Yutaka Yata

Aim: Metabolic syndrome (MetS) is a known risk factor for hepatocellular carcinoma (HCC), but the impact of cumulative MetS burden and changes in MetS status over time remains unclear. This study aimed to assess these associations using a large‐scale Japanese health dataset. Methods: We analysed medical data from 2.71 million Japanese individuals collected between 2005 and 2020. The study evaluated the incidence of HCC in relation to MetS, preMetS (an early stage of MetS), and five MetS components: triglycerides ≥ 150 mg/dL, HDL‐C < 40 mg/dL in men or < 50 mg/dL in women, fasting blood glucose ≥ 100 mg/dL, blood pressure ≥ 130/85 mmHg, and waist circumference ≥ 90 cm in men or ≥ 80 cm in women. For the dynamic analysis, participants were classified into four groups based on MetS status during two predefined periods, 2010–2011 and 2012–2013: MetS‐free, MetS‐developed, MetS‐persistent, and MetS‐recovered. As Type 2 diabetes (T2D) is an extreme metabolic state and a strong independent risk factor for HCC, this study assessed the impact of MetS on HCC risk excluding T2D. Results: Among the 2.71 million individuals, 63 435 developed HCC. Compared with the non‐MetS group, both the MetS group (HR 1.42, 95% CI 1.39–1.45) and the preMetS group (HR 1.26, 95% CI 1.22–1.29) had significantly increased HCC risk. A higher number of MetS components was associated with progressively increased HCC incidence. Individuals who developed or maintained MetS over time had a higher risk of HCC than MetS‐free individuals, whereas those who recovered from MetS had a reduced risk. Conclusion: MetS and even preMetS are significant risk factors for HCC. Importantly, improvement in MetS status may help prevent HCC. These findings suggest that early identification and management of MetS could play a key role in liver cancer prevention.

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 and Aims: For unresectable hepatocellular carcinoma (HCC), atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are widely used first‐line immunotherapies; however, biomarkers to guide regimen selection before treatment initiation remain undefined. We investigated whether baseline des‐γ‐carboxy prothrombin (DCP) modifies objective response rate (ORR) according to treatment regimen. Methods: We analysed 1464 patients with unresectable HCC treated with first‐line systemic therapy between 2020 and 2025 across multiple centers. Patients were divided into training and validation cohorts. Restricted cubic spline‐based interaction models were used to evaluate the association between baseline DCP and ORR according to treatment regimen. The predicted absolute difference in ORR (ΔORR) between regimens was examined across continuous DCP values, with a prespecified 10% threshold considered clinically meaningful. Robustness was assessed using leave‐one‐center‐out and repeated random‐split sensitivity analyses. Results: Overall ORR did not differ significantly between Atez/Bev and Dur/Tre. However, a significant interaction between baseline DCP and treatment regimen was observed in both cohorts. Atez/Bev showed a relatively stable ORR across DCP concentrations, whereas Dur/Tre showed a DCP‐dependent increase in ORR. At low DCP levels, Atez/Bev was favoured; with increasing DCP levels, the relative benefit shifted toward Dur/Tre. Sensitivity analyses confirmed a consistent DCP‐dependent transition pattern, although the DCP level at which ΔORR exceeded 10% varied across analyses, supporting a transition zone rather than a fixed cutoff. Conclusions: Baseline DCP may modify the relative treatment benefit between Atez/Bev and Dur/Tre in unresectable HCC. Rather than defining a rigid cutoff, DCP appears to delineate a continuum in which higher levels increasingly favour Dur/Tre, providing a practical framework for individualized immunotherapy selection.

Background and Aim: Atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre) are widely used first‐line immune checkpoint inhibitor (ICI)‐based regimens for unresectable hepatocellular carcinoma (uHCC). However, reliable biomarkers to inform treatment choice remain limited. This study evaluated whether the simplified BALAD‐based score (BALAD‐S) is associated with differential treatment outcomes. Materials and Methods: This multicenter retrospective study included 752 Japanese patients with uHCC who received first‐line Atez/Bev ( n = 645) or Dur/Tre ( n = 107) between October 2020 and March 2026. BALAD‐S was calculated using bilirubin, albumin, AFP, AFP‐L3, and des‐γ‐carboxy prothrombin, and patients were stratified into BALAD‐S low (≤ 2) and high (≥ 3) groups. Treatment response, progression‐free survival (PFS), and overall survival (OS) were evaluated. Results: In the BALAD‐S low group, Atez/Bev showed longer PFS than Dur/Tre (10.5 vs. 4.3 months; p < 0.001), with longer OS also observed (28.3 vs. 19.4 months; p = 0.049). In the BALAD‐S high group, PFS did not differ significantly (7.0 vs. 5.3 months with Dur/Tre and Atez/Bev, respectively, p = 0.210), whereas OS was longer with Dur/Tre than with Atez/Bev (27.3 vs. 16.4 months; p = 0.022). Treatment effects differed by BALAD‐S category (HR for Dur/Tre vs. Atez/Bev: 1.50 in BALAD‐S low and 0.55 in BALAD‐S high; p for interaction = 0.005). In patients treated from 2023 onward, similar treatment‐effect heterogeneity was observed (HR 1.61 in BALAD‐S low and 0.59 in BALAD‐S high; p for interaction = 0.007). Conclusion: Outcomes with Atez/Bev and Dur/Tre differed according to BALAD‐S score. BALAD‐S may help identify patients with differential outcomes between first‐line ICI‐based regimens and represents a candidate stratification marker requiring validation.

Background and Aim: This study evaluated clinical outcomes in patients with hepatocellular carcinoma (HCC) treated with durvalumab plus tremelimumab (Dur/Tre) in routine practice, stratified by whether they fulfilled the eligibility criteria of the phase 3 HIMALAYA trial. Methods: A total of 412 patients with unresectable HCC receiving Dur/Tre at 30 Japanese institutions were enrolled. Of these, 92 fulfilled the HIMALAYA trial eligibility criteria (HIMALAYA group) and 320 did not (non‐HIMALAYA group). Results: Median progression‐free survival (PFS) was 5.4 months in the HIMALAYA group and 3.0 months in the non‐HIMALAYA group ( p = 0.012). Multivariable analysis identified body mass index ≥ 25 kg/m ² (hazard ratio [HR], 0.780; 95% confidence interval [CI], 0.612–0.993; p = 0.044) and portal vein invasion (HR, 1.509; 95% CI, 1.049–2.170; p = 0.027) as independent predictors of PFS. Median overall survival (OS) was 19.4 months in the HIMALAYA group versus 15.4 months in the non‐HIMALAYA group ( p = 0.014). Multivariable analysis showed Eastern Cooperative Oncology Group performance status ≥ 1 (HR, 1.878; 95% CI, 1.253–2.814; p = 0.002) and albumin–bilirubin grade ≥ 2 (HR, 2.032; 95% CI, 1.319–3.318; p = 0.001) as independent determinants of OS. Any‐grade endocrine dysfunction occurred in 13 (14.1%) and 21 (6.6%) patients ( p = 0.030), with grade ≥ 3 events in 5 (5.4%) and 2 (0.6%), respectively ( p = 0.007). Subgroup analysis suggested that non‐HIMALAYA patients with ALBI grade 1 may have OS comparable to the HIMALAYA group. Conclusions: Patients fulfilling the HIMALAYA trial eligibility criteria and those who did not but had preserved hepatic function demonstrated favorable survival outcomes with Dur/Tre.

Background: Patients with unresectable hepatocellular carcinoma (HCC) who initially achieve disease control with atezolizumab plus bevacizumab (Atez/Bev) eventually develop progressive disease (PD). Treatment is usually shifted to subsequent systemic therapy, whereas ablation is rarely considered. We investigated whether ablation at PD could serve as a salvage option in selected patients after initial disease control with Atez/Bev. Methods: From a multicenter database involving 16 institutions, we identified 186 patients with unresectable HCC who achieved partial response or stable disease with first‐line Atez/Bev and subsequently developed PD between 2020 and 2025. Postprogression survival (PPS) and overall survival (OS) were compared between ablation and nonablation groups using propensity score matching (PSM). Multivariable Cox regression was performed for both OS and PPS. Inverse probability of treatment weighting (IPTW) and landmark analysis were used as sensitivity analyses. Results: After PSM, 20 matched pairs were analyzed. OS tended to be longer in the ablation group than in the nonablation group (not reached vs. 25.7 months and p = 0.090). PPS was significantly longer in the ablation group (37.7 vs. 9.17 months and p = 0.043). In multivariable analyses adjusted for ALBI score and tumor number, ablation showed a trend toward improved OS (HR 0.393 and p = 0.063) and was associated with prolonged PPS (HR 0.335 and p = 0.035), although residual confounding limits causal inference. Sensitivity analyses showed consistent results. Conclusion: In selected patients who initially achieved disease control with Atez/Bev, ablation at PD may be a potential salvage approach associated with prolonged PPS. These exploratory and hypothesis‐generating findings warrant prospective validation of ablation‐based salvage strategies.

Aim: Atezolizumab plus bevacizumab (Atez/Bev) in unresectable hepatocellular carcinoma (uHCC) is a standard first‐line therapy, but bleeding‐related adverse events (BL‐AEs) remain clinically concerning, particularly in real‐world patients with advanced tumors, portal hypertension, or undergoing antithrombotic therapy (ATT). We aimed to evaluate whether ATT increases bleeding risk, identify pretreatment factors associated with BL‐AEs, and assess the impact of bleeding on progression‐free survival (PFS) and overall survival (OS) in patients with uHCC treated with Atez/Bev. Methods: This multicenter retrospective study included 981 patients with uHCC treated with Atez/Bev. BL‐AEs were identified by clinical assessment, imaging, or endoscopy. Predictors of BL‐AEs were analyzed using logistic regression. Survival outcomes were compared by Kaplan–Meier method, with inverse probability weighting (IPW) applied to adjust for baseline imbalances. Results: BL‐AEs occurred in 102 patients (10.4%) and led to treatment discontinuation in 2.7% patients. Independent predictors of BL‐AEs included advanced tumor burden components, such as Vp ≥ 3 portal vein invasion and extrahepatic metastasis. Neither ATT nor portal hypertension–related factors were associated with bleeding risk. PFS did not differ between groups, whereas OS was significantly shorter in the BL group before IPW adjustment than after IPW adjustment. Conclusions: During Atez/Bev therapy, BL‐AEs were primarily associated with advanced tumor burden rather than with ATT or baseline portal hypertension–related factors. Although BL‐AEs were associated with poorer OS, this should be interpreted cautiously, as bleeding may reflect aggressive tumor biology rather than a direct mortality cause. Careful monitoring for bleeding complications may be required in patients with advanced tumor burden receiving Atez/Bev.

Background & Aims: Systemic therapy is the standard care for patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. However, the relative prognostic importance of the intrahepatic tumor burden versus the extent of extrahepatic disease in the era of immune checkpoint inhibitor‐based therapy remains unclear. This study aimed to clarify the prognostic impact of intrahepatic tumor burden in patients with metastatic HCC treated with atezolizumab plus bevacizumab (Atez/Bev). Methods: We conducted a multicenter retrospective study of patients with HCC and extrahepatic metastases who received first‐line Atez/Bev therapy. The intrahepatic tumor burden was assessed using established radiologic parameters, including tumor size, number, and vascular invasion, and the patients were stratified according to the intrahepatic disease severity. Overall survival (OS) was defined as the primary endpoint. Survival analyses were carried out using the Kaplan–Meier method and Cox proportional hazards models. Results: Overall, 306 patients were included in the study. During a median follow‐up of 13.5 months, the OS differed markedly according to the intrahepatic tumor burden and macrovascular invasion. The median OS was 17.8 months in the mild MVI group, 12.2 months in the severe MVI group, 29.8 months in the UT7 in group, and 15.2 months in the UT7 out group ( p < 0.001). In multivariate analysis, the intrahepatic tumor burden remained an independent predictor of OS, whereas the extent and number of extrahepatic metastatic sites were not significantly associated with prognosis. Conclusions: In metastatic HCC treated with atezolizumab plus bevacizumab, intrahepatic tumor burden was associated with overall survival and may be useful for risk stratification and treatment optimization.

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 and Aims: This multicenter retrospective study in Japan aimed to investigate the prognostic significance of lymphocyte‐to‐monocyte ratio (LMR) in patients with unresectable hepatocellular carcinoma (HCC) treated with durvalumab plus tremelimumab (Dur/Tre). Methods: A total of 377 patients with HCC and treated with Dur/Tre across 30 institutions in Japan were included in this multicenter study. Time‐dependent receiver operating characteristic (ROC) analysis was performed to determine the optimal LMR cut‐off value. Hazard ratio (HR) spline curve analysis was used to identify the optimal LMR range for predicting progression‐free survival (PFS) and overall survival (OS). Results: Time‐dependent ROC analysis identified an optimal LMR cut‐off value of 2.52 for predicting median OS. Multivariate analysis demonstrated that an LMR of ≥ 2.52 was independently associated with superior PFS (HR: 0.777) and OS (HR: 0.657). The median PFS was 2.6 months in patients with an LMR of < 2.52, compared with 3.5 months in those with an LMR of ≥ 2.52 ( p = 0.022). The median OS was 12.8 months in patients with an LMR of < 2.52, compared with 23.4 months in those with an LMR of ≥ 2.52 ( p < 0.001). The disease control rate was significantly higher in the high LMR group ( p = 0.032). The HR spline curve analysis revealed that an LMR range of approximately 1.8–2.6 represents an optimal cut‐off for predicting both PFS and OS. Conclusions: LMR is a readily accessible prognostic biomarker for both PFS and OS in patients with unresectable HCC treated with Dur/Tre, and may serve as a practical tool for risk stratification in clinical practice.