Primary liver cancer is the fourth most common malignancy and the second leading cause of cancer-related death in China[1].Most patients are diagnosed at an advanced stage,which renders them ineligible for curative surgical resection.

BACKGROUND AND AIMS:Laparoscopic common bile duct exploration (LCBDE) is a safe and effective method for the treatment of choledocholithiasis. However, there is still controversy in clinical practice over whether primary duct closure (PDC) or T-tube drainage (TTD) should be selected after choledochotomy. Therefore, this study aimed to compare the two methods of closing the common bile duct in order to identify the safer and more effective approach. APPROACH AND RESULTS:A retrospective analysis was conducted on data from 745 patients who underwent LCBDE at the Department of Hepatobiliary and Pancreatic Surgery, Zhongshan Hospital, Xiamen University, between January 2017 and December 2021. Using propensity score matching (PSM), 433 patients were selected and divided into two groups: the primary duct closure group (PDC group, 287 patients) and the T-tube drainage group (TTD group, 146 patients). The study compared preoperative baseline characteristics, Intraoperative conditions, and postoperative conditions between the two groups. The results showed that the PDC group had significantly shorter operative time and less intraoperative blood loss compared to the TTD group, along with a lower incidence of postoperative infections. Despite no significant differences between the two groups in terms of postoperative hospital stay, bile leakage, biliary stricture, residual stones, postoperative bleeding, and recurrence, the overall performance of the PDC group was superior to that of the TTD group. CONCLUSION:The study concluded that primary duct closure (PDC) after LCBDE is safer and more effective than T-tube drainage (TTD), without increasing the risk of postoperative complications.

Transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) is a promising therapy for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the characteristics and identify predictors of long-term survival (LTS) in advanced uHCC treated with triple therapy. Retrospectively reviewed patients with uHCC who underwent triple therapy between June 2018 and May 2023 at 8 hospitals in China. LTS was defined as an overall survival (OS) ≥ 24 months. Kaplan-Meier curves were used to estimate survival. Univariate and multivariate logistic regression analyses were performed to identify predictors of LTS. A total of 110 patients were included in this study. With a median follow-up of 31.3 months, the median OS and progression-free survival for the entire cohort were 17.9 months (95% confidence interval [CI], 13.8-21.2) and 11.8 months (95% CI, 9.9-15.3), respectively. Thirty-nine (35.5%) patients had LTS, with 36- and 48-month OS rates of 95.8% and 82.1%, respectively. In contrast, the median OS for patients with non-LTS was 10.9 months (95% CI, 9.9-13.2). The independent predictors of LTS were the absence of portal vein tumor thrombus (odds ratio [OR], 13.71; 95% CI, 3.19-88.08; p < .001), absence of extrahepatic metastasis (OR, 7.81; 95% CI, 2.76-25.82; p < .001), and platelet-albumin-bilirubin grade 1 (OR, 3.15; 95% CI, 1.17-9.15; p = .023). The absence of portal vein tumor thrombus, absence of extrahepatic metastasis, and platelet-albumin-bilirubin grade 1 were significantly associated with LTS. These findings help guide treatment decisions in advanced uHCC.

Hepatocellular carcinoma is a common lethal malignancy, with most patients diagnosed at an advanced stage, precluding surgical resection. Conversion therapy combining locoregional and systemic treatments has emerged as an effective approach to downstage tumors and facilitate curative-intent surgery. However, the prognosis after conversion therapy varies significantly among patients. Case reports can reveal differences in clinical outcomes following conversion therapy and their underlying causes. Here, we report two patients of advanced hepatocellular carcinoma with vascular invasion who underwent conversion therapy consisting of hepatic artery infusion chemotherapy, transarterial chemoembolization, targeted therapy (lenvatinib), and immunotherapy (programmed cell death protein 1 inhibitors). Both patients experienced significant tumor shrinkage, allowing successful surgical resection, and postoperative pathology confirmed pathological complete response. However, their long-term prognoses differed markedly: one patient, a 38-year-old male patient of Asian descent, remained recurrence-free for over 4 years, while the other patient, a 47-year-old male patient of Asian descent, experienced recurrence within 11 months after surgery. These differences might be associated with adverse baseline features and imaging findings, including preoperative portal vein tumor thrombus, markedly elevated alpha-fetoprotein, insufficient tumor shrinkage despite radiological complete response, and the coexistence of intrahepatic/extrahepatic bile duct stones, all of which may have predisposed the second patient to early recurrence. Although conversion therapy can significantly downstage advanced hepatocellular carcinoma and allow curative-intent resection, the variability in long-term outcomes highlights the critical importance of preoperative tumor characteristics and treatment response assessment. Optimizing patient selection and enhancing postoperative surveillance and intervention strategies may improve long-term outcomes for these patients.

PURPOSE:Retinol metabolism is intricately linked to the occurrence and progression of hepatocellular carcinoma (HCC); however, the precise pathogenic relationship between them remains elusive. The aim of this study was to elucidate the characteristics of retinol metabolism in HCC through Mendelian randomization, prognostic model and experimental validation. METHODS:We used transcriptomic data related to HCC in TCGA and GEO databases for a variety of machine learning, including differential gene expression analysis, functional enrichment analysis, protein-protein network interaction, ceRNA regulatory network, and single-cell sequencing analysis. Mendelian randomization analysis was used to elucidate the causal analysis of retinol metabolism and the occurrence of HCC. Consensus cluster analysis was performed based on 11 retinol metabolism-related genes, and the prognostic model was constructed by Lasso regression and Cox regression analysis. The expression level of RDH16 gene was detected in cell lines and clinical samples, and finally the function of RDH16 gene and its regulatory relationship with miR- 665 were verified by in vitro cell experiments. RESULTS:Differentially expressed genes were mainly concentrated in the retinol metabolic pathway. Mendelian randomization analysis showed that decreased retinol metabolic activity was causally associated with the occurrence of HCC. RDH16 gene was significantly lower expressed in HCC, and inhibition of RDH16 gene expression could promote the proliferation, migration and invasion of HCC cells and inhibit cell apoptosis. miR- 665 is an upstream regulator of RDH16 gene, which can inhibit the expression and function of RDH16. CONCLUSION:The decrease of retinol metabolic activity can promote the occurrence and development of HCC. Targeting retinol metabolic pathway may be a new direction for the treatment of HCC.

IntroductionHepatocellular carcinoma (HCC) is a leading cause of cancer-related death, with most patients diagnosed at advanced stages, often precluding surgical resection. Recently, immune checkpoint inhibitors, particularly PD-1 inhibitors, have emerged as promising therapies, though long-term disease-free survival (DFS) remains rare. We report a case of an advanced HCC patient who achieved complete remission (CR) after just four cycles of reduced-dose pembrolizumab and maintained a disease-free status for more than seven years.Case reportA 55-year-old male with chronic hepatitis B and alcohol-related liver disease presented with a ruptured HCC. After initial treatments, including surgery and chemotherapy, the patient was started on reduced-dose pembrolizumab (100 mg). After four cycles, the patient achieved CR.ConclusionThis case highlights the potential for long-term survival with reduced-dose PD-1 inhibitor therapy in advanced HCC. The patient’s exceptional response provides important insights into the role of personalized dosing, immune checkpoint inhibitors, and the management of immune-related adverse events.

Hepatocellular carcinoma (HCC) is known for its high invasiveness, high fatality rate. Both hypoxia and senescence play crucial roles in the initiation and progression of cancer, yet their prognostic implications in HCC are yet to be fully understood. The hypoxia-senescence co-related genes (HSCRGs) were screened from public databases. Transcriptome data and clinical information were obtained from patients with HCC using the Cancer Genome Atlas, GSE76427, and International Cancer Genome Consortium (ICGC). The random forest tree algorithm was used to identify the characteristic genes of the disease, and the genes were verified by related experiments. SVM algorithm was used to classify HCC patients based on HSCRGs. The prediction model based on HSCRGs was established by LASSO, univariate and multivariate COX regression analysis. We used the ICGC for outside validation. The risk score model was analyzed from subgroup analysis, immune infiltration, and functional strength. The expression patterns of key prognostic genes in tumor microenvironment were decoded by single cell analysis. A total of 184 HSCRGs were identified. The expression pattern and functional characteristics of MLH1 gene in HCC were verified. Two HCC subtypes were identified based on HSCRGs. Then, a prediction model based on HSCRGs was established, and risk score was identified as an independent prognostic indicator of HCC. A new nomogram is constructed and shows good prediction ability. We further determined that the level of infiltration of immune cells and the expression of immune checkpoints are significantly affected by the risk score. The immune microenvironment was different between the two risk groups. The high-risk group was dominated by immunosuppressed cells, and the prognosis was poor. Single-cell analysis revealed the expression of seven key prognostic genes in the tumor microenvironment. Finally, qPCR results further verified the expression levels of seven prognostic genes. HSCRGs are of great significance in the prognosis prediction, risk stratification and targeted therapy of patients with HCC.

Background: Transcatheter arterial chemoembolization combined with lenvatinib plus PD-1 inhibitors (triple therapy) is a promising treatment modality for uHCC. Identifying variables influencing prognosis can facilitate more personalized treatment. This study aimed to determine predictors of short-term survival (STS) and long-term survival (LTS) in patients with uHCC treated with triple therapy. Methods: This multicenter retrospective study reviewed patients with uHCC who underwent triple therapy at seven tertiary hospitals in China between June 2018 and May 2023. STS was defined as survival <12 months from the initiation of treatment, and LTS was defined as survival ≥24 months. Univariate and multivariate logistic regression analyses were performed to identify predictors of STS and LTS. Variables examined were: age, gender, hepatitis B virus infection, performance status, alpha-fetoprotein, macrovascular invasion, extrahepatic metastasis, tumor size, tumor number, total bilirubin, albumin, alanine aminotransferase, aspartate transaminase, and albumin-bilirubin grade. Findings: 289 patients were included, with the following baseline characteristics: median age 55.7 years, 88.2% male, 87.2% hepatitis B virus infection, 26.3% Barcelona Clinic Liver Cancer stage B, and 73.7% stage C. Treatment-related adverse events occurred in 88.2% of patients, with 29.8% experiencing grade 3–5 adverse events. Median overall survival was 29.2 months (95% confidence interval, 23.1–NA). Sixty-five (22.5%) patients had STS and 89 (30.8%) had LTS. The independent predictors of STS were alpha-fetoprotein level ≥400 ng/mL [odds ratio (OR), 2.04; p = 0.033], extrahepatic metastasis (OR, 3.83; p < 0.001), and maximum tumor size ≥5 cm (OR, 3.79; p = 0.039). Absence of macrovascular invasion (OR, 1.99; p = 0.019), absence of extrahepatic metastasis (OR, 3.01; p = 0.008), and maximum tumor size <5 cm (OR, 2.85; p = 0.002) were independent predictors of LTS. Interpretation: Higher alpha-fetoprotein levels, extrahepatic metastasis, and larger tumor size were predictors of STS, while no macrovascular invasion, no extrahepatic metastasis, and smaller tumor size predicted LTS in patients with uHCC treated with triple therapy. These findings may help guide treatment decisions in uHCC. Funding: This study was funded by the Medical Innovation Project of Health and Family Planning Commission of Fujian Province (Grant number: 2022CXA002).

Introduction: Accurately predicting the outcomes of conversion therapy among patients with initially unresectable hepatocellular carcinoma (uHCC) remains a challenge. Clinical complete response (cCR) has been proposed as a predictor of prognosis. However, information on its prognostic value in these patients is limited. We aimed to explore the prognostic value of cCR in patients with uHCC following conversion therapy and identify predictors of cCR. Methods: We included 241 patients with uHCC who underwent transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) as first-line treatment. The prognostic value of cCR, predictive factors of cCR, and the relationship between cCR and pathological complete response (pCR) were analyzed. Results: The cCR rate of the 241 patients included was 17.4%. Patients with cCR showed better overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) than those without. cCR was an independent risk factor for OS (hazard ratio [HR]: 0.11, 95% confidence interval [CI]: 0.03–0.42, p = 0.001) and PFS (HR: 0.29, 95% CI: 0.15–0.56, p < 0.001). Serum α-fetoprotein levels ≥400 ng/mL (odds ratio [OR]: 0.47, 95% CI: 0.22–0.95, p = 0.040) and extrahepatic metastasis (OR: 0.13, 95% CI: 0.01–0.62, p = 0.046) were independent negative predictors of cCR. A total of 107 patients (44.4%) underwent conversion surgery. Among these patients, cCR was associated with better OS (p =0.009) and recurrence-free survival (p = 0.007). cCR was significantly correlated with pCR (Φ = 0.61, p < 0.001). Albumin levels ≥35 g/L (OR: 0.12, 95% CI: 0.02–0.69, p = 0.018) and cCR (OR: 30.32, 95% CI: 9.19–128.00, p < 0.001) were independent predictors of pCR. Conclusion: cCR after triple therapy has an excellent long-term survival advantage and is significantly related to pCR. cCR may be a surrogate marker for predicting prognosis and pCR in patients with uHCC receiving triple therapy.

Dysregulated metabolism in tumor tissues and para-tumor tissues alike can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib, which specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of hepatocellular carcinoma (HCC) in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity toward HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We also found that HCC tissues in aldometanib-treated mice were massively infiltrated with CD8+ T cells, which was not seen in mice with liver-specific knockout of AMPKα. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumor microenvironment to allow cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumor tissues. The finding that metabolic intervention can make cancer a lifelong manageable disease may usher in a new era of cancer therapy.

Hepatocellular carcinoma (HCC), the sixth most prevalent cancer globally, is characterized by high recurrence rates and poor prognosis. Investigating the heterogeneity of relapsed HCC and identifying key therapeutic targets may facilitate the design of effective anticancer therapies. In this study, integrative analysis of single-cell RNA sequencing data of primary and early-relapsed HCC revealed increased proportions of infiltrating CD8(+) T cells along with malignant cells and a decrease in CD4(+) T cells in relapsed HCC. Cellular interaction and immunohistochemical analysis proposed MIF-(CD74 + CXCR4) signaling pathway as a key mechanism by which malignant cells influence immune cells within the tumor microenvironment. Notably, primary malignant cells showed greater differentiation and proliferation potential, whereas relapsed cells exhibited enhanced epithelial-mesenchymal transition and inflammation, along with upregulated glycogen synthesis and metabolism-related gene expression. Using machine learning techniques on bulk RNA-seq data, we developed a relapsed tumor cell-related risk score (RTRS) that independently predicts overall and recurrence-free survival time with higher accuracy compared with conventional clinical variables. Prognostic biomarkers and potential therapeutic targets were validated via RT-qPCR using mouse implantation models. This comprehensive investigation elucidates the heterogeneity of relapsed HCC and constructs a novel postoperative recurrence prognostic model, paving the way for targeted therapies and improved patient outcomes.

Background:Forsythiae Fructus (FF), a widely used traditional Chinese medicine, possesses anti-inflammatory, antiviral, and anticancer properties. However, the precise anticancer mechanisms of FF against hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain poorly understood. This study therefore aims to investigate the therapeutic potential of FF in HBV-related HCC and elucidate its underlying mechanisms. Methods:The active components of FF and their putative target proteins were identified through network pharmacology, and their interactions were further validated via molecular docking and molecular dynamics (MD) simulations. In vitro assays were performed to evaluate the effects of FF extract on the viability, proliferation, and apoptosis of HBV-related HCC (HepG2.2.15) cells, along with the underlying molecular mechanisms. In vivo studies were performed to investigate the inhibitory effects of FF extract on subcutaneous xenograft tumors in nude mice, quantify serum cytokine levels, and evaluate the expression of key target proteins by immunohistochemistry. Results:A total of 23 active components of FF and their 201 associated targets were identified using the TCMSP database, whereas 1,296 differentially expressed genes related to HBV-related HCC were retrieved from the GEO database. We identified 42 overlapping target genes between FF and HBV-related HCC. KEGG pathway analysis revealed the IL-17 signaling pathway as a pivotal pathway, with three core genes (c-Jun, ESR1, and MMP9) demonstrating prognostic significance in survival outcomes. Ten compounds were classified as high-quality candidates. Molecular docking studies demonstrated that Bicuculline exhibited the strongest binding affinity toward the core target genes, while MD simulations confirmed the stability of Bicuculline-JUN/ESR1/MMP9 complexes. In vitro experiments demonstrated that FF extract significantly inhibited the viability and proliferation of HepG2.2.15 cells, induced apoptosis, and exerted its effects via modulation of the IL-17/MAPK signaling pathway. Notably, adenovirus-mediated overexpression experiments showed that ESR1 enhanced FF's anti-HCC effects, whereas JUN and MMP9 partially counteracted them, confirming their roles as functional targets. In vivo studies further confirmed that FF suppressed tumor growth, reduced serum levels of ALT, AST, TNF-α, and IL-17B in mice, and modulated the expression of core target genes. Conclusions:The therapeutic potential of FF in HBV-related HCC was demonstrated, with its mechanism likely involving the regulation of multiple components, targets, and pathways. These findings establish a solid scientific foundation for exploring FF as a therapeutic option for HBV-related HCC.

BackgroundPortal vein tumor thrombus (PVTT) seriously affects the prognosis of hepatocellular carcinoma (HCC). However, whether bile duct tumor thrombus (BDTT) significantly affects the prognosis of HCC as much as PVTT remains unclear. We aimed to compare the long-term surgical outcomes of HCC with macroscopic PVTT (macro-PVTT) and macroscopic BDTT (macro-BDTT).MethodsThe data of HCC patients with macro-BDTT or macro-PVTT who underwent hemihepatectomy were retrospectively reviewed. A propensity score matching (PSM) analysis was performed to reduce the baseline imbalance. The recurrence-free survival (RFS) and overall survival (OS) rates were compared between the cohorts.ResultsBefore PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.043 and P = 0.008, respectively). Multivariate analyses identified PVTT (hazard ratio [HR] = 1.835, P = 0.016) and large HCC (HR = 1.553, P = 0.039) as independent risk factors for poor OS and RFS, respectively. After PSM, the PVTT group had worse RFS and OS rates than the BDTT group (P = 0.037 and P = 0.004, respectively). The 3- and 5-year OS rates were significantly higher in the BDTT group (59.5% and 52.1%, respectively) than in the PVTT group (33.3% and 20.2%, respectively).ConclusionAggressive hemihepatectomy provides an acceptable prognosis for HCC patients with macro-BDTT. Furthermore, the long-term surgical outcomes of HCC patients with macro-BDTT were significantly better than those of HCC patients with macro-PVTT.

Background:This study aimed to assess the effect of adjuvant therapy with different durations in patients with initially unresectable hepatocellular carcinoma (uHCC) after conversion surgery. Methods:This study included 85 patients with initially uHCC who received conversion surgery between May 2019 and November 2022. They were divided into the long duration group (n = 57) and short duration group (n = 28) based on postoperative medication duration. Recurrence-free survival (RFS) and overall survival (OS) were analyzed and compared between the cohorts. Results:No significant difference in RFS or OS was found between the two groups [RFS: hazard ratio (HR) = 0.486; 95% confidence interval (CI), 0.229-1.034, P = 0.061; OS: HR = 0.377; 95% CI, 0.119-1.196, P = 0.098]. Patients without major pathologic response (MPR) in the long duration group had better RFS and OS results compared to those in the short duration group (RFS: HR = 0.242; 95% CI, 0.092-0.634, P = 0.004; OS: HR = 0.264; 95% CI, 0.079-0.882, P = 0.031). No significant difference was detected in RFS or OS between the two groups in patients with MPR (RFS: HR = 1.250; 95% CI, 0.373-4.183, P = 0.718; OS: HR = 7.389; 95% CI, 0.147-372.4, P = 0.317). After propensity score matching, 25 pairs of patients were selected and the results remained consistent. Conclusion:At least 6 months of adjuvant therapy may be beneficial for patients without MPR after conversion surgery. However, in patients with MPR, the effect of adjuvant therapy remains unclear. Further studies are needed to confirm the optimal duration of adjuvant therapy.

PURPOSE:The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti-programmed cell death-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT. MATERIALS AND METHODS:This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child-Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles. RESULTS:During a median follow-up of 11.23 months (range, 3.07 to 34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The 2-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively. CONCLUSION:Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

Introduction: Transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor (triple therapy) has displayed encouraging clinical outcomes for unresectable hepatocellular carcinoma (uHCC). We aimed to explore the prognostic value of pathological response (PR) in patients with initially uHCC who underwent conversion surgery following triple therapy and identify predictors of major pathological response (MPR). Methods: A total of 76 patients with initially uHCC who underwent conversion surgery following triple therapy were retrospectively analyzed. PR was calculated as the proportion of nonviable tumor cell surface area of the whole tumor bed surface area. MPR was identified when PR was ≥90%. Pathological complete response (pCR) was defined as the absence of viable tumor cells. Results: MPR and pCR were identified in 53 (69.7%) and 25 (32.9%) patients, respectively. The 1- and 2-year overall survival in patients with MPR were significantly higher than in those without MPR (100.0% and 91.3% vs. 67.7% and 19.4%; p < 0.001). The corresponding recurrence-free survival was also improved in patients with MPR compared to those without (75.9% and 50.8% vs. 22.3% and 11.2%; p < 0.001). Similar results were observed among patients with pCR and those without. Patients who achieved MPR without pCR exhibited survival rates comparable to those of patients who achieved pCR. Baseline neutrophil-to-lymphocyte ratio ≥2.6 (p = 0.016) and preoperative alpha-fetoprotein level ≥400 ng/mL (p = 0.015) were independent predictors of MPR. Conclusion: The presence of MPR or pCR could improve prognosis in patients with initially uHCC who underwent conversion surgery following triple therapy. The PR may become a surrogate marker for predicting the prognosis of these patients.

Dysregulated metabolism in tumour tissues, and para-tumour tissues alike, can lead to immunosuppression, which may underlie cancer development. However, metabolic intervention as a therapeutic strategy has been of no avail. In this study, we explored the anti-cancer therapeutic effect of aldometanib that specifically targets lysosome-associated aldolase to mimic glucose starvation and thereby activates the lysosomal AMP-activated protein kinase (AMPK), a master regulator of metabolic homeostasis. We show that aldometanib inhibits the growth of HCC in an AMPK-dependent manner, allowing hepatoma-bearing mice to survive to mature ages, although aldometanib does not possess cytotoxicity towards HCC or normal cells. Intriguingly, aldometanib exerts anti-cancer effects only in immune-competent host mice, but not in immune-defective mice. We have further found that the HCC tissues in aldometanib-treated mice are massively infiltrated with CD8+ T cells, which is not seen in mice with liver-specific knockout of AMPKalpha. Our findings thus suggest that the metabolic regulator AMPK rebalances the tumour microenvironment to allow the cytotoxic immune cells inside the body to eliminate cancer cells and effectively contain the tumour tissues. The finding that metabolic intervention can make cancer a life-long manageable disease, may potentially usher in a new era of cancer therapy. ### Competing Interest Statement The authors have declared no competing interest.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with a 5-year survival rate still below 20%. Alterations in the levels of metabolites involved in retinol metabolism (RM) have been observed during HCC progression. However, the precise mechanisms underlying the involvement of RM-related genes in HCC development remain elusive. In this study, we conducted comprehensive bulk RNA sequencing analysis using publicly available databases and identified significant enrichment of retinol metabolism pathways in HCC. Furthermore, through Mendelian randomization analysis, we elucidated the causal relationship between retinol metabolism and HCC development. Subsequently, employing clustering analysis based on RM-related genes and utilizing univariate Cox proportional hazards regression, we constructed a prognostic risk model for HCC patients. Finally, our investigation into RDH16—a pivotal gene implicated in RM disorders—unveiled its potential functional role. Collectively, these findings highlight the diagnostic and prognostic value of distinct features associated with retinol metabolism for identifying HCC patients who would benefit from timely treatment interventions and achieve optimal prognosis.

Background Combination treatment with transcatheter arterial chemoembolization (TACE), lenvatinib, and anti-programmed death-1 (anti-PD-1) antibodies (triple therapy) has a high rate of tumor response and converted resection for initially unresectable hepatocellular carcinoma (uHCC) patients. This study aimed to assess the outcomes of salvage surgery in uHCC patients after conversion therapy with triple therapy. Methods uHCC patients who met the criteria for hepatectomy after receiving triple therapy as first-line treatment were eligible for inclusion in this study. The overall survival (OS) and progression-free survival (PFS) rates in patients who received salvage surgery (SR group) and those who did not (non-SR group) were compared. Results Of the 144 patients assessed, 91 patients underwent salvage surgery and 53 did not. The OS rates in the SR group were significantly better than those in the non-SR group. The 1- and 2-year OS rates in the SR group were 92.0% and 79.9%, respectively, whereas those in the non-SR group were 85.5% and 39.6 %, respectively ( p = 0.007); however, there was no significant difference in the PFS rates. Upon further stratification, OS and PFS were significantly better in the SR group than in the non-SR group in patients who were assessed as partial responses (PR), while there was no significant difference in patients who were assessed as complete response (CR). Conclusions Salvage surgery is recommended and is associated with a favorable prognosis for uHCC patients who were assessed as PR after conversion therapy, however it may not be necessary for uHCC if CR was achieved.

目的 探讨腹腔镜胆囊切除+胆总管切开取石+胆管一期缝合术(LC+LCBDE+PDC)在胆总管结石合并胆囊结石患者中的应用价值.方法 选取2020年6月—2022年6月分别接受腹腔镜胆囊切除+胆总管切开取石+胆管一期缝合术(LC+LCBDE+PDC)治疗的51例胆总管结石合并胆囊结石患者作为LCBDE组,同期选取接受内镜逆行性胰胆管造影(ERCP)+LC治疗的29例胆总管结石合并胆囊结石患者作为ERCP组;对两组患者临床资料进行回顾性分析.结果 LCBDE组手术时间、住院时间、结石清除率均显著优于ERCP组(P<0.05),两组术后肛门排气时间比较差异不显著(P>0.05);治疗前两组焦虑自评量表(SAS)、抑郁自评量表(SDS)、SF-36评分比较差异不显著(P>0.05),治疗后两组SAS、SDS、SF-36评分均得到显著改善(P<0.05),且术后LCBDE组SAS、SDS、SF-36评分均显著优于ERCP组(P<0.05);LCBDE组并发症发生率显著低于ERCP组(P<0.05).结论 与ERCP+LC相比,LC+LCBDE+PDC用于治疗胆总管结石合并胆囊结石有效性和安全性均更高,且能更好地改善患者负面情况和生活质量,值得临床借鉴推广.