Tomomi Okubo

Aim The lymphocyte-to-monocyte ratio (LMR) has emerged as a potential immune-related biomarker; however, its prognostic significance in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev) remains unclear. To investigate the prognostic significance of the LMR in patients with unresectable HCC treated with Atezo/Bev. Methods This multicentre study included 941 patients with unresectable HCC treated with Atezo/Bev therapy at 30 institutions in Japan. The optimal LMR cutoff value was determined using time-dependent receiver operating characteristic (ROC) analysis. Multivariate survival analyses were performed for progression-free survival (PFS) and overall survival (OS). The prognostic utility of the LMR was compared with that of the neutrophil-to-lymphocyte ratio (NLR) using integrated discrimination improvement and net reclassification improvement. Results Time-dependent ROC analysis identified an optimal LMR cutoff value of 3.6 based on median OS. The median PFS was 5.6 months in patients with an LMR < 3.6 and 8.9 months in those with an LMR ≥ 3.6 (P<0.01). The disease control rate was significantly higher in the high LMR group (P<0.01). Multivariate analysis identified the LMR as an independent factor associated with prolonged PFS (hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90–0.98; P<0.01) and OS (HR, 0.90; 95% CI, 0.85–0.96; P<0.01). Compared with NLR, LMR demonstrated a significantly greater improvement in prognostic predictive performance for both PFS and OS (P<0.01). Conclusions The LMR is a simple and clinically useful prognostic biomarker for predicting both PFS and OS in patients with unresectable HCC treated with Atezo/Bev therapy.

Background: Abnormalities in energy and amino acid metabolism are potentially involved in hepatocellular carcinoma (HCC) development. This study aimed to identify serum metabolites predictive of HCC following sustained virological response (SVR) with hepatitis C virus (HCV) treatment. Methods: Comparative metabolomics was conducted using time-course serum samples from patients who failed interferon-based therapy but subsequently achieved SVR with direct-acting antivirals (DAAs), minimizing inter-individual variability. Predictive biomarkers for post-SVR HCC were extracted from the results and validated by comparing 29 patients who developed post-SVR HCC with 58 age-matched patients who remained HCC-free during follow-up. Results: Metabolite concentrations changed more markedly after treatment in SVR cases than in non-SVR cases. Significant changes in methionine (Met), methionine sulfoxide (MetO), and ornithine (Orn) levels before and after treatment (Pre- and Post-Tx) were found only in the non-HCC group. Regression and survival analyses identified high levels of Pre- and Post-Tx Orn, Pre-Tx Met, and Post-Tx MetO as predictors of post-SVR HCC and enabled risk stratification. The integration of these metabolites with the fibrosis-4 (FIB-4) index and alpha-fetoprotein (AFP) facilitated risk stratification and discriminated between high- and low-risk patients. The Pre-Tx FIB-4/Met model and the Post-Tx AFP/MetO/Orn model identified low- and high-risk groups with 3-year HCC incidence rates of 6.4% and 81.8%, respectively. Conclusions: Serum Met, MetO, and Orn were identified as candidate biomarkers associated with post-SVR HCC development, which remains a concern in the fight against hepatitis C. Combining these metabolites with established clinical markers may improve post-SVR HCC risk stratification.

Introduction: Atezolizumab plus bevacizumab (Atez/Bev) was the first immune checkpoint inhibitor regimen approved in 2020 for unresectable hepatocellular carcinoma (uHCC), followed by durvalumab plus tremelimumab (Dur/Tre) in 2023. There is very little data available comparing the efficacy and safety of Atez/Bev with those of Dur/Tre. This study aimed to clarify the therapeutic outcomes and safety of Atez/Bev and Dur/Tre. Methods: We retrospectively analyzed patients with uHCC (BCLC-B/C and Child-Pugh class A) treated with Atez/Bev (n = 302) or Dur/Tre (n = 129) as first-line systemic therapy across multiple institutions between 2023 and 2025. A retrospective comparison of the treatment outcomes and safety of Atez/Bev and Dur/Tre was conducted. Results: The objective response rate and disease control rate were comparable between the Atez/Bev and Dur/Tre groups (31.8%/71.9% vs. 28.7%/63.6%, p = 0.570/p = 0.110, respectively). Median progression-free survival (PFS) was longer with Atez/Bev (9.1 vs. 5.0 months, p = 0.002), while OS was comparable (25.6 vs. 22.1 months, p = 0.172). Similar results were shown after adjusting with inverse probability weighting (IPW). Grade 5 immune-related adverse events occurred in 0.3% (n = 1, interstitial pneumonia) of the patients receiving Atez/Bev and 0.8% (n = 1, colitis) of those receiving Dur/Tre. In the Cox hazard analysis adjusted with IPW, Dur/Tre demonstrated a favorable trend in OS (hazard ratio [HR] <0.75) in patients with elevated alpha-fetoprotein (AFP) (≥100 ng/mL) (HR 0.72, interaction p = 0.006) or double positive elevation of tumor marker (AFP and des-gamma-carboxy prothrombin [≥100 mAU/mL]) (HR 0.66, interaction p = 0.005). Conclusion: Although Atez/Bev was associated with a longer PFS, OS did not differ significantly between Atez/Bev and Dur/Tre. This dissociation between PFS and OS may reflect differences in disease biology, treatment sequencing, and post-progression management rather than intrinsic superiority of either regimen. These findings highlight the importance of individualized treatment selection and careful consideration of tumor characteristics and hepatic reserve when choosing first-line immunotherapy for uHCC.

Background: Osteoporosis is a common complication in patients with primary biliary cholangitis (PBC). This study aimed to compare the efficacy and safety of denosumab and zoledronic acid (ZOL) in treating osteoporosis in PBC patients. Methods: This multicenter, randomized, open-label trial enrolled Japanese patients with PBC and osteoporosis. Patients were randomized to receive either subcutaneous denosumab 60 mg every 6 months (denosumab group) or i.v. zoledronic acid 5 mg yearly (ZOL group). The primary endpoint was the mean percent change in bone mineral density (BMD) at the lumbar spine and total hip from baseline to 12 months. Results: Of 47 enrolled patients, 41 (87.2%) completed the study (denosumab: n=21; ZOL: n=20). At 12 months, lumbar spine BMD increased by 7.5% in the denosumab group and 6.4% in the ZOL group, demonstrating the non-inferiority of denosumab (95% CI: −1.6% to 3.8%). Although the total hip BMD increased more in the denosumab group than in the ZOL group (5.0% vs. 2.6%, pp=0.013). Conclusions: Denosumab is a safe and effective treatment option for osteoporosis in patients with PBC.

Aims: Sustained virological response (SVR) is a favorable prognostic factor for patients with hepatocellular carcinoma (HCC) caused by hepatitis C virus (HCV) treated curatively. This study aimed to evaluate the impact of SVR on atezolizumab plus bevacizumab (Atez/Bev) therapy for unresectable HCC (uHCC) caused by HCV. Methods: A retrospective analysis of 364 uHCC patients treated with Atez/Bev (September 2020–April 2025) and divided into SVR (n = 284) and non-SVR (n = 80) groups was performed, with clinical characteristics, prognosis, and adverse events compared. Results: There were no significant differences between the groups for age, sex, platelet count, AFP, or BCLC stage. However, the SVR group showed a significantly better ALBI score (−2.50 vs. −2.16) and lower AST (33 vs. 57 IU/L) and ALT (23 vs. 40 IU/L) levels (p < 0.01). Median progression-free survival (PFS) was 7.1 months in the SVR group and 6.1 months in the non-SVR group (p = 0.443), and median overall survival (OS) was 20.9 months in the SVR group and 18.9 months in the non-SVR group, with no significant differences between the groups (p = 0.560). Following IPW adjustment for factors related to OS, there was no significant difference regarding PFS (p = 0.921) and OS (p = 0.927). Multivariate analysis identified age ≥75 years and poor hepatic function (mALBI grade 2b/3) as independent predictors of poor OS; SVR status was not an independent factor. Changes in ALBI and Child-Pugh scores over time were not significantly different between the groups. In the non-SVR group, adverse events were more common as compared to the SVR group, including liver dysfunction (27.5% vs. 13.0%, p < 0.001) and edema/ascites (12.5% vs. 9.2%, p = 0.015). Conclusions: Although SVR was not independently associated with better survival, patients with SVR had preserved liver function and experienced fewer adverse events. These factors may indirectly support improved tolerability and therapeutic options during Atez/Bev therapy for HCV-related uHCC.

Background: Atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are standard first-line therapies for unresectable hepatocellular carcinoma (HCC). However, predictive biomarkers to guide treatment selection remain undefined. In this study, we aimed to evaluate the prognostic utility of a modified tumor marker (mTM) score, incorporating alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), for selecting between Atez/Bev and Dur/Tre and in stratifying treatment outcomes of unresectable HCC. Methods: We conducted a multicenter retrospective study of 1,313 patients with unresectable HCC treated with either Atez/Bev (n = 1,157) or Dur/Tre (n = 156). The mTM score was defined based on baseline AFP (≥100 ng/mL) and DCP (≥100 mAU/mL), assigning one point to each elevated marker. Patients were categorized as mTM low (score 0) or mTM high (score 1–2). Survival outcomes were analyzed using Kaplan-Meier curves and Cox proportional hazards models, with inverse probability of treatment weighting applied for confounder adjustment. Results: Among the mTM low patients, Atez/Bev was associated with significantly longer progression-free survival (PFS) (11.5 vs. 4.4 months, p < 0.001) and overall survival (30.6 vs. 17.0 months, p = 0.023) than Dur/Tre. In contrast, in mTM high patients, PFS was comparable between Atez/Bev and Dur/Tre (6.6 vs. 6.5 months, p = 0.873). However, in patients with DCP >400 mAU/mL, Dur/Tre was associated with improved PFS. Conclusion: The mTM score is a clinically relevant biomarker for treatment stratification in unresectable HCC. Atez/Bev may be preferable in mTM low patients, whereas Dur/Tre may provide greater benefit in those with elevated DCP levels. Prospective validation is warranted to refine the optimal cutoff values for clinical implementation.

INTRODUCTION: High-risk stigmata (HRS) and worrisome features (WFs) are imaging findings that reflect malignant potential of intraductal papillary mucinous neoplasms (IPMNs). The aim of this study was to determine the potential utility of stratifying malignant potential of IPMNs using apolipoprotein-A2 isoforms (apoA2-i) as a blood biomarker. METHODS: A total of 212 patients with IPMNs diagnosed by either magnetic resonance cholangiopancreatography or contrast-enhanced computed tomography, and endoscopic ultrasound were retrospectively enrolled. ApoA2-i and CA19-9 of all patients and 295 healthy individuals were measured. The distributions of apoA2-i and CA19-9 were analyzed in association with the malignant potential evaluated by imaging. RESULTS: In 212 patients with IPMN, 17 had HRS (HRS group), 70 had WFs (WF group), and 125 had no endoscopic ultrasound findings of HRS or WFs (non-WF group). The median of the apoA2-i Index in the HRS, WF, non-WF, and healthy groups were 57.7, 72.4, 87.5, and 87.9 μg/mL, respectively, with significantly lower levels in the HRS and WF groups (P < 0.001). By contrast, CA19-9 showed no significant difference among the 4 groups. The area under the curve of the apoA2-i Index to differentiate patients in the HRS and WF groups from the non-WF group was significantly higher than that of the CA19-9 (0.676 vs 0.554, P = 0.029). DISCUSSION: The diagnostic performance of apoA2-i for detecting IPMN with malignant potential was superior to that of CA19-9. The apoA2-i Index could serve as a useful biomarker for risk stratification and surveillance of IPMNs.

Background/Objective: Recently, there has been an increasing need to implement the diagnosis of the presence of covert hepatic encephalopathy (CHE) in patients with cirrhosis. The aim of this study was to identify novel factors associated with CHE in clinical practice. Methods: This retrospective study enrolled a total of 402 patients with cirrhosis at 17 institutions. The Stroop test was performed to diagnose CHE at each center. Results: The patients comprised 233 males and 169 females, with a median age of 69 (IQR, 61–75) years. The median albumin and 25(OH)D3 levels were 3.9 (3.5–4.3) g/dL and 15.4 (11.0–21.0) ng/mL, respectively. This cohort included 181 patients with esophageal varices (EV). Multivariate analysis revealed that low 25(OH)D3 (p < 0.05) and EV (p < 0.05) were independent risk factors for CHE. When limited to only laboratory factors, low albumin (p < 0.01) and low 25(OH)D3 (p < 0.05) were independent factors for CHE. The optimal cut-off values of albumin and 25(OH)D3 for predicting CHE were 3.7 g/dL and 16.5 ng/mL, respectively. The prevalence of CHE was 59.2% for 25(OH)D3 < 16.5 ng/mL and EV, 53.8% for albumin < 3.7 g/dL and 25(OH)D3 < 16.5 ng/mL, and 66.7% for albumin < 3.7 g/dL, EV, and 25(OH)D3 < 16.5 ng/mL. Conclusions: Low 25(OH)D3 and albumin levels, and the EV were positively associated with CHE in patients with cirrhosis. Specifically, the prevalence of CHE increased with a decrease in 25(OH)D3 levels. Patients with such risk factors should be actively and carefully examined for the presence of CHE.

Introduction: Rapid development of systemic treatments has resulted in improved prognosis for unresectable hepatocellular carcinoma (uHCC) patients. Since immune therapy shows a favorable therapeutic efficacy, use of tumor markers as biomarkers for monitoring treatment response is necessary. This study aimed to elucidate changes in positive rates of 3 available tumor markers in Japan, including alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and lens culinaris agglutinin-reactive AFP (AFP-L3) in uHCC patients treated with systemic therapies over time. Methods: From 2009 to 2023, 1,470 uHCC patients with data of tumor markers before starting treatment were enrolled. The positivity cutoff value for AFP was 20 ng/mL, for AFP-L3 was 10%, and for DCP was 40 mAU/mL. After dividing the 15 years examined into three periods of 5 years each (period I, II, and III), clinical features of the enrolled patients were evaluated, retrospectively. Results: The percentage of Barcelona Clinic Liver Cancer stage B patients who received systemic therapy increased from period I to III (27.7%, 38.5%, 46.6%, respectively, p < 0.001), which was also seen for HCC patients with a nonviral etiology (alcohol and others) (29.9%, 39.7%, 49.6%, respectively p < 0.001). Positive rates for AFP (67.8%, 62.1%, 50.8%, respectively) and DCP (84.1%, 80.5%, 72.7%, respectively) were decreased (each p < 0.001), while the AFP-L3 rate did not show a significant change (54.4%, 57.7%, 51.9%, respectively, p = 0.390). Among the AFP-negative patients, the rate of positive for DCP or AFP-L3 was increased (24.4%, 28.1%, 35.4%, respectively, p = 0.002). Conclusion: Based on introduction of systemic treatment in an early stage and increasing numbers of HCC cases with a nonviral etiology, the positive rate of AFP level has been declining. Thus, determination of DCP and AFP-L3 in addition to AFP as markers should be more actively utilized in clinical practice, as well as clinical trials for monitoring and evaluating treatment response in this era of combination immunotherapy as a powerful treatment.

Introduction: The most frequently used first-line treatment in patients with advanced hepatocellular carcinoma (HCC) is atezolizumab plus bevacizumab. Upon progression after this treatment, the standard of care in many countries is sorafenib, due to the lack of reimbursement for other drugs. Several randomized trials are currently underway to clarify the best second-line therapy in patients with HCC. This real-world study aimed to compare outcomes reached by lenvatinib and sorafenib second-line therapy in this setting. Methods: The overall cohort included 891 patients with HCC from 5 countries treated with atezolizumab plus bevacizumab in first-line setting between October 2018 and April 2022. At the data cut-off (May 2022), 41.5% of patients were continuing a first-line treatment, 5.5% were lost at follow-up, and 53.0% of patients had progressive disease after first-line therapy. 51.5% of patients with progressive disease received a second-line treatment, while 48.5% did not receive any subsequent therapy. Between patients receiving second-line treatment, 11.1% of patients underwent transarterial chemoembolization, 21.0% received sorafenib, 35.4% underwent lenvatinib, and 32.5% were treated with other drugs. Results: Lenvatinib second-line subgroup achieved a median overall survival (mOS) of 18.9 months, significative longer (p = 0.01; hazard ratio [HR]: 2.24) compared to sorafenib subgroup that reached a mOS of 14.3 months. The multivariate analysis highlighted albumin-bilirubin 1 grade (p < 0.01; HR: 5.23) and lenvatinib second-line therapy (p = 0.01; HR: 2.18) as positive prognostic factors for OS. The forest plot highlighted a positive trend in terms of OS in favor of patients treated with lenvatinib second-line regardless of baseline characteristics before first-line therapy. Conclusion: These results suggest that, in patients with HCC progressed to first-line atezolizumab plus bevacizumab, lenvatinib second-line therapy is associated to an improved survival compared to sorafenib.