ObjectiveThis study aims to analyze global trends in cancer deaths and disability-adjusted life years (DALYs) attributable to smoking from 1990 to 2021 using the Global Burden of Disease (GBD) database, and to predict trends over the next 20 years.MethodsThis study utilized the 2021 GBD database to extract annual mortality, DALYs, and age-standardized rates for cancer attributable to smoking across 204 countries from 1990 to 2021. Joinpoint regression assessed temporal trends, calculating average annual percentage change (AAPC). Autoregressive Integrated Moving Average (ARIMA) modeling forecasted future disease burden for 20 years.ResultsFrom 1990 to 2021, global cancer attributable to smoking deaths and DALYs increased, with deaths rising from 1,328.88 to 2,012.85 thousand and DALYs from 35,581.64 to 47,976.55 thousand, despite declining age-standardized mortality (ASMR) from 33.76 to 23.31 per 100,000 (AAPC: -1.19) and DALYs (ASDR) from 863.94 to 546.86 per 100,000 (AAPC: -1.47). Males exhibited a higher burden, with ASMR at 42.68 and ASDR at 978.15 per 100,000 in 2021, compared to females (7.01 and 161.30). High Socio-demographic Index (SDI) regions showed the steepest ASMR decline (AAPC: -1.80). Tracheal, bronchus, and lung, esophageal, and stomach cancers dominated the burden. In 2021, specific regions within Greenland, Eastern Europe, Central Asia, East Asia, and the Middle East demonstrated notably higher compared to other regions. The ARIMA model predicts that the ASMR and ASDR for cancer attributable to smoking in both males and females will continue to decline from 2022 to 2041.ConclusionThis study reveals a rising global burden of cancer attributable to smoking deaths and DALYs. However, ASMR and ASDR have decreased, with males bearing a higher burden, indicating a relative reduction in disease burden. High SDI regions exhibit steeper declines in the burden of cancer attributable to smoking. Tracheal, bronchus, and lung, esophageal, and stomach cancers dominate, with ARIMA forecasts predicting continued reductions through 2041. It remains imperative to enhance tobacco control, especially in low SDI regions, to sustain this declining trend.

Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer-related mortality. Current guidelines and staging systems provide coarse categories, but often miss within-stage heterogeneity and the clinical context in electronic medical records (EMRs). We present HCC-STAR (Hepatocellular Carcinoma Staging, Treatment And pRognosis), a clinically aligned large language model that reads routine EMR narratives and jointly outputs risk score-based staging, ranked guideline-consistent treatments with evidence-based rationales, and individualized survival estimates. We curated about 30,000 HCC cases from SEER and expanded them into EMR-style narrative training data using a clinician-validated, prompt-based augmentation workflow. On this corpus, we developed a knowledge-aligned reasoning framework optimized with a step-verifiable composite reward, moving beyond text-level memorization of clinical guidelines. In a multi-center cohort of 6,668 patients from 12 hospitals in China, HCC-STAR achieved state-of-the-art performance in treatment recommendation and risk stratification compared with clinical guidelines and competitive models, including GPT-5 and Gemini-2.5 Pro. Hypothetical overall-survival analysis showed a median survival of 51 months under adherence to HCC-STAR recommendations, compared with 29 and 32 months under BCLC and CNLC. In clinician-centric evaluations, blinded hepatobiliary specialists rated HCC-STAR's reasoning and evidence-based justifications as trustworthy. The model surpassed resident and attending physicians in treatment accuracy and helped physicians make more accurate decisions faster when used as an assistant. These findings support HCC-STAR as a reliable and verifiable decision-support system for risk stratification and precision therapy in HCC.

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.

Hepatocellular carcinoma (HCC) is a malignant tumour with high global incidence and mortality rates, particularly prevalent in Asia and Africa. Despite advances in diagnostic and therapeutic techniques, most patients are diagnosed at an intermediate or advanced stage, where conventional treatments yield limited efficacy. For patients with tumours that are too large or whose residual liver volume is insufficient, we have innovatively employed a dual-conversion integrated treatment strategy. This approach combines tumour biological transformation (such as molecular targeted therapy and immunotherapy) with residual liver volume transformation (such as portal vein embolization and portal vein ligation), aiming to simultaneously curb tumour progression and enhance postoperative hepatic functional reserve. This review summarises recent research advances and clinical applications of dual conversion therapy in HCC, analysing its potential and challenges in improving surgical resectability rates and prognosis. It also outlines future development directions, providing theoretical foundations and practical guidance for comprehensive HCC management.

Objective: To develop a non-invasive model integrating clinical features with intra-and peritumoral pre-fusion radiomic features to predict portal hypertension (PHT) in hepatocellular carcinoma (HCC) patients. Materials and Methods: This retrospective study included 884 HCC patients who underwent partial hepatectomy with intraoperative portal venous pressure measurement (January 2013-January 2020). Patients were randomly assigned to training (n = 707, 89 with PHT) and validation (n = 177, 23 with PHT) cohorts. Clinical predictors were identified using logistic regression. Radiomic features were extracted from intratumoral and peritumoral regions on portal venous phase CT images. Key features were selected using t-tests, correlation analysis, and LASSO regression. Following comparison of multiple feature sets via K-Nearest Neighbors, intra-and peritumoral pre-fusion radiomic features were selected. A logistic regression-based nomogram combining clinical predictors with this radiomic set was developed and compared with traditional models. Results: Portal vein diameter (PVD), Child-Pugh score, and FIB-4 score were identified as independent risk factors for PHT. The combined clinical-radiomic model achieved superior predictive performance in both the training (AUC: 0.938, 95% CI: 0.918-0.959) and validation (AUC: 0.847, 95% CI: 0.760-0.935) cohorts. Conclusion: The clinical-only model outperformed all radiomics-based models in this study, suggesting that routinely available clinical parameters may provide a robust foundation for portal hypertension screening. This finding may serve as a reference for clinical resource allocation and indicates the potential existence of a simplified, cost-effective screening pathway without reliance on complex radiomic analysis. Notably, the combined clinical-radiomic model demonstrated superior predictive performance, highlighting the complementary value of radiomic features to clinical indicators to a certain extent. However, the incremental benefit should be carefully weighed against the added complexity and challenges of standardization. This study further suggests that portal vein diameter, Child-Pugh score, and FIB-4 score may serve as independent predictors, offering a preliminary reference for future exploration of non-invasive tools for portal hypertension prediction. External validation is still needed to further confirm the model's generalizability and clinical utility.

Analysis of proteins and other molecular components in induced sputum provides critical insights for the diagnosis, pathological assessment, and therapeutic monitoring of respiratory diseases. In this study, we collected three distinct types of induced sputum samples from patients with chronic obstructive pulmonary disease (COPD) and subjected them to proteomic and phosphoproteomic analysis using three different enzymatic digestion methods. We found that raw sputum samples yielded a higher number of uniquely identified proteins and phosphoproteins (1313 proteins and 1603 phosphorylation sites, corresponding to 782 phosphoproteins) and provided a more comprehensive characterization of COPD pathology. Furthermore, compared to in-gel digestion and in-solution digestion, the filter-aided sample preparation method increased protein identification by approximately 30% and yielded the highest number of unique protein identifications. Our study is the first to demonstrate that raw induced sputum can serve as a viable alternative source for liquid biopsy in respiratory diseases. We have also established the first methodological framework and dataset for proteomic and phosphoproteomic analysis of raw induced sputum, generating a preliminary map of the COPD sputum proteome and phosphoproteome. This novel proteomic and phosphoproteomic approach has untangled biologically relevant pathways in respiratory physiology, highlighting potential avenues for future research. Significance In this study, we aimed to investigate the feasibility of establishing and evaluating proteomic research methods using sputum samples from patients with chronic obstructive pulmonary disease (COPD). The ultimate goal was to develop analytical approaches suitable for sputum proteomics and phosphoproteomics and to preliminarily map the sputum proteome and phosphoproteome in COPD. It was found that raw sputum samples more comprehensively reflect the disease characteristics of COPD and are therefore more suitable for proteomic and phosphoproteomic studies of COPD. Among three mainstream enzymatic digestion methods, the Filter-Aided Sample Preparation (FASP) method demonstrated superior identification rates and was deemed most suitable for processing raw sputum samples. Furthermore, this study reports for the first time a draft map of the proteome and phosphoproteome of COPD sputum. This research provides valuable insights into sputum proteomic analysis and offers a useful resource for the study of respiratory diseases.

OBJECTIVE AND BACKGROUND:The optimal surgical strategy for patients with hepatocellular carcinoma (HCC) and liver fibrosis/cirrhosis presenting with a future liver remnant to standard liver volume (FLR/SLV) ratio of 30%-40% remains a subject of clinical controversy. This study aimed to evaluate the safety and efficacy of one-stage hepatectomy (OSH) versus Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) and to validate the feasibility of OSH by benchmarking it against the standard safety criterion (FLR/SLV ≥40%). METHODS:We conducted a retrospective analysis of 219 patients with HBV-related HCC and liver fibrosis/cirrhosis who underwent right hemihepatectomy. Patients were stratified into three groups: the OSH group (FLR/SLV 30%-40%, n = 62), the ALPPS group (FLR/SLV 30%-40%, n = 20), and the standard control group (FLR/SLV ≥40% undergoing OSH, n = 137). Perioperative outcomes, including post-hepatectomy liver failure (PHLF) and complications, as well as long-term overall survival (OS) and disease-free survival (DFS), were compared. RESULTS:In the 30%-40% cohort, the incidence of severe PHLF (ISGLS Grade B or C) in the ALPPS group was comparable to that of the one-stage hepatectomy group (P = 0.128), and no 90-day mortality was observed in either group. However, in terms of severe postoperative complications (Clavien-Dindo grade ≥ IIIa), the ALPPS group demonstrated a higher incidence rate compared to the one-stage hepatectomy group, although the difference did not reach statistical significance (P = 0.082). Long-term oncological outcomes, including OS and DFS, were comparable between the OSH and ALPPS groups (p > 0.05). Furthermore, benchmarking analysis revealed preliminary observations that patients in the OSH group (30%-40%) achieved perioperative and long-term outcomes comparable to those in the standard control group (≥40%) (p > 0.05). CONCLUSIONS:For selected HCC patients with liver fibrosis/cirrhosis and FLR/SLV ratio of 30%-40% undergoing standardized right hemihepatectomy, one-stage hepatectomy might serve as a safe and feasible alternative to ALPPS, though large-scale prospective validation is warranted.

The neural precursor cell expressed developmentally down-regulated protein 1 (NEDD1) is implicated in tumorigenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to explore the oncogenic role, regulatory mechanisms, and tumor microenvironment interactions of NEDD1 in HCC. Multi-omics analyses were performed using public datasets (TCGA, GEO) and in-house clinical samples. These included expression and survival analysis, epigenetic (DNA methylation) and post-translational (phosphorylation) profiling, functional pathway enrichment, and drug sensitivity prediction. Functional validation was conducted via NEDD1 knockdown in HCC cells and a subcutaneous xenograft model. The co-expression and spatial distribution of NEDD1 and its predicted partner MZT2B were investigated using single-cell (GSE140228) and spatial transcriptomic (HRA000437) datasets. NEDD1 was significantly overexpressed in HCC tissues and correlated with poor prognosis. Its overexpression was potentially linked to promoter hypomethylation and aberrant phosphorylation. NEDD1 knockdown suppressed HCC cell proliferation, migration, and tumor growth in vivo. Notably, NEDD1 expression positively correlated with immune checkpoint molecules (PD-1, CTLA-4), and low NEDD1 expression was associated with better predicted response to immunotherapy. Single-cell and spatial transcriptomics revealed that NEDD1 and MZT2B co-expression was highly enriched in specific macrophage subsets (e.g., APOE+) and exhibited cell context-dependent heterogeneity, suggesting they may constitute a dynamic functional module within the HCC microenvironment. This multi-omics study suggests NEDD1 as a potential prognostic biomarker and therapeutic target in HCC. We propose a novel model wherein the NEDD1-MZT2B module may operate in both tumor cells and immunosuppressive macrophages, potentially influencing disease progression and immunotherapy response.

Massive hepatocellular carcinoma (HCC) is not suitable for radical surgery due to the factors of high tumor burden and poor postoperative liver function tolerance. There are few reports on the conversion therapy for HCC with insufficient future liver remnant (FLR) volume using a combination of two - stage hepatectomy (TSH), hepatic arterial infusion chemotherapy (HAIC), and lenvatinib - sintilimab. We report a case of a 62-year-old male with massive HCC (81mm×11.5mm×95mm). At the initial diagnosis, the ratio of his FLR to standard liver volume (SLV) was 34%. After multidisciplinary team (MDT) discussion, the patient decided to undergo conversion therapy. After three formal cycles (9 weeks) of conversion therapy, the FLR/SLV ratio increased to 65%, and then right hepatectomy was performed. The lesion achieved a partial response (PR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The second hepatectomy was successfully performed, and there was no recurrence during the 36-month postoperative follow-up. In this case, portal vein ligation (PVL) surgery, HAIC, and targeted immunotherapy contributed to the conversion therapy of HCC through different dimensions, including mechanical blood flow blockage, local chemotherapy, and immune regulation, laying the foundation for the safety of radical surgery and long-term postoperative survival.

Epstein-Barr virus (EBV), a member of gamma herpesvirus subfamily, infects more than 90% of the people in the world. There are some studies on EBV-mediated regulation of type I interferon (IFN-I) signaling, however, the underlying mechanism is still not fully understood. In this study, we demonstrated that the EBV encoded tegument protein BKRF4 could suppress RIG-I-like receptor (RLR) signaling pathway-induced IFN-β promoter activity and the mRNA transcription of IFN-β and downstream IFN-stimulated genes, which is favorable for RNA and DNA viral replications. Mechanically, BKRF4 was shown to interact with IRF3 and restrain its phosphorylation, dimerization, and nuclear translocation. Specifically, aa71-95 of BKRF4 was essential for its association with IRF3 and the inhibition of IFN-β promoter activity. Moreover, BKRF4 also could interplay with activated IRF7 but didn’t affect the formation of IRF7 homodimer or IRF3/IRF7 heterodimer, yet it could impede the nuclear accumulation of IRF7. In addition, knockdown of BKRF4 during EBV lytic replication significantly enhanced IFN-β promoter activity and the phosphorylation and dimerization of IRF3. Taken together, our findings suggested that BKRF4 could negatively regulate the RLR-mediated IFN-β antiviral signaling, which provides new evidence for the molecular mechanism exploited by EBV to evade the host innate immunity.

Hepatocellular carcinoma (HCC) is one of the most common cancer worldwide. In this study, we performed a two-stage exome-chip association analysis and found that the aldo-keto reductase family7 member A3 (AKR7A3) rs1738023 may be a potential susceptibility locus for HCC in females. We aimed to explore its role and mechanism. The association between genotype and phenotype was analyzed through GWAS method. The expression of AKR7A3 in cancer tissue and blood analysis by qRT-PCR. The relationship of AKR7A3 and aflatoxin B1 (AFB1) was also analyzed. The effect of AKR7A3 on the biological behavior of HCC cell line was investigated on proliferation and invasion. The potential mechanism was analyzed by transcriptome analysis and western blot. Through genome-wide association analysis (GWAS), AKR7A3 (rs1738023), KIF2C (rs4342887), and CYP3A5 (rs6977165 and rs4646450) were found to be associated with susceptibility to hepatocellular carcinoma (HCC) in women. Further expression quantitative trait loci (eQTL) analysis showed that only AKR7A3 (rs1738023) was significantly associated with gene expression. The expression of AKR7A3 was significantly lower in HCC than adjacent non-tumorous tissues (P < 0.001). The genotype of rs1738023 was significantly associated with AKR7A3 expression (P = 0.0085). Rs1738023[C] genotype had a low AKR7A3 expression level and limited detoxification ability of AFB1. Literature data showed that AKR7A3 is involved in the metabolism of aflatoxin B1 (AFB1). Functional experimental results showed that overexpression of AKR7A3 in the normal liver cell line HL-7702 could significantly reduce AFB1-induced ROS levels and DNA adduct formation, suggesting that it plays a protective role in AFB1 metabolic detoxification. Cell function test showed that overexpression of AKR7A3 inhibit the proliferation, migration and invasion of HCC cells, and block the cell cycle. Transcriptome sequencing and KEGG pathway enrichment analysis revealed that overexpression of AKR7A3 affected the PI3K signaling pathway and led to downregulation of HIF1A and its downstream VEGFA protein expression. The validation results were confirmed in HCC cell lines Huh-7 and SUN-387. Overexpression of AKR7A3 contributes to inhibition of HCC progression and reduction of aflatoxin toxicity. AKR7A3 may serve as a potential prognostic and therapeutic target for HCC patients, although further validation is needed.

Herpes simplex virus 1 (HSV-1) is a member of alphaherpesvirus that can cause some important human diseases, and type I interferon (IFN-I)-mediated antiviral effect plays a vital role in the innate immune response, whereas this reaction can be negatively regulated by some HSV-1 encoded proteins. However, it remains unknown whether additional HSV-1 factors contribute to this process. Here, we found that the HSV-1 encoded uracil-DNA glycosylase, UL2, can inhibit Sendai virus (SeV)-induced IFN-β activity. Mechanically, UL2 interacts with the components of RIG-I-like receptor (RLR) signaling pathway, including TBK1 and activated IRF3. While UL2 does not affect the ubiquitination of TBK1 or IRF3, it rather hinders the SeV-stimulated phosphorylation of IRF3 at Ser396. Simultaneously, UL2 blocks the formation of IRF3 dimer and its nuclear translocation. Therefore, these results suggested a crucial connection between UL2 and IFN-β signaling pathway, which may take considerable role in the HSV-1 evasion of the host antiviral response.

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:Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and Clonorchis sinensis (C. sinensis) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown. METHODS:We compiled a cohort of 269 primary HCC patients to assess the clinical impact of C. sinensis and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from C. sinensis-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes. RESULTS:C. sinensis infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with SPP1+ macrophages, exhausted CD8+ T cells and COL1A1+ fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and ENPP2+ liver vascular endothelial cells, respectively. CONCLUSION:These findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.

FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil)-based hepatic arterial infusion chemotherapy (FOLFOX-HAIC) has emerged as a promising locoregional strategy in the multimodal management of hepatocellular carcinoma (HCC), particularly for patients with intermediate or advanced-stage disease. This narrative review summarizes recent clinical evidence on the application of FOLFOX-HAIC across the therapeutic continuum: in conversion, neoadjuvant, and adjuvant settings. We conducted an analysis based on a search of PubMed, Embase, China National Knowledge Infrastructure (CNKI) and conference abstracts, which incorporated phase II/III trials, retrospective cohort studies, multicenter real-world studies, and meta-analyses. Evidence indicates that FOLFOX-HAIC, especially when combined with targeted therapy and immunotherapy, yields superior objective response rates and higher rates of conversion to curative resection compared to conventional transarterial chemoembolization (TACE). Furthermore, as postoperative adjuvant therapy, it significantly reduces recurrence risk and prolongs survival in high-risk patients, such as those with microvascular invasion. In the neoadjuvant setting, these combinations can induce profound pathological responses, potentially improving outcomes for resectable patients at high risk of recurrence. Consequently, FOLFOX-HAIC represents an evolving cornerstone of HCC therapy. However, current evidence is largely derived from retrospective and small prospective studies, underscoring the urgent need for large-scale phase III randomized controlled trials to standardize regimens, optimize patient selection, and confirm long-term survival benefits.

BACKGROUND:TACE is the standard treatment for intermediate-stage hepatocellular carcinoma but has limited survival benefits. TALENTACE evaluated adding atezolizumab and bevacizumab to on-demand TACE versus on-demand TACE alone in patients with systemically untreated, intermediate-to-high tumour burden unresectable hepatocellular carcinoma. METHODS:In this randomised, open-label, phase 3 study at 40 centres in China and Japan, patients aged 18 years or older with confirmed, unresectable hepatocellular carcinoma and an anticipated life expectancy of 12 months or more were eligible for inclusion. Eligible patients were required to have an Eastern Cooperative Oncology Group performance status of 0-1, Child-Pugh class A liver function, no previous systemic therapy, and a sum of tumour maximum diameter (cm) and lesion number of six or more based on the six-and-twelve score. Patients were randomly assigned (1:1), using a permuted-block method implemented via an interactive voice and web response system, to on-demand TACE plus atezolizumab 1200 mg intravenously and bevacizumab 15 mg/kg intravenously once every 3 weeks (initiated 14 days to 8 weeks after TACE), or on-demand TACE alone, with TACE administered at the investigators' discretion. The randomisation sequence was generated by an independent biostatistician at the system vendor and was concealed from the sponsor study team and investigators until randomisation; allocation was stratified by baseline α-fetoprotein, prior locoregional therapy, and baseline Vp1/2 (and geographic region in earlier protocol versions). Primary endpoints were investigator-assessed TACE progression-free survival (TACE-PFS; time from randomisation to untreatable [unTACEable] progression, TACE failure or refractoriness, or death), and overall survival, both analysed in the intention-to-treat population. Overall survival was assessed under a prespecified adaptive (group sequential) design comprising two interim analyses and one final analysis. Safety was evaluated in the as-treated population, defined as all randomised patients who received any study treatment, analysed according to the treatment received. This study is registered with ClinicalTrials.gov (NCT04712643) and is ongoing. FINDINGS:Between Feb 23, 2021, and August 11, 2023, 342 patients were randomly assigned to TACE plus atezolizumab and bevacizumab (n=171) or on-demand TACE alone (n=171). Median age was 61·0 years (range 21·0-90·0), 66 (19%) of 342 participants were female, 276 (81%) were male, 308 (90%) were Chinese, and 34 (10%) were Japanese. The mean size of the largest target lesion per RECIST 1.1 was 7·7 cm (SD 4·3) in both arms. In the TACE plus atezolizumab and bevacizumab group, 36 (21%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 100 (58%) were stage B, and 35 (20%) were stage C; in the TACE alone group, 42 (25%) of 171 patients were Barcelona Clinic Liver Cancer stage A, 105 (61%) were stage B, and 24 (14%) were stage C. At data cutoff (Feb 28, 2025; median follow-up 26·25 months [IQR 21·16-33·74]), median TACE-PFS was 11·30 months (95% CI 7·52-15·01) with TACE plus atezolizumab and bevacizumab versus 7·03 months (95% CI 5·32-8·41) with TACE alone (hazard ratio [HR] 0·71 [95% CI 0·55-0·92]; two-sided stratified log-rank p=0·0089). Overall survival remains immature and was assessed at the first of the prespecified interim analyses; median overall survival was 34·53 months (99·62% CI 24·80-not evaluable) in the TACE plus atezolizumab and bevacizumab group compared with 35·38 months (99·62% CI 24·74-not evaluable) in the TACE alone group (HR 0·96 [99·62% CI 0·58-1·58]). The most common grade 3-4 adverse events in the TACE plus atezolizumab and bevacizumab group were decreased platelet count (23 [14%] of 166), hypertension (23 [14%]), and post-embolisation syndrome (21 [13%]); in the TACE alone group, the most common were post-embolisation syndrome (23 [13%] of 173), decreased platelet count (12 [7%]), and increased aspartate aminotransferase (12 [7%]). The most common serious adverse event was ascites (eight [5%]) in the TACE plus atezolizumab and bevacizumab group and post-embolisation syndrome (six [3%]) in the TACE alone group. Treatment-related deaths occurred in five patients in the TACE plus atezolizumab and bevacizumab group (gastrointestinal haemorrhage, liver abscess, haemolytic anaemia, hypertension, and unknown death) and three patients in the TACE alone group (post-procedural haemorrhage, ascites, and unknown death). No new safety signals were identified. INTERPRETATION:On-demand TACE plus atezolizumab and bevacizumab significantly improved TACE-PFS versus on-demand TACE alone. Overall survival follow-up is ongoing. FUNDING:Shanghai Roche Pharmaceuticals.

This study aims to analyze the predictive value of preoperative hepatitis B surface antigen (HBsAg) level in terms of recurrence after radical resection in treatment-naïve patients with hepatitis B virus (HBV)-related primary hepatocellular carcinoma (HCC) who have not received antiviral therapy. This study performed a retrospective analysis of the clinical data of 301 patients with or without high HbsAg levels who underwent partial hepatectomy for HCC. The primary end point of this study was relapse-free survival (RFS). After a follow-up period of 25.9 ± 16.3 months, recurrence was observed in 227 (75.4%) patients with HCC. Among all the patients, RFS was better for those with low serum level of HbsAg, and RFS was better for those who received postoperative antiviral therapy. And RFS was similar for patients who did not receive antiviral treatment no matter HbsAg level. High preoperative serum level of HBsAg was associated with poor RFS of HBV-related HCC. This finding suggest HBsAg as a predictor of short-term prognosis, as well as an indicator for follow-up in postoperative HBV-related HCC patients. In addition, postoperative antiviral therapy may improve prognosis of patients with HBV-associated HCC, with more significant benefits observed in patients with low preoperative serum HBsAg levels.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide, and its progression is closely linked to the establishment of an immunosuppressive tumor microenvironment. Myristoylated alanine-rich C kinase substrate (MARCKS) has been implicated in tumor biology; however, its role in regulating immune interactions in HCC remains poorly defined. Here, we performed an integrated multi-omics analysis combining bulk transcriptomics, single-cell RNA sequencing, and spatial transcriptomics to systematically investigate the expression pattern and functional relevance of MARCKS in HCC. We found that MARCKS was significantly upregulated in HCC tissues and that high MARCKS expression was associated with aggressive clinicopathological features and unfavorable prognosis. Single-cell and spatial analyses revealed that MARCKS expression was enriched in myeloid cell populations within the tumor microenvironment. Functional annotation and mIF(Multiple immunofluorescence) validation demonstrated that MARCKS expression was associated with enhanced JAK/STAT3 signaling and M2-like macrophage polarization. Consistently, MARCKS silencing in HCC cell lines reduced STAT3 phosphorylation, suppressed malignant phenotypes in vitro, inhibited tumor growth in vivo, and diminished the capacity of tumor-derived conditioned media to promote macrophage M2 polarization. Together, these findings identify MARCKS as a key regulator of the immunosuppressive tumor microenvironment in HCC and highlight its potential as a therapeutic target for overcoming immune evasion.