Therapeutic Modifications without Discontinuation of Atezolizumab Plus Bevacizumab Therapy Are Associated with Favorable Overall Survival and Time to Progression in Patients with Unresectable Hepatocellular Carcinoma.

We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) (median observation period: 9.40 months). One hundred uHCC from five hospitals were included. Therapeutic modifications without discontinuation of both Atezo and Bev (n = 46) were associated with favorable overall survival (median not reached; hazard ratio (HR): 0.23) and time to progression (median: 10.00 months; HR: 0.23) with no therapeutic modification defined as the reference. In contrast, the discontinuation of both Atezo and Bev without other therapeutic modifications (n = 20) was associated with unfavorable overall survival (median: 9.63 months; HR: 2.72) and time to progression (median: 2.53 months; HR: 2.78). Patients with modified albumin-bilirubin grade 2b liver function (n = 43) or immune-related adverse events (irAEs) (n = 31) discontinued both Atezo and Bev without other therapeutic modifications more frequently (30.2% and 35.5%, respectively) than those with modified albumin-bilirubin grade 1 (10.2%) and without irAEs (13.0%). Patients with objective response (n = 48) experienced irAEs more frequently (n = 21) than those without (n = 10) (p = 0.027). Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of uHCC.

Pilot study of tenofovir disoproxil fumarate and pegylated interferon-alpha 2a add-on therapy in Japanese patients with chronic hepatitis B.

BACKGROUND: A prospective pilot study of tenofovir disoproxil fumarate (TDF) and pegylated interferon alpha 2a (P-IFN) add-on therapy was conducted to evaluate its efficacy in reducing viral antigen levels in Japanese patients with chronic hepatitis B (UMIN 000020179). METHODS: Patients with chronic hepatitis B receiving maintenance TDF therapy and exhibiting hepatitis B surface antigen (HBsAg) level > 800 IU/ml were divided into two arms. P-IFN was added for 48 weeks in the add-on arm (n = 32), while TDF monotherapy was maintained in the control arm (n = 51). Both groups were followed for 96 weeks after baseline measurements. RESULTS: Almost all patients in the control arm displayed a slow and constant reduction in HBsAg during follow-up. In contrast, roughly half of the add-on arm exhibited a sharp decline in HBsAg during P-IFN administration, which disappeared after halting P-IFN. At 96 weeks after baseline, 41% (13/32) of patients in the add-on arm had shown a rapid decrease in HBsAg, versus 2% (1/51) in the control arm (p < 0.001). Add-on therapy and increased cytotoxic T-cell response were significant factors associated with a rapid decrease in HBsAg according to multivariate analysis. In addition, higher HB core-related antigen (HBcrAg) level at baseline (p = 0.001) and add-on therapy (p = 0.036) were significant factors associated with a rapid reduction in HBcrAg. CONCLUSIONS: TDF and P-IFN add-on therapy in Japanese patients with chronic hepatitis B facilitated rapid decreases in HBsAg and HBcrAg. Further studies are needed to improve early HBsAg clearance rate.

Usefulness of virtual touch quantification for staging liver fibrosis in patients with hepatitis C, and factors affecting liver stiffness measurement failure compared with liver biopsy.

AIM: The assessment of liver fibrosis in patients with hepatitis C is important to predict carcinogenesis. In this study, we evaluated the usefulness of virtual touch quantification (VTQ) for staging liver fibrosis, and investigated factors causing discrepancies between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. METHODS: Patients with hepatitis C (n = 302) were assessed using VTQ and underwent pathological liver investigation within 1 week before and after VTQ. A receiver operator characteristic (ROC) curve was obtained for VTQ, fibrosis-4 (FIB-4) index, and aspartate aminotransferase-to-platelet ratio index (APRI), and each area under the ROC curve (AUROC) was compared to predict fibrosis stage. We used univariate and multivariate analyses to investigate the factors related to the discrepancy between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. RESULTS: At any stage, VTQ was the most accurate for staging liver fibrosis. The VTQ cut-off values were 1.33 m/s (AUROC = 0.822) for ≥F2, 1.51 m/s (AUROC = 0.836) for ≥F3, and 1.92 m/s (AUROC = 0.890) for F4. Skin liver capsule distance (SCD) was the most relevant factor for the discrepancy between the estimated fibrosis stage using VTQ and the pathological fibrosis stage. The SCD cut-off value was 17.5 mm. CONCLUSIONS: Virtual touch quantification is a non-invasive, simple method that is more accurate for staging liver fibrosis than the FIB-4 index and APRI. However, when the SCD is longer than 17.5 mm, there may be measurement failures.

Combinational use of hepatitis B viral antigens predicts responses to nucleos(t)ide analogue/peg-interferon sequential therapy.

BACKGROUND: This prospective cohort study searched for factors associated with a response to nucleos(t)ide analogue/peg-interferon (NUC/peg-IFN) sequential therapy. METHODS: A total of 95 patients with chronic hepatitis B being treated with NUCs were enrolled. Immediately following NUC cessation, peg-IFN was administered at 180 µg/dose weekly for 48 weeks. RESULTS: Twenty-six patients (27%) were judged to be responders at 48 weeks after the completion of peg-IFN. Analysis of baseline factors revealed that hepatitis B surface antigen (HBsAg) <3.1 log IU/ml and HB core-related antigen (HBcrAg) <3.9 log U/ml were significant indicators of a treatment response. The levels of the markers decreased in both responders and non-responders during peg-IFN therapy but continued falling in responders only after halting peg-IFN. Lower HBsAg (<2.0 log IU/ml) and HBcrAg (<3.8 log U/ml) levels at the time of response judgment were also significantly associated with a favorable response. While lower HBcrAg at baseline was the sole predictor of decreased HBcrAg levels at judgment, lower HBsAg, lower HBcrAg, and the use of adefovir dipivoxil at baseline predicted decreased HBsAg levels at the study endpoint. The use of adefovir dipivoxil was also associated with higher serum IFN-λ3, which might have contributed to the reduction in patient HBsAg levels. CONCLUSIONS: The combinational use of HBsAg and HBcrAg levels at baseline and their changes throughout sequential therapy may be useful for predicting a response to NUC/peg-IFN sequential therapy.

Factors associated with the effect of interferon-α sequential therapy in order to discontinue nucleoside/nucleotide analog treatment in patients with chronic hepatitis B.

AIM: The factors associated with the outcome of sequential therapy with interferon-α (IFN-α) in order to halt nucleoside/nucleotide analog (NUC) maintenance treatment for chronic hepatitis B were analyzed. METHODS: A total of 50 patients with chronic hepatitis B who underwent IFN-α sequential therapy for cessation of NUC were enrolled retrospectively. The subjects received NUC plus IFN-α for 4 weeks followed by IFN-α alone for 20 weeks. Natural IFN-α of 6-MU doses was administrated three times a week. A successful response to NUC/IFN-α sequential therapy was defined as serum hepatitis B virus (HBV) DNA below 4.0 log copies/mL, serum alanine aminotransferase (ALT) below 30 IU/L, and hepatitis B e-antigen negativity at 24 months after completing the treatment. RESULTS: Multivariate analysis revealed that hepatitis B surface antigen (HBsAg) of 3.0 log U/mL or more (P < 0.002) and hepatitis B core-related antigen (hepatitis B core-related antigen [HBcrAg]) of 4.5 log U/mL or more (P < 0.003) at the start of IFN-α administration were significant factors associated with a 24-month non-response. Maximal levels of ALT and HBV DNA during the follow-up period after completing IFN-α therapy were significantly related (P < 0.001), and receiver operating characteristic analysis showed that both maximal ALT (P < 0.001) and HBV DNA (P < 0.001) were significantly related to the final 24-month response. CONCLUSION: The combinational use of HBsAg and HBcrAg levels may be useful to predict the 24-month outcome of NUC/IFN-α sequential therapy. Maximal levels of ALT and HBV DNA during post-treatment follow-up may also help monitor responses to IFN-α sequential therapy.

Randomized trial of peginterferon α-2a plus ribavirin versus peginterferon α-2b plus ribavirin for chronic hepatitis C in Japanese patients.

BACKGROUND: Pegylated interferon (PegIFN) plus ribavirin is the standard therapy for patients with chronic hepatitis C genotype 1. Although several randomized clinical trials have compared PegIFNα-2a with PegIFNα-2b, these 2 regimens have not been directly compared in Asian patients. We, therefore, compared the safety and antiviral efficacy of these agents in Japanese patients. METHODS: A total of 201 PegIFN-naïve, chronic hepatitis C patients were randomly assigned to once-weekly PegIFNα-2a (180 µg) or PegIFNα-2b (60-150 µg) plus ribavirin. We compared the sustained virological response (SVR) rates between the 2 regimens and analyzed their effects in relation to baseline characteristics, including single nucleotide polymorphisms (SNPs) near the interleukin-28B (IL28B) gene (rs8099917). RESULTS: PegIFNα-2a was associated with a higher SVR rate than PegIFNα-2b (65.3 vs. 51.0%, P = 0.039). PegIFNα-2a and SNPs near IL28B independently predicted SVR (odds ratio 2.36; 95% confidence interval [CI] 1.19-15.50, and odds ratio 7.31; 95% CI 3.45-4.68, respectively) in logistic regression analysis. PegIFNα-2a was more effective than PegIFNα-2b (81.8 vs. 62.7%, P = 0.014) in IL28B TT genotype patients, despite similarly low SVR rates in patients with TG or GG genotypes (36.4 vs. 35.9%). Patients weighing <60 kg, women, and patients aged >60 years had significantly higher SVR rates with PegIFNα-2a than with PegIFNα-2b (63.9, 61.3, and 67.3% vs. 43.8, 43.3,and 39.2%, respectively). CONCLUSIONS: PegIFNα-2a plus ribavirin resulted in higher SVR rates than PegIFNα-2b plus ribavirin in Japanese patients. PegIFNα-2a-based treatment should therefore be the preferred choice for women, older or low-weight patients, and those with the IL28B TT genotype.

High serum alanine aminotransferase levels for the first three successive years can predict very high incidence of hepatocellular carcinoma in patients with Child Stage A HCV-associated liver cirrhosis.

Abstract Objective. To assess retrospectively whether continuously high serum alanine aminotransferase (ALAT) levels (<80 IU) in the first three successive years after the diagnosis of liver cirrhosis (LC) are predictive of a subsequent high incidence of hepatocellular carcinoma (HCC) in patients with Child Stage A hepatitis C virus (HCV)-LC. Material and methods. The study comprised 132 HCV-LC (Child Stage A) patients who had not received interferon therapy but had been treated with anti-inflammatory agents. At the end of a 3-year follow-up after the diagnosis of LC, the patients were subdivided into three groups according to their serum ALAT levels and the subsequent incidence of HCC was assessed. Results. The cumulative incidence of HCC starting from 3 years after the diagnosis of LC in the continuously high ALAT group (annual average over 3 years always > or =80 IU; n=41; Group A) was markedly higher than that in the continuously low ALAT group (always <80 IU; n=48; Group B) (p<0.005) during an observation period of 7.9+/-3.7 years. The incidence of HCC in Group A was 11.8%/year. The odds ratios of developing HCC in Group A and Group C (mixed high and low ALAT levels; n=43) were 5.1-fold and 1.5-fold that of Group B, respectively. A multivariate analysis revealed that the ALAT group was independently associated with HCC development. Conclusions. Continuously high ALAT levels for three successive years following the diagnosis of LC can be predictive of a very high incidence of HCC in Child A HCV-LC patients. Prospective trials using therapeutic approaches aimed at decreasing ALAT levels are necessary in order to confirm a positive impact of ALAT reduction on the incidence of HCC in patients with HCV-LC.

Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus.

Hepatoblastoma is a rare malignancy in adults. It is often diagnosed after the appearance of symptoms, therefore, the tumor size tends to be larger. In patients with no indication for a hepatic resection, the prognosis of adult hepatoblastoma is quite poor. A 54-year-old man with hepatitis C virus-associated liver cirrhosis was initially treated with a hepatic resection for a hepatic tumor, 3 cm in diameter. The tumor consisted of osteoid-like and cartilaginous foci, myxomatous stroma, and poorly differentiated hepatocellular carcinomatous cells and was diagnosed as a mixed epithelial and mesenchymal hepatoblastoma. Two years after the first operation, multicentric hepatocellular carcinomas developed in the remnant liver and were successfully treated with a secondary hepatic resection combined with radio-frequency ablation. The patient is now alive with no recurrence at 5 years after the initial hepatectomy. To the best of our knowledge, the primary hepatoblastoma was the smallest such tumor reported and this is the first report of a metachronous hepatoblastoma and hepatocellular carcinoma in an adult hepatitis patient.

Differential regulation of Rad18 through Rad6-dependent mono- and polyubiquitination.

Rad18 is involved in postreplication repair mainly through monoubiquitination of proliferating cell nuclear antigen (PCNA). Here we show that Rad18 protein was detected in human cells as two major bands at 75 and 85 kDa by Western blot. The bands were identified as nonubiquitinated and monoubiquitinated forms of Rad18, respectively, by mass spectrometry. Multiple ubiquitinated bands of Rad18 were detected in vitro in the presence of E1, E2 (Rad6), and methylated ubiquitin, indicating that Rad18 was monoubiquitinated at multiple sites through autoubiquitination. Rad18 self-associates, and this interaction was abolished by replacing one of the conserved cysteine residues with phenylalanine in the zinc finger domain (C207F). In the C207F mutant Rad18, monoubiquitination of Rad18 was not observed in vivo, suggesting that self-association was critical for monoubiquitination. Monoubiquitinated Rad18 was detected mainly in the cytoplasm, whereas nonubiquitinated Rad18 was detected predominantly in the nuclei. Furthermore, Rad18 was shown to be polyubiquitinated in cells treated with proteasome inhibitors. Purified Rad18 was also polyubiquitinated in an in vitro system containing E1, E2 (Rad6), and ubiquitin, and it was degraded by the addition of proteasomes. These results suggest that the amount of Rad18 in the nucleus is regulated differentially by mono- and polyubiquitination.