Peripheral T Cell Subpopulations as a Potential Surrogate Biomarker during Atezolizumab plus Bevacizumab Treatment for Hepatocellular Carcinoma.

The therapeutic benefits of the immunotherapeutic combination of atezolizumab and bevacizumab (Atez/Bev) in hepatocellular carcinoma (HCC) vary. Therapeutic biomarkers might help improve outcomes for HCC patients receiving Atez/Bev therapy. The role of systemic immune profiles in HCC progression also remains unclear. This study aimed to evaluate the status and dynamics of peripheral T cell subpopulations in HCC patients receiving Atez/Bev treatment and to explore biomarkers predictive of a therapeutic response. We enrolled 83 unresectable advanced HCC patients who commenced Atez/Bev treatment at our hospital between October 2020 and June 2022. Peripheral T cell subpopulations in peripheral blood mononuclear cells at baseline and 3 weeks post-treatment were investigated using flow cytometry and compared with those in control samples from 18 healthy individuals. We retrospectively analyzed the association between peripheral T cell subpopulation profiles and clinical outcomes. Baseline peripheral T cell subpopulations could be profiled in 70 patients with sufficient cell counts, among whom 3-week subpopulations could be evaluated in 51 patients. Multivariate analysis showed that a high baseline proportion of CD8+ central memory T (TCM) cells was independently associated with longer progression-free survival (PFS). Further, overall survival (OS) was significantly prolonged in patients with increased CD8+ effector memory T (TEM) cell proportions. In conclusion, TCM proportion at baseline might be a good indicator of the efficacy of Atez/Bev therapy. Furthermore, observation of increasing TEM proportions might be an early predictor of the potential clinical benefits of treatment.

Efficacy and safety of atezolizumab plus bevacizumab in patients with portal hypertension for unresectable hepatocellular carcinoma.

AIM: Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is used as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). Serious adverse events (AEs), including rupture of esophagogastric varices, have been seen during treatment. Therefore, the relationships of efficacy, safety, and portal hypertension (PH) were analyzed. METHODS: A total of 146 patients with u-HCC and Child-Pugh Scores of 5-7 received Atezo + Beva. Prophylactic treatment for varices was performed for patients with the risk of rupture of varices before the start of Atezo + Beva. A propensity score-matched cohort was created to minimize the risk of potential confounders. Efficacy was assessed in 41 propensity score-matched pairs. AEs were assessed between patients without PH (n = 80) and with PH (n = 66). RESULTS: In patients without PH and with PH, median overall survival was 18.4 months and 18.8 months (p = 0.71), and median progression-free survival was 8.6 months and 5.8 months (p = 0.92), respectively. On the best radiological response evaluation for Response Evaluation Criteria in Solid Tumors, the objective response rate was 31.7% and 26.8% (p = 0.81), respectively. Variceal rupture occurred in three patients with PH, but there were no significant differences in the occurrence of variceal rupture (p = 0.090) and Grade 3-4 AEs between patients without and with PH. CONCLUSIONS: No significant differences in efficacy and safety were observed with PH. Prophylactic treatment for varices before the start of Atezo + Beva would allow treatment to continue relatively safely.

Value of autotaxin for hepatocellular carcinoma risk assessment in chronic hepatitis B patients treated with nucleos(t)ide analogs.

AIM: Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics. METHODS: This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX. RESULTS: The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis. CONCLUSIONS: A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.

Impact of MAFLD criteria on postoperative recurrence of non-B, non-C HCC.

BACKGROUND: This study aimed to clarify the population in whom the presence of metabolic dysfunction-associated fatty liver disease (MAFLD) especially contributes to recurrence after liver resection for non-B, non-C hepatocellular carcinoma (NBNC-HCC). METHODS: Of the 199 patients who underwent liver resection for NBNC-HCC, those who exceeded Milan criteria and with pathologically proven vascular invasion, intrahepatic metastasis, and positive resection margins were excluded, and the remaining 94 were eligible for this study. We explored factors contributing to postoperative recurrence in populations with and without advanced liver fibrosis. RESULTS: Independent factors contributing to postoperative recurrence in the study population were male sex ( P  = 0.023) and presence of type 2 diabetes (DM) ( P  = 0.006) and advanced liver fibrosis ( P  < 0.001). Factors in cases with advanced liver fibrosis (n = 43) were non-overweight ( P  = 0.02), type 2 DM ( P  = 0.006), and preoperative alpha-fetoprotein level of 8.2 ng/ml or higher ( P  = 0.021). In cases without advanced liver fibrosis (n = 51), only presence of all three MAFLD criteria was related to recurrence. CONCLUSION: Liver fibrosis is a strong factor contributing to postoperative recurrence of NBNC-HCC, as previously reported. In patients with advanced liver fibrosis, presence of type 2 DM was the only factor associated with recurrence among MAFLD criteria. On the other hand, in patients without advanced liver fibrosis, the combination of all MAFLD criteria, rather than a specific criterion alone, contributed to recurrence. MAFLD criteria were found to have utility as predictors of postoperative recurrence in NBNC-HCC.

Clinical Outcomes of Switching from Zoledronic Acid to Denosumab for the Management of Severe Bone Metastasis from Hepatocellular Carcinoma: A Single-Center, Open-Label, Prospective Intervention Trial.

Background: Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma. Methods: This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration. Results: Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol ·â€†Cre (P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L (P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch. Conclusion: Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited.

Therapeutic Efficacy and Safety of Lenvatinib after Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

A total of 137 HCC patients treated with atezolizumab plus bevacizumab from October 2020 to September 2022 were enrolled. The median overall survival (OS) and progression-free survival (PFS) from the beginning of atezolizumab plus bevacizumab were 21.1 months (range, 18.8 months-not reached) and 10.5 months (range, 8.2-12.1 months), respectively. Fifty patients were diagnosed with progressive disease after atezolizumab plus bevacizumab. Of this group, 24 patients were administered lenvatinib, and the median OS and PFS from the beginning of lenvatinib were 15.3 months (range, 10.5 months-not reached) and 4.0 months (range, 2.5-6.4 months), respectively. The objective response rates based on the response evaluation criteria in solid tumors (RECISTs) criteria version 1.1 and modified RECISTs were 33.3% and 54.2%, respectively. There was no significant difference in the median serum alpha-fetoprotein level between before and after lenvatinib. In the multivariate analysis, Child-Pugh class A (hazard ratio 0.02, 95% confidence interval (CI) 0.02-0.76, p = 0.02) and intrahepatic tumor occupancy rate < 50% (hazard ratio < 0.01, 95% CI 0.003-0.35, p < 0.01) were the significant factors for OS. There were some frequent adverse events (AEs) in patients treated with lenvatinib such as hypertension, fatigue, anorexia, proteinuria, and so on, but none directly caused death. In conclusion, lenvatinib after atezolizumab plus bevacizumab for unresectable HCC should be considered an effective treatment option.

Lenvatinib activates anti-tumor immunity by suppressing immunoinhibitory infiltrates in the tumor microenvironment of advanced hepatocellular carcinoma.

BACKGROUND: Lenvatinib, a multiple receptor tyrosine kinase inhibitor, might exert antitumor effects via tumor immune modulation. However, changes in the tumor immune microenvironment induced by lenvatinib are poorly understood. We investigated the effect of lenvatinib on immune features in clinical samples from patients with hepatocellular carcinoma. METHODS: Fifty-one patients with advanced hepatocellular carcinoma who received lenvatinib monotherapy as first-line treatment were enrolled. We collected blood sample (n = 51) and tumor tissue (n, baseline/four weeks after treatment initiation/post-progression = 50/8/12). DNA, RNA, and proteins extracted from the tissues were subjected to multi-omics analysis, and patients were classified into two groups according to baseline immune status. Each group was investigated in terms of the dynamics of tumor signaling. We also longitudinally analyzed circulating immune proteins and chemokines in peripheral blood. RESULTS: Here we show that lenvatinib has similar anti-tumor efficacy with objective response rate and progression-free survival in both Immune-Hot and Immune-Cold subtypes. Immune signatures associated with T-cell functions and interferon responses are enriched in the early phase of treatment, while signatures associated with immunoinhibitory cells are downregulated along with efficient vascular endothelial growth factor receptor and fibroblast growth factor receptor blockades. These findings are supported by imaging mass cytometry, T-cell receptor repertoire analysis and kinetics of circulating proteins. We also identify interleukin-8 and angiopoietin-2 as possible targets of intervention to overcome resistance to existing immunotherapies. CONCLUSIONS: Our findings show the ability of lenvatinib to modulate tumor immunity in clinical samples of hepatocellular carcinoma.

Two types of therapy for liver cancer are immunotherapy and anti-angiogenic therapy. Immunotherapy helps the patient's immune system to attack the tumor. Anti-angiogenic therapy blocks the formation of new blood vessels (angiogenesis) in the tumor, and this type of therapy might also impact the immune system. We analyzed changes in the immune characteristics of human liver cancer samples induced by lenvatinib, an anti-angiogenic therapy. Patient outcomes on lenvatinib did not depend on the immune features of the tumor before treatment. However, immune characteristics of the tumors did change after treatment, and this may mean these tumors become easier to treat with immunotherapies. These findings help us to understand the effects of lenvatinib in liver cancer and whether, for example, it might be useful to combine this drug with immunotherapy.

Association of Hepatobiliary Phase of Gadoxetic-Acid-Enhanced MRI Imaging with Immune Microenvironment and Response to Atezolizumab Plus Bevacizumab Treatment.

It has been reported that high intensity in the hepatobiliary (HB) phase of Gd-EOB-DTPA-enhanced MRI (EOB-MRI) is associated with an immune-cold microenvironment in HCC. The aim of this study is to reveal whether non-high-intensity HCCs are homogeneous with respect to the immune microenvironment and to investigate the predictive ability of EOB-MRI for the response to atezolizumab + bevacizumab therapy (Atezo/Bev). The association between differences in stepwise signal intensity of HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment was investigated in 65 HCC patients (cohort 1). The association between EOB-MRI and the therapeutic effect of Atezo/Bev was evaluated in the Atezo/Bev cohort (60 patients in cohort 2). The proportion of HCCs having CTNNB1 mutations and classified as Chiang CTNNB1 and Hoshida S3 was high in the high-intensity HB-phase group. Infiltration of tumor-associated macrophages (TAM) and regulatory T-lymphocytes (Treg) was characteristic of the high-intensity and low-intensity groups, respectively. Although EOB-MRI could not predict the response to Atezo/Bev treatment, our results demonstrate that EOB-MRI could serve as a surrogate marker predicting the immune microenvironment. This suggests that Atezo/Bev treatment can be selected regardless of signal intensity in the EOB-MRI HB phase.

Risk Factors for Early Onset of Proteinuria in Patients Receiving Atezolizumab Plus Bevacizumab for Unresectable Hepatocellular Carcinoma.

Introduction: Proteinuria is one of the adverse events of atezolizumab plus bevacizumab combination therapy (Atezo + Bev) and can cause interruption in the use of Bev. However, the risk factors for proteinuria in patients with hepatocellular carcinoma (HCC) who are receiving Atezo + Bev have not yet been investigated. The aim of this study was to identify the risk factors for early onset of proteinuria in Atezo + Bev for patients with unresectable HCC. Methods: Sixty-four patients with Child-Pugh scores of 5-7, an Eastern Cooperative Oncology Group performance status of 0 or 1, and low level of proteinuria (1+ or less on a dipstick test and urine protein-to-creatinine ratio (UPCR) less than 2.0 g/g Cr) at the initiation of therapy were analyzed. The level of proteinuria was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0. We adopted the UPCR for the quantitative test instead of a 24-h urine collection. The incidence of proteinuria and changes in liver function were retrospectively investigated. Results: The cumulative incidence of proteinuria over a 24-week period was 34.4%. Multivariate analysis showed that a low estimated glomerular filtration rate (hazard ratio [HR], 3.807; 95% confidence interval [CI], 1.579-9.180; p = 0.003), treatment for hypertension (HR, 6.224; 95% CI, 1.614-24.010; p = 0.008), and high systolic blood pressure (SBP) (HR, 2.649; 95% CI, 1.133-6.194; p = 0.025) were risk factors for proteinuria. Serum albumin levels and albumin-bilirubin scores in patients with proteinuria worsened. In addition, a mean SBP ≥135 mm Hg during treatment was the only risk factor for the development of severe proteinuria (UPCR >2 g/g Cr). Conclusion: Our study found that controlling blood pressure is extremely important for the management of proteinuria in patients with HCC who are receiving Atezo + Bev.

Correlation between serum pro-inflammatory cytokine levels and the prognosis of the patients with acute liver failure.

BACKGROUND AND AIM: The prognosis of acute liver failure (ALF) remains poor, and liver transplantation is an alternative treatment option. Assessing the prognosis of ALF is important in determining treatment strategies. Here, we investigated clinical factors including serum pro-inflammatory cytokine levels that are associated with the prognosis of ALF. METHODS: Sixty-six patients who developed ALF were enrolled in this study. Serum concentrations of 12 pro-inflammatory cytokines were measured on admission. The prognosis and factors associated with survival and development of hepatic coma were analyzed. RESULTS: Of 66 patients, 4 patients underwent liver transplantation, and 49 patients were rescued without liver transplantation, while the remaining 13 patients died. Serum concentrations of interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-13, TNF, IFN -γ, IP-10, and G-CSF were significantly elevated in ALF patients. IL-4 and IL-8 levels were higher in patients who underwent liver transplantation or died than in rescued patients. Multivariable analysis identified age ≥ 55 years and IL-4 ≥ 1.2 pg/mL on admission as independent factors for mortality. Serum IL-8 levels were higher in patients with hepatic coma, and prothrombin-international normalized ratio ≥ 3.5 and IL-8 ≥ 77.2 pg/mL on admission were associated with development of hepatic coma after admission. CONCLUSION: Serum levels of several pro-inflammatory cytokines were elevated in ALF patients. IL-4 and IL-8 were correlated with survival and development of hepatic coma after admission, respectively. Measurement of serum pro-inflammatory cytokines seems to be useful for the management of ALF.

The Analysis of Muscle Volume Measured by Bioelectrical Impedance in Patients with Hepatocellular Carcinoma Treated with First-Line Atezolizumab plus Bevacizumab Combination Therapy or First-Line Lenvatinib.

INTRODUCTION: Measurements of body composition, such as the skeletal muscle index (SMI), are useful for predicting prognosis in hepatocellular carcinoma (HCC). This study aimed to analyze the relationship between skeletal muscle changes during therapy with atezolizumab plus bevacizumab (Atezo + Beva) or lenvatinib (Len) and the association between SMI and prognosis. METHODS: Patients with advanced HCC and Child-Pugh A status received Atezo + Beva or Len as first-line systemic chemotherapy. We assessed prognosis and body composition obtained by bioelectrical impedance analysis. RESULTS: A total of 109 patients received treatment (Atezo + Beva, n = 47; Len, n = 62). During treatment, the arm SMI was reduced in the Len group and maintained in the Atezo + Beva group. The extracellular water to total body water ratio (ECW/TBW) increased significantly in both groups during treatment. In the Atezo + Beva group, no factor was associated with prognosis. Multivariate analysis showed that in the Len group, the arm SMI (hazard ratio [HR], 0.5; 95% CI: 0.26-0.89; p = 0.02), ECW/TBW (HR: 2.7; 95% CI: 1.21-6.01; p = 0.01), and Child-Pugh score (HR: 2.3; 95% CI: 1.31-6.13; p = 0.004) were associated with progression-free survival. CONCLUSION: Assessing body composition with BIA before Atezo + Beva and Len treatment may be useful.

Sodium-glucose cotransporter-2 inhibitors improve FibroScan-aspartate aminotransferase scores in patients with nonalcoholic fatty liver disease complicated by type 2 diabetes.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by excessive lipid accumulation in the liver, and its global incidence is increasing. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are oral antidiabetes drugs that promote glucose excretion into the urine and have been reported to exert therapeutic effects in NAFLD, but liver stiffness measurements (LSMs) determined by transient elastography are inconsistent. In addition, the effects of SGLT2is on the FibroScan-aspartate aminotransferase (FAST) scores have not been reported. We evaluated the effect of SGLT2is on patients with NAFLD complicated by type 2 diabetes using biochemical tests, transient elastography, and FAST scores. METHODS: Fifty-two patients with type 2 diabetes complicated by NAFLD who started SGLT2i treatment between 2014 and 2020 at our hospital were selected from the database. Pre- and post-treatment serum parameters, transient elastography, and FAST scores were compared. RESULTS: After 48 weeks of SGLT2i treatment, body weight, fasting blood glucose, hemoglobin A1c, AST, alanine aminotransferase, gamma-glutamyltransferase, uric acid, fibrosis-4 index, and AST to platelet ratio index improved. Median LSM decreased from 7.0 kPa to 6.2 kPa ( P  = 0.023) and the median controlled attenuation parameter decreased from 304 dB/m to 283 dB/m ( P  = 0.022). Median FAST score decreased from 0.40 to 0.22 ( P  < 0.001), and the number of cases with a cutoff value of ≥0.35 decreased from 15 to 6 ( P  = 0.001). CONCLUSION: SGLT2i use not only improves weight loss and blood glucose levels but also improves hepatic fibrosis by ameliorating hepatic steatosis and inflammation.

Impact and usefulness of the transition to the new MAFLD classification for non-B, non-C HCC: a retrospective cohort study.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new classification system for fatty liver disease. In this study, we investigated the clinical characteristics of patients with MAFLD-hepatocellular carcinoma (HCC) in comparison with those with nonalcoholic fatty liver disease (NAFLD) and considered the validity and challenges of the new criteria. METHODS: This study included 237 untreated non-B, non-C HCC patients with hepatic steatosis. We examined the profile and laboratory findings of patients with MAFLD-HCC and NAFLD-HCC. We also classified MAFLD-HCC patients according to the factors on which the diagnosis was based and compared their clinical characteristics. RESULTS: A total of 222 (94%) and 101 (43%) patients were diagnosed with MAFLD and NAFLD, respectively. MAFLD-HCC patients were more likely to be male than NAFLD-HCC, but there were no significant differences in metabolic indices, noninvasive liver fibrosis score or HCC status. In a study of MAFLD-HCC patients by diagnostic factor, those with overweight only were younger and had advanced liver fibrosis histologically, and when limited to patients younger than 70 years, the majority were overweight. Redefinition of overweight as BMI ≥ 25 reduced the number of MAFLD-HCC patients by only 5, from 222 to 217. CONCLUSIONS: MAFLD accounted for the majority of non-B, non-C HCC cases with hepatic steatosis. Examination of additional cases and revision of the detailed criteria is needed so that it can be used to efficiently select patients with fatty liver who are at high risk of developing HCC.

Evaluation of Response to Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma Using the Combination of Response Evaluation Criteria in Solid Tumors and Alpha-Fetoprotein.

Atezolizumab plus bevacizumab combination therapy (Atezo + Beva) is currently positioned as the first-line therapy for unresectable hepatocellular carcinoma (u-HCC). It may be difficult to decide whether to continue this treatment if radiological response is assessed as stable disease (SD). Therefore, the relationship between radiological response and prognosis was analyzed. A total of 109 patients with u-HCC and Child-Pugh Score of 5-7 received this treatment. Radiological response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST at the first and second evaluations. Of SD patients (n = 71) at the first RECIST evaluation, partial response, SD, and progressive disease (PD) were seen in 10, 55, and 6 patients, respectively, at the second evaluation. On multivariate analysis, in patients with SD at the first RECIST evaluation, a 25% or greater increase in the alpha-fetoprotein (AFP) value from initiation of treatment (odds ratio, 7.38; p = 0.037) was the independent factor for PD at the second evaluation. In patients with SD (n = 59) at the second RECIST evaluation, decreased AFP from initiation of treatment (hazard ratio, 0.46; p = 0.022) was the independent factor related to progression-free survival on multivariate analysis. AFP trends could help decide the Atezo + Beva treatment strategy.

Serum interleukin-6 level predicts the prognosis for patients with alcohol-related acute-on-chronic liver failure.

AIM: Heavy alcohol consumption is the most common etiology of acute-on-chronic liver failure (ACLF) in Japan. In some patients, ACLF is associated with a fatal outcome in less than 6 months. We evaluated the prognosis of patients with alcohol-related ACLF in our cohort and explored the prognostic factors. METHODS: Forty-six patients with alcoholic liver cirrhosis who fulfilled the Japanese diagnostic criteria for ACLF, including those classified as extended and/or probable, were enrolled in this study. Serum concentrations of inflammatory cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNFα) were measured. We assessed prognosis and identified factors associated with survival. RESULTS: During the median 33-day observation period, 19 patients died, and 3 patients underwent living donor liver transplantation. Cumulative survival rates of patients treated without liver transplantation were 69, 48, 41, and 36% at 1, 3, 6, and 12 months, respectively. Eighteen of the 19 deceased patients died within 6 months after ACLF diagnosis. Serum concentrations of inflammatory cytokines were significantly elevated, and patients who underwent liver transplantation or who died within 6 months after admission had significantly higher serum IL-6 levels than the survival group. Multivariate analysis identified IL-6 > 23.3 pg/mL at admission and model for end-stage liver disease (MELD) score ≥ 25 on day 4 of admission as significant independent factors for mortality within 6 months. CONCLUSION: Serum IL-6 level and Day-4 MELD were prognostic factors for alcohol-related ACLF. Early liver transplantation is a potential treatment option for patients whose prognosis is expected to be poor.

Effectiveness of Repeated Stereotactic Body Radiation Therapy for Hepatocellular Carcinoma-Consideration of the Locations of Target Lesions.

The present study retrospectively evaluated the efficacy of stereotactic body radiation therapy (SBRT), including repeated SBRT, for hepatocellular carcinoma. Participants comprised 220 HCC patients treated with SBRT in Hiroshima University Hospital between December 2008 and December 2021. Median overall survival (OS) and disease-free survival were 52 months (range, 45-64 months) and 17 months (range, 14-23 months), respectively. The 5-year local tumor recurrence rate was 3.4% (95% confidence interval (CI), 1.3-6.9%). Fifty-three patients underwent repeated SBRT (twice, 53 cases; three times, 10 cases; four times, 4 cases; five times, 1 case). Median interval between first and second SBRT was 20 months. Median OS from first SBRT was 76 months (95% CI, 50-102 months). Among patients with repeated SBRT, only one case showed local recurrence after second SBRT. Albumin-bilirubin score increased significantly from 6 to 12 months after repeated SBRT, both in the same segment and in remote segments, but the increase was not significant in the same segment. Only one case of grade 3 bile duct stricture was observed in patients who were treated with repeated SBRT. In conclusion, repeated SBRT provides good local control and a low risk of side effects.

Hepatitis B Virus (HBV) Upregulates TRAIL-R3 Expression in Hepatocytes Resulting in Escape From Both Cell Apoptosis and Suppression of HBV Replication by TRAIL.

BACKGROUND: Hepatitis B virus (HBV) evades host immunity by regulating intracellular signals. To clarify this immune tolerance mechanism, we performed gene expression analysis using HBV-infected humanized mouse livers. METHODS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 3 (TRAIL-R3) was significantly upregulated in livers of HBV-infected human hepatocyte transplanted mice by cDNA microarray and next-generation sequencing. We analyzed the significance of TRAIL-R3 upregulation in HBV infection using human hepatocyte transplanted mice and HepG2 cell lines. RESULTS: TRAIL-R3 induction by HBV infection was verified by in vitro and in vivo HBV replication models, and induction was inhibited by antiviral nucleot(s)ide analogue treatment. TRAIL-R3 transcription was regulated by the TRAIL-R3 promoter at -969 to -479 nucleotides upstream from the transcription start site, and by hepatitis B x (HBx) via activation of nuclear factor-κB (NF-κB) signal. TRAIL not only induced cell apoptosis but also inhibited HBV replication. TRAIL-R3 upregulation could inhibit both TRAIL-dependent apoptosis in HBV-infected hepatocytes and TRAIL-mediated suppression of HBV replication. CONCLUSIONS: These results suggest a mechanism by which HBV persists by escaping host immunity through upregulation of TRAIL-R3. Development of novel drugs to inhibit this escape system might lead to complete HBV elimination from human hepatocytes.

Evaluation of atezolizumab plus bevacizumab combination therapy for hepatocellular carcinoma using contrast-enhanced ultrasonography.

PURPOSE: Previous reports suggest that contrast-enhanced ultrasonography (CEUS) is useful for predicting the efficacy of sorafenib and lenvatinib treatment. However, there are no reports on the utility of CEUS for predicting the efficacy of atezolizumab plus bevacizumab combination therapy (Atezo + Bev). This study aimed to identify CEUS parameters for predicting the efficacy of Atezo + Bev. METHODS: A total of 30 patients with hepatocellular carcinoma (HCC) treated with Atezo + Bev who underwent CEUS before and 5 weeks after treatment initiation were included. RESULTS: Post area under the curve (post AUC) was identified as a predictive factor for early progressive disease (PD). The optimal cut-off value of post AUC for predicting progression-free survival (PFS) was 61.3. CONCLUSION: The results of this study suggest that CEUS at 5 weeks after initiation of Atezo + Bev may predict PFS in HCC patients. Changes to the treatment plan may need to be considered in patients with post AUC > 61.3.