Background:Hepatocellular carcinoma (HCC) imposes a substantial global burden. Triple therapy including transarterial chemoembolization, immune checkpoint inhibitors, and targeted therapy offers survival benefits but increases toxicity risk. We aimed to evaluate the impact of age or its related comorbidities on the efficacy and safety of triple therapy. Methods:This multicenter retrospective study included 627 HCC patients receiving triple therapy from CLEAP database (2019-2023). Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. Treatment response and treatment-related adverse events (TRAEs) were the secondary endpoints. Cox/logistic regression models were used to assess the risk factors of outcomes. Results:Of 627 patients, 177 were classified as elderly (≥65 years) and 450 as younger (<65 years), as defined according to World Health Organization criteria. Elderly patients present with lower tumor burden compared with younger patients. After propensity score matching (1:2), two cohorts were comparable in objective response rate, disease control rate, PFS, OS, and grade ≥3 TRAEs. Age, either continuous or categorical data, was not associated with outcomes. In contrast, stratification by Charlson Comorbidity Index (CCI), there were significant outcome disparities for PFS and OS among low- (0-1), intermediate- (2-3), and high-risk (≥4) groups. The age-adjusted CCI (aCCI) could not only discriminate survival outcomes but also predict the risk of TRAEs among low- (0-3), intermediate- (4-5), and high-risk (≥6) groups. Multivariable analyses demonstrated that high aCCI score (≥6) independently predicted shorter PFS (hazard ratio: 1.36, p = 0.02) and OS (hazard ratio: 1.75, p = 0.001) and increased grade ≥ 3 TRAEs (odds ratio: 1.96, p = 0.005). Conclusion:aCCI was a potent predictor of efficacy and safety in triple therapy for HCC.

Introduction: Cholangiocarcinoma (CCA) is an aggressive malignancy with poor prognosis and limited treatment options. Molecular heterogeneity and the tumor immune microenvironment play crucial roles in CCA progression and therapeutic response, but comprehensive stratification remains insufficient for guiding treatment decisions. Methods: This study performed integrated multi-omics profiling as well as immunohistochemical validation on 424 CCA patients. Multidimensional data, including genomic, epigenomic, transcriptomic, and immune profiling, were analyzed to identify clinically relevant molecular subtypes. Results: Four distinct molecular subtypes of CCA were identified, each exhibiting unique clinical and immunological features: C1 (proliferation): driven by TP53/KRAS mutations and CpG island methylator phenotype (CIMP+) hypermethylation, showing T helper 17 cells infiltration and poor outcomes; C2 (Immune-Suppressed Macro_LYVE1 [ISM_LYVE1]): stroma-rich with LYVE1+ macrophages and epithelial-mesenchymal transition (EMT) activation; C3 (immune-activated Macro_C1QC (IAM_C1QC)): enriched in C1QC+ macrophages, CD8+ T-cells, and metabolic pathways, highly responsive to immune checkpoint blockade (ICB; 75% overall response rate); C4 (immune exclusion): FGFR2-altered and IDH1-mutant, with an immunologically cold phenotype. Conclusion: We validated ATP2B1 as a novel prognostic biomarker and developed a 160-gene classifier for subtype prediction. The C3 subtype's exceptional ICB response, independent of conventional biomarkers (PD-L1/microsatellite instability/tumor mutational burden), highlights the clinical utility of this classification system in guiding precision immunotherapy for CCA.

Abstract Background and objective Conversion or downstaging therapy for intermediate and advanced unresectable hepatocellular carcinoma (HCC) has emerged as a major focus of clinical practice and research in recent years. This study aims to investigate the current clinical application of conversion therapy in China and determine the factors that physicians consider when selecting eligible patients for conversion therapy and choosing the appropriate conversion modality. Methods Physicians who met predefined inclusion criteria were invited to complete an online questionnaire between January and July 2024. The collected data were subsequently pooled and analyzed descriptively. Results A total of 120 valid questionnaires were gathered, mainly from surgical (n = 83, 69.2%) and interventional (n = 37, 30.8%) departments. The survey revealed that approximately 51% of CNLC stage Ib-IIIa patients were selected for conversion or downstaging treatment. Three primary factors were prioritized by physicians for the determination of conversion therapy: portal vein tumor thrombus (PVTT) type (116/120, 97%), future liver volume (108/120, 90%), and Child–Pugh classification (108/120, 90%). Currently, the predominant conversion therapy approach involves a combination of local and systemic therapies, which is utilized in approximately 73% of cases. Among systemic treatments, the combination of lenvatinib and immunotherapy is the most widely adopted. Besides, a higher objective response rate (ORR) was the foremost consideration for 83% (99/120) of physicians, followed by rapid response (82/120, 68%), adherence to guidelines and consensus (76/120, 63%), and lower tumor progression rate (70/120, 58%). Conclusion This survey demonstrated the current status of conversion therapy for HCC in China. Over half of the newly diagnosed HCC patients were eligible for treatment modalities aimed at achieving surgical resection through conversion therapy, and the most popular indications were the presence of PVTT, insufficient FLR and Child–Pugh classification.

Background: Immunotherapy has revolutionized hepatocellular carcinoma (HCC) treatment, increasingly being incorporated into various stages of treatment, including preoperative therapy. However, preoperative immunotherapy alters both physiological status and tumor biology, potentially impacting the perioperative risk. We aimed to explore the association between the implementation details of preoperative immunotherapy and perioperative risk. Methods: This study retrospectively enrolled HCC patients who received immune checkpoint inhibitor (ICI)-based immunotherapy prior to radical surgery. A comprehensive dataset encompassing baseline characteristics and immunotherapy-specific parameters was collected. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors, followed by validation through machine learning algorithms to evaluate the predictive performance of the derived determinants. Results: This multicenter retrospective study enrolled 303 HCC patients who received preoperative immunotherapy across 26 participating centers. Based on specified perioperative risk stratification criteria, 182 patients (60.07%) were stratified into the low-risk cohort, while 121 patients (39.93%) constituted the high-risk cohort. Multivariate logistic regression analysis identified several independent risk factors of elevated perioperative risk: ICI duration exceeding four cycles [odds ratio (OR), 2.00; 95% confidence interval (CI) 1.20-3.32]; the occurrence of grade >= 3 immune-related adverse events (irAEs) (OR, 2.36; 95% CI: 1.13-4.92); the presence of major vein thrombus (OR, 2.05; 95% CI: 1.25-3.38); multiple tumor nodules (OR, 1.74; 95% CI: 1.02-2.98); and maximal tumor diameter >5 cm (OR, 2.02; 95% CI: 1.10-3.73). Subgroup analyses consistently demonstrated these associations. Machine learning algorithms quantified feature importance for perioperative risk predictors, with extended ICIs duration (mean importance rank =2.88) and grade >= 3 irAEs (mean importance rank =2.38) emerging as top-ranked variables. Conclusions: This multicenter retrospective study reveals ICIs duration and high-grade irAEs were associated with elevated perioperative risk in HCC patients undergoing preoperative immunotherapy, providing actionable insights for optimizing perioperative management protocols.

BACKGROUND AND AIMS:Nonperipheral washout is a major imaging feature of hepatocellular carcinoma (HCC) with prognostic value, but whether its temporal differentiation can refine prognostic stratification remains understudied. This study aimed to investigate the prognostic implications of nonperipheral washout timing in HCC. METHODS:This multicentre, retrospective cohort study included patients who underwent curative resection for single BCLC stage 0/A HCC and preoperative extracellular contrast agent-enhanced MRI at seven tertiary centres (March 2011 to April 2023). Three masked radiologists independently evaluated nonperipheral washout patterns, which were classified as early (present in the portal venous phase), late (present only in the delayed phase), or absent. Early recurrence-free survival (eRFS; ≤ 2 years) and 5-year RFS were assessed using Kaplan-Meier and Cox regression analyses. RESULTS:A total of 611 patients (median age, 55 years; 520 men) were included. Early, late, and no washout were observed in 367 (60.1%), 95 (15.5%), and 149 (24.4%) patients, respectively. Inter- and intra-reader agreements were substantial to excellent (κ range, 0.67-0.94). Early washout was associated with microvascular invasion (p = 0.01) and Edmondson-Steiner G3/4 (p = 0.002). The eRFS rates were 67.3%, 82.1%, and 85.2% for the early, late, and no-washout groups (p < 0.001); the 5-year RFS rates were 53.4%, 62.1%, and 71.8% (p = 0.002). In multivariable Cox analysis adjusting for factors, early washout independently predicted eRFS (HR, 1.86; p < 0.001) and 5-year RFS (HR, 1.46; p = 0.006). CONCLUSIONS:In patients undergoing curative resection for single BCLC 0/A HCC, temporal differentiation of nonperipheral washout refines prognostic stratification, with early washout identifying patients at higher risk of recurrence.

BACKGROUND:No neoadjuvant treatment has been considered to be standard therapy for patients with resectable intrahepatic cholangiocarcinoma with high-risk factors for recurrence. The GOLP regimen (gemcitabine-oxaliplatin, lenvatinib, and an anti-programmed death 1 antibody) has shown promising efficacy with a manageable safety profile in advanced intrahepatic cholangiocarcinoma and biliary tract cancer. METHODS:In a phase 2-3 trial, we randomly assigned, in a 1:1 ratio, patients with resectable high-risk intrahepatic cholangiocarcinoma to the neoadjuvant group (intravenous gemcitabine-oxaliplatin plus toripalimab every 3 weeks for three cycles and oral lenvatinib once daily for 9 weeks, followed by curative resection) or the control group (curative resection and no neoadjuvant treatment). All patients received adjuvant capecitabine for eight cycles after surgery. The primary end point was event-free survival. Secondary end points included overall survival and safety. RESULTS:A total of 178 patients underwent randomization (88 patients to the neoadjuvant group and 90 to the control group). At the interim analysis at a median follow-up of 16.9 months, the median event-free survival was significantly longer in the neoadjuvant group (18.0 months; 95% confidence interval [CI], 13.8 to 27.6) than in the control group (8.7 months; 95% CI, 7.2 to 12.4) (P<0.001). Overall survival at 24 months was 79% (95% CI, 70 to 90) in the neoadjuvant group and 61% (95% CI, 50 to 75) in the control group (hazard ratio for death, 0.43; 95% CI, 0.23 to 0.79; P = 0.005, which did not meet the significance criterion [two-sided alpha, 0.0019]). Across all treatment phases, adverse events occurred in 97% of the patients in the neoadjuvant group and in 70% of those in the control group. During the neoadjuvant phase, adverse events of grade 3 or higher occurred in 28% of the patients, and treatment-related adverse events of grade 3 or higher in 26%. No treatment-related adverse event led to death. CONCLUSIONS:Neoadjuvant GOLP led to significantly longer event-free survival than control therapy, with mainly low-grade adverse events, among patients with resectable high-risk intrahepatic cholangiocarcinoma. (Funded by the Clinical Research Plan of Shanghai Hospital Development Center and others; ZSAB-neoGOLP ClinicalTrials.gov number, NCT04669496.).

The mechanisms underlying the interactions between disseminated tumor cells (DTCs) and their tissue microenvironment during metastatic colonization are currently poorly understood. We integrated multimodal single-cell and spatial profiling from liver cancer mouse models and human metastases to track the spatiotemporal dynamics of DTCs and their microenvironments from single-cell seeding to overt lung metastasis. We identified a residual population of quiescent Phgdhhigh DTCs that survived initial innate immune clearance and became transiently enriched in micrometastases. These cells shaped an immune-scarce microenvironment through PHGDH-dependent, H3K27me3-mediated epigenetic silencing of chemokine transcription, thereby promoting metastatic expansion. Cx3cr1high interstitial macrophages were also transiently enriched before DTC expansion, creating an immune-privileged niche for metastatic outgrowth by recruiting immunosuppressive cells. Inactivating the PHGDH-H3K27me3 axis in DTCs or depleting interstitial macrophages restored immune surveillance and inhibited metastatic colonization. These findings provide insights into the development of micrometastasis-targeting regimens.

This follow-up analysis of the phase 2 HERIZON-BTC-01 trial evaluates the efficacy, patient-reported outcomes, and safety profile of zanidatamab in patients with ERBB2 -amplified biliary tract cancer with a HER2 immunohistochemistry score of 3+ or 2+ after 33 months of follow-up.

Background & Aims:Intrahepatic cholangiocarcinoma (ICC) with multiple liver tumours is staged as T2 disease in the 8th edition of the AJCC staging system. However, tumour multiplicity is frequently associated with poor prognosis in ICC. We aimed to elucidate the prognosis of ICC with multiple tumours and the impact of the number of liver tumours on survival. Methods:Patients who were diagnosed with ICC with solitary liver tumours or multiple liver tumours between May 2008 and December 2019 at three tertiary referral centres in Hong Kong, Seoul and Shanghai were enrolled. Kaplan-Meier analyses and multivariable Cox proportional hazards models were used to analyse the association between tumour multiplicity and overall survival (OS). Results:A total of 849 patients were included in the analysis. Among the 563 patients without distant metastasis, 434 (77.1%) and 129 (22.9%) had solitary and multiple liver tumours at baseline, respectively. The median follow-up period was 91.9 months (IQR 69.6-131.5). Median OS for patients with a solitary liver tumour, multiple liver tumours, and distant metastasis was 39.5 months (95% CI 34.4-49.2), 14.8 months (11.4-20.3), and 7.1 months (95% CI 6.1-8.3), respectively (log-rank p <0.001). Among N0M0 patients with multiple liver tumours, those with 2-3 tumours and those with ≥4 tumours had a median OS of 36.9 months (16.0-NA) and 15.5 months (11.0-23.7), respectively. In multivariable analysis, N0M0 patients with ≥4 liver tumours had similar survival as those with N1 disease (adjusted hazard ratio 1.01, 95% CI 0.58-1.75). Conclusions:Tumour multiplicity in ICC is associated with inferior OS compared with solitary liver tumours, particularly in patients with ≥4 tumours. Future ICC staging systems should consider the prognostic significance of tumour number. Impact and implications:Our research provides critical insights into the prognosis of intrahepatic cholangiocarcinoma (ICC) with multiple liver tumours, highlighting the significant impact of tumour multiplicity on survival outcomes. This work addresses the gap in the current staging system, which does not adequately reflect the poor prognosis associated with multiple tumours, especially with the presence of ≥4 tumours. Incorporating these insights into clinical practice could aid in treatment decision-making, risk stratification, and potentially improve patient care and outcomes in ICC management.

Supplementary materials and methods, Supplementary Figures and figure legends, Supplementary Tables

TPS4254 Background: Spontaneous rupture of hepatocellular carcinoma (srHCC) is a life-threatening complication associated with acute hemorrhage, aggressive tumor biology, and an exceptionally high risk of postoperative recurrence. Even after successful hemostasis and curative (R0) resection, outcomes remain poor, with early relapse—particularly peritoneal dissemination—being a dominant failure pattern. Patients with srHCC have been systematically excluded from most pivotal phase III adjuvant trials in hepatocellular carcinoma, resulting in a critical evidence gap for postoperative systemic management. Current adjuvant strategies are largely extrapolated from non-ruptured HCC or based on retrospective analyses, and no prospective studies have specifically evaluated immunotherapy-based adjuvant therapy in this population. Immune checkpoint inhibitor–based combinations with anti-angiogenic agents have demonstrated survival benefits in advanced HCC and have recently been explored in the adjuvant setting for high-risk resected disease. Given the unique biological behavior of srHCC, characterized by tumor cell spillage at rupture and a strong propensity for early systemic and peritoneal relapse, adjuvant systemic therapy targeting micrometastatic disease is biologically rational and urgently needed. The CLEAR-2 study is designed to prospectively explore the efficacy and safety of adjuvant sintilimab combined with bevacizumab following curative resection of srHCC. Methods: CLEAR-2 is a prospective, multicenter, single-arm, exploratory phase II study. Eligible patients are adults (18–75 years) with radiologically or intraoperatively confirmed spontaneous rupture of HCC who have undergone curative (R0) hepatic resection, with Child-Pugh A liver function and ECOG performance status 0–1. Preoperative transarterial embolization (TAE) for hemostasis is permitted if performed once and within 2 weeks prior to surgery, without chemotherapeutic agents. A total of 35 patients will be enrolled. Adjuvant treatment is initiated 4–8 weeks postoperatively and consists of sintilimab 200 mg plus bevacizumab 15 mg/kg intravenously every 3 weeks for up to 1 year or until recurrence, unacceptable toxicity, or withdrawal. Radiologic assessment is performed every 12 weeks. The primary endpoint is disease-free survival (DFS). Secondary endpoints include overall survival (OS), safety graded per CTCAE v5.0, and recurrence patterns (intrahepatic, extrahepatic, and peritoneal). Clinical trial information: NCT07331883 .

Most patients with hepatocellular carcinoma (HCC) present at intermediate or advanced stages. Current guidelines generally recommend transarterial chemoembolization (TACE) for intermediate-stage disease and systemic therapy for advanced-stage disease. Whether combining locoregional therapy (e.g., TACE) with systemic treatment confers additional benefit remains debated. Immunotherapy combinations may have a synergistic effect with locoregional treatments. Four recent trials conducted mainly in intermediate-stage populations showed that adding an immunotherapy combination to TACE increased response rates and prolonged progression-free survival, but did not clearly improve overall survival (OS) and, at best, suggested a trend toward OS benefit. These mixed results have fueled ongoing controversy about how best to integrate locoregional and systemic treatments. In the present narrative review, based on the current evidence, attempts were made to stratify intermediate-stage HCC into resectable, potentially resectable, and unresectable disease. Advanced HCC was stratified into potentially resectable and unresectable disease. Resectable intermediate-stage HCC should undergo surgical resection, with consideration of perioperative immunotherapy combinations. Patients with potentially resectable intermediate or advanced disease should receive potent systemic therapy, with or without locoregional treatment, to facilitate conversion to resection. Unresectable intermediate-stage HCC can be further categorized by tumor burden, small, intermediate, or large, guiding treatment selection toward TACE, TACE plus systemic therapy, or systemic therapy, respectively. Unresectable advanced-stage HCC should be managed with systemic therapy, adding locoregional treatment as appropriate based on response. The aim for this framework is to inform clinical decision-making on the integration of locoregional and systemic therapies for unresectable HCC.

BACKGROUND & AIMS:Very early recurrence (within 1 year after resection) of hepatocellular carcinoma (HCC) indicates aggressive tumor biology and poor prognosis; however, non-invasive prediction tools remain scarce. This study aimed to develop and validate MRI-based models for predicting very early recurrence and to explore their biological underpinnings. METHODS:This international, multicenter cohort study retrospectively included 1,811 consecutive patients who underwent curative-intent resection for a single BCLC 0/A HCC and preoperative contrast-enhanced MRI or CT at 14 tertiary care hospitals in China, South Korea, Singapore, France, and the USA, as well as 40 eligible patients from the TCGA-LIHC dataset. To predict 1-year recurrence-free survival (RFS), MRI for Very Early Recurrence Prediction (MERP) models were developed using either preoperative variables alone (MERP-pre) or a combination of pre- and postoperative variables (MERP-post) in the derivation cohort (n = 628). The models were externally validated in Eastern (n = 775) and Western (n = 178) test cohorts and further evaluated in a CT test cohort (n = 230). Biological correlates were investigated using whole-exome and RNA sequencing. RESULTS:MERP-pre incorporated alpha-fetoprotein, tumor size, portal venous phase peritumoral hypoenhancement, and intratumoral blood products, whereas MERP-post replaced tumor size with microvascular invasion (MVI). Both models outperformed major staging systems and the IMbrave050 criteria across all test cohorts (C-index, 0.685-0.790 vs. 0.524-0.682; p values, <0.001 to 0.046) and improved risk reclassification (net reclassification improvement [NRI], 0.004-0.372). The MERP models consistently stratified patients into high- and low-risk groups with distinct 1-year RFS rates (all p <0.001). MERP-pre further improved MVI-based risk reclassification (NRI, 0.323) and survival risk stratification. Tumors classified as low risk by MERP-pre exhibited features of the non-proliferative class, increased lipid catabolism, and an immunoactive microenvironment. CONCLUSIONS:The MERP models may serve as robust, generalizable, and biologically informed tools for predicting very early HCC recurrence and may help refine risk-stratified management strategies. IMPACT AND IMPLICATIONS:Very early recurrence (VER) of hepatocellular carcinoma (HCC) within 1 year after resection reflects aggressive tumor biology and is associated with poor prognosis, yet reliable tools for predicting VER remain scarce. In this large, international, multicenter cohort of patients with a single Barcelona Clinic Liver Cancer stage 0/A HCC undergoing curative-intent resection, we developed and externally validated two MRI-based models (MERP-pre and MERP-post) that integrate routinely available clinicopathological and imaging variables. The MERP models consistently outperformed existing prognostic systems and effectively stratified patients into high- and low-risk groups with distinct 1-year recurrence-free survival across diverse cohorts. These findings highlight the potential of the MERP models to complement existing prognostic systems and optimize risk-stratified management of HCC.

Background:Spontaneous rupture of hepatocellular carcinoma (srHCC) is a life-threatening complication associated with high perioperative mortality and increased postoperative recurrence, particularly peritoneal dissemination. Although timely haemostasis and curative-intent resection allow selected patients to achieve meaningful survival, postoperative management remains poorly defined, and patients with srHCC are usually excluded from major adjuvant trials. Methods:CLEAR-2 is a prospective, exploratory, multicentre, single-arm study evaluating adjuvant sintilimab plus bevacizumab biosimilar after R0 resection of srHCC. Thirty-five patients with imaging- or intraoperatively confirmed spontaneous rupture, China Liver Cancer (CNLC) stage I-II disease, complete radiological response 4-8 weeks after surgery, ECOG performance status 0-1, Child-Pugh class A liver function, and adequate organ function will be enrolled. Preoperative transarterial embolisation for haemostasis is permitted as a single bridging procedure without chemotherapeutic agents, followed by surgery within 2 weeks. Treatment consists of sintilimab 200 mg plus bevacizumab biosimilar 15 mg/kg intravenously every 3 weeks for up to 1 year or until recurrence, unacceptable toxicity, or withdrawal. The primary endpoint is disease-free survival. Secondary endpoints include overall survival, safety, and recurrence patterns. Tumour assessments will be performed every 12 weeks using contrast-enhanced CT or MRI according to RECIST version 1.1. Conclusion:CLEAR-2 is designed to generate preliminary prospective evidence on the feasibility, safety, and antitumour activity of adjuvant sintilimab plus bevacizumab in a highly selected, high-risk srHCC population. The findings may inform future randomized or comparative studies of postoperative strategies for srHCC. Trial Registration:NCT07331883.

BACKGROUND:Resection might offer additional benefit in patients with advanced-stage hepatocellular carcinoma treated with systemic therapy. However, high-quality evidence supporting the procedure is absent. We aimed to establish whether resection can provide survival benefit in patients with advanced hepatocellular carcinoma who respond to systemic therapy. METHODS:In this randomised, open-label, multicentre, phase 3 trial, we recruited treatment-naive patients with hepatocellular carcinoma, macrovascular invasion, and no extrahepatic metastasis from 24 hospitals in China. These patients were treated in the induction phase with three cycles of intravenous atezolizumab (1200 mg every 3 weeks) plus intravenous bevacizumab (15 mg/kg bodyweight every 3 weeks) and one cycle of atezolizumab monotherapy. Patients who completed the induction phase, had a partial response or stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and were considered feasible for resection were randomly assigned (1:1) to undergo surgical resection followed by 12 months of atezolizumab plus bevacizumab initiated 4-6 weeks after surgery (ie, the surgery group), or to maintenance atezolizumab plus bevacizumab until loss of clinical benefit or intolerable toxicity (the maintenance therapy group). Randomisation was by computer-generated sequence with permuted blocks via a central interactive web response system, stratified by tumour response and Eastern Cooperative Oncology Group performance status. Treatment administered to patients was not masked. The primary endpoint was time to treatment failure, assessed by an independent review facility and analysed by intention to treat. Time to treatment failure was defined as the time from randomisation to the first documented treatment failure (ie, local recurrence or disease progression according to RECIST 1.1, emergence of extrahepatic spread, or death). This study is registered with ClinicalTrials.gov (NCT04649489) and is ongoing. FINDINGS:Between April 4, 2021, and July 18, 2024, a total of 489 patients were enrolled in the induction phase. Of them, 201 were randomly assigned to the surgery group (n=101; 93 male, eight female) or the maintenance therapy group (n=100; 87 male, 13 female). After a median follow-up of 18·4 months, the median time to treatment failure was 20·4 months in the surgery group and 11·8 months in the maintenance therapy group (hazard ratio 0·60, 95% CI 0·39-0·91; p=0·015). Grade 3 or 4 treatment-related adverse events occurred in 32 (39%) of 83 patients in the surgery group and 21 (21%) of 100 in the maintenance therapy group, the most common of which were increased alanine aminotransferase (seven patients [8%] in the surgery group vs one [1%] in the maintenance therapy group), reduced platelet count (seven [8%] vs three [3%]), and proteinuria (three [4%] vs seven [7%]). Two treatment-related deaths occurred in the surgery group due to abnormal liver function (considered related to atezolizumab) and liver failure (considered related to atezolizumab, bevacizumab, or surgery). INTERPRETATION:In patients with advanced hepatocellular carcinoma with macrovascular invasion after systemic therapy, time to treatment failure was longer in those who had liver resection than in those who received maintenance therapy. FUNDING:Shanghai Roche Pharmaceuticals and Ministry of Science and Technology of China.

4001 Background: The combination of C (anti–PD-1 antibody) + R (VEGFR2 tyrosine kinase inhibitor) significantly improved progression-free survival (PFS) and overall survival (OS) vs sorafenib as first-line treatment for advanced HCC, and improved event-free survival vs surgery alone as perioperative treatment for resectable HCC. We conducted a phase 3 trial evaluating C+R with TACE in intermediate-stage HCC and here present data from the protocol-specified PFS interim analysis (IA). Methods: In this multicenter, open-label, phase 3 trial, patients (pts) with TACE-eligible uHCC, Child-Pugh A, ECOG performance status (PS) 0–1 and no extrahepatic spread were randomized 1:1 to receive C (200 mg, iv, Q3W) + R (250 mg, po, QD) + TACE or TACE alone. TACE (cTACE or DEB-TACE) was administered at the investigator (INV)’s discretion; C+R continued until loss of clinical benefits, unacceptable toxicities, or other protocol-specified criteria. The primary endpoint was PFS by BIRC per mRECIST. As of Sep.13, 2025, 214 PFS events occurred and a preplanned IA was performed. Results: 423 pts (ECOG PS 1, 22.9%; AFP ≥400 ng/mL, 26.7%; portal vein invasion [vp1/2], 9.7%) were randomized to C+R+TACE (n=214) or TACE (n=209). As of data cutoff, median follow-up was 16.4 mo. Median PFS by BICR per mRECIST was significantly longer with C+R+TACE vs. TACE (11.1 vs. 8.3 mo; HR 0.73 [95% CI 0.56–0.96]; 1-sided p=0.0127). PFS by BICR per RECIST v1.1 (13.9 vs 9.5 mo; HR 0.67 [95% CI 0.50–0.91]) and by INV per mRECIST (13.8 vs 7.0 mo; HR 0.61 [95% CI 0.47–0.81]) and per REIST v1.1 (15.7 vs 8.4 mo; HR 0.61 [95% CI 0.45–0.81]) showed consistent findings (Table 1). PFS benefits with addition of C+R persisted across most prespecified subgroups. OS was not mature, with an early trend favoring C+R+TACE (HR 0.76 [95% CI 0.46–1.24]); OS was 91.4% vs 85.5% at 12 mo, and 82.0% vs 73.3% at 24 mo. Among treated pts, grade ≥3 TRAEs occurred in 73.7% (157/213) in C+R+TACE arm vs. 28.7% (60/209) in TACE arm; of them, the most common in C+R+TACE arm were increased AST (20.7% vs 12.9%), hypertension (19.7% vs 4.3%), increased ALT (17.8% vs 9.6%), and decreased platelet count (11.3% vs 2.9%). Conclusions: C+R+TACE provided statistically significant and clinically meaningful improvement in PFS vs TACE, with manageable safety, supporting this regimen as a potential new treatment option for TACE-eligible uHCC. Follow-up for OS is ongoing. Clinical trial information: NCT05320692 . PFS outcomes (ITT set). BIRC INV C+R+TACE (n=214) TACE (n=209) C+R+TACE (n=214) TACE (n=209) Per mRECIST Median (95% CI), mo 11.1 (7.8–14.0) 8.3 (6.9–9.5) 13.8 (8.5–17.3) 7.0 (5.7–9.5) HR (95% CI)* 0.73 (0.56–0.96); 1-sided p=0.0127 † 0.61 (0.47–0.81) Per RECIST v1.1 Median (95% CI), mo 13.9 (10.9–19.4) 9.5 (8.1–11.1) 15.7 (10.3–19.6) 8.4 (6.9–10.8) HR (95% CI)* 0.67 (0.50–0.91) 0.61 (0.45–0.81) *Stratified Cox proportional hazard model. †Stratified Log-Rank test.

BACKGROUND:Preoperative hypoalbuminemia is a risk factor for complications after hepatectomy for hepatocellular carcinoma (HCC). The impacts of preopeRative sErum Albumin Levels on postoperative outcomes in Chinese HCC Patients treated with surgical operation (REAL) studyaimed to evaluate the impact of preoperative human albumin administration on postoperative outcomes in patients with HCC and hypoalbuminemia undergoing hepatectomy. METHODS:This retrospective study analyzed patients with HCC and preoperative hypoalbuminemia (serum albumin < 36 g/L) who underwent liver resection at Zhongshan Hospital, Fudan University. Patients were categorized into those who received albumin supplementation and those who did not. Surgical outcomes included durations of hospital and intensive care unit (ICU) stay, incidence and grade of posthepatectomy liver failure (PHLF), 30-day complication rates, and hospital mortality. RESULTS:Patients with hypoalbuminemia who did not receive supplementation had significantly higher rates of PHLF grades A/B and 30-day complications compared with the normal albumin group, along with a shorter overall survival. However, patients with hypoalbuminemia who received supplementation achieved outcomes comparable to those of the normal albumin group, with no significant differences in hospital stay, ICU stay, PHLF grade distribution, or 30-day complication rates. Among patients with hypoalbuminemia, those who received albumin supplementation had a significantly lower PHLF rate. No in-hospital mortality occurred in any group. CONCLUSION:Preoperative albumin supplementation in patients with hypoalbuminemiais associated with significantly improved postoperative outcomes in this retrospective cohort. These real-world findings provide preliminary evidence supporting targeted albumin supplementation to reduce surgical risk among such vulnerable patients. However, large prospective randomized controlled trials are still required to validate our conclusions before widespread clinical application.

BACKGROUND AND AIMS:Pathological complete response (pCR) following conversion therapy for initially unresectable hepatocellular carcinoma (uHCC) remains challenging to predict preoperatively. This study developed and validated a model integrating clinicopathological and radiomic features of the tumor to predict pCR. METHODS:In this multicenter retrospective study, temporal radiomics features were extracted from baseline, post-treatment, and delta (change) MRIs. Serum AFP response was calculated as log₁₀(preoperative AFP)/log₁₀(baseline AFP). Univariate analysis, collinearity assessment, LASSO, and random forest were employed to perform feature selection. Fourteen machine learning models were benchmarked, with performance evaluated by using comprehensive metrics AUC, NPV, PPV, sensitivity, specificity, calibration, and decision curve analysis. RESULTS:The model was developed and validated in a training (n=78), an internal test (n=32), and an independent validation cohort (n=44). The delta radiomic model significantly outperformed both baseline (test AUC: 0.835 vs. 0.483, p <0.05; validation AUC: 0.783 vs. 0.434, p <0.05) and preoperative models (test AUC: 0.685, p <0.05; validation AUC: 0.506, p <0.05), demonstrating superior predictive performance and generalization capability in predicting lesion-level pCR. Notably, when predicting patient-level pCR, the radiomic model also showed robust discrimination, with AUCs of 0.819 in the test set and 0.781 in the validation set. The combined radiomics-AFP model achieved even higher AUCs of 0.920 (test) and 0.857 (validation) in predicting lesion-level pCR. CONCLUSIONS:Dynamic radiomic changes effectively predict pCR in uHCC after conversion therapy. Combining delta radiomics with AFP response significantly improves predictive performance, offering a non-invasive method for assessing pCR and potentially guiding personalized treatment decisions.

Background:The criteria for identifying patients with potentially resectable hepatocellular carcinoma (HCC) at the baseline stage have helped identify patients who are more likely to achieve successful conversion. However, the suitable timing and selection of candidates for conversion surgery after systemic therapy remained underexplored. Methods:Based on real-world evidence, we analyzed a cohort of 222 patients with potentially resectable HCC treated with immune-based therapy between January 2019 and May 2024. The treatment response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and modified RECIST (mRECIST). Depth of response (DpR) was defined as the maximum tumor shrinkage from baseline, based on the sum of the longest diameters, as assessed by an independent review facility per RECIST v1.1. Conversely, stable disease (SD) with a DpR < 0%/> 0% was categorized as SD_shrink/SD_non-shrink. Survival outcomes were compared between patients who underwent surgery and those who did not, with different DpRs, and assessed using Kaplan-Meier methods. Results:A total of 85 patients with partial response (PR), 86 with SD_shrink, and 51 with SD_non-shrink were included in this study. Generally, patients who underwent surgery had a better prognosis than those who did not (p < 0.001). Patients with PR and SD_shrink significantly benefited from the surgery in both overall survival and event-free survival. However, patients with SD_non-shrink failed to obtain the same benefits. Additionally, surgical patients with a DpR <0% had a better prognosis than those with a DpR >0% (p < 0.001 and p = 0.004, respectively), whereas the survival of patients who did not undergo surgery did not differ. Conclusion:DpR is an important factor in choosing the right candidates and the timing of conversion therapy. Patients only at a DpR <0% receiving various immune-based treatments who met the "potentially resectable" criteria can benefit from surgical resection. These findings can help increase the success rate of conversion therapy in patients with advanced HCC.