Search

Abstract Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1–3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1–3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0–2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1–2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group.

Abstract Background and Aim We conducted a study using the Fibrosis‐3 (FIB‐3) index, which is the established age‐independent index of fibrosis in nonviral liver disease and addresses the limitations of the FIB‐4 index in older age group, to assess the liver fibrosis risk among diverse demographic groups in the general population. Methods We analyzed 31 327 individuals who underwent health examinations between 2013 and 2020 and investigated the distribution of the FIB‐3 index by age group. In addition, we examined the age distribution of the FIB‐3 index stratified by background factors, such as sex, body mass index (BMI), alcohol consumption habits, and the presence or absence of fatty liver. Results In terms of age‐specific distribution, the FIB‐3 index remained below 1.5 in >90% of cases until the age of 50 years but exceeded 1.5 beyond the age of 50 years, in approximately 30% among those aged 70 years. Notably, the FIB‐3 index above 31 years old was significantly higher in men than in women. Among the different BMI categories, individuals with BMI

Background/Aim The aim of this study was to compare the therapeutic efficacy of ablation and surgery in solitary hepatocellular carcinoma (HCC) measuring ≤5 cm with a large HCC cohort database. Methods The study included consecutive 2,067 patients with solitary HCC who were treated with either ablation (n=1,248) or surgery (n=819). Th e patients were divided into three groups based on the tumor size and compared the outcomes of the two therapies using propensity score matching. Results No significant difference in recurrence-free survival (RFS) or overall survival (OS) was found between surgery and ablation groups for tumors measuring ≤2 cm or >2 cm but ≤3 cm. For tumors measuring >3 cm but ≤5 cm, RFS was significantly better with surgery than with ablation (3.6 and 2.0 years, respectively, P=0.0297). However, no significant difference in OS was found between surgery and ablation in this group (6.7 and 6.0 years, respectively, P=0.668). Conclusion The study suggests that surgery and ablation can be equally used as a treatment for solitary HCC no more than 3 cm in diameter. For HCCs measuring 3-5 cm, the OS was not different between therapies; thus, ablation and less invasive therapy can be considered a treatment option; however, special caution should be taken to prevent recurrence.

Purpose The effect of hepatic fibrosis stage on quantitative ultrasound based on the attenuation coefficient (AC) for liver lipid quantification is controversial. The objective of this study was to determine how the degree of fibrosis assessed by magnetic resonance (MR) elastography affects AC based on the ultrasound-guided attenuation parameter according to the grade of hepatic steatosis, using magnetic resonance imaging (MRI)–derived proton density fat fraction (MRI-derived PDFF) as the reference standard. Methods Between February 2020 and April 2021, 982 patients with chronic liver disease who underwent AC and MRI-derived PDFF measurement as well as MR elastography were enrolled. Multiple regression was used to investigate whether AC was affected by the degree of liver stiffness. Results AC increased as liver stiffness progressed in 344 patients without hepatic steatosis (P=0.009). In multivariable analysis, AC was positively correlated with skin-capsule distance (P

Chronic inflammation of the pancreas is considered to be one of the causes of pancreatic cancer. However, the diagnosis of chronic pancreatitis (CP) is very difficult in the pancreas, where biopsies are difficult to perform. The prevalence of CP is estimated to be many times more common than in patients with actual symptomatic CP. In recent years, abnormal cleavage of certain proteins has attracted attention as a biomarker for CP other than pancreatic enzymes. Connective tissue growth factor (CTGF) is one of the growth factors involved in tissue repair and other processes and is increased by stimulation of transforming growth factor-β, suggesting a relationship of CTGF with fibrosis. In this study, we measured the total length of CTGF in blood and N-terminal fragment CTGF in 48 cases of chronic pancreatitis, 64 cases of pancreatic cancer and 45 healthy volunteers (HV). Interestingly, we found that blood N-terminal fragment CTGF level was significantly increased in CP and pancreatic cancer patients. Multiple logistic regression analysis showed serum levels of N-terminal fragment CTGF, CRP and amylase were significant and independent variables for the differential diagnosis of CP from HV. Receiver operating characteristic analysis showed that area under the curve (AUC) value of serum N-terminal fragment CTGF level was 0.933, which can differentiate between CP and HV. Several factors would be involved in the increase in serum N-terminal fragment CTGF level. In conclusion, serum N-terminal fragment CTGF level is a promising new biomarker for CP.

Abstract Aims The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment. Methods A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression‐free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c‐index) and Akaike information criterion (AIC) results. Results Cox‐hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI‐De) scoring system. For IMABALI‐De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p

Introduction The impact of etiology on response to immunotherapy in advanced hepatocellular carcinoma (HCC) is being debated, with contrasting findings between early and recent post-hoc analyses of IMbrave-150 and metanalyses of clinical trials of PD-1/PD-L1 blockers. As a results, it is not clear whether the first-line systemic treatment atezolizumab plus bevacizumab is equally effective in viral and non-viral patients. Methods We retrospectively analyzed 885 HCC patients treated with first-line A + B from multiple centers from Eastern and Western countries, 53.9% having viral and 46.1% non-viral etiology. Baseline clinical and laboratory characteristics were analyzed with uni- and multi-variate models to explore potential differences on overall survival (OS), time to progression (TTP), disease control rates based on etiology and to identify putative prognostic factors in etiology subgroups. Treatment toxicities and access to second-line treatments and outcomes were also reported and compared between etiologies. Results Overall, no statistically significant differences were found in OS (mOS: viral 15.9 months; non-viral 16.3 months), TTP (mTTP: viral 8.3 months; non-viral 7.2 months), and disease control rates (DCR: viral 78.1%; non-viral 80.8%) based on etiology. Prognostic factors of survival and progression were mainly shared between viral and non-viral etiologies, including alpha-fetoprotein, aspartate transaminase, neutrophil-to-lymphocyte ratio (NLR) and ALBI score. Exploratory analyses highlighted a possible stronger association of immunological factors, i.e. NLR and eosinophil count, to treatment outcomes in viral patients. The toxicity profile, the access to and type of second-line treatments and their outcome in terms of OS almost overlap in the two etiology subgroups. Conclusion Atezolizumab plus bevacizumab efficacy does not vary according to underlying etiology of HCC in a multicenter, real-world population, matching recent post-hoc findings from the IMbrave-150 trial. Preliminary analyses suggest that some prognostic factors differ between viral and non-viral patients, potentially due to biological and immunological differences. Prospective and comparative trials stratifying by etiology are warranted to validate these findings and guide clinical practice.

Abstract 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

Abstract Aim Multiple studies have revealed the correlation between gut microbiome and the response to checkpoint inhibitors (CPIs) in patients with cancer, and oral administration of butyrate‐producing enterobacteria has been reported to enhance the efficacy of CPIs. However, the effects of enterobacteria on patients with hepatocellular carcinoma (HCC) are not well understood. Methods In this retrospective multicenter study, we enrolled 747 patients with advanced HCC, treated with atezolizumab and bevacizumab combination therapy. Tumor response, survival, and adverse effects were compared between 99 patients who ingested drugs containing butyric acid‐producing enterobacteria (butyric acid group) and the remaining patients (control group). Results Objective response and disease control rates in butyric acid group (29.7% and 77.8%, respectively) were higher than those in the control group (26.4% and 72.7%, respectively). However, the differences were not statistically significant (p = 0.543 and p = 0.222, respectively). No difference in median survival time was observed between the two groups (20.0 months and 21.4 months, respectively; p = 0.789), even after matching the backgrounds of the patients with propensity scores (p = 0.714). No adverse effects occurred upon the administration of butyrate‐producing bacteria. However, proteinuria (41.4% vs. 30.9%; p = 0.041), fever (17.2% vs. 10.2%, p = 0.036), and diarrhea (15.2% vs. 6.2%; p = 0.001) occurred more frequently in the butyric acid group. Conclusion Butyrate‐producing bacteria does not enhance the efficacy of atezolizumab–bevacizumab combination therapy in patients with HCC.

Abstract 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

Abstract 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

Abstract 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.

Abstract 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 (

Abstract 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

Abstract Aims This retrospective study compared the survival between elderly and non‐elderly patients. Methods A total of 5545 treatment‐naive patients with hepatocellular carcinoma (HCC) who visited 7 different hospitals from January 2000 to December 2018 were included. Patients ≥80 years old were defined as elderly patients. We divided the patients into three groups based on the timing of the initial treatment: Early, middle, and late periods defined as 2000 to 2005, 2006 to 2012, and 2013 to 2018, respectively. Results There were 132 (8.9%), 405 (17.5%), and 388 (22.2%) elderly patients in the early, middle, and late period, respectively, showing a significant increase over time (p

Purpose Quantitative elastography methods, such as ultrasound two-dimensional shear-wave elastography (2D-SWE) and magnetic resonance elastography (MRE), are used to diagnose liver fibrosis. The present study compared liver stiffness determined by 2D-SWE and MRE within individuals and analyzed the degree of agreement between the two techniques. Methods In total, 888 patients who underwent 2D-SWE and MRE were analyzed. Bland-Altman analysis was performed after both types of measurements were log-transformed to a normal distribution and converted to a common set of units using linear regression analysis for differing scales. The expected limit of agreement (LoA) was defined as the square root of the sum of the squares of 2D-SWE and MRE precision. The percentage difference was expressed as (2D-SWEMRE)/ mean of the two methods×100. Results A Bland-Altman plot showed that the bias and upper and lower LoAs (ULoA and LLoA) were 0.0002 (95% confidence interval [CI], -0.0057 to 0.0061), 0.1747 (95% CI, 0.1646 to 0.1847), and -0.1743 (95% CI, -0.1843 to -0.1642), respectively. In terms of percentage difference, the mean, ULoA, and LLoA were -0.5944%, 19.8950%, and -21.0838%, respectively. The calculated expected LoA was 17.1178% (95% CI, 16.6353% to 17.6002%), and 789 of 888 patients (88.9%) had a percentage difference within the expected LoA. The intraclass correlation coefficient of the two methods indicated an almost perfect correlation (0.8231; 95% CI, 0.8006 to 0.8432; P

Summary: Background: Atezolizumab-bevacizumab (atezo-bev) is recommended as first-line therapy for patients with unresectable hepatocellular carcinoma (uHCC). However, its effectiveness and safety in other populations, including those with Child-Turcotte-Pugh (CTP) class B cirrhosis, is unclear. Methods: For this systematic review and meta-analysis, electronic databases, including PubMed, Embase, and Scopus, were searched from 1st May, 2020 till 5th October, 2022; the last date of access was January 31, 2023. Pooled progression-free survival (PFS), overall survival (OS), and radiological response rate among patients receiving atezo-bev were compared between patients with CTP-A and CTP-B cirrhosis, with tyrosine kinase inhibitors (TKIs) and among those receiving the drug as first-line and later line therapy. The protocol was registered in Prospero (CRD42022364430). Findings: Among 47 studies (n = 5400 patients), pooled PFS and OS were 6.86 (95% CI, 6.31–7.41) and 13.8 months (95% CI, 11.81–15.8), respectively. Objective response rate (ORR) and disease control rate were 26.7% (24.6–29.1) and 75.3% (73.1–77.4) using RECIST criteria, and 34% (30.3–37.8) and 73.6% (68.8–78) using mRECIST criteria, respectively. Among those receiving atezo-bev, patients with CTP-B cirrhosis had similar ORRs by RECIST (odds ratio [OR], 1.42 [0.77–2.6]; P = 0.25) and mRECIST criteria (OR, 1.33 [0.52–3.39]; P = 0.53) but shorter PFS (mean difference [MD]:3.83 months [1.81–5.84]) than those with CTP-A cirrhosis. Compared to patients receiving TKIs, those receiving atezo-bev had longer PFS (MD: 2.27 months [0.94–3.5]) and higher ORR (RECIST: OR, 1.44 [1.01–2.04] and mRECIST: OR, 1.33 [1.01–1.75]). Compared to first-line therapy, later-line therapy had lower ORR (RECIST: OR, 1.82 [1.3–2.53]; P

Abstract 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.

Abstract Background and Aim The relationship between the characteristics of hepatocellular carcinoma (HCC) diagnosed after sustained virological response (SVR) with direct‐acting antiviral (DAA) therapy and surveillance status has not been sufficiently investigated. This study investigated the clinical risk factors for HCC development and HCC characteristics according to which type of physician performed follow‐up after SVR. Methods A total of 1070 patients in whom hepatitis C virus (HCV) was eradicated with DAA therapy were evaluated. Results There were 458 patients followed by hepatologists (specialist group) and 612 followed by non‐hepatologists (non‐specialist group) after SVR. During the follow‐up period, 54 patients developed HCC. The 1‐, 2‐, 3‐, 4‐, and 5‐year cumulative incidence rates of HCC were 1.8, 4.1, 6.9, 10.5, and 17.2%, respectively. Multivariate Cox proportional hazards analysis showed that male sex (hazard ratio [HR], 3.139; 95% confidence interval [CI], 1.732–5.690), α‐fetoprotein level (HR, 1.056; 95% CI, 1.035–1.077), and fibrosis‐4 (FIB‐4) index (HR, 1.051; 95% CI, 1.017–1.085) were significantly associated with HCC development, while the follow‐up physician type after SVR was not. There were 25 patients with stage I HCC, 17 with stage II, 9 with stage III, and 3 with stage IV. Multivariate ordinal logistic regression showed that follow‐up physician type (non‐specialist) (HR, 39.100; 95% CI, 9.350–224.00) was independently associated with HCC stage, while α‐fetoprotein level and FIB‐4 index were not. Conclusion When patients have more risk factors for HCC development after SVR (i.e., male sex, elevated α‐fetoprotein, or elevated FIB‐4 index), they should be followed by a hepatologist for HCC surveillance.

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 (p < 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 >30.6% might be a predictor of maintenance of CR. Use of these indicators have the potential to impact systemic chemotherapy for HCC.

Abstract Background Fatty liver is frequently found in a general population, and it is critical to detect advanced fibrosis. FIB-4 index is considered a useful marker for evaluating liver fibrosis but the distribution of FIB-4 index in the general population remains unknown. Methods This cross-sectional study included residents who underwent ultrasonography at health checkups in Hiroshima or Iwate prefectures. The distribution of FIB-4 index in the total study population (N = 75,666) as well as in non-alcoholic fatty liver disease (NAFLD) populations (N = 17,968) and non-drinkers without fatty liver populations (N = 47,222) was evaluated. The distribution of aspartate aminotransferase (AST) levels, alanine aminotransferase (ALT) levels was also evaluated. Results The mean FIB-4 index in the total study population was 1.20 ± 0.63. FIB-4 index ≥ 2.67, which indicates a high risk of liver fibrosis, was found in 16.4% of those aged ≥ 70 years. In the NAFLD population, 58.1% of those in their 60 s and 88.1% of those ≥ 70 years met the criteria for referral to hepatologists by using the recommended FIB-4 index cutoff value (≥ 1.3). The mean FIB-4 index in the NAFLD population (1.12 ± 0.58) was significantly lower than in the non-drinkers without fatty liver (1.23 ± 0.63, p 1.0), whereas the results in the NAFLD population were opposite (14.8% with AST/ALT > 1.0). AST > ALT resulted in a higher FIB-4 index in non-drinkers without fatty liver due to the nature of FIB-4 index formula. Conclusions The cutoff value of FIB-4 index (≥ 1.3) for triaging the elderly people with fatty liver for referral to hepatologists should be reconsidered to avoid over-referral. Due to the impact of age and characteristics of AST/ALT ratios, there is no prospect of using FIB-4 index for primary screening for liver fibrosis in a general population of unknown presence or absence of liver disease, even though it can be easily calculated using routine clinical indices. It is desired to develop a non-invasive method for picking up cases with advanced fibrosis latent in the general population.

Abstract 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

Backgrounds and Aims: Cirrhosis and hepatocellular carcinoma (HCC) are potentially fatal complications of chronic hepatitis C virus (HCV) infection. We investigated how compensated cirrhosis and a history of curatively treated HCC influenced patient mortality after HCV eradication, that is, sustained virologic response (SVR). Methods: We studied 5458 patients with confirmed SVR who were prospectively followed up for more than 1 year after SVR achieved with direct-acting antivirals. Mortality and the incidence of HCC development after SVR were analyzed based on the presence or absence of compensated cirrhosis or a history of curatively treated HCC before the start of therapy. Results: Mortality and the incidence of post-SVR HCC were significantly higher in patients with compensated cirrhosis and those with a history of curatively treated HCC than in those without these complications. Multivariate analysis showed that a history of HCC was associated with high mortality after SVR. In patients with no history of HCC, cirrhosis was associated with high mortality. Although both liver-related and nonliver-related mortality rates were significantly higher in patients with a history of HCC or cirrhosis, nonliver-related mortality did not differ based on HCC history, and liver-related and nonliver-related mortality were comparable regardless of cirrhosis after propensity score matching with age, gender, alcohol intake, and comorbidities. Conclusion: Mortality after SVR was significantly higher in patients with compensated cirrhosis or a history of HCC. While a history of HCC significantly increased mortality after SVR, even following curative treatment, the impact of pre-SVR compensated cirrhosis on post-SVR mortality was modest.

Background and Aims: The Fibrosis-4 (FIB-4) index has been used to predict liver fibrosis in various liver diseases, including nonalcoholic fatty liver disease (NAFLD). Because the FIB-4 formula uses age, different cutoff values may be required for different age groups, making the interpretation difficult. To avoid the influence of age, we attempted to create a new score, the Fibrosis-3 (FIB-3) index. Methods: The FIB-3 index was created using a training cohort of 735 NAFLD cases using aspartate aminotransferase, alanine amino transferase, and platelet for predicting fibrosis. The abilities of the FIB-3 and FIB-4 indices were compared among different age groups in the training cohort and validation cohort with 324 patients. The FIB-3 index was also compared with other liver fibrosis indices. Results: The area under the receiver operating characteristic curve (AUROC) values of the FIB-3 and FIB-4 indices for predicting F3–F4 fibrosis were 0.764 and 0.762, respectively, in the training cohort. No difference in the AUROC values was observed between the 2 indices in the validation cohort. The differences in the accuracies of FIB-3 between elderly and nonelderly patients were 0.140 and 0.178, respectively, in each cohort and were smaller than those of FIB-4 index (0.199 and 0.336, respectively). Analysis using a joined cohort revealed that the AUROC of FIB-3 for predicting F3–F4 fibrosis (0.774) was the highest among the 5 fibrosis scores examined and was comparable to that of FIB-4. Conclusion: The FIB-3 index is an improved version of the FIB-4 index and can effectively predict liver fibrosis in patients with NAFLD.

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use maybe limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy (UGE) available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence and risk factors for the presence of EGV and high risk EGV at baseline, impact of EGV bleeding on patients’ survival. Results: 535 patients were enrolled in the study [median age 72 years, 78% male, 63% viral aetiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis (nPVT), 56% BCLC-C]: 234 had EGV (44%): 70 (30%) at high-risk and 59 on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high risk EGV (HR 6.94, 95% CI 2.23-21.57, p=0.001). In these patients the 12-month risk was 17%. High risk varices were independently associated with Child-Pugh B score (OR 2.12; 95%CI 1.08-4.17, p=0.03), nPVT (OR 2.54; 95%CI 1.40-4.61, p=0.002) and platelets

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.

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%); 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), modified albumin-bilirubin (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

Abstract Background and Aim Hepatic angiography procedures such as transarterial chemoembolization (TACE) are essential procedures for managing patients with hepatocellular carcinoma (HCC), and are usually performed with femoral access. However, femoral access causes patient discomfort and may be associated with the risk of hematoma or pseudoaneurysm at puncture site. We evaluated the safety, feasibility, and patient comfort of hepatic angiography procedures performed with radial access. Methods In this single‐institution, retrospective, time‐frame study, a total of 206 patients who underwent hepatic angiography procedures with radial access, which were first used on October 2017 at our institution, were compared with 240 patients who underwent the same procedures with femoral access before this period. Several measures were assessed, including procedure time and safety. In addition, a questionnaire was used to compare the access types regarding procedure‐associated discomfort. Results Hepatic angiography procedures performed with radial access, including TACE, were completed in all patients without complications. The procedure time was comparable between radial access and femoral access. Most patients preferred radial to femoral access. Patients taking anticoagulants were able to complete the procedures without discontinuing these drugs. Conclusions Hepatic angiography procedures with radial access resulted in less discomfort than those with femoral access, and the two approaches showed similar feasibility and safety. Radial access can be introduced as a routine technique for hepatic angiography procedures.

Abstract 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

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

Abstract 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.

Introduction: In the REFLECT trial, lenvatinib was found to be non-inferior 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 to identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included Western and Eastern populations from 23 centres in five countries. Results: We included 1325 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 aetiology 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 as 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 that the appearance of decreased appetite Grade ≥ 2 versus Grade 0-1 as an independent prognostic factor for worse Progression Free Survival. 924 patients on 1325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over two-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 candidate to locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib.

Background/Aim: Because of recent developments in treatments for hepatocellular carcinoma (HCC), methods for determining suitable therapy for initial or recurrent HCC have become important. This study used artificial intelligence (AI) findings to establish a system for predicting prognosis of HCC patients at time of reoccurrence based on clinical data as a reference for selection of treatment modalities. Material/Methods: As a training cohort, 5701 observations obtained at the initial and each subsequent treatment for recurrence from 1985 HCC patients at a single center from 2000 to 2021 were used. The validation cohort was 5692 observations from patients at multiple centers obtained at the time of the initial treatment. An AI calculating system (PRAID) was constructed based on 25 clinical factors noted at each treatment from the training cohort, then predictive prognostic values for one- and three-year survival in both cohorts were evaluated. Results: After exclusion of patients lacking clinical data regarding albumin-bilirubin grade (ALBI) and/or tumor-node-metastasis stage (TNM), ALBI-TNM (ALBI-T) and modified ALBI-T scores confirmed that prognosis for patients in both cohorts was similar. The area under the curve (AUC) for prediction of both one- and three-year survival in the validation cohort were 0.841 [sensitivity 0.933 (95%CI 0.925-0.940), specificity 0.517 (95%CI 0.484-0.549)] and 0.796 [sensitivity 0.806 (95%CI 0.790-0.821), specificity 0.646 (95%CI 0.624-0.668)], respectively. Conclusion: The present PRAID system might provide useful prognostic information related to short and medium survival for decision making regarding best therapeutic modality for both initial and recurrent HCC cases.

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.

Abstract 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.

Introduction: The ALBI score is acknowledged as the gold standard for the assessment of liver function in patients with hepatocellular carcinoma (HCC). Unlike the Child-Pugh score, the ALBI score uses only objective parameters, albumin (Alb) and total bilirubin (T.Bil), enabling a better evaluation. However, the complex calculation of the ALBI score limits its applicability. Therefore, we developed a simplified ALBI score, based on data from a large-scale HCC database.We used the data of 5,249 naïve HCC cases registered in eight collaborating hospitals. Methods: We developed a new score, the EZ (Easy)-ALBI score, based on regression coefficients of Alb and T.Bil for survival risk in a multivariate Cox proportional hazard model. We also developed the EZ-ALBI grade and EZ-ALBI-T grade as alternative options for the ALBI grade and ALBI-T grade and evaluated their stratifying ability. Results: The equation used to calculate the EZ-ALBI score was simple {[T.Bil (mg/dL)] – [9 × Alb (g/dL)]}; this value highly correlated with the ALBI score (correlation coefficient, 0.981; p < 0.0001). The correlation was preserved across different Barcelona clinic liver cancer grade scores (regression coefficient, 0.93–0.98) and across different hospitals (regression coefficient, 0.98–0.99), indicating good generalizability. Although a good agreement was observed between ALBI and EZ-ALBI, discrepancies were observed in patients with poor liver function (T.Bil, ≥3 mg/dL; regression coefficient, 0.877). The stratifying ability of EZ-ALBI grade and EZ-ALBI-T grade were good and their Akaike’s information criterion values (35,897 and 34,812, respectively) were comparable with those of ALBI grade and ALBI-T grade (35,914 and 34,816, respectively). Conclusions: The EZ-ALBI score, EZ-ALBI grade, and EZ-ALBI-T grade are useful, simple scores, which might replace the conventional ALBI score in the future.

Abstract 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

This paper presents the first version of clinical practice guidelines for intrahepatic cholangiocarcinoma (ICC) established by the Liver Cancer Study Group of Japan. These guidelines consist of 1 treatment algorithm, 5 background statements, 16 clinical questions, and 1 clinical topic, including etiology, staging, pathology, diagnosis, and treatments. Globally, high incidence of ICC has been reported in East and Southeast Asian countries and the incidence has been gradually increasing in Japan and also in Western countries. Reported risk factors for ICC include cirrhosis, hepatitis B/C, alcohol consumption, diabetes, obesity, smoking, nonalcoholic steatohepatitis, and liver fluke infestation, as well as biliary diseases, such as primary sclerosing cholangitis, hepatolithiasis, congenital cholangiectasis, and Caroli disease. Chemical risk factors include thorium-232, 1,2-dichloropropane, and dichloromethane. CA19-9 and CEA are recommended as tumor markers for early detection and diagnostic of ICC. Abdominal ultrasonography (US), CT, and MRI are effective imaging modalities for diagnosing ICC. If bile duct invasion is suspected, imaging modalities for examining the bile ducts may be useful. In unresectable cases, tumor biopsy should be considered when deemed necessary for the differential diagnosis and drug therapy selection. The mainstay of treatment for patients with Child-Pugh class A or B liver function is surgical resection and drug therapy. If the patient has no regional lymph node metastasis and has a single tumor, resection is the treatment of choice. If both regional lymph node metastasis and multiple tumors are present, drug therapy is the first treatment of choice. If the patient has either regional lymph node metastasis or multiple tumors, resection or drug therapy is selected depending on the extent of metastasis or the number of tumors. If distant metastasis is present, drug therapy is the treatment of choice. Percutaneous ablation therapy may be considered for patients who are ineligible for surgical resection or drug therapy due to decreased hepatic functional reserve or comorbidities. For unresectable ICC without extrahepatic metastasis, stereotactic radiotherapy (tumor size ≤5 cm) or particle radiotherapy (no size restriction) may be considered. ICC is generally not indicated for liver transplantation, and palliative care is recommended for patients with Child-Pugh class C liver function.

Abstract 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.

Background: Background liver function in patients with hepatocellular carcinoma (HCC) has improved remarkably with advances in various treatments. Recently, the Child-Pugh classification (CPC) system has been recognized as limited in its ability to assess patients with good hepatic reserve. We compared the albumin-bilirubin (ALBI) grade, which is suitable for a more detailed evaluation of patients with good liver function, with CPC over a 30-year period. Methods: A total of 2,347 patients were analyzed. Patients were stratified by year of diagnosis into 6 groups: Group A (1990–1994, n = 376), Group B (1995–1999, n = 434), Group C (2000–2004, n = 438), Group D (2005–2009, n = 444), Group E (2010–2014, n = 392), and Group F (2015–2018, n = 263). We compared ALBI grade and CPC across the groups. Results: The prevalence of patients with CPC A at diagnosis increased throughout the study period, reaching nearly 80% in Groups E and F (p < 0.001). By contrast, the percentage of patients with ALBI grade 1 disease remained approximately 50% in Groups E and F (p < 0.001). Modified ALBI (mALBI) grade 2a corresponds to patients with CPC A who have poor hepatic function. There were significant survival differences between patients with mALBI grade 1 versus 2a, 1 versus 2b, and 2a versus 2b disease, respectively (p < 0.0001), in patients with CPC A. Conclusions: CPC is not suitable for assessing patients with recently diagnosed HCC and good remnant hepatic function. In such patients with HCC, the prognosis can be stratified by ALBI grade rather than CPC.

We developed and evaluated a modified albumin-bilirubin grade and α-fetoprotein (mALF) score, a nutritional and oncological assessment tool for patients with hepatocellular carcinoma (HCC) after surgical resection. Patients (n = 480) who underwent R0 resection between 2010 and 2020 were analyzed retrospectively. The mALF score assigned one point for a modified albumin-bilirubin (mALBI) grade 2b or 3 and one point for an α-fetoprotein (AFP) level ≥ 100 ng/mL. Patients were classified by mALF scores of 0 (mALBI grade 1/2a, AFP < 100 ng/mL), 1 (mALBI grade 2b/3 or AFP ≥ 100 ng/mL), or 2 (mALBI grade 2b/3, AFP ≥ 100 ng/mL) points. Liver reserve deteriorated and cancer progressed with increasing score. Postoperative complications (Clavien–Dindo classification ≥ 3) differed significantly among groups. The 5-year recurrence-free survival (RFS) rates were 34.8%, 11.2%, and 0.0% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The 5-year overall survival (OS) rates were 66.0%, 29.7%, and 17.8% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The mALF score was an independent prognostic predictor of RFS and OS. In HCC, the mALF score was effective for predicting postoperative complications and long-term survival.

Abstract 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

Introduction: The International Association for the Study of Lung Cancer proposed a new grading criteria for invasive adenocarcinoma. However, its utility has not been validated. Methods: Patients who underwent complete resection of lung adenocarcinoma were included in this study. Then, they were divided into the following three groups on the basis of the criteria recently proposed by the International Association for the Study of Lung Cancer: grade 1, lepidic predominant tumor, with less than 20% of high-grade patterns; grade 2, acinar or papillary predominant tumor, with less than 20% of high-grade patterns; and grade 3, any tumor with greater than or equal to 20% of high-grade patterns. Results: Recurrence-free survival (RFS) was significantly different among the proposed grades (p < 0.001). The RFS of patients upgrading from current grade 2 (papillary or acinar predominant tumor) to proposed grade 3 (5-y RFS, 65.2%) was significantly worse than that of patients with proposed grade 2 (77.1%, hazard ratio = 1.882, 95% confidence interval: 1.236–2.866) but not significantly different from that of patients with grade 3 in both the current (micropapillary or solid predominant tumor) and proposed criteria (53.2%, hazard ratio = 0.761, 95% confidence interval: 0.456–1.269). Among patients with pathologic stage 0 or I, RFS was well stratified by the new grading system (p < 0.001) but not among patients with stage II or III (p = 0.334). In the multivariable analysis, the new grading was not a predictive factor of RFS. Conclusions: Although the proposed grading system well stratified RFS in patients with pathologic stage 0 or I lung adenocarcinoma, there is room for improvement.

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. The selection of therapeutic modalities and the prognosis of affected patients are well known to be dependent not only on the tumor burden but also on the hepatic reserve function. Antiviral treatments for chronic hepatitis related to a viral infection and an increase in cases of nonviral HCC associated with the aging of society have resulted in dramatic changes regarding the characteristics of HCC patients. With recent developments in therapeutic modalities for HCC, a more detailed assessment of hepatic function has become an important need. Studies in which the relationship of albumin-bilirubin (ALBI) grade with the prognosis of HCC patients was investigated were reviewed in order to evaluate the usefulness of newly developed ALBI and modified ALBI (mALBI) grades for HCC treatment, as those scoring methods are considered helpful for predicting the prognosis and selecting therapeutic modalities based on the expected prognosis.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is sufficient epidemiological cohort data to recommend the surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommends that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) consider HCC surveillance. NITs include the fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US), which is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US, or if an US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, the lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and the protein induced by the absence of vitamin K or antagonist-II (PIVKA-II), can help identify a high risk of HCC in NAFLD patients. Innovative parameters, including a Mac-2 binding protein glycated isomer, type IV collagen 7S, free apoptosis inhibitor of the macrophage, and a combination of single nucleoside polymorphisms, are expected to be established. Considering the large size of the NAFLD population, optimal screening tests must meet several criteria, including high sensitivity, cost effectiveness, and availability.

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called “diabetic hepatopathy or diabetic liver disease”. NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

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.

The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy.

Background: Most integrated scores for predicting the prognosis of patients with hepatocellular carcinoma (HCC) comprise tumor progression factors and liver function variables. The FIB4 index is an indicator of hepatic fibrosis calculated on the basis of age, aspartate aminotransferase (AST) levels, alanine aminotransferase (ALT) levels, and platelet count, but it does not include variables directly related to liver function. We propose a new staging system, referred to as “FIB4-T,” comprising the FIB4 index as well as tumor progression factors, and examine its usefulness. Method: Subjects included 3800 cases of HCC registered in multiple research centers. We defined grades 1, 2, and 3 as a Fibrosis-4 (FIB4) index of 6.70 as FIB4, respectively, and calculated the FIB4-T in the same manner in which the JIS (Japan Integrated Staging Score) scores and albumin-bilirubin tumor node metastasis (ALBI-T) were calculated. We compared the prognostic prediction ability of FIB4-T with that of the JIS score and ALBI-T. Results: Mean observation period was 37 months. The 5-year survival rates (%) of JIS score (0/1/2/3/4/5), ALBI-T (0/1/2/3/4/5) and FIB4-T (0/1/2/3/4/5) were 74/60/36/16/0, 82/66/45/22/5/0 and 88/75/65/58/32/10, respectively. Comparisons of the Akaike information criteria among JIS scores, ALBI-T, and FIB4-T indicated that stratification using the FIB4-T system was comparable to those using ALBI-T and JIS score. The risk of mortality significantly increased (1.3–2.8 times/step) with an increase in FIB4-T, and clear stratification was possible regardless of the treatment. Conclusions: FIB4-T is useful in predicting the prognosis of patients with HCC from a new perspective.

Hepatitis B virus (HBV) is prevalent worldwide and causes liver diseases, including acute and chronic hepatitis. Ten HBV genotypes (A-J) with distinct geographic distributions have been reported. Cases of acute HBV infection with genotype A have increased in Japan nationwide since the 1990s, mainly through sexual transmission. To investigate the molecular evolution and phylodynamics of HBV genotypes, we collected acute HBV isolates acquired in Japan from 1992-2002. Full genomes were obtained for comprehensive phylogenetic and phylodynamic analysis, with other Japanese HBV sequences from GenBank that were isolated during 1991-2010. HBV genotypes were classified using the maximum-likelihood and Bayesian methods. The GMRF Bayesian Skyride was used to estimate the evolution and population dynamics of HBV. Four HBV genotypes (A, B, C, and H) were identified, of which C was the major genotype. The phylodynamic results indicated an exponential growth between the 1960s and early 1990s; this was followed by a population bottleneck after 1995, possibly linked with successful implementation of a nationwide vaccination program. However, HBV/A increased from 1990 to 2003-2004, and then started to decrease. The prevalence of genotype A has increased over the past 10 years. Phylodynamic inference clearly demonstrates a steady population growth compatible with an ongoing subepidemic; this might be due to the loss of immunity to HBV in adolescents and people being born before the vaccination program. This is the first phylodynamic study of HBV infection in Japan and will facilitate understanding the molecular epidemiology and long-term evolutionary dynamics of this virus in Japan.