ABSTRACT Durvalumab plus tremelimumab (Dur/Tre) is the first‐line treatment for unresectable hepatocellular carcinoma (uHCC). Immune‐mediated adverse events (imAEs) are common; however, the impact of specific imAE types on treatment persistence and outcomes remains unclear. This study evaluated the clinical features and prognostic implications of common imAEs during Dur/Tre therapy. This multicenter retrospective analysis included 351 patients with uHCC treated with Dur/Tre (January 2023 and February 2025), of whom 69 developed imAEs and had a follow up period of > 1 month. Baseline characteristics, period to onset and severity of imAEs, corticosteroid use, treatment continuation and subsequent therapies, progression‐free survival (PFS) and overall survival (OS) were analyzed according to imAE types. Among 69 patients, 34 developed colitis, 19 developed hepatitis and 16 developed endocrine disorders. The median age was 72 years, with 13% classified as Child‐Pugh B. The median period to imAE onset was 0.75 months (interquartile range, 0.38–1.25). Steroids at a dose equivalent to > 20 mg of prednisolone were administered to 46 patients (66.7%). Two‐thirds of the patients continued Dur/Tre despite imAE onset. Colitis occurred the earliest (median 0.54 months) and had the highest steroid requirement (82.4%), frequently resulting in treatment interruption. Endocrine disorders showed the highest continuation rate (75%). Although not statistically significant in PFS (median 11.2 months: 95% CI, 1.96–not achieved (NA), p = 0.450) and OS (95% CI, NA–NA, p = 0.134), compared with colitis (PFS; 4.3 months, OS; not reached) and hepatitis (PFS; 3.4 months, OS: 14.6 months). These findings should be interpreted cautiously given the small sample size. Subsequent systemic or locoregional therapies, including tyrosine kinase inhibitors, atezolizumab plus bevacizumab and interventional therapies, were administered to more than 65% of the patients. In Dur/Tre therapy, imAE impact varied by type; endocrine disorders are linked to better treatment continuation and prognosis, whereas colitis and hepatitis often lead to treatment interruption. Trial Registration: Takasaki General Medical Center (IRB No. TGMC2024–03)

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: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/m2 (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.

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:Real-world treatment trajectories and predictors of transition to best supportive care (BSC) in unresectable pancreatic cancer (UPC) remain underexplored. METHODS:This single-center retrospective study (2014-2025) included 274 patients. Overall survival (OS) and time-to-BSC were evaluated using Kaplan-Meier methods and a complete-case multivariable Cox model. Proportional hazards were assessed using Schoenfeld residuals, and treatment-line exposure using a 90-day landmark analysis. RESULTS:Among 274 patients, 248 (90.5%) initiated chemotherapy; 61.3% and 21.8% received ≥2 and ≥3 lines, respectively. Median OS was 9.7 months and increased across treatment-line categories (p < 0.001), and 84.7% transitioned to BSC. Higher C-reactive protein-to-albumin ratio (CAR) was associated with shorter BSC-free survival (p < 0.001). Although baseline CAR did not differ significantly between the chemotherapy and upfront-BSC groups (p = 0.076), it was independently associated with worse OS (HR 2.75), together with ECOG performance status ≥2 (HR 2.64) and liver metastasis (HR 1.62), and its association with mortality attenuated over time. In the 90-day landmark cohort (n = 215), receipt of ≥2 lines by day 90 was associated with longer subsequent OS (13.0 vs. 8.3 months, p = 0.012). CONCLUSIONS:Real-world treatment trajectories in UPC involved frequent transitions to BSC across successive therapy lines. Baseline CAR was independently associated with worse OS and earlier BSC transition and may provide prognostic information beyond performance status. CAR should not be used alone for treatment decisions but may identify patients at risk of early deterioration and prompt timely goals-of-care discussions. Prospective validation, including serial assessment, is warranted.

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/OBJECTIVES:Atezolizumab plus bevacizumab (Atez/Bev) is a standard treatment for unresectable hepatocellular carcinoma (HCC), but its anti-tumor efficacy remains limited. Combining intrahepatic locoregional treatment (IHLRT) with Atez/Bev has been explored as a strategy to overcome this limitation. This study aimed to clarify the significance of IHLRT in Atez/Bev treatment for unresectable HCC. METHODS:Eighty consecutive patients with unresectable HCC treated with Atez/Bev were retrospectively analyzed. IHLRT was performed in patients with residual viable hepatic lesions amenable to locoregional treatment during Atez/Bev therapy. Anti-tumor response was evaluated by RECIST; and progression-free survival (PFS), overall survival (OS), potential biomarkers, and contributing factors to OS were also assessed. RESULTS:IHLRT was selectively performed in 20 patients based on individual clinical conditions. Pretreatment characteristics were comparable between patients who did and did not receive IHLRT. Both best and initial tumor responses were superior in the IHLRT group, and PFS was significantly longer (16.2 vs. 8.4 months, p = 0.019), with comparable rates of severe treatment-related adverse events. On multivariate analysis, hepatic reserve function, objective response, neutrophil-to-lymphocyte ratio (NLR) and IHLRT were independent predictors of OS (HR: 2.17, 3.13, 0.58, and 1.62; p = 0.02, <0.01, 0.03 and 0.03, respectively). Although high NLR was a negative predictive factor, IHLRT appeared to mitigate the negative prognostic impact of an elevated NLR. CONCLUSIONS:On-demand, selective IHLRT during Atez/Bev treatment is well tolerated and provides superior and more durable tumor control, particularly in patients achieving an initial objective response.

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 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.

BACKGROUND AND AIMS:Atezolizumab plus bevacizumab is administered for unresectable HCC, with bevacizumab dosed by body weight, which may not adequately reflect body composition. This study evaluated the association between body surface area (BSA)-adjusted bevacizumab dosing, expressed as the bevacizumab-BSA index (BBI), and outcomes. APPROACH AND RESULTS:This retrospective study included 1507 patients with unresectable HCC treated with atezolizumab plus bevacizumab at 30 Japanese institutions. BBI was the ratio of actual to standard dose per BSA. Restricted cubic spline analyses identified the optimal BBI range. Outcomes were compared among BBI groups. Spline analysis revealed a nonlinear association between BBI and overall survival (OS), with an optimal BBI range of 106%-121%. Accordingly, the patients were classified into under (n=924), target (n=522), and over (n=61) groups. The median progression-free survival was significantly longer in the target group than in the nontarget group (10.3 vs. 6.5 mo, p <0.001), and the median OS was prolonged (24.9 vs. 19.2 mo, p =0.008). Multivariable analysis demonstrated that the target BBI group was independently associated with improved progression-free survival (HR, 0.807; 95% CI: 0.715-0.910; p <0.001) and OS (HR, 0.850; 95% CI: 0.733-0.985; p =0.031). The objective response rate was significantly higher in the Target group ( p =0.023), while treatment-related adverse event rates were comparable across the BBI groups, with no significant differences in proteinuria, hypertension, or other toxicities. CONCLUSIONS:BSA-adjusted bevacizumab dosing was associated with improved efficacy without increased toxicity in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

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.

ABSTRACT Background Findings regarding long‐term outcomes of unresectable hepatocellular carcinoma (uHCC) patients treated with atezolizumab and bevacizumab (Atez/Bev) have yet to be reported. This study was performed to evaluate results regarding 3 year survival of such patients treated in real‐world clinical settings. Methods This multicenter retrospective study included 555 patients with Child‐Pugh A and BCLC stage B or C, for whom Atez/Bev treatment was initiated in the period from 2020 to 2021. Best treatment response, progression‐free survival (PFS), overall survival (OS), post‐progression survival (PPS), and immune‐related adverse events (irAEs) were analyzed. Results Median age was 73 years and 80.2% were male. Atez/Bev was given as first‐line therapy in 55.3%. Objective response rate (ORR) was 41.3% and disease control rate (DCR) was 79.4%. Median PFS was 6.2 months, while median OS was 21.6 months with a 3 year survival rate of 29.7%. Patients treated with Atez/Bev as first‐line therapy showed a higher 3 year survival rate of 35.9%. Post‐progression treatment was administered to 54.1% of the patients and median PPS in those was 10.9 months. Conversion therapy was performed in 5.9%. IrAEs occurred in 13.3% (grade 5: 0.7%). Conclusions uHCC patients treated with Atez/Bev in clinical practice settings showed good ORR and DCR, as well as favorable long‐term survival with a 3 year survival rate of approximately 30%, including 35.9% for first‐line users.

BACKGROUND:Signal intensity on the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-magnetic resonance imaging (MRI) reflects Wnt/β-catenin signaling activity in hepatocellular carcinoma (HCC), and has been associated with poor response to immune monotherapy. However, whether such imaging findings predict resistance to combination immunotherapy has not been prospectively validated. METHODS:This multicenter prospective study enrolled 152 patients with unresectable HCC treated with atezolizumab plus bevacizumab across 12 Japanese centers. All had Child-Pugh class A liver function and underwent Gd-EOB-DTPA-MRI prior to treatment. Hyperintensity was defined as a relative enhancement ratio ≥ 0.9. Treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and time to partial response (TtPR), were compared between patients with and without hyperintense nodules. RESULTS:Of the 152 patients, 82 received immunotherapy as the first-line and 70 as a later-line therapy. Hyperintense nodules were identified in 57 (37.5%) patients. The hyperintense group showed a higher ORR (36.8% vs. 22.1%) and comparable PFS (8.9 vs. 7.9 months) and OS (16.7 vs. 23.9 months), though not statistically significant. The TtPR was significantly shorter in the hyperintense group (median 26.0 months vs. not reached, p = 0.033), although mainly influenced by prior systemic therapy. Overall, hyperintense lesions were not associated with reduced efficacy and tended to show more favorable responses. CONCLUSION:This prospective multicenter study demonstrates that hepatobiliary hyperintensity on Gd-EOB-DTPA-enhanced MRI-an imaging surrogate of Wnt/β-catenin activation-does not indicate resistance to atezolizumab plus bevacizumab. These findings support the use of combination immunotherapy in molecularly "immune-cold" HCC.

AIM:Evidence regarding the optimal first-line immune checkpoint inhibitor (ICI) regimen for treating unresectable hepatocellular carcinoma (uHCC) with Child-Pugh class B (CP-B) liver function remains limited. This study compared atezolizumab plus bevacizumab (Atez/Bev) and durvalumab plus tremelimumab (Dur/Tre group) in real-world settings. METHODS:In this multicenter retrospective study, 211 consecutive patients with uHCC and CP-B liver function who underwent ICI-based therapy as a first-line therapy were analyzed. Treatment responses, survival outcomes, albumin-bilirubin (ALBI) score changes, and adverse events were evaluated. Survival analyses were adjusted using inverse probability weighting (IPW). RESULTS:The median progression-free survival associated with the Atez/Bev and Dur/Tre regimens was 5.0 and 3.5 months, respectively; the median corresponding overall survival was 10.5 and 12.4 months. After IPW adjustment, no significant differences were observed in progression-free or overall survival. The Atez/Bev regimen-associated disease control rate was significantly higher (75.2% vs. 55.0%, p = 0.02). The Dur/Tre regimen, meanwhile, was associated with a significantly higher immune-related adverse event incidence (10.5% vs. 32.7%, p < 0.01) and a greater need for high-dose corticosteroid treatment. In contrast, the Atez/Bev regimen resulted in a progressive decrease in ALBI scores, whereas the Dur/Tre regimen maintained the hepatic functional reserve. CONCLUSIONS:The Atez/Bev and Dur/Tre regimens afforded comparable survival outcomes but differed substantially in safety and effects on the hepatic functional reserve. Given the trade-off between immunotoxicity and liver function preservation, treatment selection for CP-B liver function should be individualized, considering baseline hepatic reserve, tolerability, and anticipated treatment trajectory.

Aim:The gut microbiome modulates immune responses, and butyrate-producing bacteria have been linked to improved immune checkpoint inhibitor (ICI) efficacy. Conversely, proton pump inhibitors (PPIs) may negatively impact ICI outcomes by altering gut microbiota. This study aims to elucidate their effects in hepatocellular carcinoma (HCC). Methods:This retrospective multicenter cohort study included 208 HCC patients treated with durvalumab plus tremelimumab at 25 hospitals in Japan. Patients were classified into a butyric acid group (n = 27), who ingested drugs containing butyrate-producing enterobacteria, and a non-butyric acid group (n = 181), as well as a PPI group (n = 107) and a non-PPI group (n = 101). Overall survival (OS) was analyzed using inverse probability of treatment weighting, and risk factors were assessed with Cox proportional hazards modeling. Tumor response was evaluated by RECIST v1.1. Results:No significant OS differences were observed between the butyric acid and non-butyric acid groups (p = 0.921), or between PPI and non-PPI groups (p = 0.917). The objective response rate was 3.7% in the butyric acid group versus 15.5% in the non-butyric acid group (p = 0.543) and 15.8% in the PPI group versus 12.1% in the non-PPI group (p = 0.222). Disease control rates were comparable. Multivariate analysis identified ECOG performance status (p = 0.019) and ALBI score (p < 0.001) as independent prognostic factors, while butyrate-producing bacteria and PPI use were not associated with survival outcomes. Conclusion:Neither butyrate-producing bacteria nor PPI use significantly influenced the efficacy of durvalumab plus tremelimumab in HCC. The liver's immunotolerant microenvironment may limit the impact of microbiome modulation on ICI efficacy.

OBJECTIVES:This study aimed to characterize the clinical features and prognosis of advanced pancreatic cancer (APC) complicated by disseminated intravascular coagulation (DIC), with a particular focus on distinguishing between tumor-related and infection-related DIC and evaluating the feasibility of chemotherapy in this high-risk population. METHODS:This single-center retrospective study analyzed 284 patients with APC. Clinicopathological features and prognosis were compared between patients with and without DIC. Outcomes were further stratified according to DIC etiology, specifically distinguishing between tumor-related and infection-related DIC. RESULTS:Of 284 patients, 19 (6.7%) developed DIC, including 10 (52.6%) with tumor-related DIC and 9 (47.4%) with infection-related DIC. Overall survival (OS) and time to treatment failure (TTF) differed significantly among the three groups (P<0.001). Patients with tumor-related DIC had the shortest survival, (median OS: 1.3 mo; TTF: 0.85 mo, whereas the non-DIC group showed longest survival (median OS: 10.4 mo; TTF 5.2 mo). In multivariable Cox regression analysis, DIC remained independently associated with poor OS (HR 3.6, 95% CI 2.2-5.8; P<0.001). Among 8 patients with tumor-related DIC who received chemotherapy with concomitant anticoagulant or antifibrinolytic therapy, 4 (50%) achieved resolution of DIC. Notably, DIC recurred upon tumor progression, suggesting that DIC control was temporary and closely tied to tumor response. CONCLUSION:APC with DIC carries a dismal prognosis, particularly when tumor-related. Chemotherapy may be feasible in carefully selected patients with tumor-related DIC when administered with appropriate supportive and anticoagulant or antifibrinolytic therapy; however, its independent contribution to DIC resolution requires cautious interpretation.

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.

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 1313 patients with unresectable HCC treated with either Atez/Bev (n = 1157) 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 for 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 (IPTW) 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.

BACKGROUND AND AIMS:To assess the outcomes of patients with hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atezo/Bev), categorised by oncological resectability criteria, which reflect tumour burden and extent of disease. METHODS:A cohort of 467 HCC patients who received Atezo/Bev was enrolled. Patients were classified into two groups based on oncological resectability criteria: BR (borderline resectable) 1 (n = 153) and BR2 (n = 314). RESULTS:The median progression-free survival (PFS) was 9.0 months in the BR1 group and 6.8 months in the BR2 group (p = 0.014). Multivariable analysis identified the following independent prognostic factors for PFS: age ≥ 75 years (hazard ratio [HR], 1.309), albumin-bilirubin (ALBI) grade ≥ 2 (HR, 1.494), neutrophil-to-lymphocyte ratio (NLR) ≥ 3 (HR, 1.289), α-fetoprotein ≥ 100 ng/mL (HR, 1.523) and BR2 classification (HR, 1.360). The median overall survival (OS) was 25.3 months in the BR1 group and 22.3 months in the BR2 group (p = 0.048). Multivariable analysis identified the following independent prognostic factors for OS: age ≥ 75 years (HR, 1.522), ALBI grade ≥ 2 (HR, 2.411), NLR ≥ 3 (HR, 1.635), α-fetoprotein ≥ 100 ng/mL (HR, 1.530) and BR2 classification (HR, 1.421). When oncological resectability factors (tumour number and size, vascular invasion and extrahepatic spread) were incorporated into the multivariable analysis, major vascular invasion emerged as a significant predictor of both PFS (HR, 3.188) and OS (HR, 2.650). CONCLUSIONS:In patients with HCC characterised by limited resectability undergoing Atezo/Bev, vascular invasion, in addition to liver function, is a critical prognostic determinant of tumour progression.