P groups. A multivariate logistic regression analysis showed that high PVS (Q4, odds ratio [OR]: 4.702, 95% CI: 2.012-20.989, P < 0.001), high fibrosis-4 index (Q4, OR: 2.627, 95% CI: 1.311-5.261, P = 0.006), and low estimated glomerular filtration rate per 10 mL/min/1.73 m2 decrease (OR: 1.996, 95% CI: 1.718-2.326, P < 0.001) were associated with high P3P values. The Kaplan-Meier curve analysis demonstrated a significantly lower survival rate, as well as a higher rate of heart failure events, in the high-P3P and high-PVS groups when compared with the other groups. A multivariate Cox regression model identified high P3P level and high PVS as an independent predictor of 365 day all-cause mortality (hazard ratio [HR]: 2.249; 95% CI: 1.081-3.356; P = 0.026) and heart failure events (HR: 1.586, 95% CI: 1.005-2.503, P = 0.048). CONCLUSION: A high P3P level during the acute phase of AHF served as a comprehensive biomarker of liver dysfunction with volume overload (i.e. liver congestion) and renal dysfunction. A high P3P level at admission may be able to predict adverse outcomes in AHF patients.

DOI： 10.1002/ehf2.13878

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Atezolizumab plus bevacizumab (Atez/Bev) treatment is recommended for unresechepatocellular carcinoma (u-HCC) patients classified as Child-Pugh A (CP-A). This study aimed to elucidate the prognosis of patients treated with Atez/Bev, especially CP-A and -B cases. MATERIALS/METHODS: From September 2020 to March 2022, 457 u-HCC patients treated with Atez/Bev were enrolled (median age 74 years, male:female = 368:89, CP-A:CP-B = 427:30, Child-Pugh score [CPS] 5:6:7:8:9 = 271:156:21:8:1). Therapeutic response was evaluated using RECIST ver.1.1. Clinical features and prognosis were retrospectively evaluated. RESULTS: There were no significant differences between CP-A and -B patients in regard to best response (CR:PR:SD:PD = 16:91:194:81 vs. 0:7:13:8, p = 0.739; objective response rate/disease control rate = 28.0%/78.8% vs. 25.0%/71.4%). Analysis performed using inverse probability weighting adjustments of clinical factors other than those related to hepatic reserve function with a p value < 0.10 for comparisons between patients with CP-A and -B showed that the progression-free survival (PFS) rate for CP-A cases was better (6-/12-/18-month: 58.2%/36.1%/27.8% vs. 49.6%/8.7%/non-estimable [NE], p < 0.001), as was overall survival (OS) rate (6-/12-/18-month: 89.9%/71.7%/51.4% versus 63.6%/18.4%/NE; p < 0.001). Median PFS (mPFS) and median OS (mOS) for the CPS-5 were 9.5 months/NE, and 5.1/14.0 months for the CPS-6 (both p < 0.001). Furthermore, for modified albumin-bilirubin grade (mALBI)-1/2a/2b, mPFS was 9.4/8.5/5.3 months (p < 0.001) and mOS was NE/17.8/13.4 months (p < 0.001). CONCLUSION: Better hepatic function, such as mALBI grade 1 or 2a are thought to indicate a better condition for obtaining sufficient prognosis with Atez/Bev treatment for u-HCC patients, whereas for CP-B patients, who mainly shown an mALBI grade of 2b or 3, Atez/Bev might have less therapeutic efficacy.

DOI： 10.1111/hepr.13797

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the impact of C-reactive protein to albumin ratio (CAR) on predicting outcomes in 522 patients with unresectable hepatocellular carcinoma (HCC) treated with lenvatinib. We determined the optimal CAR cutoff value with time-dependent receiver operating characteristic curve analysis. Additionally, we clarified the relationship between CAR and liver function or HCC progression. Median overall survival was 20.0 (95% confidence interval (CI), 17.2-22.6) months. The optimal CAR cutoff value was determined to be 0.108. Multivariate analysis showed that high CAR (≥ 0.108) (hazard ratio (HR), 1.915; 95% CI, 1.495-2.452), Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.429), and α-fetoprotein ≥ 400 ng/mL (HR, 1.604) were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high CAR (p < 0.001). Median progression-free survival was 7.5 (95% CI, 6.7-8.1) months. Multivariate analysis showed that age, CAR ≥ 0.108 (HR, 1.644; 95% CI, 1.324-2.043), and non-hepatitis B, non-hepatitis C etiology (HR, 0.726) were independently associated with progression-free survival. Cumulative progression-free survival differed significantly between patients with low versus high CAR (p < 0.001). CAR values were significantly higher as Japan Integrated Staging score increased (p < 0.001). In conclusion, CAR can predict outcomes in patients with unresectable HCC treated with lenvatinib.

DOI： 10.1038/s41598-022-12058-y

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: To assess the utility of measurement of the computed tomography (CT) attenuation value (CTav) in predicting tumor necrosis in hepatocellular carcinoma (HCC) patients who achieve a complete response (CR), defined using modified Response Evaluation Criteria in Solid Tumors (mRECIST), after lenvatinib treatment. METHOD: We compared CTav in arterial phase CT images with postoperative histopathology in four patients who underwent HCC resection after lenvatinib treatment, to determine CTav thresholds indicative of histological necrosis (N-CTav). Next, we confirmed the accuracy of the determined N-CTav in 15 cases with histopathologically proven necrosis in surgical specimens. Furthermore, the percentage of the tumor with N-CTav, i.e., the N-CTav occupancy rate, assessed using Image J software in 30 tumors in 12 patients with CR out of 571 HCC patients treated with lenvatinib, and its correlation with local recurrence following CR were examined. RESULTS: Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off value of CTav of 30.2 HU, with 90.0% specificity and 65.0% sensitivity in discriminating between pathologically identified necrosis and degeneration, with a CTav of less than 30.2 HU indicating necrosis after lenvatinib treatment (N30-CTav). Furthermore, the optimal cut-off value of 30.6% for the N30-CTav occupancy rate by ROC analysis was a significant indicator of local recurrence following CR with 76.9% specificity and sensitivity (area under the ROC curve; 0.939), with the CR group with high N30-CTav occupancy (≥30.6%) after lenvatinib treatment showing significantly lower local recurrence (8.3% at 1 year) compared with the low (&lt;30.6%) N30-CTav group (p &lt; 0.001, 61.5% at 1 year). CONCLUSION: The cut-off value of 30.2 HU for CTav (N30-CTav) might be appropriate for identifying post-lenvatinib necrosis in HCC, and an N30-CTav occupancy rate of &gt;30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

DOI： 10.3390/curroncol29050266

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jiac.2022.04.024

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The safety and efficacy of atezolizumab plus bevacizumab (Atez/Bev) in elderly patients with unresectable hepatocellular carcinoma (HCC) have not been sufficiently investigated. METHODS: A total of 317 patients with HCC treated with Atez/Bev were studied. We compared the survival and frequency of adverse events in elderly versus non-elderly patients with HCC who were treated with Atez/Bev using an analysis of inverse probability weighting (IPW). RESULTS: Univariate analysis adjusted with IPW showed that being elderly is not associated with worse overall or progression-free survival (hazard ratio [HR], 1.239; 95% confidence interval [CI], 0.640-2.399; p = 0.526 and HR, 1.256; 95% CI, 0.871-1.811; p = 0.223, respectively). Regarding treatment-related adverse events, any grade of fatigue, proteinuria, decreased appetite, hypertension, and liver injury occurred in ≥10% of patients. There were no significant differences in treatment-related adverse events between the elderly and non-elderly groups. In a subgroup analysis of elderly patients aged 75-79, 80-84, or ≥ 85 years, there were no significant differences in cumulative overall or progression-free survival among these age groups (p = 0.960 and 0.566, respectively). In addition, there were no significant differences in treatment-related adverse events among these three age groups, except for proteinuria of any grade. In a subgroup analysis of patients treated with Atez/Bev as first-line systemic therapy, there were no significant differences in cumulative overall or progression-free survival between the elderly and non-elderly groups (p = 0.728 and 0.805, respectively). CONCLUSIONS: Atez/Bev can be used efficaciously and safely in spite of age in patients with unresectable HCC.

DOI： 10.1002/cam4.4763

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Lusutrombopag effectively increases platelet count in patients with severe thrombocytopenia. However, no multicenter studies analyzing the effects of Lusutrombopag on patients with mild thrombocytopenia (platelet count > 50 000/µL) have been performed. In this study, we aimed to clarify the efficacy of Lusutrombopag on these patients by unifying background factors by propensity score matching. METHODS: A total of 139 patients with thrombocytopenia were enrolled, and matched for age, sex, etiology, disease, treatment, liver function, renal function, peripheral blood count, and spleen index. The primary endpoint was to compare the increase in platelet count from baseline between the high-platelet group (>50 000/µL) and the low-platelet group (<50 000/µL) after Lusutrombopag treatment, using propensity score matching. The secondary endpoint was to clarify platelet transfusion avoidance rate and adverse events, moreover, to identify independent predictors associated with the increase in platelet count. RESULTS: The mean increase in platelet count was 67 000/μL vs 48 000/μL in all patients (high- vs low-platelet group, P = .024), and 64 000/μL vs 48 000/μL (P = .12) after propensity score matching. The increase in platelet count and the platelet transfusion avoidance rate tended to be higher in the high-platelet group. There was no significant difference between adverse events. Predictors associated with an increase in platelet count were sex, estimated glomerular filtration rate, and spleen index by multivariate analysis. CONCLUSION: Lusutrombopag has a little stronger effect in patients with mild thrombocytopenia than those with severe thrombocytopenia and showed a more substantial effect in patients with impaired renal function and small spleen.

DOI： 10.1002/jhbp.1099

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1002/hep4.1941

researchmap

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/hep4.1941

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1111/hepr.13739

researchmap

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13739

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To investigate whether neutrophil-to-lymphocyte ratio (NLR) can predict outcomes in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atez/Bev). METHODS: A total of 249 patients with unresectable HCC treated with Atez/Bev were included. We analyzed survival and discontinuation of this therapy in this cohort. RESULTS: Cumulative overall survival at 2, 4, 6, and 8 months was 97.6%, 94.9%, 88.9%, and 82.8%, respectively. Cumulative overall survival differed significantly between patients with low (<3.0) versus high (≥3.0) NLR (P = 0.001). Conversely, cumulative progression-free survival did not differ between patients with low versus high NLR. The distribution of response was 1.5% for complete response, 17.1% for partial response, 60.5% for stable disease, and 21.0% for progressive disease. Responses were not different between patients with low and high NLR. Regarding adverse events, immune-related liver injury of any grade and grade of at least 3, decreased appetite of any grade, grade of at least 3 proteinuria, and other adverse events of any grade differed significantly between patients with low and high NLR. There were 56, 18, and 2 patients who discontinued Atez/Bev therapy due to progression of disease, adverse event, and other reasons, respectively. The cumulative discontinuation rate for Atez/Bev therapy due to adverse events differed significantly between patients with low versus high NLR (P = 0.022). Cox proportional hazards modeling analysis with inverse probability weighting showed that NLR of at least 3.0 was significantly associated with overall survival (hazard ratio, 3.369; 95% confidence interval, 1.024-11.080). CONCLUSIONS: NLR can predict outcomes in patients with unresectable HCC treated with Atez/Bev.

DOI： 10.1097/MEG.0000000000002356

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The present study focused on the association of early bevacizumab (Bev) interruption with the clinical outcome of atezolizumab plus bevacizumab. METHODS: This retrospective study included 239 patients with advanced hepatocellular carcinoma receiving atezolizumab/Bev from September 2020 to June 2021 at 16 different institutions in Japan. We conducted a 9-week landmark analysis to investigate the association of Bev interruption due to adverse events with the therapeutic efficacy. RESULTS: The median age was 73.0 (68.0-80.0) years old, with 195 (81.6%) men. The objective response rate was significantly higher in patients without Bev interruption than in those with it (34.5% vs. 17.3%, p = 0.038). The median progression-free survival (PFS) was 6.5 months (95% confidence interval [CI] 4.5-9.7) and 9.0 months (95% CI 7.1-not applicable) in patients with and without Bev interruption, respectively, with statistical significance (p = 0.021). The 12-month overall survival (OS) rates in patients with and without Bev interruption were 49.4% (CI 27.7%-67.9%) and 82.2% (95% CI 70.3%-89.6%), respectively, showing a significant difference (p = 0.004). The presence of Bev interruption was a significant factor associated with the PFS (p = 0.021) and OS (p = 0.008). A multivariate analysis showed that modified albumin-bilirubin 2b (p < 0.001) and later-line treatment (p = 0.018) were unfavorable factors associated with Bev interruption. Liver injury, appetite loss, protein urea, and ascites or hepatic edema were more frequently found in patients with Bev interruption than in those without it. CONCLUSIONS: Early Bev interruption was an unfavorable factor associated with the PFS and OS. Good liver function and treatment settings may be associated with maintaining Bev treatment.

DOI： 10.1111/hepr.13748

PubMed

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.gastha.2022.02.018

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We examined the association between serum miRNA (-192-5p, -122-3p, -320a and -6126-5p) levels and the efficacy of pegylated interferon (Peg-IFN) monotherapy for chronic hepatitis B (CHB) patients. We enrolled 61 CHB patients treated with Peg-IFNα-2a weekly for 48 weeks, of whom 12 had a virological response (VR) and 49 did not VR (non-VR). A VR was defined as HBV DNA < 2,000 IU/ml, hepatitis B e antigen (HBeAg)-negative, and nucleos(t)ide analogue free at 48 weeks after the end of treatment. The non-VR group showed a significantly higher HBeAg-positivity rate, ALT, HBV DNA, and serum miR-192-5p levels at baseline (P = 0.024, P = 0.020, P = 0.007, P = 0.021, respectively). Serum miR-192-5p levels at 24-weeks after the start of treatment were also significantly higher in the non-VR than the VR group (P = 0.011). Multivariate logistic regression analysis for predicting VR showed that miR-192-5p level at baseline was an independent factor (Odds 4.5, P = 0.041). Serum miR-192-5p levels were significantly correlated with the levels of HBV DNA, hepatitis B core-related antigen, and hepatitis B surface antigen (r = 0.484, 0.384 and 0.759, respectively). The serum miR-192-5p level was useful as a biomarker for the therapeutic efficacy of Peg-IFN in CHB treatment.

DOI： 10.1371/journal.pone.0263844

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA. METHODS: In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks. RESULTS: At week 48, 3/74 participants (4%) achieved 0.25 log10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was -0.14 log10 IU/mL and 12% (9/74) achieved 0.25 log10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%]). CONCLUSIONS: In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1.

DOI： 10.1186/s12876-021-02008-9

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Data regarding the influence of patatin-like phospholipase domain-containing 3 (PNPLA3) polymorphism for patients with liver cirrhosis (LC) are scarce. OBJECTIVE: This study assesses the role of the PNPLA3 polymorphism for the development of LC and its complications by the findings of genetic examinations. METHODS: Patients with LC caused by virus (n = 157), alcohol (n = 104), nonalcoholic fatty liver disease (NAFLD) (n = 106), or autoimmune disease (n = 33) and without LC (n = 128) were enrolled. LC were composed of the present and absent of complications, such as variceal bleeding, hepatic ascites, and/or hepatic encephalopathy. To assess the role of the PNPLA3 polymorphism, odds ratio (OR) for the rs738409 variant was calculated for the patients between (i) with LC and without LC in the entire cohort, and (ii) the present and absent of complications in the patients with LC. RESULTS: There was a significant difference among the patients without LC and those with alcohol, NAFLD related LC in the frequency of G alleles (p < 0.001, both). According to complications of LC, the OR for NAFLD related cirrhosis significantly increased in the presence of the two mutated alleles (OR = 3.165; p = 0.046) when the wild type was used as the reference. However, there were no significant risks for the complications in the virus and alcohol related cirrhosis unless there was a presence of G alleles. CONCLUSION: The PNPLA3 polymorphism was associated with the risk of NAFLD related LC and its complications.

DOI： 10.1159/000521062

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Although systemic therapy is recommended for patients with multiple intermediate stage unresectable hepatocellular carcinoma (u-HCC) classified as beyond the up-to-7 criteria (UT-7 out/multiple) as a transcatheter arterial chemoembolization (TACE) unsuitable condition, few reports have examined the therapeutic efficacy of atezolizumab plus bevacizumab combination therapy (Atez/Bev) in such cases. This study aimed to elucidate the therapeutic response of Atez/Bev in u-HCC patients classified as UT-7 out/multiple. MATERIAL/METHODS: From September 2020 to September 2021, 95 u-HCC Japanese patients classified as UT-7 out/multiple/Child-Pugh A were enrolled from 21 institutions (median age 76 years, males 73, Child-Pugh 5:6 = 68:27, TNM stage II:III = 17:78). Therapeutic response was retrospectively evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1 and modified RECIST (mRECIST). RESULTS: Atez/Bev was given as first-line treatment to 52 (54.7%). Objective response rate (ORR)/disease control rate (DCR) at six weeks of RECIST and mRECIST were 17.7%/84.7% and 42.5%/86.2%, respectively. Median PFS was 8.0 months (median observation period: 6.0 months). Child-Pugh A/modified Albumin-bilirubin grade (mALBI) 1 and 2a at baseline, 3, 6, and 9 weeks, were 100%/69.4%, 89.8%/57.3%, 94.8%/65.3%, and 91.4%/60.0%, respectively. Among adverse events (any-grade, >10%) during the present observation period, general fatigue was most frequent (23.2%), followed by urine protein (21.1%), appetite loss (20.0%), and hypertension (13.7%). CONCLUSION: Atez/Bev treatment showed favorable therapeutic response with less influence on hepatic function, suggesting it as a useful therapeutic option for patients with such condition.

DOI： 10.1111/hepr.13734

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: There is no standard posttreatment for patients with advanced hepatocellular carcinoma (HCC) in whom lenvatinib therapy has failed. This study aimed to investigate rates of migration to posttreatment after lenvatinib and to explore candidates for second-line agents in the patients with failed lenvatinib therapy. METHODS: We retrospectively collected data on patients with advanced HCC who received lenvatinib as the first-line agent in 7 institutions. RESULTS: Overall survival and progression-free survival (PFS) of 178 patients who received lenvatinib as the first-line agent were 13.3 months (95% confidence interval [CI], 11.5-15.2) and 6.7 months (95% CI, 5.6-7.8), respectively. Sixty-nine of 151 patients (45.7%) who discontinued lenvatinib moved on to posttreatment. The migration rates from lenvatinib to the second-line agent and from the second-line agent to the third-line agent were 41.7 and 44.4%, respectively. Based on multivariate analysis, response to lenvatinib (complete or partial response according to modified RECIST) and discontinuation of lenvatinib due to radiological progression, as well as male were associated with a significantly higher probability of migration to posttreatment after lenvatinib. On the other hand, alpha-fetoprotein levels of 400 ng/mL or higher was correlated with a significantly lower probability of migration to posttreatment after lenvatinib. Of 63 patients who received second-line systemic therapy, 53 (84.2%) were administered sorafenib. PFS, objective response rate (ORR), and disease control rate (DCR) for sorafenib treatment were 1.8 months (95% CI, 0.6-3.0), 1.8%, and 20.8%, respectively. According to the Cox regression hazard model, Child-Pugh class B significantly contributed to shorter PFS. PFS, ORR, and DCR of 22 patients who received regorafenib after lenvatinib in any lines were 3.2 months (range, 1.5-4.9 months), 13.6%, and 36.3%, respectively. Similarly, PFS, ORR, and DCR of 17 patients who received regorafenib after lenvatinib in the third-line (after sorafenib) were 3.8 months (range, 1.1-6.5 months), 17.6%, and 41.2%, respectively. CONCLUSION: Sorafenib may not be a candidate for use as a posttreatment agent after lenvatinib, according to the results of the present study. Regorafenib has the potential to become an appropriate posttreatment agent after lenvatinib.

DOI： 10.1159/000515552

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

It was recently reported that hepatocellular carcinoma (HCC) patients with non-alcoholic steatohepatitis (NASH) are not responsive to immune-checkpoint inhibitor (ICI) treatment. The present study aimed to evaluate the therapeutic efficacy of lenvatinib in patients with non-alcoholic fatty liver disease (NAFLD)/NASH-related unresectable-HCC (u-HCC). Five hundred thirty u-HCC patients with Child-Pugh A were enrolled, and divided into the NAFLD/NASH (n = 103) and Viral/Alcohol (n = 427) groups. Clinical features were compared in a retrospective manner. Progression-free survival (PFS) was better in the NAFLD/NASH than the Viral/Alcohol group (median 9.3 vs. 7.5 months, P = 0.012), while there was no significant difference in overall survival (OS) (20.5 vs. 16.9 months, P = 0.057). In Cox-hazard analysis of prognostic factors for PFS, elevated ALT (≥ 30 U/L) (HR 1.247, P = 0.029), modified ALBI grade 2b (HR 1.236, P = 0.047), elevated AFP (≥ 400 ng/mL) (HR 1.294, P = 0.014), and NAFLD/NASH etiology (HR 0.763, P = 0.036) were significant prognostic factors. NAFLD/NASH etiology was not a significant prognostic factor in Cox-hazard analysis for OS (HR0.758, P = 0.092), whereas AFP (≥ 400 ng/mL) (HR 1.402, P = 0.009), BCLC C stage (HR 1.297, P = 0.035), later line use (HR 0.737, P = 0.014), and modified ALBI grade 2b (HR 1.875, P < 0.001) were significant. Lenvatinib can improve the prognosis of patients affected by u-HCC irrespective of HCC etiology or its line of treatment.

DOI： 10.1038/s41598-021-96089-x

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.

DOI： 10.1038/s41598-021-95581-8

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Multiple molecular agents have been developed for treating unresectable hepatocellular carcinoma. This study aimed to elucidate the clinical efficacy of sequential treatment with lenvatinib after regorafenib failure. METHODS: From June 2017 to October 2020, 63 patients with Child-Pugh A and treated with regorafenib followed by sorafenib were enrolled (median age 71 years, 52 men, Barcelona Clinic Liver Cancer B:C = 23:40). They were divided into two groups, those treated with lenvatinib after regorafenib treatment (R-L group, n = 47) and those who did not receive lenvatinib after regorafenib (non-R-L group, n = 16). Prognostic factors were retrospectively analyzed after adjustment with inverse probability weighting. RESULTS: Serum albumin level at the start of regorafenib and reasons for discontinuation of regorafenib were significantly different between the R-L and non-R-L groups, whereas the albumin-bilirubin score, Child-Pugh class, and tumor burden were not. Progression-free survival was also not significantly different (median 4.1 vs. 3.8 months, p = 0.586). As for overall survival, the R-L group showed better prognosis after introducing regorafenib and after introducing sorafenib, following inverse probability weighting adjustment (MST 19.7 vs. 10.3 months, 33.8 vs. 15.3 months, p < 0.001 and p = 0.022, respectively). Modified albumin-bilirubin grade 2b (score >-2.27) at the start of regorafenib (HR 2.074, p = 0.041) and the presence of lenvatinib treatment after regorafenib failure (HR 0.355, p = 0.004) were found to be significant prognostic factors in Cox proportional hazards multivariate analysis, after inverse probability weighting adjustment. CONCLUSION: These results show that lenvatinib is a good sequential treatment option after progression under regorafenib therapy in unresectable hepatocellular carcinoma patients with better hepatic reserve function.

DOI： 10.1111/hepr.13644

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Real-world data for treatment effectiveness and renal outcomes in chronic hepatitis B (CHB) patients who were switched to the new and safer prodrug tenofovir alafenamide (TAF) from tenofovir disoproxil fumarate (TDF) are limited. Therefore, we aimed to evaluate treatment and renal outcomes of this population. APPROACH AND RESULTS: We analyzed 834 patients with CHB previously treated with TDF for ≥12 months who were switched to TAF in routine practice at 13 US and Asian centers for changes in viral (HBV DNA < 20 IU/mL), biochemical (alanine aminotransferase [ALT] < 35/25 U/L for male/female), and complete (viral+biochemical) responses, as well as estimated glomerular filtration rate (eGFR; milliliters per minute per 1.73 square meters) up to 96 weeks after switch. Viral suppression (P < 0.001) and ALT normalization (P = 0.003) rates increased significantly after switch, with a trend for increasing complete response (Ptrend = 0.004), while the eGFR trend (Ptrend  > 0.44) or mean eGFR (P > 0.83, adjusted for age, sex, baseline eGFR, and diabetes, hypertension, or cirrhosis by generalized linear modeling) remained stable. However, among those with baseline eGFR < 90 (chronic kidney disease [CKD] stage ≥2), mean eGFR decreased significantly while on TDF (P = 0.029) but not after TAF switch (P = 0.90). By week 96, 21% (55/267) of patients with CKD stage 2 at switch improved to stage 1 and 35% (30/85) of CKD stage 3-5 patients improved to stage 2 and 1.2% (1/85) to stage 1. CONCLUSIONS: Overall, we observed continued improvement in virologic response, ALT normalization, and no significant changes in eGFR following switch to TAF from TDF.

DOI： 10.1002/hep.31793

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The Fibrosis-4 (FIB4) index could indicate the liver fibrosis in patients with chronic hepatic diseases. It was calculated using the following formula: (age × aspartate aminotransferase [U/L]) / (platelet count [103/μL] × √alanine aminotransferase [U/L]). However, the clinical impact of the FIB4 index in the acute phase of acute heart failure (AHF) has not been sufficiently investigated.A total 1,468 AHF patients were analyzed. The median FIB4 index was 2.71 [1.85-4.22]. The patients were divided into three groups according to the quartiles of their FIB4 index (low-FIB4 [Q1, ≤ 1.847], middle-FIB4 [Q2/Q3, 1.848-4.216], and high-FIB4 [Q4, ≥ 4.216] groups). A Kaplan-Meier curve analysis showed that the prognosis, such as all-cause mortality and HF events within 365 days, was significantly poorer in the high-FIB4 group than in the middle-FIB4 and low-FIB4 groups. A multivariate Cox regression model identified high FIB4 index as an independent predictor of 365-day all-cause death (hazard ratio (HR): 1.660, 95% CI: 1.136-2.427) and HF events (HR: 1.505, 95% CI: 1.145-1.978). The multivariate logistic regression analysis showed that the high plasma volume status (PVS) (Q4, odds ratio [OR]: 2.099, 95% CI: 1.429-3.082), low systolic blood pressure (SBP) (< 100 mmHg, OR: 3.825, 95% CI: 2.504-5.840), and low left ventricular ejection fraction (< 40%, OR: 1.321, 95% CI: 1.002-1.741) were associated with a high FIB4 index.A high FIB4 index can predict adverse outcomes in AHF patients, which indicate that congestive liver and liver hypoperfusion occur due to low cardiac output in the acute phase of AHF.

DOI： 10.1536/ihj.20-793

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

We investigated the impact on survival of modified albumin-bilirubin (mALBI) grade versus Child-Pugh classification in patients with hepatocellular carcinoma (HCC) who received lenvatinib. A total of 524 patients with HCC who received lenvatinib were included. Univariate analysis showed that mALBI grade 2b/3 and Child-Pugh class B/C were significantly associated with survival [hazard ratio (HR), 2.471; 95% confidence interval (CI), 1.944-3.141 and HR, 2.178; 95%CI, 1.591-2.982]. In patients with a Child-Pugh score of 5, multivariate analysis showed that mALBI grade 2b/3 was independently associated with survival (HR, 1.814; 95%CI, 1.083-3.037). Conversely, among patients with mALBI grade 1/2a, there was no difference in survival between those with a Child-Pugh class of 5 or 6 (p = 0.735). Time-dependent receiver operating characteristic analysis showed that the ALBI score predicted survival better than the Child-Pugh score. The optimal cut-off value of the ALBI score for predicting survival was nearly the same as the value separating mALBI grades 2a and 2b. In conclusion, the mALBI grade was a better predictor of survival than the Child-Pugh classification in patients with unresectable HCC who received lenvatinib therapy.

DOI： 10.1038/s41598-021-93794-5

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: Lenvatinib is a standard of care option in first-line therapy of advanced hepatocellular carcinoma (HCC). In the present study, we aim to identify, in patients with HCC treated with lenvatinib, a possible association between occurrence and grading of adverse events (AEs) and outcome. METHODS: We performed a retrospective analysis of 606 Japanese and Italian patients treated with lenvatinib in first-line setting and investigated the possible correlation between the onset of AEs, toxicity grade (G) and outcome measures such as overall survival (OS) and progression-free survival (PFS). RESULTS: The appearance of arterial hypertension G ≥ 2 independently predicted prolonged OS [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.46-0.93, P = .0188], whereas decreased appetite G ≥ 2 independently predicted decreased OS (HR 1.70, 95% CI 1.25-2.32, P = .0007) by multivariate analysis. Appearance of hand-foot skin reaction independently predicted prolonged PFS (HR 0.72, 95% CI 0.56-0.93, P = .0149), whereas decreased appetite G ≥ 2 predicted decreased PFS (HR 1.36, 95% CI 1.04-1.77, P = .0277). CONCLUSIONS: Our main findings are that the occurrence of arterial hypertension G ≥ 2 is a predictor of longer survival, whereas decreased appetite G ≥ 2 predicts for a poor prognosis. A careful management of AEs under lenvatinib treatment for HCC is required, to improve patients' quality of life, minimize the need for treatment discontinuation and achieve optimal outcome.

DOI： 10.1111/liv.15014

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hepatocellular carcinoma (HCC) can de novo develop in patients with chronic hepatitis C even after the achievement of sustained virologic response (SVR). We characterized de novo HCC after SVR, comparing it with HCC that developed in patients during persistent hepatitis C virus (HCV) infection. Characteristics, survival rates, and recurrence rates after curative treatment in 178 patients who developed initial HCC after SVR diagnosed between 2014 and 2020 were compared with those of 127 patients with initial HCC that developed during persistent HCV infection diagnosed between 2011 and 2015; HCC was detected under surveillance in both groups. HCC was less advanced and liver function worsened less in patients with SVR than in patients with persistent HCV. The survival rate after diagnosis was significantly higher for patients with SVR than for patients with persistent HCV (1-, 3-, and 5-year survival rates, 98.2%, 92.5%, and 86.8% versus 89.5%, 74.7%, and 60.8%, respectively; P < 0.001). By contrast, the recurrence rate after curative treatment was similar between groups (1-, 3-, and 5-year recurrence rates, 11.6%, 54.6%, and 60.4% versus 24.0%, 46.7%, and 50.4%, respectively; P = 0.7484). Liver function improved between initial HCC diagnosis and recurrence in patients with SVR (P = 0.0191), whereas it worsened in the control group (P < 0.001). In addition, patients with SVR could receive curative treatment for recurrence more frequently than patients with persistent HCV (80.4% versus 47.8%, respectively; P = 0.0008). Conclusion: Survival of patients with de novo HCC after SVR was significantly higher than that of patients in whom HCC developed during persistent HCV infection, despite similar rates of recurrence after curative treatment. A higher prevalence of curative treatment for recurrent HCC and improved liver function contributed to this result.

DOI： 10.1002/hep4.1716

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: This study aimed to elucidate the clinical importance of muscle volume loss (pre-sarcopenia) in patients receiving lenvatinib as treatment for unresectable hepatocellular carcinoma (u-HCC). METHODS: Of 437 u-HCC patients treated with lenvatinib at specific institutions in Japan between March 2018 and May 2020, 151 with available computed tomography imaging data from the time of lenvatinib introduction were enrolled. Pre-sarcopenia was diagnosed based on a previously reported cut-off value calculation formula [psoas muscle area at level of middle of third lumbar vertebra (cm2 )/height (m)2 ]. Clinical features and prognostic factors for overall survival (OS) with inverse probability weighting were investigated retrospectively for their relationship with pre-sarcopenia. RESULTS: Cox hazard multivariate analysis showed alpha-fetoprotein (≥400 ng/mL) (hazard ratio [HR] 2.271, P < 0.001), Barcelona Clinic Liver Cancer stage (C and D) (HR 1.625, P = 0.018), and positive for pre-sarcopenia (HR 1.652, P = 0.042) to be significant prognostic factors. OS rates for the pre-sarcopenia group (n = 41) were worse than those for the non-pre-sarcopenia group (n = 110) (0.5-, 1-, and 1.5-year OS: 72.5%, 27.9%, and 7.0% vs 80.7%, 56.7%, and 46.1%, respectively; P < 0.001), as was progression-free survival (P = 0.025). Time to stopping lenvatinib or disease progression was better in the non-pre-sarcopenia group (0.5-, 1-, and 1.5-year OS: 48.0%, 24.5%, and 8.4% vs 20.0%, 10.3%, and 4.2%, respectively; P < 0.001). Also, the frequency of the adverse event appetite loss (any grade) was greater in the pre-sarcopenia group (43.9% vs 18.2%, P = 0.003). CONCLUSION: Pre-sarcopenia was shown to be a significant prognostic factor in patients treated with lenvatinib for u-HCC.

DOI： 10.1111/jgh.15336

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Chronic hepatitis C virus (HCV) infection can progress to liver cirrhosis and hepatocellular carcinoma. Interferon-based treatment was previously the only antiviral therapy for chronic hepatitis C infection; however, development of interferon-free, direct-acting antivirals, in 2014, markedly improved treatment efficacy and safety. Treatment indications were expanded to include elderly adults, patients with advanced liver fibrosis, and patients with chronic hepatitis C infection complicated by chronic kidney disease, for whom antiviral therapy had been difficult or contraindicated. The median age of patients with chronic HCV infection in Japan is 70 years, older than in other countries. Because diminished renal function is common in elderly adults, a safe and effective treatment for chronic hepatitis C complicated by chronic kidney disease has been expected in Japan. In addition, the HCV antibody-positive rate is higher in hemodialysis patients than in non-hemodialysis patients in Japan. Numerous studies have reported that direct-acting antivirals are safe and effective for hepatitis C patients on hemodialysis. This review summarizes treatments available in Japanese clinical practice for patients with chronic HCV infection complicated by chronic kidney disease, including hemodialysis patients.

DOI： 10.1272/jnms.JNMS.2021_88-316

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Although atezolizumab plus bevacizumab (Atez/bev) treatment has been developed for unresectable hepatocellular carcinoma (u-HCC), changes in hepatic function during therapy have yet to be reported. AIM: This retrospective clinical study aimed to elucidate early responses to Atez/Bev. METHODS: From September 2020 to April 2021, 171 u-HCC patients undergoing Atez/Bev treatment were enrolled (BCLC stage A:B:C:D = 5:68:96:2). Of those, 75 had no prior history of systemic treatment. Relative changes in hepatic function and therapeutic response were assessed using albumin-bilirubin (ALBI) score and Response Evaluation Criteria in Solid Tumors (RECIST), ver. 1.1, respectively. RESULTS: In initial imaging examination findings, objective response rates for early tumor shrinkage and disease control after 6 weeks (ORR-6W/DCR-6W) were 10.6%/79.6%. Similar response results were observed in patients with and without a past history of systemic treatment (ORR-6W/DCR-6W = 9.7%/77.8% and 12.2%/82.9%), as well as patients in whom Atez/Bev was used as post-progression treatment following lenvatinib (ORR-6W/DCR-6W = 7.7%/79.5%), for which no known effective post-progression treatment has been established. In 111 patients who underwent a 6-week observation period, ALBI score was significantly worsened at 3 weeks after introducing Atez/Bev (-2.525 ± 0.419 vs -2.323 ± 0.445, p < .001), but then recovered at 6-weeks (-2.403 ± 0.452) as compared to 3-weeks (p = .001). During the observation period, the most common adverse events were appetite loss (all grades) (12.3%), general fatigue/hypertension (all grades) (11.1%, respectively), and urine protein (all grades) (10.5%). CONCLUSION: Atez/Bev might have therapeutic potential not only as first but also later-line treatment of existing molecular target agents. In addition, this drug combination may have less influence on hepatic function during the early period, as the present patients showed a good initial therapeutic response.

DOI： 10.1002/cnr2.1464

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch. METHODS: ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL). RESULTS: We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR. DISCUSSION: After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.

DOI： 10.14309/ajg.0000000000001157

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Data from common clinical practice were used to generate balanced cohorts of patients receiving either sorafenib or lenvatinib, for unresectable hepatocellular carcinoma, with the final aim to investigate their declared equivalence. METHODS: Clinical features of lenvatinib and sorafenib patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint and occurrence of adverse events was the secondary. RESULTS: The analysis included 385 patients who received lenvatinib, and 555 patients who received sorafenib. In the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI 0.70-1.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.62-1.07) even in presence of balanced baseline characteristics. Lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69). CONCLUSION: Present results confirmed randomized controlled trial in the real-life setting, but also suggests that in earlier stages some benefit can be expected.

DOI： 10.1111/liv.14817

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Sarcopenia worsens patient prognoses in chronic liver disease. This study aimed to elucidate the effects of vitamin D supplementation on skeletal muscle volume and strength in patients with decompensated cirrhosis. METHODS: Thirty-three patients were entered into the study based on the criteria and then randomly assigned to two groups: Group A (n = 17), the control group, and Group B (n = 16), those who received oral native vitamin D3 at a dose of 2000 IU once a day for 12 months. RESULTS: SMI values in Group B were significantly increased at 12 months (7.64 × 10-3). The extent of changes in the SMI and grip strength in Group B were significantly greater than that in Group A at 12 months (p = 2.57 × 10-3 and 9.07 × 10-3). The median change rates in the SMI were +5.8% and the prevalence of sarcopenia was significantly decreased from 80.0% (12/15) to 33.3% (5/15; p = 2.53 × 10-2) in Group B. CONCLUSIONS: Vitamin D supplementation might be an effective and safe treatment option for patients with decompensated cirrhosis to increase or restore the skeletal muscle volume and strength or prevent the muscle volume and strength losses.

DOI： 10.3390/nu13061874

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: NAFLD is increasing in Asia including Japan, despite its lower obesity rate than the West. However, NAFLD can occur in lean people, but data are limited. We aimed to investigate the epidemiology of NAFLD in Japan with a focus on lean NAFLD. METHODS: We searched PubMed, Cochrane Library, EMBASE, Web of Science, and the Japan Medical Abstracts Society (inception to 5/15/2019) and included 73 eligible full-text original research studies (n = 258,531). We used random-effects model for pooled estimates, Bayesian modeling for trend and forecasting, contacted authors for individual patient data and analyzed 14,887 (7752 NAFLD; 7135 non-NAFLD-8 studies) patients. RESULTS: The overall NAFLD prevalence was 25.5%, higher in males (p < 0.001), varied by regions (p < 0.001), and increased over time (p = 0.015), but not by per-person income or gross prefectural productivity, which increased by 0.64% per year (1983-2012) and is forecasted to reach 39.3% in 2030 and 44.8% in 2040. The incidence of NAFLD, HCC, and overall mortality were 23.5, 7.6 and 5.9 per 1000 person-years, respectively. Individual patient-level data showed a lean NAFLD prevalence of 20.7% among the NAFLD population, with lean NAFLD persons being older and with a higher all-cause mortality rate (8.3 vs. 5.6 per 1000 person-years for non-lean NAFLD, p = 0.02). Older age, male sex, diabetes, and FIB-4 were independent predictors of mortality, but not lean NAFLD. CONCLUSION: NAFLD prevalence has increased in Japan and may affect half of the population by 2040. Lean NAFLD individuals makeup 20% of the NAFLD population, were older, and had higher mortality.

DOI： 10.1007/s12072-021-10143-4

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Lenvatinib is used for unresectable hepatocellular carcinoma (u-HCC) as first-line, as well as second- and third-line therapy in Japan. We evaluated the therapeutic efficacy of newly developed ramucirumab when given after lenvatinib for post-progression treatment. Methods: Of 385 patients with u-HCC and treated with lenvatinib at 16 different institutions in Japan between May 2018 and January 2020, 28 who received ramucirumab as the next treatment were enrolled and therapeutic responses were evaluated in a retrospective manner. Results: The median age of the 28 patients given ramucirumab was 70 years and the median albumin-bilirubin score was -2.19. Of the 28 patients, 23 were male, 21 were classified as Child-Pugh A and 7 as Child-Pugh B, and 25 were Barcelona Clinic Liver Cancer Stage C. Ramucirumab was given as second-line therapy in 14, third-line in 9, and fourth-line in 5. Therapeutic response was obtained in only 26 patients; the objective response rate was 3.8% (1/26) and the disease-control rate was 42.3% (11/26), with a median period to progression of 2.0 months. The reasons for discontinuation of ramucirumab were progression of disease in 16 and Grade 3 adverse events (gastrointestinal bleeding, ascites) in 2. Conclusions: The anticipated therapeutic efficacy of ramucirumab for post-progression treatment following lenvatinib was not seen in our early experience.

DOI： 10.1093/gastro/goaa042

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: An effective postprogression treatment of lenvatinib (LEN) against unresectable hepatocellular carcinoma (u-HCC) has not been established. We aimed to elucidate the clinical role of continuing LEN beyond progression of disease (PD). Methods: From March 2018 to October 2020, 99 u-HCC patients, in whom PD was confirmed (male:female = 78:21, median age 72 years, Child-Pugh A = 99, Barcelona Clinic Liver Cancer stage A:B:C = 2:43:54, LEN as first-line = 55), were enrolled (stopped LEN at PD [A group], n = 26; continued LEN beyond PD [B group], n = 73). Radiological response was evaluated with RECIST 1.1. Clinical features and prognostic factors for overall survival (OS) were retrospectively investigated using inverse probability weighting (IPW) calculated by propensity score. Results: Median time to progression, best response, and modified albumin-bilirubin grade (mALBI) at both baseline and PD did not show significant difference between the groups. Postprogression treatment in the A group was best supportive care in 17, sorafenib in 4, regorafenib in 3, ramucirumab in 1, and hepatic arterial infusion chemotherapy in 1. After adjusting with IPW, the B group showed better prognosis in regard to OS after PD and OS after introducing LEN than the A group (10.8/19.6 vs. 5.8/11.2 months, p < 0.001, respectively). In IPW-adjusted Cox hazard multivariate analysis, significant prognostic factors for OS after PD were mALBI 2b/3 at PD (HR 1.983, p = 0.021), decline of Eastern Cooperative Oncology Group performance status (ECOG PS) from baseline at PD (HR 3.180, p < 0.001), elevated alpha-fetoprotein (≥100 ng/mL) at introducing LEN (HR 2.511, p = 0.004), appearance of new extrahepatic metastasis (HR 2.396, p = 0.006), positive for hand-foot skin reaction (HFSR) before PD (any grade) (HR 0.292, p < 0.001), and continuing LEN beyond PD (HR 0.297, p < 0.001). Conclusion: When ECOG PS and hepatic reserve function permit, continuing LEN treatment beyond PD, especially in u-HCC patients showed HFSR during LEN treatment, might be a good therapeutic option, at least until a more effective drug as a postprogression treatment after LEN failure is developed.

DOI： 10.1159/000513355

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The real-world virological efficacy and safety of interferon-free direct-acting antiviral (DAA) therapy with ledipasvir (LDV) plus sofosbuvir (SOF) were assessed in patients who were chronically infected with hepatitis C virus (HCV) genotype 2. METHODS: A total of 126 patients with chronic hepatitis C due to HCV genotype 2 infection who were treated with the LDV/SOF regimen were enrolled. The sustained virological response (SVR) rate and safety were analyzed. SVR was assessed in the intention-to-treat (ITT) population as well as in the modified intention-to-treat (mITT) population, which excluded patients with non-virological failure, including those who dropped out before the SVR assessment. RESULTS: The overall SVR rates of the ITT and mITT populations were 87.3% (95% confidence interval [CI] 80.2-92.6) (110/126) and 97.3% (95% CI 92.4-99.4) (110/113), respectively. In the mITT population, the percentages of patients with undetectable HCV RNA at 4, 8, and 12 weeks after the start of therapy were 92.9% (95% CI 86.5-96.9) (105/113), 99.1% (95% CI 95.2-100.0) (112/113), and 100.0% (95% CI 97.4-100.0) (113/113), respectively. Subgroup analyses of the mITT population showed no significant differences in SVR rates according to age, sex, HCV genotype (subtype), history of interferon-based therapy, baseline FIB-4 index, or baseline estimated glomerular filtration rate. In all subpopulations, the SVR rates were > 90%. There were no severe adverse events associated with the treatment. CONCLUSION: The LDV/SOF regimen showed high virological efficacy and acceptable safety in patients with HCV genotype 2 infection. TRIAL REGISTRATION: UMIN registration no. 000038604.

DOI： 10.1007/s40121-020-00364-9

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Lenvatinib, a newly developed molecularly targeted agent, has become available as a first-line therapy in patients with unresectable hepatocellular carcinoma (HCC). The platelet-to-lymphocyte ratio (PLR) has been associated with poor outcome in various malignancies, including HCC. In this study, we investigated the ability of PLR to predict outcomes in patients with unresectable HCC who received lenvatinib. METHODS: Multivariate survival analysis was performed in 283 patients with unresectable HCC who received lenvatinib. In addition, the utility of PLR for predicting survival was clarified using an inverse probability weighting (IPW) analysis. RESULTS: Cumulative overall survival at 100, 200, 300, 400, and 500 days was 95.2, 83.8, 68.3, 60.3, and 49.9%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that PLR (≥150) [hazard ratio, 1.588; 95% confidence interval (CI), 1.039-2.428; P = 0.033], α-fetoprotein level, and Barcelona clinic liver cancer stage were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high PLR (P = 0.029). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that PLR (≥150) (hazard ratio, 1.396; 95% CI, 1.051-1.855; P = 0.021) was significantly associated with overall survival. Conversely, univariate analysis with Cox proportional hazards modeling adjusted only by IPW showed that PLR (≥150) (hazard ratio, 1.254; 95% CI, 1.016-1.549; P = 0.035) was significantly associated with progression-free survival. PLR values were not independently associated with therapeutic responses before or after IPW-adjusted logistic regression analysis. CONCLUSIONS: PLR predicted overall survival in patients with unresectable HCC who received lenvatinib.

DOI： 10.1097/MEG.0000000000001734

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). METHODS: A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. RESULTS: The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). CONCLUSIONS: Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

DOI： 10.1111/hepr.13592

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: To eliminate hepatitis B virus (HBV) infection, scale-up of testing and treatment in resource-limited countries is crucial. However, access to nucleic acid testing to quantify HBV DNA, an essential test to examine treatment eligibility, remains severely limited. We assessed the performance of a novel immunoassay, HBV core-related antigen (HBcrAg), as a low-cost (less than US $15/assay) alternative to nucleic acid testing to indicate clinically important high viremia in chronic HBV patients infected with different genotypes. METHODS: We searched Medline, Embase, Scopus, and Web of Science databases through June 27, 2018. Three reviewers independently selected studies measuring HBV DNA and HBcrAg in the same blood samples. We contacted authors to provide individual participant data (IPD). We randomly allocated each IPD to a derivation or validation cohort. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity/specificity. RESULTS: Of 74 eligible studies, IPD were obtained successfully for 60 studies (81%). Meta-analysis included 5591 IPD without antiviral therapy and 4806 treated with antivirals. In untreated patients, the pooled area under the receiver operating characteristic curve and optimal cut-off values were as follows: 0.88 (95% CI, 0.83-0.94) and 3.6 log U/mL to diagnose HBV DNA level of 2000 IU/mL or greater; and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/mL for 200,000 IU/mL or greater, respectively. In the validation set, the sensitivity and specificity were 85.2% and 84.7% to diagnose HBV DNA level of 2000 IU/mL or greater, and 91.8% and 90.5% for 200,000 IU/mL or greater, respectively. The performance did not vary by HBV genotypes. In patients treated with anti-HBV therapy the correlation between HBcrAg and HBV DNA was poor. CONCLUSIONS: HBcrAg might be a useful serologic marker to indicate clinically important high viremia in treatment-naïve, HBV-infected patients.

DOI： 10.1016/j.cgh.2020.04.045

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background and Aim: Although tenofovir alafenamide (TAF), as well as entecavir (ETV), is widely used as first-line treatment for patients with chronic hepatitis B, there are only a few studies comparing sequential therapy from ETV to TAF and continuous ETV monotherapy in patients with maintained virologic response to ETV. Methods: In a retrospective multicenter study, we investigated the efficacy and safety of sequential therapy from ETV to TAF (ETV-TAF group) and compared them with continuous ETV monotherapy (ETV group), using propensity score matching, in chronic hepatitis B patients. Results: From 442 patients, we analyzed 142 patients from each group comprising 71 patients matched for several data, including age, HBV genotype, hepatitis B envelope antigen, cirrhosis, alanine aminotransferase, platelet count, prior ETV monotherapy period, and hepatitis B surface antigen (HBsAg) change during prior ETV monotherapy. In the ETV-TAF group, HBsAg levels significantly decreased from baseline to 48 weeks after switching to TAF (-0.02 log IU/mL, P = 0.038). HBcrAg levels also significantly decreased after switching to TAF (-0.1 log IU/mL, P = 0.004). However, there were no significant differences in the reduction of HBsAg and HBcrAg levels between the ETV-TAF and ETV groups. There was no significant difference in the change of estimated glomerular filtration rate levels from baseline to 48 weeks between the two groups. Conclusions: The present study indicated that the efficacy, especially of the HBsAg-reducing action, and safety of sequential therapy from ETV to TAF were similar to those of continuous ETV monotherapy among chronic hepatitis B patients with maintained virologic response to ETV.

DOI： 10.1002/jgh3.12443

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To make an accurate estimate of the response to thrombopoietin (TPO) receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at 2 hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analyzed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/μL with an increased platelet count of ≥2 × 104/μL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/μL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (regression coefficient [B] = 0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for TPO receptor agonists in patients with chronic liver disease.

DOI： 10.1159/000510692

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Evaluating liver fibrosis is crucial for disease severity assessment, treatment decisions, and hepatocarcinogenic risk prediction among patients with chronic hepatitis C. In this retrospective multicenter study, we aimed to construct a novel model formula to predict cirrhosis. A total of 749 patients were randomly allocated to training and validation sets at a ratio of 2:1. Liver stiffness measurement (LSM) was made via transient elastography using FibroScan. Patients with LSM ≥12.5 kPa were regarded as having cirrhosis. The best model formula for predicting cirrhosis was constructed based on factors significantly and independently associated with LSM (≥12.5 kPa) using multivariate regression analysis. Among the 749 patients, 198 (26.4%) had LSM ≥12.5 kPa. In the training set, multivariate analysis identified logarithm natural (ln) type IV collagen 7S, ln hyaluronic acid, and ln Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+-Mac-2 BP) as the factors that were significantly and independently associated with LSM ≥12.5 kPa. Thus, the formula was constructed as follows: score = -6.154 + 1.166 × ln type IV collagen 7S + 0.526 × ln hyaluronic acid + 1.069 × WFA+-Mac-2 BP. The novel formula yielded the highest area under the curve (0.882; optimal cutoff, -0.381), specificity (81.5%), positive predictive values (62.6%), and predictive accuracy (81.6%) for predicting LSM ≥12.5 kPa among fibrosis markers and indices. These results were almost similar to those in the validated set, indicating the reproducibility and validity of the novel formula. The novel formula scores were significantly, strongly, and positively correlated with LSM values in both the training and validation data sets (correlation coefficient, 0.721 and 0.762; p = 2.67 × 10-81 and 1.88 × 10-48, respectively). In conclusion, the novel formula was highly capable of diagnosing cirrhosis in patients with chronic hepatitis C and exhibited better diagnostic performance compared to conventional fibrosis markers and indices.

DOI： 10.1371/journal.pone.0257166

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM/BACKGROUND: Transarterial chemoembolization (TACE) is recommended for patients with intermediate-stage hepatocellular carcinoma (HCC). In this study, we investigated the impact of early lenvatinib administration in patients with intermediate-stage HCC, especially those with tumors beyond the up-to-7 criteria. MATERIALS/METHODS: A total of 208 patients with intermediate-stage HCC whose initial treatment was early lenvatinib administration or TACE were enrolled. Multivariate overall survival analysis was performed in this cohort. In addition, the impact of early lenvatinib administration on survival in patients with HCC beyond the up-to-7 criteria was clarified using inverse probability weighting (IPW) analysis. RESULTS: The overall cumulative survival rates at 6, 12, 18, and 24 months were 94.4, 79.9, 65.8, and 50.1%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that HCC treatment with lenvatinib (hazard ratio [HR], 0.199; 95% confidence interval [CI], 0.077-0.517; p < 0.001), α-fetoprotein ≥100 ng/mL (HR, 1.687), Child-Pugh class B disease (HR, 1.825), and beyond the up-to-7 criteria (HR, 2.016) were independently associated with overall survival. The 6-, 12-, 18-, and 24-month cumulative survival rates were 96.0, 90.4, 65.7, and 65.7%, respectively, in patients treated with lenvatinib, and 94.1, 78.5, 65.3, and 48.4%, respectively, in patients who received TACE (p < 0.001). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that lenvatinib therapy was significantly associated with overall survival in patients with HCC beyond the up-to-7 criteria (HR, 0.230; 95% CI, 0.059-0.904; p = 0.035). CONCLUSIONS: Lenvatinib may be a suitable first-line treatment for patients with intermediate-stage HCC beyond the up-to-7 criteria.

DOI： 10.1159/000515896

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objective Pegylated-interferon monotherapy is the standard treatment for patients with chronic hepatitis B; however, the factors associated with its therapeutic effects remain unclear. Methods Patients with chronic hepatitis B were treated with pegylated interferon α-2a for 48 weeks. We evaluated the kinetics of hepatitis B surface antigen (HBsAg) during treatment and follow-up periods and the factors associated with an HBsAg response (defined as a change in HBsAg of ≥-1 log IU/mL from baseline). Results The study population comprised 50 patients. The median baseline levels of hepatitis B virus DNA and HBsAg were 5.00 and 3.40 log IU/mL. The median values of HBsAg reduction from baseline were -0.44 (n=48), -0.41 (n=40), and -0.68 (n=11) log IU/mL at the end of treatment and at 48 and 144 weeks post-treatment, respectively. The rates of HBsAg response were 24.0% and 22.5% at the end of treatment and at 48 weeks post-treatment, respectively. A multivariate analysis identified HBsAg <3.00 log IU/mL as an independent baseline factor contributing to the HBsAg response at the end of treatment and 48 weeks post-treatment (p=1.07×10-2 and 4.42×10-2, respectively). There were significant differences in the reduction of the HBsAg levels at 12 weeks of treatment and in the incidence of serum ALT increase during treatment between patients with and without an HBsAg response. Conclusion These findings suggest that the baseline HBsAg level, HBsAg kinetics at 12 weeks of treatment, and ALT increase during treatment are important factors contributing to the HBsAg response in pegylated interferon α-2a monotherapy for patients with chronic hepatitis B.

DOI： 10.2169/internalmedicine.5432-20

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Although sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) improve not only glycemic control but also liver inflammation and fatty changes in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM), its sustainability and effect on liver fibrosis have remained unclear. The current study aimed to clarify the effects of 48-week SGLT2-I therapy on liver inflammation, fatty changes, and fibrosis in NAFLD patients with T2DM. Methods: This study evaluated the effects of SGLT2-I on NAFLD, including liver fibrosis assessed via transient elastography, in 56 patients with NAFLD who received SGLT2-I for 48 weeks. Moreover, changes in each clinical parameter between patients receiving SGLT2-I (the SGLT2-I group) and those receiving other oral hypoglycemic agents (OHAs) (the non-SGLT2-I group) were compared, using 1:1 propensity score matching to adjust for baseline factors. Results: The SGLT2-I group exhibited a significant decrease in controlled attenuation parameter (312 dB/m at baseline to 280 dB/m at week 48) and liver stiffness measurement (9.1-6.7 kPa) (p < 0.001 for both). After propensity score matching (44 patients each in the SGLT2-I and non-SGLT2-I groups), no significant difference in HbA1c decrease was observed between the two groups. However, compared with the non-SGLT2-I group, the SGLT2-I group showed a significant decrease in body weight (p < 0.001), alanine aminotransferase (p = 0.02), uric acid (p < 0.001), and Fibrosis-4 (FIB-4) index (p = 0.01) at week 48. The improvement in FIB-4 index, defined as a ⩾10% decline from baseline at week 48, was 56.8% (25/44) in the SGLT2-I group and 20.5% (9/44) in the non-SGLT2-I group (p < 0.001). Conclusion: SGLT2-Is improved not only glycemic control but also liver fatty infiltration and fibrosis in patients with NAFLD and T2DM, suggesting their possible superiority to other OHAs concerning these effects.

DOI： 10.1177/20420188211000243

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Non-alcoholic fatty liver disease (NAFLD) is a progressive disorder that can develop into liver fibrosis and hepatocellular carcinoma. Natural killer (NK) cells have been shown to protect against liver fibrosis and tumorigenesis, suggesting that they may also play a role in the pathogenesis of NAFLD. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a family of inhibitory and activating receptors expressed by many cell types, including NK cells. Here, we investigated the phenotypic profiles of peripheral blood and intrahepatic NK cells, including expression of Siglecs and immune checkpoint molecules, and their association with NK cell function in patients with NAFLD. Immune cells in the peripheral blood of 42 patients with biopsy-proven NAFLD and 13 healthy volunteers (HVs) were identified by mass cytometry. The function of various NK cell subpopulations was assessed by flow cytometric detection of intracellular IFN-γ and CD107a/LAMP-1, a degranulation marker, after in vitro stimulation. We found that peripheral blood from NAFLD patients, regardless of fibrosis stage, contained significantly fewer total CD56+ NK cell and CD56dim NK cell populations compared with HVs, and the CD56dim cells from NAFLD patients were functionally impaired. Among the Siglecs examined, NK cells predominantly expressed Siglec-7 and Siglec-9, and both the expression levels of Siglec-7 and Siglec-9 on NK cells and the frequencies of Siglec-7+CD56dim NK cells were reduced in NAFLD patients. Notably, Siglec-7 levels on CD56dim NK cells were inversely correlated with PD-1, CD57, and ILT2 levels and positively correlated with NKp30 and NKp46 levels. Further subtyping of NK cells identified a highly dysfunctional Siglec-7-CD57+PD-1+CD56dim NK cell subset that was increased in patients with NAFLD, even those with mild liver fibrosis. Intrahepatic NK cells from NAFLD patients expressed elevated levels of NKG2D and CD69, suggesting a more activated phenotype than normal liver NK cells. These data identify a close association between NK cell function and expression of Siglec-7, CD57, and PD-1 that could potentially be therapeutically targeted in NAFLD.

DOI： 10.3389/fimmu.2021.603133

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. METHODS: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. RESULTS: The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child-Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5-13). The albumin-bilirubin (ALBI) score ranged from - 3.01 to - 0.45 (median - 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child-Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10-4 and 2.42 × 10-4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. CONCLUSION: Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. TRIAL REGISTRATION: UMIN registration no, 000038587.

DOI： 10.1007/s40121-020-00329-y

PubMed

researchmap

記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

＜文献概要＞肝臓の線維化や機能の評価は,慢性肝疾患の重症度判定や適切な治療選択に必要であり,近年では簡便かつ非侵襲的に肝臓の線維化や機能を評価することを目的としたさまざまなスコアリングシステムやバイオマーカーが開発・提唱されている.また肝臓の線維化は従来肝生検による評価がgold standardであるが,近年ではMRIや超音波を用いたエラストグラフィーの有用性が報告されている.本稿では,これら肝臓の線維化および機能評価に関するバイオマーカー,スコアリングシステム,画像診断法について近年のトピックスをまとめた.

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Portopulmonary hypertension (PoPH) is a well-known complication of liver cirrhosis. The aim of this study was to clarify the pulmonary hemodynamics and the prevalence and characteristics of PoPH in patients with portal hypertension. METHODS: The subjects were 335 patients with portal hypertension diagnosed by hepatic vein pressure gradient (HVPG). Among them, 186 patients received measurements of pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance (PVR). PoPH was diagnosed by PAP >20 mmHg, PVR ≥3 Wood units (WU) and PAWP ≤15 mmHg. RESULTS: The Child-Pugh classification was class A in 53, B in 92 and C in 41 patients. Median (range) values of HVPG, PAP, PVR and PAWP were 18.4 (5.5-39.0) mmHg, 12.9 (6.6-40.8) mmHg, 0.8 (0.1-4.5) WU and 7.5 (2.2-15.4) mmHg, respectively. Of six patients with PAP >20 mmHg, four had autoimmune hepatitis or primary biliary cholangitis, with the prevalence being significantly higher than that in patients with PAP ≤20 mmHg. Meanwhile, no significant difference was noted in the hepatic functional reserve or HVPG between patients with PAP >20 mmHg and ≤20 mmHg. Only two patients met the diagnostic criteria of PoPH and both patients were Child-Pugh B. The Child-Pugh score and HVPG were not associated with PoPH. CONCLUSIONS: Our study demonstrated that only two patients were complicated by PoPH. High PAP values were noted in patients with primary biliary cholangitis or autoimmune hepatitis. However, the presence of PoPH and high PAP were not associated with the degree of hepatic functional reserve or HVPG.

DOI： 10.1111/hepr.13560

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: Clinical trials of direct-acting antivirals for patients with decompensated cirrhosis have been conducted, but there is limited information on the medicinal applications in clinical settings. We aimed to evaluate the safety and efficacy of sofosbuvir/velpatasvir for decompensated cirrhotic patients with genotypes 1 and 2 in real-world clinical practice. METHODS: A prospective, multicenter study of 12-week sofosbuvir/velpatasvir was conducted for patients with decompensated cirrhosis at 33 institutions. RESULTS: The cohort included 71 patients (52 genotype 1, 19 genotype 2): 7 with Child-Pugh class A, 47 with class B, and 17 with class C (median score 8; range 5-13). The albumin-bilirubin (ALBI) score ranged from - 3.01 to - 0.45 (median - 1.58). Sixty-nine patients (97.2%) completed treatment as scheduled. The overall rate of sustained virologic response at 12 weeks post-treatment (SVR12) was 94.4% (67/71). SVR12 rates in the patients with Child-Pugh classes A, B, and C were 85.7%, 97.9%, and 88.2%, respectively. Among 22 patients with a history of hepatocellular carcinoma treatment, 20 (90.9%) achieved SVR12. The Child-Pugh score and ALBI grade significantly improved after achieving SVR12 (p = 7.19 × 10-4 and 2.42 × 10-4, respectively). Notably, the use of diuretics and branched-chain amino acid preparations significantly reduced after achieving SVR12. Adverse events were observed in 19.7% of the patients, leading to treatment discontinuation in two patients with cholecystitis and esophageal varices rupture, respectively. CONCLUSION: Twelve weeks of sofosbuvir/velpatasvir in real-world clinical practice yielded high SVR rates and acceptable safety profiles in decompensated cirrhotic patients with genotypes 1 and 2. Achievement of SVR not only restored the liver functional reserve but also reduced or spared the administration of drugs for related complications. TRIAL REGISTRATION: UMIN registration no, 000038587.

DOI： 10.1007/s40121-020-00329-y

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Portopulmonary hypertension (PoPH) is a well-known complication of liver cirrhosis. The aim of this study was to clarify the pulmonary hemodynamics and the prevalence and characteristics of PoPH in patients with portal hypertension. METHODS: The subjects were 335 patients with portal hypertension diagnosed by hepatic vein pressure gradient (HVPG). Among them, 186 patients received measurements of pulmonary artery pressure (PAP), pulmonary artery wedge pressure (PAWP) and pulmonary vascular resistance (PVR). PoPH was diagnosed by PAP >20 mmHg, PVR ≥3 Wood units (WU) and PAWP ≤15 mmHg. RESULTS: The Child-Pugh classification was class A in 53, B in 92 and C in 41 patients. Median (range) values of HVPG, PAP, PVR and PAWP were 18.4 (5.5-39.0) mmHg, 12.9 (6.6-40.8) mmHg, 0.8 (0.1-4.5) WU and 7.5 (2.2-15.4) mmHg, respectively. Of six patients with PAP >20 mmHg, four had autoimmune hepatitis or primary biliary cholangitis, with the prevalence being significantly higher than that in patients with PAP ≤20 mmHg. Meanwhile, no significant difference was noted in the hepatic functional reserve or HVPG between patients with PAP >20 mmHg and ≤20 mmHg. Only two patients met the diagnostic criteria of PoPH and both patients were Child-Pugh B. The Child-Pugh score and HVPG were not associated with PoPH. CONCLUSIONS: Our study demonstrated that only two patients were complicated by PoPH. High PAP values were noted in patients with primary biliary cholangitis or autoimmune hepatitis. However, the presence of PoPH and high PAP were not associated with the degree of hepatic functional reserve or HVPG.

DOI： 10.1111/hepr.13560

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: To make an accurate estimate of the response to thrombopoietin receptor agonists for thrombocytopenia associated with chronic liver disease, we evaluated the influence of antiplatelet autoantibodies on the response to lusutrombopag in thrombocytopenic patients with liver disease. METHODS: A prospective study was conducted at two hospitals. Thrombocytopenic patients with liver disease received oral lusutrombopag 3.0 mg once daily for up to 7 days. We analysed changes in platelet counts from baseline to the maximum platelet count on days 9-14. The definition of clinical response was a platelet count of ≥5 × 104/μL with an increased platelet count of ≥2 × 104/μL from baseline. We assessed the correlation between the response to treatment drug and antiplatelet autoantibodies measured by anti-GPIIb/IIIa antibody-producing B cells. RESULTS: Thirty patients received the trial drug. There were 25 responders and 5 nonresponders. The median change in platelet counts was 3.9 × 104/μL (95% CI 2.8-4.6, p < 0.0001). The correlation between change in platelet counts and the frequency of the anti-glycoprotein (GP) IIb/IIIa antibody-producing B cells was moderate (r = 0.414, 95% CI 0.064-0.674, p = 0.023). In multivariate analysis of factors affecting the change in platelet counts, the anti-GPIIb/IIIa antibody-producing B cells were identified as an independent factor (Regression coefficient (B)=0.089; CI 0.021-0.157, p = 0.013). CONCLUSION: Anti-GPIIb/IIIa antibody-producing B cells may be a predictor for thrombopoietin receptor agonists in patients with chronic liver disease.

DOI： 10.1159/000510692

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The present study aimed to assess the efficacy and safety of lenvatinib and verify the possibility of lenvatinib for the expanded indication from the REFLECT trial in patients with advanced hepatocellular carcinoma (HCC) in real-world practice, primarily focusing on the population that was excluded in the REFLECT trial. Methods: We retrospectively collected data on patients with advanced HCC who were administered lenvatinib in 7 institutions in Japan. Results: Of 152 advanced HCC patients, 95 and 57 patients received lenvatinib in first-line and second- or later-line systemic therapies, respectively. The median progression-free survival in Child-Pugh class A patients was nearly equal between first- and second- or later-line therapies (5.2 months; 95% CI 3.7-6.9 for first line, 4.8 months; 95% CI 3.8-5.9 for second or later line, p = 0.933). According to the modified Response Evaluation Criteria in Solid Tumors, the objective response rate of 27 patients (18%) who showed a high burden of intrahepatic lesions (i.e., main portal vein and/or bile duct invasion or 50% or higher liver occupation) at baseline radiological assessment was 41% and similar with that of other population. The present study included 20 patients (13%) with Child-Pugh class B. These patients observed high frequency rates of liver function-related adverse events due to lenvatinib. The 8-week dose intensity of lenvatinib had a strong correlation with liver function according to both the Child-Pugh and albumin - bilirubin scores. Conclusion: Lenvatinib had potential benefits for patients with advanced HCC with second- or later-line therapies and a high burden of intrahepatic lesions. Dose modification should be paid increased attention among patients with poor liver function, such as Child-Pugh class B patients.

DOI： 10.1159/000507022

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: The presence of cirrhosis is an important factor for the management of patients with hepatitis C virus (HCV) infection and it determines the duration of treatment for HCV with the direct-acting antiviral (DAA) regimen of glecaprevir (GLE) and pibrentasvir (PIB), that is, 8 or 12 weeks, if patients do not have a history of DAA failure. However, in real-world settings, determination of cirrhosis depends on the discretion of the attending hepatologists, and it is unclear whether compensated cirrhosis was homogenously diagnosed or not. In this study, we investigated the real-world diagnosis of cirrhosis by characterizing DAA-naïve patients who underwent a 12-week GLE/PIB regimen in whom cirrhosis was diagnosed, comparing their characteristics with those of patients who underwent an 8-week regimen in whom cirrhosis was absent. METHODS: In a large, multicenter cohort study, we compared background characteristics and treatment outcomes among DAA-naïve patients who underwent an 8-week versus a 12-week GLE/PIB regimen. RESULTS: Among 977 patients enrolled, 296 (30.3%) were determined to have cirrhosis and underwent a 12-week regimen. Some patient characteristics largely overlapped between the two groups, including liver fibrosis indices. Sustained viral response rates were similar between groups after adjusting liver fibrosis index with propensity score matching. CONCLUSION: Although adequately diagnosed, the determination of cirrhosis varied widely among institutions or by hepatologists in real-world settings, and the severity of liver fibrosis overlapped significantly between patients in whom compensated cirrhosis was determined to be present and patients in whom cirrhosis was absent. Virologic efficacy was similar after adjusting for the degree of liver fibrosis.

DOI： 10.1111/jgh.14982

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: The prognosis of cirrhotic patients with hepatic edema is poor. Although several short-term predictors of tolvaptan (novel diuretic agent) treatment for such patients have been reported, the factors related to long-term survival are still unclear. METHODS: Among 459 patients with hepatic edema enrolled in a retrospective, multicenter collaborative study, we analyzed 407 patients who received tolvaptan. RESULTS: Patients consisted of 266 men and 141 women, with the median age of 68 years (range, 28-93 years). The frequency of short-term responders to tolvaptan was 59.7% (243/407). In the Cox regression analysis, short-term response to tolvaptan, low average dosages of furosemide and spironolactone during tolvaptan treatment, Child-Pugh classification A and B, and absence of hepatocellular carcinoma were independent factors contributed to 1-year survival. The 1-year and long-term cumulative survival rates in short-term responders were significantly higher than those in non-responders (P = 0.011 and 0.010, respectively). Using a receiver operating characteristic curve analysis, the optimal cut-off values of average daily dosages of furosemide and spironolactone for predicting 1-year survival were 19 and 23 mg/day, respectively. The long-term cumulative survival rates in patients who received a mean dosage of spironolactone < 23 mg/day during tolvaptan treatment were significantly higher than those receiving a mean dosage of ≥ 23 mg/day (P = 0.001). CONCLUSIONS: The present study suggests that the short-term response to tolvaptan and low dosages of conventional diuretics during tolvaptan treatment might improve the 1-year and long-term survival rates in cirrhotic patients with hepatic edema.

DOI： 10.1111/jgh.14965

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(株)アークメディア  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会-関東支部  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: In clinical trials, a pangenotype direct-acting antiviral (DAA) regimen consisting of glecaprevir (GLE) and pibrentasvir (PIB) exhibited high virologic efficacy and tolerability in patients with hepatitis C virus (HCV) infection. This study sought to confirm these findings in real-world settings, focusing on patients with cirrhosis, history of DAA failure, or HCV genotype 3 who were treated with a 12-week regimen in a large multicenter study from Japan. METHODS: In a nationwide multicenter prospective cohort study, we analyzed background characteristics, tolerability, and treatment outcome of patients who underwent a 12-week GLE/PIB regimen. RESULTS: Of 1190 patients, 509 (42.8%) underwent the 12-week regimen, and the remaining patients underwent an 8-week regimen. The rate of sustained virologic response (SVR) of patients treated with the 12-week regimen was 99.0%, comparable with that of patients treated with the 8-week regimen. The adverse events were observed in 29.1% of patients. The main adverse event was pruritus, which was observed in 14.7%. Ten patients (2.0%) discontinued therapy during treatment period. CONCLUSION: The 12-week GLE/PIB regimen was well-tolerated with high virologic efficacy in patients with cirrhosis, experience of DAA, or HCV genotype 3; tolerability and SVR rate were comparable with those of DAA-naïve, non-cirrhotic, non-genotype 3 patients who underwent 8-week regimen.

DOI： 10.1111/jgh.14874

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Although the association of vitamin D with primary sarcopenia has been extensively investigated, its relationship with secondary sarcopenia in patients with liver disease remains unclear. This study aimed to identify factors associated with sarcopenia in patients with chronic liver disease with a focus on serum vitamin D levels. METHODS: The study included 204 patients with chronic liver disease. Independent factors significantly associated with sarcopenia were determined using multiple logistic regression analysis. The sarcopenia diagnosis was based on the sarcopenia criteria proposed by the Japan Society of Hepatology. Serum 25-hydroxyvitamin D3 (25[OH]D3 ) levels to represent serum vitamin D levels were measured using double-antibody radioimmunoassay, and vitamin D deficiency was defined as a serum 25(OH)D3 level of ≤20 ng/mL. RESULTS: The prevalence of sarcopenia in the cirrhotic patients (28/76, 36.8%) was significantly higher than that in the non-cirrhotic patients (18/128, 14.1%; P = 2.48 × 10-4 ). Sarcopenia was diagnosed in 44 (27.5%) of the 160 patients with vitamin D deficiency, and two (4.5%) of the 44 patients without vitamin D deficiency (P = 4.90 × 10-3 ). On multivariate analysis, advanced age (odds ratio 1.11; P = 2.10 × 10-4 ), low body mass index (odds ratio 1.42; p = 2.08 × 10-5 ), and low serum 25(OH)D3 level (odds ratio 1.13; p = 1.20 × 10-2 ) were significant, independent factors associated with sarcopenia. Serum 25(OH)D3 was positively correlated with grip strength and skeletal muscle mass index. CONCLUSION: Sarcopenia complicated by chronic liver disease was associated with advanced age, low body mass index, and low serum 25(OH)D3 level.

DOI： 10.1111/hepr.13485

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会-関東支部  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本消化器内視鏡学会-関東支部  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND & AIMS: Scale-up of tests and treatments is needed to eliminate hepatitis B virus (HBV) infection from resource-limited countries. However, access to nucleic acid tests that quantify HBV DNA, to determine treatment eligibility, is severely limited. We performed a systematic review and meta-analysis to assess the performance of the hepatitis B core-related antigen (HBcrAg) immunoassay, a low-cost (less than $15/assay) alternative to the nucleic acid test, to identify highly viremic patients, infected with any HBV genotype. METHODS: We searched Medline, Embase, Scopus, and Web of Science through June 27, 2018 for studies that measured HBV DNA and HBcrAg in the same blood samples. We contacted study authors to obtain data from each study participant, and randomly assigned each participant to the derivation or validation cohorts. We applied optimal HBcrAg cut-off values derived from the derivation set to the validation set to estimate sensitivity and specificity of HBcrAg to indicate high viremia. RESULTS: Of 74 eligible studies found in the systematic review, we obtained individual participant data from 60 studies (81%). We performed a meta-analysis of individual participant data of 5591 HBV-infected patients who did not receive antiviral therapy and 4806 HBV-infected patients who received antiviral agents. In untreated patients, the pooled area under the receiver operating characteristic curve and the optimal cut-off value for the HBcrAg assay were 0.88 (95% CI, 0.83-0.94) and 3.6 log U/ml for identifying patients with a level of HBV DNA ≥2000 IU/ml, and 0.96 (95% CI, 0.94-0.98) and 5.3 log U/ml for identifying patients with a level of HBV DNA ≥200,000 IU/ml, respectively. In the validation set, the HBcrAg assay identified patients with ≥2000 IU/ml HBV DNA with 85.2% sensitivity and 84.7% specificity; the assay identified patients with ≥200,000 IU/ml HBV DNA with 91.8% sensitivity and 90.5% specificity. Performance did not vary among HBV genotypes. In patients receiving anti-HBV therapy, there was no correlation between levels of HBcrAg and HBV DNA. CONCLUSIONS: In a systematic review and meta-analysis of individual participant data, we found that the assay for HBcrAg identifies treatment-naïve patients with high levels of HBV DNA with high sensitivity and specificity, regardless of genotype. The HBcrAg assay is a good, low-cost alternative to the nucleic acid test to identify highly viremic patients infected with different genotypes.

DOI： 10.1016/j.cgh.2020.04.045

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Lenvatinib, a newly developed molecularly targeted agent, has become available as a first-line therapy in patients with unresectable hepatocellular carcinoma (HCC). The platelet-to-lymphocyte ratio (PLR) has been associated with poor outcome in various malignancies, including HCC. In this study, we investigated the ability of PLR to predict outcomes in patients with unresectable HCC who received lenvatinib. METHODS: Multivariate survival analysis was performed in 283 patients with unresectable HCC who received lenvatinib. In addition, the utility of PLR for predicting survival was clarified using an inverse probability weighting (IPW) analysis. RESULTS: Cumulative overall survival at 100, 200, 300, 400, and 500 days was 95.2, 83.8, 68.3, 60.3, and 49.9%, respectively. Multivariate analysis with Cox proportional hazards modeling showed that PLR (≥150) [hazard ratio, 1.588; 95% confidence interval (CI), 1.039-2.428; P = 0.033], α-fetoprotein level, and Barcelona clinic liver cancer stage were independently associated with overall survival. Cumulative overall survival differed significantly between patients with low versus high PLR (P = 0.029). In addition, univariate analysis with Cox proportional hazards modeling adjusted by IPW showed that PLR (≥150) (hazard ratio, 1.396; 95% CI, 1.051-1.855; P = 0.021) was significantly associated with overall survival. Conversely, univariate analysis with Cox proportional hazards modeling adjusted only by IPW showed that PLR (≥150) (hazard ratio, 1.254; 95% CI, 1.016-1.549; P = 0.035) was significantly associated with progression-free survival. PLR values were not independently associated with therapeutic responses before or after IPW-adjusted logistic regression analysis. CONCLUSIONS: PLR predicted overall survival in patients with unresectable HCC who received lenvatinib.

DOI： 10.1097/MEG.0000000000001734

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIMS: Lenvatinib, a newly developed molecularly targeted agent, has become available for patients with unresectable hepatocellular carcinoma (HCC). Neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor outcomes in numerous malignancies. In this study, we investigated the impact of NLR on associating outcomes in patients with HCC treated with lenvatinib. METHODS: A total of 237 patients with HCC treated with lenvatinib were included. We performed univariate and multivariate analyses in this cohort. In addition, we clarified appropriate cut-off NLR levels for associating overall survival using hazard ratio (HR) spline curves. RESULTS: Cumulative overall survival at 100, 200 and 300 days was 95.2%, 83.4% and 66.6% respectively. Multivariate analysis showed that NLR ≥ 4 (HR, 1.874; 95% confidence interval [CI], 1.097-3.119), α-foetoprotein ≥ 400 ng/mL (HR, 1.969; 95% CI, 1.188-3.265) and modified albumin-bilirubin grade 2b or 3 (HR, 2.123; 95% CI, 1.267-3.555) were independently associated with overall survival. Cumulative progression-free survival at 100, 200 and 300 days was 72.4%, 49.8% and 38.7% respectively. Multivariate analysis showed that NLR ≥ 4 (HR, 1.897; 95% CI, 1.268-2.837) and BCLC stage ≥ C (HR, 1.516; 95% CI, 1.028-2.236) were independently associated with progression-free survival. Disease control rate was significantly different between the patients with low NLR (<4) (85.5%) and high NLR (≥4) (67.3%) (P = .007). Spline curve analysis revealed that NLR of approximately 3.0-4.5 is an appropriate cut-off for associating overall survival. CONCLUSIONS: NLR can be associated with outcomes in patients with HCC treated with lenvatinib.

DOI： 10.1111/liv.14405

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Direct-acting anti-virals (DAAs) have markedly improved the effectiveness of anti-viral therapy for chronic hepatitis C (CHC) patients. In a phase III trial in Japan, treatment with the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir (G/P) resulted in a small number of patients with refractory factors. We aimed to evaluate the effectiveness and safety of G/P, especially among patients with these refractory factors, and the influence of these factors on treatment. METHODS: In a prospective, multicenter study involving 33 medical institutions, 1439 patients were treated with G/P, and their efficacy, safety, and most frequent adverse effects (AEs) were analyzed. RESULTS: Overall SVR12 rates were 99.1% (1397/1410) in the per-protocol-analysis, and genotype sustained virologic response SVR12 rates were: genotype 1, 99.4% (707/711); genotype 2, 99.4% (670/674); genotype 3, 80.0% (16/20). DAA-naïve patients (p = 0.008) with HCV genotype except 3 (genotype 1 vs. 3, p = 2.68 × 10-5; genotype 2 vs. 3, p = 3.28 × 10-5) had significantly higher SVR12 rates. No significant difference was observed between CKD stage 1-3 (99.1% [1209/1220]) and chronic kidney disease (CKD) stage 4-5 (98.9% [188/190]) patients, or between cirrhotic (99.0% [398/402]) and non-cirrhotic (99.1% [999/1008]) patients. Multiple logistic regression analysis revealed that genotype 3 [OR 33.404, 95% CI (7.512-148.550), p value (p = 4.06 × 10-5)] and past experience of IFN-free DAAs [OR 3.977, 95% CI (1.153-13.725), p value (p = 0.029)] were both significantly independent predictors of non-SVR12. AEs were reported in 28.2% of patients, and 1.6% discontinued treatment owing to drug-related AEs. AEs were significantly higher in CKD stage 4-5 (41.6% [79/190]) than CKD stage 1-3 (26.1% [319/1220]) patients (p = 2.00 × 10-5). AEs were also significantly higher in cirrhotic (38.6% [155/402]) than in non-cirrhotic (24.1% [243/1008]) (p = 2.91 × 10-18) patients. CONCLUSIONS: G/P regimen is highly effective and safe to treat CHC patients even with refractory factors such as CKD and advanced liver fibrosis. However, patients with past experience of IFN-free DAA treatment and genotype 3, CKD stage 4 or 5, and advanced liver fibrosis should be more closely observed.

DOI： 10.1007/s12072-020-10019-z

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s12072-020-10019-z

PubMed

researchmap

その他リンク： http://link.springer.com/article/10.1007/s12072-020-10019-z/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background Conversion from sorafenib to regorafenib is primarily an evidence-based treatment strategy in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess the safety and efficacy of sequential therapy with sorafenib and regorafenib in patients with advanced HCC by analysis of outcomes in clinical practice with the aim to complement phase III findings. Methods The medical records of patients with advanced HCC receiving regorafenib were retrieved to collect data on sorafenib administration at seven Japanese institutions. Radiological responses and adverse events were evaluated using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Common Terminology Criteria for Adverse Events version 4.0, respectively. Results Before March 2018, 44 patients were administered regorafenib for advanced HCC. The median sorafenib treatment duration was 8.4 months. The most common adverse events were similar to those reported by the RESORCE trial. The median overall survival (OS) was 17.3 months (95% confidence interval [CI] 11.4-22.9), and 17 of 37 patients (45.9%) discontinued regorafenib and received sequential systemic therapy after regorafenib. These patients had significantly longer OS than those who were treated by the best supportive care or sub-optimal therapy (not reached versus 8.7 months [95% CI 5.8-11.7]; P < 0.001). Conclusion The results based on Japanese clinical practices verified the tolerability of regorafenib in advanced HCC. Major regorafenib-associated adverse events were similar to those related to sorafenib. OS was significantly longer than expected, which might be associated with the sequential systemic therapies after regorafenib, mainly lenvatinib.

DOI： 10.1007/s10637-019-00801-8

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

DOI： 10.3390/cancers12020293

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Autotaxin (ATX) has been reported as a direct biomarker for estimating the evaluation of liver fibrosis. But available data on ATX as a useful biomarker for the complications of liver cirrhosis (LC) are scant. AIM: To assess the clinical usefulness of ATX for assessing the complications of LC. METHODS: This multicenter, retrospective study was conducted at six locations in Japan. We include patients with LC, n = 400. The ATX level was evaluated separately in men and women because of its high level in female patients. To assess the clinical usefulness of ATX for the complications of LC, the area under the curve (AUC) of ATX assessing for the severe complications was analyzed in comparison with the model for end-stage liver disease score, albumin-bilirubin (ALBI) score, fibrosis-4 index, and aspartate aminotransferase-to-platelet ratio index. RESULTS: The mean age was 68.4 ± 11.4 years, 240 patients (60.0%) were male. A total of 213 (53.3%) and 187 (46.8%) patients were compensated and decompensated, respectively. The numbers of patients with varix rupture, hepatic ascites, and hepatic encephalopathy were 35 (8.8%), 131 (32.8%), and 103 (25.8%), respectively. The AUCs of ATX in men for hepatic encephalopathy, hepatic ascites, and varix ruptures were 0.853, 0.816, and 0.706, respectively. The AUCs of ATX in women for hepatic encephalopathy, hepatic ascites, and varix rupture were 0.759, 0.717, and 0.697, respectively. The AUCs of ATX in men were higher than those in women, as were all the other biomarkers used to detect encephalopathy and varix ruptures. However, for detecting ascites, the AUC of ALBI in men was more effective than using ATX. CONCLUSION: ATX in men was more effective than any other biomarkers for detecting hepatic encephalopathy and varix ruptures.

DOI： 10.3748/wjg.v26.i1.97

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background/Aim: Post-progression treatment following tyrosine-kinase inhibitor (TKI) failure in patients with unresectable hepatocellular carcinoma (u-HCC) is important to prolong post-progression survival (PPS), which has a good correlation with overall survival (OS). This study aimed to elucidate the clinical features of progressive disease (PD) in patients treated with lenvatinib (LEN). Materials/Methods: From March 2018 to June 2019, 156 u-HCC patients with Child-Pugh A were enrolled (median age: 71 years, Child-Pugh score 5:6 = 105:51, BCLC A:B:C = 8:56:92, modified albumin-bilirubin grade (mALBI) 1:2a:2b = 59:42:55, past history of sorafenib:regorafenib = 57:17). Clinical features were retrospectively evaluated. Results: The median observation period was 8.5 months. Median OS was not obtained, while median time to decline to Child-Pugh B (CPB) was 11.4 months, median time to progression (TTP) was 8.4 months, and the period of LEN administration was 7.3 months. When we compared predictive values for time to decline to CPB based on Child-Pugh score and mALBI, values for Akaike information criterion (AIC) score and c-index of mALBI were superior as compared to Child-Pugh score (AIC: 592.3 vs. 599.7) (c-index: 0.655 vs. 0.597). Of the 73 patients with PD, 32 (43.8%) showed no decline to CPB or death. After excluding 3 without alpha-fetoprotein data at PD determination, only 14 (20.0%) of 70 showed REACH-2 eligibility. Non-mALBI 1/2a at the start of LEN was a significant risk factor for decline to CPB during LEN treatment (HR 2.552, 95% CI: 1.577-4.129; p < 0.001). Conclusion: Introduction of TKI therapy including LEN for u-HCC patients with better hepatic function (mALBI 1/2a: ALBI score ≤-2.27), when possible, increases the chance of undergoing post-progression treatment, which can improve PPS.

DOI： 10.1159/000503031

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Lenvatinib has become available as first-line therapy for patients with unresectable hepatocellular carcinoma (HCC). However, the safety and efficacy of lenvatinib in elderly patients with HCC has not been sufficiently investigated. We compared the frequency of adverse events and prognosis between elderly and non-elderly patients with HCC who received lenvatinib. METHODS: A total of 100 patients with HCC who received lenvatinib were selected using propensity score matching: 50 patients were elderly (age ≥75 years) and 50 patients were non-elderly. RESULTS: In the elderly group, >20% of patients experienced fatigue (36.0%), decreased appetite (26.0%), hypothyroidism (24.0%), proteinuria (22.0%), palmar-plantar erythrodysesthesia (22.0%), and hypertension (20.0%) of any grade as treatment-related adverse events. In addition, >10% of patients experienced grade ≥3 treatment-related fatigue (12.0%). In the non-elderly group, >20% of patients experienced palmar-plantar erythrodysesthesia (42.0%), fatigue (28.0%), decreased appetite (22.0%), and diarrhea (20.0%) of any grade as treatment-related adverse events. In addition, >10% of patients experienced grade ≥3 treatment-related proteinuria (10.0%). There were no significant differences between the elderly and non-elderly groups in the frequency of adverse events. Regarding overall and progression-free survival, there were no significant differences between the elderly and non-elderly groups (hazard ratio 0.972, 95% confidence interval 0.374-2.529; and hazard ratio 1.362, 95% confidence interval 0.687-2.700, respectively). Palmar-plantar erythrodysesthesia (hazard ratio 0.117, 95% confidence interval 0.015-0.916) was independently associated with overall survival in a multivariate analysis. CONCLUSIONS: Lenvatinib can be used safely and efficaciously regardless of age in patients with HCC.

DOI： 10.1111/hepr.13427

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Few studies have examined the details of nutritional status in patients with unresectable hepatocellular carcinoma (u-HCC) undergoing systemic chemotherapy with lenvatinib. We evaluated the prognostic/predictive value of nutritional status using Onodera's prognostic nutritional index (O-PNI) for overall survival among patients with u-HCC treated with lenvatinib. METHODS: Three-hundred and seventy-five u-HCC patients treated with lenvatinib were enrolled (median age 72 years; Child-Pugh class A/B/C: n = 312/60/3; BCLC stage A/B/C/D: n = 2/159/212/2). We examined median survival time (MST) and time to progression (TTP) in all patients (n = 375), prognosis according to the O-PNI (high/low: >40/≤40) in 298 patients with lymphocyte findings, and the prognostic/predictive values of Child-Pugh stage, albumin-bilirubin (ALBI)/modified ALBI (mALBI) grade, and O-PNI for Chemotherapy grade (OPNIC grade 1/2/3: O-PNI >40/≤40 to >36/≤36). RESULTS: The MST and TTP were 16.6 and 8.0 months, respectively. The MST and TTP according to the O-PNI (>40/≤40) were "not reached" (NR)/12.4 months (p < 0.001) and 10.0/6.1 months (p = 0.012), respectively. There was a good correlation noted between ALBI score and O-PNI (r = -0.939, p < 0.001). The predictive value of the O-PNI for mALBI grade 2a was 36.0 (specificity/sensitivity = 0.894/0.942; area under the curve [AUC] = 0.978), while that for mALBI grade 1 was 39 (specificity/sensitivity = 0.920/0.929; AUC = 0.972), which was very similar to a high O-PNI. The MST analyzed with the OPNIC in the 298 patients was NR/16.2/10.4 months for OPNIC grade 1/2/3 (p < 0.001), respectively, and the c-index was 0.632, the same as that for mALBI grade (0.632), while that for Child-Pugh class was 0.571. CONCLUSIONS: OPNIC grading might have a potential for easy substitution of mALBI grading. A good nutritional status (OPNIC grade 1) or mALBI grade 1 is the best indication for lenvatinib use, while with an OPNIC grade 3, lenvatinib might be not suitable.

DOI： 10.1159/000506293

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jvh.13170

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Vitamin D has promising anti-proliferative and anti-fibrotic properties, but its clinical utility in nonalcoholic fatty liver disease (NAFLD) is unclear. AIMS: This study aimed to clarify the association between vitamin D levels, single nucleotide polymorphisms (SNPs) in vitamin D-related genes, and the histopathological severity of disease in patients with biopsy-proven NAFLD. METHODS: SNPs in CYP2R1, DHCR7, vitamin D binding protein (GC), CYP27B1, and vitamin D receptor (VDR) were determined for 229 consecutive patients with biopsy-proven NAFLD. RESULTS: In this study, vitamin D deficiency defined as 25-hydroxyvitamin-D3 levels of ≤20 ng/mL was found in 151 patients (65.9%). Multivariate analysis revealed that cold season, advanced fibrosis, and CYP2R1 rs1993116 genotype non-AA were independent factors significantly associated with vitamin D deficiency. Old age (p = 5.05 × 10-8), high body mass index (p = 2.13 × 10-2), low total-cholesterol (p = 1.46 × 10-4), low serum vitamin D level (p = 7.34 × 10-3), and VDR rs1544410 genotype CC (p = 9.15 × 10-3) were independent factors associated with advanced liver fibrosis. CONCLUSION: Serum 25-hydroxyvitamin-D3 levels and the VDR gene SNP were significantly and independently associated with the severity of liver fibrosis in patients with biopsy-proven NAFLD.

DOI： 10.1016/j.dld.2018.12.022

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: We assessed suitable factors indicating newly developed lenvatinib (LEN) treatment for unresectable hepatocellular carcinoma (u-HCC) by investigating real-world clinical features of patients. MATERIALS/METHODS: One hundred fifty two u-HCC patients, who receive LEN treatment from March to December 2018, were enrolled. (Child-Pugh score [CPS] 5/6/7/8 = 76/61/13/2, modified albumin-bilirubin grade [mALBI] 1/2a/2b/3 = 53/35/60/4). Clinical features were evaluated retrospectively. RESULTS: Overall-response rate (ORR)/disease control rate (DCR) at 1 month after starting LEN were 38.7%/86.0%, respectively. Estimated median time to progression (TTP) was 7.0 months, while median survival time was not reached within the observation period. CPS (≥7) and past history of tyrosine-kinase inhibitor (TKI) were not significant prognostic factors. mALBI ≥2b was an only significant prognostic factor (HR 4.632, 95%CI 1.649-13.02, P = 0.004) in Cox-hazard multivariate analysis. In patients with Child-Pugh A, c-index/Akaike's information criterion (AIC) of prognostic predictive value of mALBI were superior to CPS (0.682/135.6 vs 0.652/138.7), while those of stopping LEN also showed that mALBI was better (0.575/447.3 vs 0.562/447.8). Additional analysis of patients with good mALBI (1/2a) revealed that time to stopping LEN was significantly shorter in those with the adverse event (AE) of appetite loss (any grade) than those without (P = 0.006) and body mass index (BMI) was also lower in patients with that AE (20.3 ± 3.0 vs 23.6 ± 4.0kg/m2 , P < 0.001), while patients with a hand-foot skin reaction (any grade) showed good ORR/DCR (59.1%/86.4%) and longer TTP as compared to patients without (P = 0.007). CONCLUSION: Good hepatic function (mALBI 1/2a) is the best indication for LEN, while potential appetite loss in association with low BMI should be kept in mind in such cases.

DOI： 10.1002/cam4.2241

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

BACKGROUND: Patients with chronic hepatitis C are often complicated by chronic kidney disease (CKD). AIM: To evaluate the efficacy, safety and pharmacokinetics of glecaprevir/pibrentasvir in patients with severe renal impairment. METHODS: In a prospective, multicentre study involving 35 medical institutions, 832 genotype 1-3 patients were treated with glecaprevir/pibrentasvir. The efficacy and safety of glecaprevir/pibrentasvir were analysed for patients with CKD stage 4 or 5. Multivariate analysis was performed to identify the factors associated with the most frequently observed adverse event. In patients undergoing haemodialysis, a pharmacokinetic study was conducted to investigate the dialysability of the drugs: plasma samples were obtained from the arterial and venous sides of a dialyser to serially measure drug concentrations. RESULTS: The subjects comprised 141 patients (32 with CKD stage 4 and 109 with CKD stage 5), of whom 100 were undergoing haemodialysis. All but one stage 5 CKD patients undergoing haemodialysis achieved sustained virologic response (99.3%). Adverse events were observed in 39.7% of subjects: pruritus was the most frequent (30.5%), and was significantly associated with haemodialysis. In the pharmacokinetic study, no arterial-venous differences in the plasma concentrations of glecaprevir/pibrentasvir were detected during the haemodialysis sessions. CONCLUSIONS: Glecaprevir/pibrentasvir was highly effective and safe in chronic hepatitis C patients with severe renal impairment. Haemodialysis was associated with increased incidence of pruritus, which was the most frequent adverse event, but had little or no influence on the drug concentrations, which indicated that their dialysability is very low and that no dose modification is required in patients undergoing haemodialysis. (UMIN registration no. 000032073).

DOI： 10.1111/apt.15218

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Background: We investigated changes in patient characteristics, rate of sustained virologic response (SVR), and factors associated with SVR after anti-hepatitis C virus (HCV) therapy with direct-acting antiviral (DAA) regimens in real-world practice in Japan, where patients with HCV are characterized by older age and high prevalence of cirrhosis and hepatocellular carcinoma (HCC). Methods: Changes in patient characteristics and SVR rates were evaluated from medical records among 10 688 patients who started interferon (IFN)-free DAA therapy between September 2014 and June 2018 in a nationwide, multicenter study. Factors associated with failure of SVR were analyzed. In particular, effects of cirrhosis or history of HCC on SVR were assessed by exact matching. Results: Patient age was becoming younger and baseline liver fibrosis was becoming milder over time. Overall SVR rate was 95.4%. The SVR rates increased over time in patients without a history of IFN-free DAA therapy. Multivariate analysis revealed that cirrhosis was unfavorably associated with achievement of SVR in both patients with genotype 1 (odds ratio, 1.68; 95% confidence interval [CI], 1.27-2.21) and genotype 2 (odds ratio, 1.69; 95% CI, 1.01-2.78). Comparisons after exact matching showed that the SVR rate was significantly lower in patients with cirrhosis than without it, whereas patients with and without a history of HCC had similar SVR rates. Conclusions: Background characteristics of patients who undergo IFN-free DAA therapy are changing in Japan. Patients without a history of IFN-free DAA therapy have high SVR rates. Exact matching confirmed that cirrhosis significantly influences the achievement of SVR in real-world settings.

DOI： 10.1093/ofid/ofz185

PubMed

researchmap

その他リンク： http://academic.oup.com/ofid/article-pdf/6/5/ofz185/28668643/ofz185.pdf

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The aim of this study was to evaluate the efficacy and safety of community-based ombitasvir/paritaprevir/ritonavir plus ribavirin therapy for non-cirrhotic patients with hepatitis C virus (HCV) genotype 2a infection in a real-world setting. METHODS: Patients with HCV genotype 2a infection were enrolled in this study and received the therapy for 16 weeks at 11 specialized centers in Japan between October 2016 and July 2017. Among the 98 patients participating in the study, four patients were excluded because of the presence of cirrhosis and/or genotype 2b infection. The remaining 94 patients were subjected to the analysis. RESULTS: The patients consisted of 38 women and 56 men, with a median age of 63 years. The rate of sustained virologic response (SVR) was 97.9%. The SVR rates were similar between patients with and without ribavirin dose reduction (96.0% vs. 98.6%, respectively). Of the two patients in whom treatment failed, one patient completed the treatment but relapsed at 4 weeks post-treatment, whereas the other did not show virologic response and therefore discontinued treatment at week 9. At baseline, both patients had non-structural protein (NS)5A resistance-associated substitution (RAS) L31M but no NS3 RAS. At the time of relapse, the patient had NS5A RAS F28S. At the premature treatment discontinuation, the non-responder had NS3 RAS D168V and NS5A RAS T24S. Ribavirin-induced anemia was the most frequent adverse event. CONCLUSION: Community-based, 16-week, ombitasvir/paritaprevir/ritonavir plus ribavirin therapy was highly efficacious and safe in non-cirrhotic patients with HCV genotype 2a infection in a real-world setting.

DOI： 10.1111/hepr.13292

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

DOI： 10.1007/s00535-018-1526-3

PubMed

researchmap

記述言語：英語  

Web of Science

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1007/s00535-018-1526-3

PubMed

researchmap

その他リンク： http://link.springer.com/article/10.1007/s00535-018-1526-3/fulltext.html

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: This study aimed to evaluate the efficacy and safety of elbasvir/grazoprevir in genotype 1b chronic hepatitis C Japanese patients with chronic kidney disease (CKD), including those undergoing hemodialysis. METHODS: This post hoc analysis of a multicenter, retrospective study included patients who had received elbasvir/grazoprevir. CKD was defined by an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 . The sustained virologic response (SVR) rate and frequency of treatment-emergent adverse events were assessed in patients with CKD. RESULTS: The study population comprised 155 men and 182 women. The median eGFR level at baseline was 69.6 mL/min/1.73 m2 (range, 3.0-128.5 mL/min/1.73 m2 ). Among the 337 patients, 109 (32.3%) had CKD: 72, 14, and 23 (including 20 hemodialysis) had CKD stages 3, 4, and 5, respectively. The SVR rates according to the baseline CKD stages were 98.1% (51/52) in stage 1, 98.3% (173/176) in stage 2, 93.9% (46/49) in stage 3a, 100% (23/23) in stage 3b, 100% (14/14) in stage 4, and 100% (23/23) in stage 5. All 20 patients undergoing hemodialysis achieved SVR. There was no significant decrease from baseline in the median eGFR level throughout the treatment period among the patients with CKD. The incidence of treatment-emergent adverse events was 6.4% (7/109) among the patients with CKD and 9.7% (22/228) among the patients without CKD (not significant, P = 0.323). CONCLUSIONS: The present study demonstrated that elbasvir and grazoprevir are highly effective and safe for genotype 1b chronic hepatitis C Japanese patients with CKD, including those undergoing hemodialysis.

DOI： 10.1111/jgh.14447

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本消化器病学会-関東支部  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Nowadays, interferon-free direct-acting antiviral (DAA) treatment is the standard of care for chronic hepatitis C patients. Some DAA regimens are highly effective and safe even for those with renal dysfunction/failure including those receiving HD. However, it remains unclear to what extent HD specialists gain knowledge about advances in anti-hepatitis C virus (HCV) treatment. To clarify the current situation and identify problems in the treatment of HD patients with chronic hepatitis C, we performed a questionnaire survey at 36 HD facilities between June 2016 and September 2017. In a total of 3418 HD patients, 179 (5.2%) were positive for anti-HCV antibody, and among these patients, 110/125 (88.0%) were positive for serum HCV RNA. Of the latter, only 42/110 (38.2%) patients received antiviral therapy. Moreover, HCV serotyping or genotyping was performed in 23/110 (20.9%) patients. In 26/49 (53.1%) of the remaining 68 untreated patients, "HD specialists do not know any HCV-specific treatments" and "HD specialists have no opportunity to consult with a hepatologist" were the reasons cited for the lack of anti-HCV treatment. This epidemiological study found that some HD patients with chronic hepatitis C had not yet received antiviral treatment despite the emergence of DAAs. To overcome such undesirable circumstances, medical cooperation between HD specialists and hepatologists should be required.

DOI： 10.1111/1744-9987.12747

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Although the development of new direct-acting antivirals (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection has markedly advanced, the effects of cirrhosis on DAA treatment remain unclear. We aimed to clarify the impact of cirrhosis on DAA treatment of patients infected with HCV. METHODS: This large-scale, multicenter, retrospective study consisted of 2130 HCV genotype 1b-infected patients who were treated with one of the following DAA combination therapies: asunaprevir/daclatasvir (ASV/DCV), ledipasvir/sofosbuvir (LDV/SOF), or paritaprevir/ombitasvir/ritonavir (PTV/OBV/r). Ninety-two patients (4.3%) previously received DAA-based treatment. Seven hundred and forty-five patients (34.9%) had cirrhosis. RESULTS: Overall, the sustained virologic response (SVR) rate was 93.0%. The SVR rates in patients who received ASV/DCV, LDV/SOF, or PTV/OBV/r were 90.0%, 96.9%, and 97.6%, respectively. The SVR rate in patients with cirrhosis (89.1%) was significantly lower than that in patients without cirrhosis (95.1%, P = 6.94 × 10-7 ). In the multivariate analysis for the overall cohort, absence of cirrhosis (P = 1.26 × 10-3 ), no previous DAA-based treatment (P = 2.54 × 10-14 ), low HCV-RNA levels (P = 1.64 × 10-6 ), wild-type non-structural protein 5A L31/Y93 (P = 7.33 × 10-13 ), and DAA regimen (LDV/SOF or PTV/OBV/r) (P = 1.92 × 10-14 ) were independent factors contributing to SVR. Except for patients with DAA-based treatment history, absence of cirrhosis (P = 2.15 × 10-3 ; odds ratio, 2.51) was an independent factor contributing to SVR in 2038 DAA-naïve patients. CONCLUSION: This study suggests that the presence of cirrhosis reduces the SVR rate of DAA treatment, regardless of the type of DAA treatment.

DOI： 10.1111/hepr.13256

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Presently, there are no therapeutic options for unresectable hepatocellular carcinoma (u-HCC) patients who are intolerant to sorafenib or regorafenib failure. There have been no reports with detailed clinical findings of lenvatinib (LEN), a newly developed first-line tyrosine kinase inhibitor (TKI), obtained in real-world practice. We aimed to elucidate the therapeutic efficacy of LEN. MATERIALS/METHODS: From March to August 2018, 105 u-HCC patients were treated with LEN. Following exclusion of those who started with a reduced LEN dose and/or had a short observation period (<2 weeks), 77 patients (72.0 ± 8.9 years, 59 males, 8 mg/12 mg = 49/28, Liver Cancer Study Group of Japan 6th [LCSGJ]-TNM stage II/III/IVa/IVb = 8/28/4/37, and American Joint Committee on Cancer/Union for International Cancer Control 8th [AJCC/UICC]-TNM stage IB:II:IIIA:IIIB:IVA:IVB = 2:27:6:5:9:28) were divided into two groups (TKI naïve [n = 33] and TKI experienced [n = 44], including 11 with regorafenib history). Therapeutic response was evaluated using mRECIST. Clinical data were retrospectively evaluated. RESULTS: There were significant differences in age (74.6 ± 11.2 vs 70.0 ± 5.9 years, P = 0.040), LCSGJ-TNM (II:III:IVa:IVb = 8:12:1:12 vs 0:16:3:25, P = 0.006), and AJCC/UICC-TNM (IB:II:IIIA:IIIB:IVA:IVB = 2:17:1:1:4:8 vs 0:10:5:4:5:20, P = 0.028), while hepatic reserve function, adverse event (AE) profiles, and progression-free survival (89.7%/80.4% vs 90.5%/80.1%, P = 0.499) and overall survival (96.7%/96.7% vs 100%/92.3%, P = 0.769) after 4 and 12 weeks were not significantly different between the TKI-naïve and TKI-experienced groups. Overall response rate and disease control rate at 4 weeks (n = 52) were 38.5% and 80.8%, respectively, and 32.4% and 70.3%, respectively, at 12 weeks (n = 37). A significant decline in log10 AFP from the baseline to 4 weeks after introducing LEN was observed in patients with PR and SD (2.047 ± 1.148 vs 1.796 ± 1.179, P < 0.001). CONCLUSION: Regardless of past TKI therapy, therapeutic response and AEs after introducing LEN were similar. LEN may be an important treatment for the present unmet need regarding TKI treatment against u-HCC.

DOI： 10.1002/cam4.1909

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Drug-induced liver damage characterized by serum alanine aminotransferase (ALT) elevation often occurs in direct-acting antiviral (DAA) combination therapy for chronic hepatitis C virus (HCV) infection. This study explored single nucleotide polymorphisms (SNPs) at drug metabolism- or transport-related genes that were associated with ALT elevation in asunaprevir plus daclatasvir therapy. METHODS: Subjects were 185 Japanese patients with chronic HCV genotype 1b infection who received asunaprevir plus daclatasvir therapy. Tag SNPs at possible metabolizing enzyme and transporter genes, which were involved in the pharmacokinetics of asunaprevir and daclatasvir, were selected. RESULTS: Among the tag SNPs analyzed, CYP3A4 rs4646437 was significantly associated with ALT elevation (p = 0.013): maximum ALT values in patients with genotype CC were higher than those in patients with genotype non-CC (allele T). The proportion of grades 2-4 in genotype CC patients were significantly greater than those in genotype non-CC patients (p = 0.028). No patients with genotype non-CC showed grade ≥2 ALT elevation. In multivariate analysis, rs4646437 genotype CC and cirrhosis were significant, independent factors associated with grade ≥1 ALT elevation (odds ratio, 2.83 and 1.88; p = 0.040 and 0.045, respectively). In exploratory analyses, although serum concentrations of asunaprevir and daclatasvir were not correlated with maximum ALT values or rs4646437 genotypes, asunaprevir concentrations in patients with grade ≥1 ALT elevation were significantly higher than those in patients with grade <1 ALT elevation (P = 0.023). CONCLUSIONS: CYP3A4 rs4646437 was found to be significantly and independently associated with ALT elevation in Japanese patients receiving ASV plus DCV therapy. Notably, none of the patients with rs4646437 genotype non-CC (allele T) had grade ≥2 ALT elevation. SNP genotyping prior to treatment might be useful for carefully monitoring patients to complete treatment safely.

DOI： 10.1371/journal.pone.0219022

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Lenvatinib (LEN) has been developed for the treatment of unresectable hepatocellular carcinoma (u-HCC). We aimed to elucidate the relative change in hepatic reserve function early following LEN treatment in affected patients. MATERIALS/METHODS: From March 2018 to April 2019, 123 u-HCC patients (median age 71 years; male:female ratio 95:28; Child-Pugh score 5:6:7 = 65:50:8; modified albumin-bilirubin [mALBI] grade 1:2a:2b:3 = 44:28:50:1, Barcelona Clinic Liver Cancer stage A:B:C = 1:49:73) were enrolled. Relative changes in hepatic reserve function at 2 and 4 weeks after starting LEN were retrospectively evaluated. RESULTS: The median survival was 11.3 months. The Child-Pugh score declined from the start to 4 weeks after commencing LEN (score 5:6:7:8:9:≥10 = 65:50:8:0:0:0 vs. 50:39:22:8:0:4, p < 0.001). A comparison among ALBI scores at the start of LEN and those at 2 and 4 weeks revealed significant relative changes (-2.36 ± 0.45 to -2.20 ± 0.49 at 2 weeks, -2.15 ± 0.50 at 4 weeks, p < 0.001, Bonferroni method), while there was no significant difference between those at 2 and 4 weeks (p= 0.210, Bonferroni method). Assessments of relative changes of ALBI score in patients divided by mALBI grade 1, 2a, and 2b or more showed a significant decline in score regardless of grade (-2.82 ± 0.17 to -2.53 ± 0.34, p < 0.001; -2.46 ± 0.10 to -2.31 ± 0.33, p = 0.017; and -1.90 ± 0.26 to -1.75 ± 0.42, p= 0.009, respectively). CONCLUSION: Decline in hepatic function is common in the early stage (≤4 weeks, especially within 2 weeks) after introducing LEN. It is important to introduce molecular targeting agent drugs for u-HCC in patients with better hepatic function, who show transarterial catheter chemoembolization failure, as much as possible, along with consideration of the negative influence of LEN on the early response of hepatic function.

DOI： 10.1159/000502095

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: We evaluated clinical factors related to improved prognosis of unresectable hepatocellular carcinoma patients (u-HCC), who were treated with tyrosine kinase inhibitor (TKI) sequential therapy, including lenvatinib (LEN). MATERIALS/METHODS: We enrolled 84 u-HCC cases treated with TKIs including LEN from March 2018 to January 2019 (median age 71 years, 63 males, Child-Pugh score (CPS) 5/6/7 = 62/21/1, tumor-node-metastasis stage of Liver Cancer Study Group of Japan 6th (TNM-LCSGJ) II/III/IVa/IVb = 12/30/5/37, Barcelona Clinic Liver Cancer stage B/C = 33:51). Clinical findings at introduction of the initial TKI were retrospectively evaluated. RESULTS: The median albumin-bilirubin (ALBI) score at introduction of the initial TKI (sorafenib [SOR]/LEN = 80/4) was -2.56, and the past number of transarterial catheter chemoembolization was 3 (IQR: 2-5) (second-line: regorafenib [REG]/LEN/SOR = 31/49/4, third-line: LEN/REG = 31:1). The total period of administration with TKIs showed a good relationship with overall survival (OS) (r = 0.946, 95% confidence interval [CI]: 0.918-0.965, p < 0.001). The prognosis of the entire cohort was good (estimated median survival time: 46.4 months, 1-/2-/3-year OS rate [OSR] = 87.7/63.0/57.2%). A modified-ALBI grade (mALBI) of 2b (ALBI score >-2.27) was the only significant factor at the start of the initial TKI for poor prognosis (hazard ratio 2.319, 95% CI: 1.064-5.052, p = 0.034), while CPS (≥6) was not. Although there was no significant difference in TNM-LCSGJ (p = 0.213), the prognosis of patients with mALBI 1/2a (n = 66) showed better prognosis as compared to those with mALBI 2b (n = 18) (1-year/2-year/3-year OSR = 89.1/69.8/66% vs. 82.4/47.1/23.5%, p = 0.029). CONCLUSION: Good hepatic function (mALBI 1/2a) at introduction of the initial TKI is a requirement for improved prognosis of u-HCC undergoing TKI sequential therapy.

DOI： 10.1159/000501281

PubMed

researchmap

記述言語：日本語   出版者・発行元：日本門脈圧亢進症学会  

71歳，女性．60歳時にC型肝硬変，食道静脈瘤，腹水，肝性脳症，肝動脈門脈短絡（A-Pシャント）と診断されたが食道静脈瘤硬化療法（EIS）と利尿剤投与などにより病状は安定していた．70歳時に再度EIS施行したところ腹水が増悪し，その後，利尿剤不耐性の難治性腹水となり当科へ入院となった（Child-Pughスコア12点）．TAEによるA-Pシャント塞栓術を施行したところ，肝静脈圧較差は26 mmHgから19 mmHgへ低下し，腹水穿刺の頻度も週に1度程度へ改善したが難治性腹水からの離脱には至らなかった．しかし，A-Pシャント塞栓術後，門脈本幹血流は求肝性となり肝性脳症が制御可能となった．そこでA-Pシャント塞栓術の38日後にTIPSを行った．TIPSにより，門脈大循環圧較差は19 mmHgから6 mmHgへ低下し，腹水は著明に改善し，腹水穿刺・利尿剤ともに中止可能となった．その後肝機能は徐々に改善し，TIPS 8か月後には腹水は完全消失し，Child-Pughスコアは6点まで改善した．76歳時にDAA（LDV/SOF）を導入したところウイルスは持続陰性化し，78歳となった現在でも健在である．

DOI： 10.11423/jsph.25.136

CiNii Research

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although the presence of nonalcoholic fatty liver disease (NAFLD) is known to be related to subclinical atherosclerosis, the relationship between the severity of NAFLD and subclinical atherosclerosis is not clear. This study aimed to clarify the factors related to subclinical arteriosclerosis, including the histopathological severity of the disease and PNPLA3 gene polymorphisms, in NAFLD patients. We measured brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness in 153 biopsy-proven NAFLD patients. The baPWV values were significantly higher in the advanced fibrosis group than in the less advanced group (median, 1679 cm/s vs 1489 cm/s; p = 5.49×10-4). Multiple logistic regression analysis revealed that older age (≥55 years) (p = 8.57×10-3; OR = 3.03), hypertension (p = 1.05×10-3; OR = 3.46), and advanced fibrosis (p = 9.22×10-3; OR = 2.94) were independently linked to baPWV ≥1600 cm/s. NAFLD patients were categorized into low-risk group (number of risk factors = 0), intermediate-risk group (= 1), and high-risk group (≥2) based on their risk factors, including older age, hypertension, and biopsy-confirmed advanced fibrosis. The prevalence of baPWV ≥1600 cm/s was 7.1% (3/42) in the low-risk group, 30.8% (12/39) in the intermediate-risk group, and 63.9% (46/72) in the high-risk group. Non-invasive liver fibrosis markers and scores, including the FIB-4 index, NAFLD fibrosis score, hyaluronic acid, Wisteria floribunda agglutinin positive Mac-2-binding protein, and type IV collagen 7s, were feasible substitutes for invasive liver biopsy. Older age, hypertension, and advanced fibrosis are independently related to arterial stiffness, and a combination of these three factors may predict risk of arteriosclerosis in NAFLD patients.

DOI： 10.1371/journal.pone.0224184

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To assess the correlation between the efficacy of lusutrombopag and clinical characteristics in patients with chronic liver disease. METHODS: In this retrospective, multicenter study, which conducted at four locations in Japan, 50 thrombocytopenic patients with chronic liver disease were enrolled. All patients received oral lusutrombopag (3.0 mg/d for 7 d) for chronic liver disease. We assessed the increase in platelet count after the trial drug administration. A treatment response was defined as a platelet count ≥ 5 × 104/μL and an increased platelet count ≥ 2 × 104/μL from baseline after drug administration. We evaluated the response to lusutrombopag compared to baseline clinical characteristics in patients with chronic liver disease. RESULTS: The numbers of responders and non-responders were 40 (80.0%) and 10 (20.0%), respectively. The patients were divided into a responder and non-responder group, and we added factors that may correspond to successful treatment with lusutrombopag. Splenic volume and body weight were lower in the responder group than in the non-responder group. White blood cell count and hemoglobin level were higher in responders compared with non-responders. Using a logistic regression model to assess the relationship between response to lusutrombopag and clinical characteristics, multivariate analysis confirmed that splenic volume was an independent factor that predicted the response of platelet counts (P = 0.025; odds ratio = 11.2; 95% confidence interval: 1.354-103.0). Splenic volume negatively correlated to changes in platelet count (r = -0.524, P = 0.001). CONCLUSION: Splenic volume influences the change in platelet counts after administration of lusutrombopag in patients with chronic liver disease.

DOI： 10.3748/wjg.v24.i46.5271

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The real-world virological efficacy and safety of an interferon (IFN)-free direct-acting antiviral (DAA) therapy with elbasvir (EBR) and grazoprevir (GZR) were evaluated in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1. METHODS: The rate of sustained virologic response (SVR) and safety were analyzed in patients who started the EBR/GZR regimen between November 2016 and July 2017. SVR rates were compared based on patient baseline characteristics. RESULTS: Overall, 371 of 381 patients (97.4%) achieved SVR. Multivariate analysis identified a history of failure to IFN-free DAA therapy and the presence of double resistance-associated substitutions (RASs) in HCV non-structural protein 5A (NS5A) as factors significantly associated with failure to EBR/GZR treatment. The SVR rates of patients with a history of IFN-free DAA therapy and those with double RASs were 55.6 and 63.6%, respectively. In all other subpopulations, the SVR rates were more than 90%. There were no severe adverse events associated with the treatment. CONCLUSIONS: The EBR/GZR regimen yielded high virological efficacy with acceptable safety. Patients with a history of failure to IFN-free DAA therapy or with double RASs in HCV-NS5A remained difficult to treat with this regimen.

DOI： 10.1007/s00535-018-1473-z

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語  

DOI： 10.1111/apt.14899

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: The aim of this study was to clarify the effects and safety of ombitasvir/paritaprevir/ritonavir (OBT/PTV/r) therapy in genotype 1b chronic hepatitis C patients with non-dialysis chronic kidney disease (CKD). METHODS: This retrospective, multicenter study of 12-week OBT/PTV/r therapy included genotype 1b patients with non-dialysis CKD. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Virologic responses and treatment-emergent adverse events (TEAEs) in patients with CKD were compared with those in patients without CKD. RESULTS: Two hundred and thirty-five patients with a median age of 67 years (range, 27-89 years) were enrolled, consisting of 181 patients without CKD and 54 patients with CKD. Overall, the rates of rapid virologic response (RVR), end of treatment response (ETR), and sustained virologic response (SVR) were 78.7%, 98.7%, and 98.7%, respectively. Among the 181 non-CKD patients, the rates were 77.3% (140/181), 98.9% (179/181), and 98.9% (179/181), respectively. Among the 54 CKD patients, the rates were 83.3% (45/54), 98.1% (53/54), and 98.1% (53/54), respectively. There were no significant differences in the virologic response rates between the two groups (P = 0.449 for RVR, 0.545 for ETR, and 0.545 for SVR). In the CKD group, the eGFR level did not significantly change throughout the treatment period. There was no significant difference in the incidence of TEAEs or treatment discontinuation due to TEAEs between the two groups. CONCLUSION: The present study showed that the effects and safety of OBV/PTV/r therapy in genotype 1b chronic hepatitis C patients with non-dialysis CKD were not inferior to those in patients without CKD.

DOI： 10.1111/hepr.13058

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND AND AIM: This study aimed to clarify the factors predictive of treatment response to tolvaptan (V2-receptor antagonist) for cirrhotic patients with hepatic edema in a real-world setting. METHODS: In this retrospective, multicenter study, tolvaptan was orally administered at a dose of 7.5 mg once a day. Patients with a decrease in body weight of 1.5 kg or greater from baseline were characterized as responders at day 7. RESULTS: Of 229 patients, 210 were subjected to this analysis. Patients consisted of 133 men and 77 women, with the median age of 67 years (range, 40-89 years). According to the Child-Pugh classification, five patients were classified as class A, 90 as class B, and 115 as class C. The frequencies of responders and nonresponders were 55.2% and 44.8%, respectively. Blood urea nitrogen (BUN) level was significantly lower in responders compared with nonresponders (P = 3.77 × 10-3 ). Using the receiver operating characteristic curve, the cutoff value of 28.2 mg/dL was the most useful in discriminating responders from nonresponders. Among 154 patients with BUN level of less than 28.2 mg/dL, 95 (61.7%) were responders. By contrast, among 56 patients with BUN level of 28.2 mg/dL or more, 21 (37.5%) were nonresponders (P = 2.70 × 10-3 ). On multivariate analysis, BUN level of <28.2 mg/dL and urine sodium >51 mEq/day were found to be independent factors associated with the response to tolvaptan. CONCLUSIONS: This study suggests that BUN level and urinary sodium excretion are closely associated with the response to tolvaptan in cirrhotic patients with hepatic edema.

DOI： 10.1111/jgh.14047

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Kowsar Medical Publishing Company  

Background: Although there are many reports on the relationship between serum 25-hydroxyvitamin D3 levels and chronic liver diseases, the relevance of the former to the latter is still unclear. Objectives: This study aimed at clarifying the relationship between serum 25-hydroxyvitamin D3 levels and HBV-related markers, such as HBV-DNA, hepatitis B surface antigen (HBsAg), and hepatitis B virus core-related antigen (HBcrAg) in patients with chronic hepatitis B. Methods: This was a multicenter retrospective study. The subjects consisted of 236 consecutive untreated patients with chronic hepatitis B. Serum 25-hydroxyvitamin D3 levels were measured by double-antibody radioimmunoassay. The 25-hydroxyvitamin D3 levels were divided to three groups: ≤ 20 ng/mL for deficiency, 21 to 29 ng/mL for insufficiency, and ≥ 30 ng/mL for sufficiency. Results: The subjects consisted of 127 males and 109 females, with a median age of 57 years (range, 15 to 84 years). The patients with positive HBeAg and genotype C accounted for 14.4% and 63.1%, respectively. The median HBV-DNA level and HBsAg level were 684 IU/mL and 750 IU/mL, respectively. The median serum 25-hydroxyvitamin D3 level was significantly lower in patients (21.0 ng/mL) than in healthy volunteers (25.0 ng/mL, P = 0.013). The median serum 25-hydroxyvitamin D3 level in patients with a serum HBsAg level ≥ 1000 IU/mL was significantly lower than that in patients with a serum HBsAg level of ≥ 1000 U/mL (P = 8.06 × 10-3). The incidence of the HBsAg level ≥ 1000 IU/mL was 55.8% in patients with vitamin D deficiency and 3 8.2% in patients with vitamin D insufficiency/sufficiency (P = 8.92 × 10-3). On multivariate analysis, female gender, the cold season, and a serum HBsAg level of ≥ 1000 IU/mL were independently associated with vitamin D deficiency. From the opposite viewpoint, vitamin D deficiency and high serum HBcrAg level were independent factors associated with an HBsAg level of ≥ 1000 IU/mL. Conclusions: This study suggests that serum vitamin D level is closely and negatively correlated with the HBsAg level in chronic hepatitis B patients.

DOI： 10.5812/hepatmon.63587

Scopus

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Unfortunately, in the original publication of this article, the copyright line was incorrectly published in PDF as "© The Author(s) 2017" instead of "©The Author(s) 2017 This article is an open access publication" and also the CC-BY description was not included. The description should be as follows.

DOI： 10.1007/s00535-017-1409-z

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: Serum Mac-2 binding protein (M2BP) and Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+ -M2BP) are used to estimate the liver fibrosis stage in chronic liver diseases. However, few head-to-head studies have been carried out to compare the two biomarkers in non-alcoholic fatty liver disease (NAFLD). METHODS: Serum M2BP and WFA+ -M2BP levels were compared against clinical characteristics and liver histological manifestations in the same samples collected from 213 biopsy-proven NAFLD patients. RESULTS: Median levels (range) of M2BP and WFA+ -M2BP were 1.58 (0.70-7.75) pg/mL and 0.85 (0.22-11.32) cut-off index (COI), respectively. Fibrosis stages 1, 2, 3, and 4 were determined in 136, 37, 17, and 23 patients, respectively. Median levels of both biomarkers increased stepwise with fibrosis progression. The M2BP and WFA+ -M2BP levels showed a significant positive correlation (r = 0.643, P = 2.91 × 10-26 ), but a marked discrepancy between both biomarkers was noted in five stage 4 and three stage 1 patients, who had high WFA+ -M2BP but relatively low M2BP levels. Most of these outliers had findings suggestive of more advanced fibrosis. For diagnosing any fibrosis severity, WFA+ -M2BP had greater area under the receiver operating characteristic curve (AUC) and predictive accuracy than M2BP. Among eight fibrosis markers/indices, WFA+ -M2BP yielded the second highest AUC (0.832) and the highest predictive accuracy (82.2%) to diagnose cirrhosis. In addition, WFA+ -M2BP showed the second highest predictive accuracy to diagnose severe fibrosis (78.4%) and significant fibrosis (76.1%). CONCLUSION: This head-to-head comparison suggests that WFA+ -M2BP is superior to M2BP for distinguishing liver fibrosis stages in NAFLD patients. A marked discrepancy between the two biomarkers may be indicative of advanced NAFLD (UMIN000023286).

DOI： 10.1111/hepr.13046

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Once-daily, orally administered, co-formulated glecaprevir (NS3/4A protease inhibitor) and pibrentasvir (NS5A inhibitor) (G/P) demonstrated pangenotypic activity and high sustained virologic response (SVR) rates in studies outside Japan. Here we report safety and efficacy in a subset of Japanese patients with chronic HCV infection who received G/P 300/120 mg in a phase 3, open-label, multicenter study (CERTAIN-1). METHODS: This analysis focuses on three difficult-to-treat subgroups: HCV GT1/2-infected patients who failed to achieve SVR after treatment with a direct acting antiviral (DAA)-containing regimen; GT1/2-infected patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2); and GT3-infected patients. Patients in the renal impairment and GT3 cohorts were treatment-naive or interferon treatment-experienced. Noncirrhotic GT1/2-infected, DAA-naïve patients in the renal impairment cohort received G/P for 8 weeks; all other patients were treated for 12 weeks. Primary outcome was SVR (HCV RNA < 15 IU/mL) 12 weeks post-treatment (SVR12). RESULTS: The study enrolled 33 GT1/2-infected patients who failed previous DAA treatment (four with cirrhosis); 12 GT1/2-infected patients with severe renal impairment (two with cirrhosis); and 12 GT3-infected patients (two with cirrhosis). SVR12 was achieved by 31/33 (93.9%), 12/12 (100%), and 10/12 (83.3%) patients, respectively. One serious adverse event (fluid overload, not related to G/P) occurred in a patient on chronic intermittent hemodialysis. CONCLUSIONS: G/P achieved high SVR12 rates and was well tolerated in three difficult-to-treat patient subgroups with limited treatment options in Japan (DAA-experienced patients, patients with severe renal impairment, and GT3-infected patients). These results support the potential suitability of this regimen for these special populations in Japan.

DOI： 10.1007/s00535-017-1396-0

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: To evaluate the efficacy and safety of ledipasvir and sofosbuvir therapy for genotype 1b in chronic hepatitis C patients with chronic kidney disease (CKD) stage 3. METHODS: In a multicenter collaborative retrospective study, 706 patients who have received ledipasvir which is NS5A inhibitor, and sofosbuvir 400 mg which is NS5B nucleoside polymerase inhibitor daily for 12 weeks between September 2015 and January 2017 were subjected to this analysis. Virologic response and adverse events in patients with CKD stage 3 were compared with those in patients with CKD stages 1 and 2. RESULTS: The rates of sustained virologic response (SVR) were 97.0% in patients with CKD stage 1, 97.1% in patients with CKD stage 2, and 94.7% in patients with CKD stage 3, respectively. There were no significant differences in the SVR rates between CKD stages 1 and 2, and CKD stage 1 and stage 3. The incidence of adverse events over than grade 2 was 0% in patients with CKD stage 1, 0.5% in patients with CKD stage 2, and 3.0% in patients with CKD stage 3, respectively. For treatment and follow-up period, eGFR levels in the patients with CKD stage 3 were not worsened compared to those at baseline. CONCLUSION: This study suggested that the virologic response of ledipasvir and sofosbuvir in patients with CKD stage 3 was not inferior to those with CKD stages 1 and 2. In addition, administration of ledipasvir and sofosbuvir did not affect eGFR levels in the patients with CKD stage 3.

DOI： 10.1007/s12072-018-9859-9

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glecaprevir (nonstructural protein 3/4A protease inhibitor) and pibrentasvir (nonstructural protein 5A inhibitor) (G/P), a coformulated once-daily, all oral, ribavirin (RBV)-free, direct-acting antiviral regimen, was evaluated for safety and efficacy in hepatitis C virus genotype 2 (GT2)-infected Japanese patients, including those with compensated cirrhosis. CERTAIN-2 is a phase 3, open-label, multicenter study assessing the safety and efficacy of G/P (300/120 mg) once daily in treatment-naive and interferon ± RBV treatment-experienced Japanese patients without cirrhosis but with GT2 infection. Patients were randomized 2:1 to receive 8 weeks of G/P (arm A) or 12 weeks of sofosbuvir (400 mg once daily) + RBV (600-1000 mg weight-based, twice daily) (arm B). The primary endpoint was noninferiority of G/P compared to sofosbuvir + RBV by assessing sustained virologic response at posttreatment week 12 (SVR12) among patients in the intent-to-treat population. SVR12 was also assessed in treatment-naive and interferon ± RBV treatment-experienced patients with GT2 infection and compensated cirrhosis who received G/P for 12 weeks in the CERTAIN-1 study. A total of 136 patients were enrolled in CERTAIN-2. SVR12 was achieved by 88/90 (97.8%) patients in arm A and 43/46 (93.5%) patients in arm B. No patient in arm A experienced virologic failure, while 2 did in arm B. The primary endpoint was achieved. In CERTAIN-1, 100% (18/18) of GT2-infected patients with compensated cirrhosis achieved SVR12. Treatment-emergent serious adverse events were experienced by 2 patients without cirrhosis in each arm and no patient with cirrhosis. Conclusion: The results demonstrate high efficacy and favorable tolerability of G/P in GT2-infected Japanese patients. (Hepatology 2018;67:505-513).

DOI： 10.1002/hep.29510

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Because human epidermal growth factor-like receptor (HER) 2 is expressed on the surface of human pancreatic carcinoma cells to varying degrees, trastuzumab, an anti-HER2 monoclonal antibody (mAb), is expected to exert antibody-dependent, natural killer (NK) cell-mediated cytotoxicity (ADCC) against the cells. However, some reports found that the effect of trastuzumab against human pancreatic carcinoma cells was limited because most express only limited HER2. We examined whether anti-CD137 stimulating mAb could enhance trastuzumab-mediated ADCC against Panc-1, a human pancreatic cancer cell line with low HER2 expression, in vitro. Supplementation of anti-CD137 mAb could improve trastuzumab-mediated ADCC against Panc-1 which was insufficient without this stimulating antibody. The ADCC differed in individual cells, and this was related to the expression of CD137 on the surface of NK cells after trastuzumab stimulation in association with the Fcγ-RIIIA polymorphism. NK cells with Fcγ-RIIIA-VV/VF showed high levels of ADCC against Panc-1, but those with Fcγ-RIIIA-FF did not show optimal ADCC. In addition, trastuzumab-mediated ADCC against the human pancreatic cancer cell line Capan-1 with high HER2 expression was generally high and not affected by the Fcγ-RIIIA polymorphism. These results demonstrated that in Fcγ-RIIIA-VV/VF-carrying healthy individuals, trastuzumab plus αCD137 mAb could induce effective ADCC against HER2-low-expressing pancreatic cancer cell lines, and that such an approach may result in similar findings in patients with pancreatic cancer.

DOI： 10.1371/journal.pone.0200664

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1272/jnms.2018_85-18

PubMed

researchmap

記述言語：日本語   出版者・発行元：一般社団法人 日本肝臓学会  

&lt;p&gt;The aim of this retrospective multicenter study was to clarify efficacy and safety of Elbasvir/Grazoprevir for chronic hepatitis C patients with chronic kidney disease (CKD). Forty-five patients with CKD were administered Elbasvir/Grazoprevir and subjected to this analysis. Overall sustained virologic response 12 rates in CKD patients were 95.6%. The sustained virologic response 4 and 12 rates were 92.9% and 92.9% in CKD G3 patients, 100% and 100% in G4 patients and 100% and 100% in G5 patients including 10 dialysis patients, respectively. The frequency of adverse event did not increase in the patients with CKD. This study suggests that Elbasvir/Grazoprevir therapy is effective and safe for genotype 1b chronic hepatitis C patients with CKD.&lt;/p&gt;

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

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 < 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. CONCLUSIONS: Prior DCV/ASV therapy is associated with failure of SOF/LDV therapy due to multiple RAVs.

DOI： 10.1111/hepr.12898

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

AIM: To evaluate the efficacy and safety of daclatasvir and asunaprevir combined therapy in genotype 1b chronic hepatitis C patients with non-dialysis chronic kidney disease (CKD). METHODS: In a multicenter collaborative study, 249 patients received 60 mg daclatasvir (NS5A inhibitor) once a day and 100 mg of asunaprevir (NS3/4A protease inhibitor) twice a day for 24 weeks between September 2014 and September 2015 and were subjected to this analysis. Virological response and adverse events in non-dialysis patients with CKD (stage 3-5, excluding 5D: dialysis), which was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 , were compared with those in patients without CKD. RESULTS: Overall, the rates of rapid viral response, end-of-treatment response, and sustained virological response (SVR) were 76.7%, 91.2%, and 86.3%, respectively. Among 55 patients with CKD, the rapid viral response, end-of-treatment response, and SVR rates were 76.4%, 87.3%, and 83.6%, respectively. Among 194 patients without CKD, they were 76.8, 92.3, and 87.1%, respectively. There were no significant differences in the virological response rates between the two groups (P = 0.999, 0.282, and 0.509, respectively). The baseline estimated glomerular filtration rate did not affect the achievement of SVR. The incidence of adverse events in patients with and without CKD were 21.8% and 13.9%, respectively (not significant, P = 0.142). CONCLUSION: The efficacy and safety of daclatasvir and asunaprevir combined therapy in genotype 1b chronic hepatitis C patients with non-dialysis CKD are not inferior to those in patients without CKD.

DOI： 10.1111/hepr.12879

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

Sorafenib, a multi-kinase inhibitor, inhibits tumor angiogenesis and is the first-line systemic therapy for patients with advanced hepatocellular carcinoma (HCC). However, due to its limited effects and frequent occurrence of side effects, biomarkers are needed to predict the effects of sorafenib. We considered the possibility of using TIE-2-expressing monocytes (TEMs) to predict the response in sorafenib-treated patients with advanced HCC. TEMs serve as a diagnostic marker of HCC and are related to angiogenesis. We analyzed 25 advanced HCC patients and prospectively evaluated TEMs before (Pre TEMs) and at 1 month after initial therapy (T1m TEMs). The radiologic response was evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST). Median survival time (MST) was significantly longer in the partial response/stable disease (PR/SD) group (21.8 months) than in the PD group (8.7 months). ΔTEMs (changes of T1m TEMs compared to Pre TEMs) were significantly lower in the PR/SD group than in the PD group. MST of the ΔTEMs low group (14.2 months) was significantly longer than that of the high group (8.7 months). Univariate and multivariate Cox regression analyses showed that ΔTEMs [hazard ratio (HR) = 8.53, 95% confidence interval (CI) = 1.51-48.16, p = 0.015] and Child-Pugh class (HR = 5.59, 95% CI = 1.06-29.63, p = 0.043) were independently associated with overall survival. Our results suggest that ΔTEMs could serve as a biomarker for predicting radiologic response and overall survival in sorafenib-treated patients with advanced HCC.

DOI： 10.1002/ijc.30804

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE INC  

BACKGROUND: The aim of this study was to clarify the effectiveness and safety of sofosbuvir/ribavirin therapy for elderly patients with genotype 2-infected chronic hepatitis C (CHC) in Japan. METHODS: A multicenter, retrospective study evaluated the effectiveness and safety of sofosbuvir/ribavirin based on real-world clinical data. RESULTS: The subjects consisted of 270 patients, 47.0% of whom were aged ≥65 years. The sustained virological response rates in patients aged <65 and ≥65 years were 98.6% and 95.3%, respectively. Hemoglobin levels decreased during treatment due to ribavirin-related hemolysis, and were significantly lower in patients aged ≥65 years than those aged <65 years at all time-points. A reduction in ribavirin dose was necessary in 31.0% (26/84) of patients with hemoglobin levels <13.0g/dL and in 70.7% (39/127) of those aged >65 years. Although the most frequent adverse event was anemia, no patients discontinued the use of either ribavirin or sofosbuvir. The incidence of ribavirin-related anemia in patients aged ≥65 years was 34.6% and significantly higher compared with that in patients aged <65 years (2.8%). CONCLUSIONS: Treatment with sofosbuvir/ribavirin for genotype 2-infected CHC was effective and safe even for elderly patients, although the incidence of adverse events including ribavirin-related anemia was relatively high.

DOI： 10.1016/j.dld.2017.04.012

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

AIM: Although interferon-free therapy with direct-acting antivirals has developed as a standard of care for chronic hepatitis C, the existence of resistance-associated variants (RAVs) has a negative impact on treatment results. Recently, several studies indicated a relationship between chronic hepatitis C and serum vitamin D levels. However, the relationship between RAVs at the hepatitis C virus non-structure 5A (NS5A) region and serum vitamin D level has not yet been examined. METHODS: Among patients with genotype 1 chronic hepatitis C who were enrolled in a multicenter cooperative study, our subjects comprised 247 patients in whom it was possible to measure RAVs at the NS5A region. These RAVs were measured using a direct sequencing method. RESULTS: The median age of patients was 70 years (range, 24-87 years), and the number of female patients was 135 (54.7%). The median serum 25(OH) D3 level was 22 ng/mL (range, 6-64 ng/mL). L31 and Y93 RAVs at the NS5A region were detected in 3.7% (9/247) and 13.4% (33/247) of patients, respectively. Multivariate analysis identified vitamin D deficiency (serum 25(OH) D3 ≤ 20 ng/mL) (P = 5.91 × 10⁻5 , odds ratio = 5.015) and elderly age (>70 years) (P = 1.85 × 10-3 , odds ratio = 3.364) as contributing independent factors associated with the presence of the L31 and/or Y93 RAVs. The Y93H RAV was detected in 25.9% (29/112) of patients with a vitamin D deficiency, and in 8.9% (12/135) of those with a serum 25(OH) D3 level >20 ng/mL (P = 4.90 × 10-3 ). CONCLUSION: We showed that RAVs at the NS5A region are associated with vitamin D deficiency and elderly age, which may have a negative influence on innate/adaptive immune responses to hepatitis C virus infection.

DOI： 10.1111/hepr.12784

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER JAPAN KK  

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

DOI： 10.1007/s00535-016-1225-x

Web of Science

Scopus

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. YKL-40, chitinase-like protein expressed in multiple tissues including liver, is involved in cell proliferation, inflammation and remodeling of the extracellular matrix. The aim of this study was to assess whether serum YKL-40 levels are associated with liver fibrosis in NAFLD patients. Serum YKL-40 levels were quantified in 111 NAFLD patients and 23 HCC patients with NAFLD. To identify the source of YKL-40, immunofluorescence staining of liver specimens from NAFLD patients was performed. Serum YKL-40 levels in NAFLD patients increased in accordance with the progression of liver fibrosis. Multivariate analysis revealed that YKL-40 was one of the independent factors significantly associated with severe fibrosis (F3-4). We established a new predictive model for fibrosis of NAFLD, using logistic regression analysis: YKL-40 based fibrosis score = -0.0545 + type IV collagen 7s * 0.3456 + YKL-40 * 0.0024. Serum YKL-40 levels of HCC patients with non-cirrhotic NAFLD were significantly higher than those without HCC. Immunofluorescence staining showed that YKL-40 was expressed by macrophages in liver tissue of NAFLD patients. In conclusion, macrophage-derived YKL-40 is a feasible biomarker of liver fibrosis in NAFLD patients.

DOI： 10.1038/srep35282

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Sorafenib is a standard of care for advanced hepatocellular carcinoma (HCC). An in vitro study showed the synergistic effects of sorafenib and interferon for HCC. To clarify the efficacy, combination therapy with sorafenib and interferon was performed for patients with advanced HCC. METHODS: Pegylated interferon α-2a was administered every 2 weeks for the initial 4 weeks. Subsequently, it was combined with sorafenib. We evaluated the anti-tumor effect and biomarkers during treatment period. RESULTS: The subjects were 13 patients with advanced HCC complicated by hepatitis C virus (HCV)-related liver cirrhosis. A partial response, stable disease and progressive disease were noted in 4, 6, and 3 patients, respectively. The response rate, the disease control rate, the mean time to progression and the median survival time (MST) were 30.8 % (4/13), 76.9 % (10/13), 12.2 months, and 17.5 months, respectively. In 8 Child-Pugh class A and 5 Child-Pugh class B patients, the MST was 22.0 and 11.0 months, respectively (p = 0.001). In plasma vascular endothelial growth factor (VEGF), serum alpha-fetoprotein (AFP), AFP-L3, a protein induced by vitamin K absence or antagonist-II (PIVKA II), and hepatocyte growth factor (HGF), there was no pretreatment factor and no biomarker during the combination therapy to predict therapeutic effect in the present study. CONCLUSIONS: The results of this study suggest that combination therapy with sorafenib and interferon could be effective and safe in advanced HCC patients with HCV-related liver cirrhosis.

DOI： 10.1007/s10147-015-0942-0

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：NATURE PUBLISHING GROUP  

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic non-viral liver disease. Activation of macrophages and hepatic stellate cells is a critical step that promotes liver fibrosis. We aimed to explore the feasibility of interleukin-34 (IL-34), a key regulator of macrophages, as a fibrosis marker in patients with NAFLD. We enrolled 197 liver biopsy-proven NAFLD patients. We evaluated the serum levels of IL-34, macrophage-colony stimulating factor (M-CSF), soluble CD163 (sCD163), 40 cytokines/chemokines, hyaluronic acid, type IV collagen 7s, and clinically-approved fibrosis scores. IL-34 increased with the progression of fibrosis and was an independent marker for liver fibrosis. Immunostaining experiments, using resected liver specimens from NAFLD patients, revealed that IL-34 was mainly expressed on liver fibroblasts. IL-34 based fibrosis score (0.0387*IL-34 (pg/ml) + 0.3623*type IV collagen 7s (ng/ml) + 0.0184*age (year)-1.1850) was a practical predictive model of liver fibrosis. Using receiver-operating characteristic analyses, the area under the curve, sensitivity, and specificity of IL-34 based fibrosis score were superior or comparable to the other fibrosis biomarkers and scores. In conclusion, the IL-34 based fibrosis score, including serum IL-34, type IV collagen 7s and age, is a feasible diagnostic marker of liver fibrosis in NAFLD patients.

DOI： 10.1038/srep28814

Web of Science

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: To elucidate influencing factors of treatment response, then tolvaptan has been approved in Japan for liquid retention. METHODS: We herein conducted this study to clarify the influencing factors in 40 patients with decompensated liver cirrhosis complicated by liquid retention. Tolvaptan was administered at a dosage of 7.5 mg once a day for patients with conventional diuretic-resistant hepatic edema for 7 d. At the initiation of tolvaptan, the estimated hepatic venous pressure gradient (HVPG) value which was estimated portal vein pressure was measured using hepatic venous catheterization. We analyzed the effects of tolvaptan and influencing factors associated with treatment response. RESULTS: Subjects comprised patients with a median age of 65 (range, 40-82) years. According to the Child-Pugh classification, class A was 3 patients, class B was 19, and class C was 18. Changes from the baseline in body weight were -1.0 kg (P = 2.04 × 10(-6)) and -1.3 kg (P = 1.83 × 10(-5)), respectively. The median HVPG value was 240 (range, 105-580) mmH2O. HVPG was only significant influencing factor of the weight loss effect. When patients with body weight loss of 2 kg or greater from the baseline was defined as responders, receiver operating characteristic curve analysis showed that the optimal HVPG cutoff value was 190 mmH2O in predicting treatment response. The response rate was 87.5% (7/8) in patients with HVPG of 190 mmH2O or less, whereas it was only 12.5% (2/16) in those with HVPG of greater than 190 mmH2O (P = 7.46 × 10(-4)). We compared each characteristics factors between responders and non-responders. As a result, HVPG (P = 0.045) and serum hyaluronic acid (P = 0.017) were detected as useful factors. CONCLUSION: The present study suggests that tolvaptan in the treatment of liquid retention could be more effective for patients with lower portal vein pressure.

DOI： 10.3748/wjg.v22.i21.5104

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Blackwell Publishing Ltd  

AIM: Protease inhibitors with pegylated interferon (PEG IFN)/ribavirin improve a sustained virological response (SVR) rate to approximately 90% in chronic hepatitis C genotype 1b patients with IL28B rs8099917 genotype TT, but yield only approximately 50% in those with the unfavorable non-TT. Among such treatment-refractory patients, serum vitamin D levels could influence the SVR rate. This randomized controlled trial was conducted to assess the effect of native vitamin D supplementation in simeprevir with PEG IFN/ribavirin for 1b patients with non-TT. METHODS: Patients were randomly assigned to receive simeprevir (100 mg/day) for 12 weeks plus PEG IFN/ribavirin for 24 weeks (control group, n = 58), or vitamin D (2000 IU/day) for 16 weeks including a lead-in phase plus PEG IFN/ribavirin for 24 weeks (vitamin D group, n = 57). The primary end-point was sustainably undetectable viremia 24 weeks after the end of treatment (SVR). RESULTS: SVR rates were 37.9% in the control group and 70.2% in the vitamin D group. In subgroup analysis, SVR rates of prior null responders were 11.8% and 54.5%, respectively. SVR rates for advanced fibrosis were 28.6% and 65.4%. SVR rates for patients with vitamin D3 deficiency at the baseline were 25.0% in the control group and 66.7% in the vitamin D group. Overall, the SVR rate was significantly higher in patients with high serum 25(OH)D3 levels at the beginning of combination therapy than in those with low serum 25(OH)D3 levels. CONCLUSION: Native vitamin D3 supplementation improved SVR rates in simeprevir with PEG IFN/ribavirin for chronic hepatitis C genotype 1b patients with refractory factors.

DOI： 10.1111/hepr.12575

Scopus

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MEDKNOW PUBLICATIONS & MEDIA PVT LTD  

Background and Rationale: Most patients with chronic hepatitis C show virological response to telaprevir-based triple therapy, and achieve an end-of-treatment response (ETR). However, some patients showing ETR develop virological relapse. This study was carried out to evaluate factors associated with relapse after triple therapy. Materials and Methods: A prospective, multicentric study was conducted in chronic hepatitis C patients who received telaprevir-based triple therapy. We evaluated independent variables such as age, with or without cirrhosis, prior treatment response to interferon (IFN) therapy, IL28B genotype, core amino acid (aa) 70 mutation, drug adherence, white blood cell counts, hemoglobin level, and serum low-density lipoprotein (LDL) cholesterol level. The characteristics of the patients who relapsed after achieving ETR were compared with those who did not. Results: Among 168 patients, 157 patients achieved ETR (93.5%) and 11 discontinued. Of these 157 patients, relapse occurred in 21 patients (13.4%). Nineteen patients (90.5%) of 21 relapsed patients had the IL28B non-TT genotype (P = 1.79 x 10(-9)). Multivariate analysis identified core amino acid 70 [ P = 0.018, crude odds ratio (OR): 6.927] and the IL28B genotype (P = 3.758 x 10(-5), crude OR: 39.311) as significantly independent factors that influenced the relapse-related variables. Among the 49 patients with the IL28B non-TT, 18 patients had core aa70 mutation and 31 patients had core aa70 wild-type. In addition, 66.7% (12/18) of those with core aa70 mutation and 22.6% (7/31) of those with core aa70 wild-type developed relapse (P = 0.005). Discussion: Core aa70 mutation and the IL28B non-TT genotype were identified as independent factors that influenced relapse after achievement of ETR for telaprevir-based triple therapy.

DOI： 10.4103/0022-3859.173191

Web of Science

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

The mechanism of action of ribavirin (RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus (HCV) infection are reviewed. RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper (Th) 1/2 cell balance to Th1 dominance. Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells, which contributes to differentiating naïve Th cells into Th2 cells while reducing their interleukin-10 production. The effects on T-regulatory (Treg) cells were also investigated, and RBV inhibited the differentiation of naïve Th cells into adaptive Treg cells by down-modulating forkhead box-P3. These findings indicate that RBV mainly down-regulates the activity of Th2 cells, resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes. Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications, regimens with RBV will be still be used because of their ability to facilitate the cellular immune response, which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.

DOI： 10.4254/wjh.v7.i25.2590

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Although several vitamin D-related gene polymorphisms were reported to affect the outcome of pegylated interferon/ribavirin (PR) therapy in chronic hepatitis C patients, there are no reports on the impact of the vitamin D-related gene polymorphisms in PR therapy combined with protease inhibitor (PI). Vitamin D-related gene polymorphisms were determined in 177 genotype 1b-infected chronic hepatitis C patients who received 12 weeks of PR therapy with telaprevir, a first-generation PI, followed by 12 weeks of PR therapy. The sustained virologic response (SVR) rate was 83.1% (147 of 177 patients). The frequencies of vitamin D-related gene polymorphisms were: 83 non-TT and 94 TT genotypes for GC, 97 non-AA and 80 AA genotypes for DHCR7, 151 non-AA and 26 AA genotypes for CYP2R1, 162 non-GG and 15 GG genotypes for CYP27B1, and 105 non-GG and 72 GG genotypes for VDR gene. Multivariate analysis extracted IL28B TT genotype (P = 2.05 × 10(-6)) and serum 25(OH) D3 level (P = 0.024) as independent factors contributing to the achieving of SVR. The SVR rate in IL28B TT genotype patients with serum 25(OH) D3 level of < 25 ng/ml was significantly low compared to other patients. None of the vitamin D-related gene polymorphisms affected the treatment outcome and serum 25(OH) D3 level. In conclusions, the IL28B polymorphism and serum 25(OH) D3 level contributed significantly and independently to SVR in PR combined with PI for genotype 1b-infected chronic hepatitis C patients. However, none of vitamin D-related gene polymorphisms had an impact on the treatment outcome and serum 25(OH) D3 level.

DOI： 10.1002/jmv.24244

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BIOMED CENTRAL LTD  

BACKGROUND: Serum 25-hydroxyvitamin D3 levels are generally lower in chronic hepatitis C patients than in healthy individuals. The purpose of this study is to clarify the factors which affect serum 25-hydroxyvitamin D3 levels using data obtained from Japanese chronic hepatitis C patients. METHODS: The subjects were 619 chronic hepatitis C patients. Serum 25-hydroxyvitamin D3 levels were measured by using double-antibody radioimmunoassay between April 2009 and August 2014. Serum 25-hydroxyvitamin D3 levels of 20 ng/mL or less were classified as vitamin D deficiency, and those with serum 25-hydroxyvitamin D3 levels of 30 ng/mL or more as vitamin D sufficiency. The relationship between patient-related factors and serum 25-hydroxyvitamin D3 levels was analyzed. RESULTS: The cohort consisted of 305 females and 314 males, aged between 18 and 89 years (median, 63 years). The median serum 25-hydroxyvitamin D3 level was 21 ng/mL (range, 6-61 ng/mL). On the other hand, the median serum 25-hydroxyvitamin D3 level in the healthy subjects was 25 ng/mL (range, 7-52), being significantly higher than that those in 80 chronic hepatitis C patients matched for age, gender, and season (p = 1.16 × 10(-8)). In multivariate analysis, independent contributors to serum 25-hydroxyvitamin D3 deficiency were as follows: female gender (p = 2.03 × 10(-4), odds ratio = 2.290, 95 % confidence interval = 1.479-3.545), older age (p = 4.30 × 10(-4), odds ratio = 1.038, 95 % confidence interval = 1.017-1.060), cold season (p = 0.015, odds ratio = 1.586, 95 % confidence interval = 1.095-2.297), and low hemoglobin level (p = 0.037, odds ratio = 1.165, 95 % confidence interval = 1.009-1.345). By contrast, independent contributors to serum 25-hydroxyvitamin D3 sufficiency were male gender (p = 0.001, odds ratio = 3.400, 95 % confidence interval = 1.635-7.069), warm season (p = 0.014, odds ratio = 1.765, 95 % confidence interval = 1.117-2.789) and serum albumin (p = 0.016, OR = 2.247, 95 % CI = 1.163-4.342). CONCLUSIONS: Serum 25-hydroxyvitamin D3 levels in chronic hepatitis C Japanese patients were influenced by gender, age, hemoglobin level, albumin and the season of measurement.

DOI： 10.1186/s12879-015-1020-y

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AIM: Single nucleotide polymorphisms (SNP) near the interleukin-28B (IL28B) gene affect the outcome of 24-week telaprevir-based triple therapy with telaprevir, pegylated interferon-α and ribavirin for chronic hepatitis C virus (HCV) genotype 1b patients. We aimed to identify factors associated with treatment outcomes in patients with the unfavorable minor IL28B SNP genotype, who have poor response to combination therapy. METHODS: Pretreatment and on-treatment factors associated with sustained virological response (SVR) for 24-week telaprevir-based triple therapy were analyzed using multiple logistic regression analysis in 106 HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype (non-TT). RESULTS: Of the 106 non-TT patients, 62 (58.5%) achieved SVR. Of the 44 remaining patients, 22 experienced relapse, 13 experienced viral breakthrough and nine were non-responders. Pretreatment factors such as treatment-naïve/prior treatment response (P = 0.0041), high fasting serum low-density lipoprotein cholesterol (LDL-C) concentration (P = 0.0068) and low serum HCV RNA levels (P = 0.0088) were significantly and independently associated with SVR. On-treatment factors such as achievement of rapid virological response (RVR) were significantly and independently associated with SVR (P = 0.0001). For both pre- and on-treatment factors, treatment-naïve/prior treatment response (P = 0.0018), low pretreatment serum fasting LDL-C (P = 0.0062) and achieving RVR (P = 0.0021) were significantly and independently associated with SVR. CONCLUSION: In HCV genotype 1b patients with the minor IL28B SNP rs8099917 genotype, evaluating prior treatment response and achieving RVR and pretreatment serum fasting LDL-C concentrations were useful for predicting SVR achievement after 24-week telaprevir-based triple therapy.

DOI： 10.1111/hepr.12360

Web of Science

PubMed

researchmap

記述言語：日本語   出版者・発行元：(一社)日本肝臓学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：日本語   出版者・発行元：(一財)日本消化器病学会  

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Pegylated-interferon/ribavirin (peg-IFN/RBV) therapy with a protease inhibitor is the standard therapy for genotype 1b chronic hepatitis C. Despite improving treatment outcomes, patients with thrombocytopenia are often difficult to treat because interferon commonly exacerbates thrombocytopenia. In this study, partial splenic embolization (PSE) was performed in patients with hypersplenism-induced thrombocytopenia to determine the effectiveness of this method as a potential treatment. METHODS: Patients were pretreated with PSE and then received triple combination therapy. The safety and efficacy of PSE was evaluated. RESULTS: Eighteen patients were analyzed, including 12 patients with the interleukin 28B (IL28B) major genotype and 12 patients with the inosine triphosphatase (ITPA) major genotype. The median embolization rate with PSE was 70% (range: 40-85%). PSE increased the patients' platelet counts from 71.5×10(3) /μL (53-99×10(3) /μL) to 121.5×10(3) /μL (70-194×10(3) /μL; p=0.0002). The patients' platelet counts fluctuated above 50×10(3) /μL during the treatment. Specifically, the increase in the platelet count was significantly associated with the ITPA major genotype compared with the minor genotype (p=0.0057 at 2 weeks, p=0.0031 at 3 weeks, and p=0.0148 at 4 weeks). Adherence to peg-IFN-α2b was sufficient (1.38 μg/kg/week). The rapid viral response rate was 72.2% (13/18), the end of treatment response rate was 88.9% (16/18), and the sustained virological response (SVR) rate was 66.7% (12/18). The SVR rate for patients with the IL28B major genotype was 83.3% (10/12). No adverse effect due to PSE pretreatment was found in any patients. Furthermore, no patient discontinued treatment due to thrombocytopenia. CONCLUSION: PSE, in conjunction with triple combination therapy, is a useful and safe method to treat genotype 1b chronic hepatitis C patients with hypersplenism-induced thrombocytopenia.

DOI： 10.2169/internalmedicine.54.3066

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Many studies have reported poor vital prognosis in hepatitis C virus (HCV)-infected dialysis patients. The rate of HCV-infected dialysis patients in Japan is as high as 9.8%, and antiviral therapy is believed to be important for improving vital prognosis. We conducted a multicenter study to examine the administration method for pegylated interferon α-2a (PEG-IFNα-2a) monotherapy in HCV-infected dialysis. We studied 56 patients: 14 with low viral loads (HCV RNA < 5.0 log IU/mL) were treated with 90 μg PEG-IFNα-2a weekly, 42 with high viral loads (HCV RNA ≥ 5.0 log IU/mL) were treated with 135 μg PEG-IFNα-2a weekly. We examined the sustained virological response (SVR), factors affecting the SVR, and treatment safety. The overall SVR rate was 39% (22/56); that for genotype 1, genotype 2, low viral loads, and high viral loads was 29%, 67%, 93%, and 21%, respectively. From receiver operating characteristic (ROC) analysis, the HCV RNA cutoff values likely to achieve SVR for genotypes 1 and 2 were <5.7 log IU/mL (SVR rate: 64% 9/14) and <6.5 log IU/mL (SVR rate: 88% 7/8), respectively. If there was HCV RNA negativation at 4 weeks (rapid virological response), the SVR rate was 94% (16/17), whereas it was 6% (1/16) if there was HCV RNA positivity at 24 weeks. The rate of treatment discontinuation from adverse events or aggravated complications was 25% (14/56). High SVR rates can potentially be achieved with PEG-IFN monotherapy by identifying the target patients, based on virus type and viral load before initiating treatment and by modifying therapy during treatment according to responsiveness.

DOI： 10.1111/1744-9987.12189

PubMed

researchmap

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

AIM: Much is unknown about the effect of 25-hydroxyvitamin D3 levels on the outcome of pegylated interferon/ribavirin (PEG IFN/RBV) therapy for hepatitis C virus-related cirrhosis. The purpose of the present study was to analyze and elucidate factors, including 25-hydroxyvitamin D3 , that contribute to a sustained virological response (SVR) in patients with cirrhosis. METHODS: We analyzed whether 25-hydroxyvitamin D3 contributes to the response to PEG IFN/RBV therapy among 134 cirrhotic patients. RESULTS: SVR was achieved in 43 patients. The median 25-hydroxyvitamin D3 level was 20 ng/mL. Univariate analysis showed that the following factors contributed to SVR: low-density lipoprotein cholesterol, albumin, 25-hydroxyvitamin D3 , core a.a.70 (a.a.70) substitutions, the number of mutations at the interferon sensitivity-determining region and IL28B genotype. Multivariate analysis identified IL28B genotype and 25-hydroxyvitamin D3 as independent factors contributing to SVR. Subsequently, SVR rate was examined by using 25-hydroxyvitamin D3 and other important factors. The SVR rate was 51.8% in patients with core a.a.70 wild and ≥15 ng/mL of 25-hydroxyvitamin D3 , whereas the SVR rate was 7.1% in patients with core a.a.70 wild and <15 ng/mL of 25-hydroxyvitamin D3 . The SVR rate was 56.9% in patients with IL28B major genotype and ≥15 ng/mL of 25-hydroxyvitamin D3 . Surprisingly, the SVR rate was 0% in patients with IL28B minor genotype and <15 ng/mL of 25-hydroxyvitamin D3 . CONCLUSION: IL28B genotype and 25-hydroxyvitamin D3 were identified as independent factors contributing to SVR. Stratified analyses according to core a.a.70 substitution and IL28B genotype suggested that 25-hydroxyvitamin D3 influences the outcome of PEG IFN/RBV therapy for cirrhosis.

DOI： 10.1111/hepr.12298

Web of Science