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Background: This study aimed to investigate the feasibility and efficacy of near-infrared fluorescence-guided laparoscopic anatomical hepatectomy (LAH) using a novel indocyanine green (ICG)-human serum albumin complex (HSA) in patients with hepatocellular carcinoma., Methods: Clinical data of hepatocellular carcinoma patients who underwent ICG-HSA fluorescence-guided LAH at our center from January 2024 to April 2024 were prospectively collected and analyzed. Ultraviolet absorption spectroscopy was used to test the absorption and stability of ICG-HSA complex solutions under different conditions. After determining the optimal ratio, the complex was administered intravenously during surgery to perform negative staining via Glissonean pedicle isolation. LAH was performed along the fluorescence-demarcated boundaries., Results: Thirty-one patients were included (24 men; mean age, 54.61 ± 13.54 years). The median maximum tumor diameter was 2.80 (interquartile range [IQR], 2.00-4.00) cm. S8 segmentectomy (22.6%) and right posterior segmentectomy (19.4%) were the most common resections performed. Successful fluorescence negative staining was achieved in all patients using ICG and HSA at a 1:6 molar ratio at room temperature. Mean operation time was 297.58 ± 85.53 min, Median intraoperative blood loss was 100.0 mL (IQR, 50.0-200.0). The median surgical margin distance was 0.90 cm (IQR, 0.40-1.50). The postoperative complication rate was 45.2% (35.5% Clavien-Dindo grade I and 9.7% grade II). The median length of hospital stay was 5.0 days (IQR, 4.0-5.0)., Conclusion: ICG-HSA-assisted LAH is safe and feasible. Compared with free ICG, the novel ICG-HSA complex exhibits better optical properties and in vivo stability, which can improve the accuracy of intraoperative liver segment localization and optimize the anatomical dissection plane. It has the potential to become an ideal fluorescent imaging agent for anatomical hepatectomy., (© 2024. The Author(s).)

Background and Aims: The practice of intraoperative blood salvage and autotransfusion (IBSA) during deceased donor liver transplantation for hepatocellular carcinoma (HCC) can potentially reduce the need for allogeneic blood transfusion. However, implementing IBSA remains debatable due to concerns about its possible detrimental effects on oncologic recurrence., Methods: This study retrospectively enrolled nationwide recipients of deceased donor liver transplantation for HCC between 2015 and 2020. The focus was on comparing the cumulative recurrence rate and the recurrence-free survival rate. Propensity score matching was conducted repeatedly for further subgroup comparison. Recipients were categorized based on the Milan criteria, macrovascular invasion, and pretransplant α-Fetoprotein (AFP) level to identify subgroups at risk of HCC recurrence., Results: A total of 6196 and 329 patients were enrolled in the non-IBSA and IBSA groups in this study. Multivariable competing risk regression analysis identified IBSA as independent risk factors for HCC recurrence ( P <0.05). Postmatching, the cumulative recurrence rate and recurrence-free survival rate revealed no significant difference in the IBSA group and non-IBSA group (22.4 vs. 16.5%, P =0.12; 60.3 vs. 60.9%, P =0.74). Recipients beyond Milan criteria had higher, albeit not significant, risk of HCC recurrence if receiving IBSA (33.4 vs. 22.5%, P =0.14). For recipients with macrovascular invasion, the risk of HCC recurrence has no significant difference between the two groups (32.2 vs. 21.3%, P =0.231). For recipients with an AFP level <20 ng/ml, the risk of HCC recurrence was comparable in the IBSA group and the non-IBSA group (12.8 vs. 18.7%, P =0.99). Recipients with an AFP level ≥20 ng/ml, the risk of HCC recurrence was significantly higher in the IBSA group. For those with an AFP level ≥400 ng/ml, the impact of IBSA on the cumulative recurrence rate was even more pronounced (49.8 vs. 21.9%, P =0.011)., Conclusions: IBSA does not appear to be associated with worse outcomes for recipients with HCC exceeding the Milan criteria or with macrovascular invasion. IBSA could be confidently applied for recipients with a pretransplant AFP level <20 ng/ml. For recipients with AFP levels ≥20 ng/ml, undertaking IBSA would increase the risk of HCC recurrence., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: The recent focus on the roles of N-linked glycoproteins in carcinogenesis across various malignancies has prompted our exploration of aberrantly expressed glycoproteins responsible for HCC progression and potential therapeutic strategy., Methods: Mass spectrometry was applied to initially identify abnormally expressed glycoproteins in HCC, which was further assessed by immunohistochemistry (IHC) staining. The role of selected glycoprotein on HCC development and underlying mechanism was systematically investigated by colony formation, mouse xenograft, RNA-sequencing and western blot assays, etc. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to explore potential transcription factors (TFs) of selected glycoprotein. The regulation of repaglinide (RPG) on expression of lumican and downstream effectors was assessed by western blot and IHC, while its impact on malignant phenotypes of HCC was explored through in vitro and in vivo analyses, including a murine NASH-HCC model established using western diet and carbon tetrachloride (CCl 4 )., Results: Lumican exhibited upregulation in both serum and tumor tissue, with elevated expression associated with an inferior prognosis in HCC patients. Knockdown of lumican resulted in significantly reduced growth of HCC in vitro and in vivo. Mechanically, lumican promoted HCC malignant phenotypes by inhibiting the p53/p21 signaling pathway. Forkhead Box O3 (FOXO3) was identified as the TF of lumican that transcriptionally enhanced its expression. Without silencing FOXO3, RPG blocked the binding of FOXO3 to the promoter region of lumican, thereby inhibiting the activation of lumican/p53/p21 axis. Mice treated with RPG developed fewer and smaller HCCs than those in the control group at 24 weeks after establishment., Conclusion: Our results indicate that RPG prevented the development and progression of HCC via alteration of FOXO3/lumican/p53 axis., (© 2024. Springer Nature Switzerland AG.)

Background: Portal hypertension (PHT) has been proven to be closely related to the development of hepatocellular carcinoma (HCC). Whether PHT before liver transplantation (LT) will affect the recurrence of HCC is not clear., Methods: 110 patients with depressurization of the portal vein (DPV) operations (Transjugular Intrahepatic Portosystemic Shunt-TIPS, surgical portosystemic shunt or/and splenectomy) before LT from a HCC LT cohort, matched with 330 preoperative non-DPV patients; this constituted a nested case-control study. Subgroup analysis was based on the order of DPV before or after the occurrence of HCC., Results: The incidence of acute kidney injury and intra-abdominal bleeding after LT in the DPV group was significantly higher than that in non-DPV group. The 5-year survival rates in the DPV and non-DPV group were 83.4% and 82.7% respectively (P = 0.930). In subgroup analysis, patients in the DPV prior to HCC subgroup may have a lower recurrence rate (4.7% vs.16.8%, P = 0.045) and a higher tumor free survival rate (88.9% vs.74.4%, P = 0.044) after LT under the up-to-date TNMI-II stage, while in TNM III stage, there was no difference for DPV prior to HCC subgroup compared with the DPV after HCC subgroup or the non-DPV group., Conclusion: Compared with DPV after HCC, DPV treatment before HCC can reduce the recurrence rate of HCC after early transplantation (TNM I-II). DPV before LT can reduce the recurrence of early HCC., (© 2024. The Author(s).)

Background: Lenvatinib is widely used in treatment of unresectable hepatocellular carcinoma (uHCC), but the benefit of its combination with immunotherapy needs to be verified. This study evaluated the efficacy and safety of tislelizumab plus lenvatinib in systemic treatment-naïve patients with uHCC., Methods: In this multicenter, single-arm, phase 2 study, systemic treatment-naïve patients with uHCC received tislelizumab 200 mg every three weeks plus lenvatinib (bodyweight ≥ 60 kg: 12 mg; < 60 kg: 8 mg; once daily). Dose-limiting toxicities (DLTs) were evaluated in safety run-in phase to determine whether to enter the expansion phase. The primary endpoint was objective response rate (ORR) assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). Based on Simon's two-stage design, > 6 responders were needed in stage 1 (n = 30) to continue the study, and ≥ 18 responders were needed by the end of stage 2 (n = 60) to demonstrate statistical superiority to a historical control of lenvatinib monotherapy., Results: Sixty-four patients were enrolled. No DLTs were reported. The study achieved statistical superiority (p = 0.0003) with 23 responders assessed by IRC per RECIST v1.1 in the first 60 patients of the efficacy evaluable analysis set (n = 62). After a median follow-up of 15.7 months, confirmed ORR and disease control rate were 38.7% (24/62, 95% confidence interval [CI], 26.6-51.9) and 90.3% (56/62, 95% CI, 80.1-96.4), respectively. Median progression-free survival was 8.2 months (95% CI, 6.8-not evaluable). Overall survival rate at 12 months was 88.6% (95% CI, 77.7-94.4). Grade ≥ 3 treatment-related adverse events occurred in 18 (28.1%) patients., Conclusions: Tislelizumab plus lenvatinib demonstrated promising antitumor activity with favourable tolerability as first-line therapy for patients with uHCC., Trial Registration: ClinicalTrials.gov (NCT04401800)., (© 2024. The Author(s).)

Recent studies suggest that circular RNA (circRNA)-mediated post-translational modification of RNA-binding proteins (RBP) plays a pivotal role in metastasis of hepatocellular carcinoma (HCC). However, the specific mechanism and potential clinical therapeutic significance remain vague. This study attempts to profile the regulatory networks of circRNA and RBP using a multi-omics approach. Has&#95;circ&#95;0006646 (circ0006646) is an unreported circRNA in HCC and is associated with a poor prognosis. Silencing of circ0006646 significantly hinders metastasis in vivo. Mechanistically, circ0006646 prevents the interaction between nucleolin (NCL) and the E3 ligase tripartite motif-containing 21 to reduce the proteasome-mediated degradation of NCL via K48-linked polyubiquitylation. Furthermore, the change of NCL expression is proven to affect the phosphorylation levels of multiple proteins and inhibit p53 translation. Moreover, patient-derived tumor xenograft and lentivirus injection, which is conducted to simulate clinical treatment confirmed the potential therapeutic value. Overall, this study describes the integrated multi-omics landscape of circRNA-mediated NCL ubiquitination degradation in HCC metastasis and provides a novel therapeutic target., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Objective: Sex-specific differences are observed in various liver diseases, but the influence of sex on the outcomes of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains to be determined. This study is the first Chinese nationwide investigation of the role of sex in post-LT outcomes in patients with HCC., Methods: Data for recipients with HCC registered in the China Liver Transplant Registry between January 2015 and December 2020 were analyzed. The associations between donor, recipient, or donor-recipient transplant patterns by sex and the post-LT outcomes were studied with propensity score matching (PSM). The survival associated with different sex-based donor-recipient transplant patterns was further studied., Results: Among 3,769 patients enrolled in this study, the 1-, 3-, and 5-year overall survival (OS) rates of patients with HCC after LT were 96.1%, 86.4%, and 78.5%, respectively, in female recipients, and 95.8%, 79.0%, and 70.7%, respectively, in male recipients after PSM ( P = 0.009). However, the OS was comparable between recipients with female donors and male donors. Multivariate analysis indicated that male recipient sex was a risk factor for post-LT survival (HR = 1.381, P = 0.046). Among the donor-recipient transplant patterns, the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival ( P < 0.05)., Conclusions: Our findings highlighted that the post-LT outcomes of female recipients were significantly superior to those of male recipients, and the male-male donor-recipient transplant pattern was associated with the poorest post-LT survival. Livers from male donors may provide the most benefit to female recipients. Our results indicate that sex should be considered as a critical factor in organ allocation., Competing Interests: No potential conflicts of interest are disclosed., (Copyright © 2024 The Authors.)

Metastasis of hepatoblastoma (HB) is a key factor that impairs the prognosis and treatment of children. The suppressor of cytokine signaling 2 (SOCS2) is a classical negative feedback protein that regulates cytokine signal transduction and has been known to be downregulated in several tumor, but the molecular mechanisms of its involvement in HB metastasis are unknown. We found that SOCS2 was a gene down-regulated in hepatoblastoma and associated with HB metastasis through bioinformatics. The qRT-PCR, Western blot and IHC showed that SOCS2 was significantly lower in HB tissues. Clinicopathological correlation analysis revealed that low expression of SOCS2 was significantly correlated with tumor metastasis (P = 0.046) and vascular invasion (P = 0.028), associated with poor prognosis. Overexpression of SOCS2 inhibited the migration and invasion of hepatoblastoma cells, while knockdown of SOCS2 expression promoted these malignant phenotypes. In vivo studies revealed overexpression of SOCS2 inhibited the formation of lung metastasis. Up-regulation of SOCS2 in HB cell inhibited EMT and JAK2/STAT5. Conversely, down-regulation of SOCS2 promoted EMT and JAK2/STAT5. The addition of the JAK2 inhibitor Fedratinib partially reversed the effects of si-SOCS2 on HB cells. SOCS2 may inhibit the migration and invasion of HB cells by inhibiting the JAK2/STAT5 signaling pathway. These results may provide guiding significance for the clinical treatment of HB., (© 2023. The Author(s).)

Introduction: In order to maximize the utilization of precious donor liver, precisely determining potential hepatocellular carcinoma (HCC) candidates who will benefit from liver transplantation (LT) is essential. As a crucial diagnostic biomarker for HCC, protein induced by vitamin K absence or antagonist-II (PIVKA-II) has become one of the key indicators for assessing tumor recurrence risk after LT. This study aims to investigate the role of PIVKA-II in recipient selection and prognostic stratification., Methods: The clinicopathologic data of HCC patients undergoing LT from 2015 to 2020 in six Chinese transplant centers were collected. Univariate and multivariate analyses were performed to determine risk factors for disease free survival (DFS). Based on these risk factors, survival analysis was made by Kaplan-Meier method and their value in prognostic stratification was assessed., Results: A total of 522 eligible HCC patients with pre-LT PIVKA-II records were finally included in this study. Tumor burden>8 cm, α-fetoprotein>400 ng/ml, histopathologic grade III and PIVKA-II>240 mAU/ml were identified as independent risk factors for DFS. DFS of patients with PIVKA-II≤240 mAU/ml ( N =288) were significantly higher than those with PIVKA-II>240 mAU/ml ( N =234) (1-year, 3-year, and 5-year DFS: 83.2, 77.3, and 75.9% vs. 75.1, 58.5, and 50.5%; P <0.001). Compared with Hangzhou criteria ( N =305), incorporating PIVKA-II into Hangzhou criteria (including tumor burden, α-fetoprotein, and histopathologic grade) increased the number of patients with eligibility for LT by 21.6% but achieved comparable DFS and overall survival., Conclusions: Incorporating PIVKA-II into existing LT criteria could increase the number of eligible HCC patients without compromising post-LT outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hepatocellular carcinoma (HCC) is the most frequently diagnosed primary liver cancer with a high mortality rate and imposes a huge burden on patients and society. Recently, ubiquitin‑specific protease 35 (USP35) was found to be involved in cell proliferation and mitosis, but its role in HCC remains largely unknown. The expression of USP35 in HCC and its association with patient prognosis in the study cohort and public databases was analyzed in the present study. The effects of USP35 on the malignant biological behavior of HCC were analyzed by cellular functional experiments. Mechanistically, the effect of USP35 deubiquitylation on the M2 splice isoform of pyruvate kinase (PKM2) and on the Warburg effect of tumor cells were verified by western blotting and ubiquitination assay. The results of the present study demonstrated that USP35 is highly expressed in HCC and its high expression is significantly associated with poor prognosis of patients with HCC. In the present study, it was also demonstrated that inhibiting the expression of USP35 can impair the malignant properties (proliferation, migration and invasion) of HCC tumor cells by elevating the ubiquitination level of PKM2, the deubiquitinated form of which is critical for glycolysis in tumor cells. The present study therefore indicated that USP35 may be a target in the treatment of HCC.

Background: Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear., Methods: We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted., Results: Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways., Conclusions: GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy., (Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Background: Inattention has been given to the pathogenesis of adolescent and young adult (AYA) hepatocellular carcinoma (HCC). Due to the more advanced tumor progression and poorer prognosis of AYA-HCC, together with a better tolerance ability, noncirrhotic background, and a stronger willingness to treat AYA-HCC, clinical and molecular biology studies are urgent and necessary, especially for those with hepatitis B infection., Methods: For clinical aspects, the overall survival, the recurrence-free survival, and the Cox analyses were performed. Then, functional analysis, gene clustering, metabolic-related analysis, immune infiltration and competing endogenous RNA (ceRNA) construction were carried out using whole transcriptome sequencing technique., Results: Based on the clinical information of our HCC cohort, the overall survival and recurrence-free survival rates were worse in the AYA group than in the elderly group as previously described. According to our whole transcriptome sequencing results, functional analysis revealed that metabolism-related pathways as well as protein translation and endoplasmic reticulum processing were enriched. Then the hub metabolism-related genes were screened by metabolite-protein interactions (MPIs) and protein-protein interactions (PPIs). Fatty acid metabolism is a crucial component of metabolic pathways, abnormalities of which may be the reason for the worse prognosis of HBV-AYA HCC. Finally, the relationship of disrupted expression of metabolism-related genes with immune infiltration was also analyzed, and the lncRNA‒miRNA‒mRNA-related ceRNA network for HBV-AYA HCC was constructed, which may provide new cues for HBV-AHA HCC prevention., Conclusion: The worse prognosis and recurrence rate of HBV-AYA HCC may be related to abnormalities in metabolism-related pathways, especially disorders of fatty acid metabolism., (© 2023. The Author(s).)

Background: This study aimed to find effective treatments for the patient within UCSF criteria., Methods: This study enrolled 1006 patients meeting UCSF criteria, undergoing hepatic resection (HR), divided into two groups: single tumor group and multiple tumors group. We compared and analyzed the risk factors between these two groups' long-term outcomes, through log-rank test, cox proportional hazards model and using neural network analysis to identify the independent risk factors., Results: The 1-, 3-, and 5-year OS rates in single tumor were significantly higher than multiple tumors (95.0%, 73.2% and 52.3% versus 93.9%, 69.7% and 38.0%, respectively, p < 0.001). The 1-, 3- and 5-year RFS rates were 90.3%, 60.7%, and 40.1% in single tumor and 83.4%, 50.7% and 23.8% in multiple tumors, respectively (p < 0.001). And tumor type, anatomic resection and MVI were the independent risk factors for the patient within UCSF criteria. MVI was the most important risk factor affecting OS and RFS rates in neural network analysis. The method of hepatic resection and the number of tumors were also affected OS and RFS rates., Conclusion: Anatomic resections should be applied to patients within UCSF criteria, especially for patients with single MVI negative tumours., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: To determine the relationship between microvascular invasion (MVI) and the clinical features of hepatocellular carcinoma (HCC) and provide a method to evaluate MVI status by neutral network analysis., Methods: The patients were divided into two groups (MVI-positive group and MVI-negative group). Univariate analysis and multivariate logistic regression analysis were carried out to identify the independent risk factors for MVI positivity. Neural network analysis was used to analyze the different importance of the risk factors in MVI prediction., Results: We enrolled 1697 patients in this study. We found that the independent prognostic factors were age, NEU, multiple tumors, AFP level and tumor diameter. By neural network analysis, we proposed that the level of AFP was the most important risk factor for HCC in predicting MVI status (the AUC was 0.704). However, age was the most important risk factor for early-stage HCC with a single tumor (the AUC was 0.605)., Conclusion: Through the neutral network analysis, we could conclude that the level of AFP is the most important risk factor for MVI-positive patients and the age is the most important risk factor for early-stage HCC with a single tumor., (© 2023. The Author(s).)

Hepatocellular carcinoma (HCC) remains a global health challenge with a low early diagnosis rate and high mortality. The Rab GTPase (RAB) family plays an essential role in the occurrence and progression of HCC. Nonetheless, a comprehensive and systematic investigation of the RAB family has yet to be performed in HCC. We comprehensively assessed the expression landscape and prognostic significance of the RAB family in HCC and systematically correlated these RAB family genes with tumor microenvironment (TME) characteristics. Then, three RAB subtypes with distinct TME characteristics were determined. Using a machine learning algorithm, we further established a RAB score to quantify TME features and immune responses of individual tumors. Moreover, to better evaluate patient prognosis, we established a RAB risk score as an independent prognostic factor for patients with HCC. The risk models were validated in independent HCC cohorts and distinct HCC subgroups, and their complementary advantages guided clinical practice. Furthermore, we further confirmed that the knockdown of RAB13, a pivotal gene in risk models, suppressed HCC cell proliferation and metastasis by inhibiting the PI3K/AKT signaling pathway, CDK1/CDK4 expression, and epithelial-mesenchymal transition. In addition, RAB13 inhibited the activation of JAK2/STAT3 signaling and the expression of IRF1/IRF4. More importantly, we confirmed that RAB13 knockdown enhanced GPX4-dependent ferroptosis vulnerability, highlighting RAB13 as a potential therapeutic target. Overall, this work revealed that the RAB family played an integral role in forming HCC heterogeneity and complexity. RAB family-based integrative analysis contributed to enhancing our understanding of the TME and guided more effective immunotherapy and prognostic evaluation.

Background & Aims: The contribution of abnormal metabolic targets to hepatocellular carcinoma (HCC) progression and the associated regulatory mechanisms are attractive research areas. High-density lipoprotein binding protein (HDLBP) is an important transporter that protects cells from excessive cholesterol accumulation, but few studies have identified a role for HDLBP in HCC progression., Methods: HDLBP expression was determined in HCC tissues and published datasets. The biological roles of HDLBP in vitro and in vivo were examined by performing a series of functional experiments., Results: An integrated analysis confirmed that HDLBP expression was significantly elevated in HCC compared with noncancerous liver tissues. The knockdown or overexpression of HDLBP substantially inhibited or enhanced, respectively, HCC proliferation and sorafenib resistance. Subsequently, a mass spectrometry screen identified RAF1 as a potential downstream target of HDLBP. Mechanistically, when RAF1 was stabilized by HDLBP, MEKK1 continuously induced RAF1 Ser259 -dependent MAPK signaling. Meanwhile, HDLBP interacted with RAF1 by competing with the TRIM71 E3 ligase and inhibited RAF1 degradation through the ubiquitin-proteasome pathway., Conclusions: Our study reveals that HDLBP is an important mediator that stabilizes the RAF1 protein and maintains its activity, leading to HCC progression and sorafenib resistance. Thus, HDLBP might represent a potential biomarker and future therapeutic target for HCC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hepatocellular carcinoma (HCC) is the world's third leading cause of cancer-related death; due to the fast growth and high prevalence of tumor recurrence, the prognosis of HCC patients remains dismal. Long non-coding RNA CEBPA-DT, a divergent transcript of the CCAAT Enhancer Binding Protein Alpha (CEBPA) gene, has been shown to participate in multiple tumor progression. However, no research has established its cancer-promoting mechanism in HCC yet., Methods: CEBPA-DT was identified in human HCC tissues through RNA sequencing. The expression level of CEBPA-DT was assessed by quantitative real-time PCR. The biological effects of CEBPA-DT were evaluated in vitro and in vivo through gain or loss of function experiments. RNA fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were applied to investigate the downstream target of CEBPA-DT. Immunofluorescence, subcellular protein fractionation, western blot, and co-immunoprecipitation were performed to analyze the subcellular location of β-catenin and its interaction with Discoidin domain-containing receptor 2 (DDR2)., Results: CEBPA-DT was upregulated in human HCC tissues with postoperative distant metastasis and intimately related to the worse prognosis of HCC patients. Silencing of CEBPA-DT inhibited the growth, migration and invasion of hepatoma cells in vitro and in vivo, while enhancement of CEBPA-DT played a contrasting role. Mechanistic investigations demonstrated that CEBPA-DT could bind to heterogeneous nuclear ribonucleoprotein C (hnRNPC), which facilitated cytoplasmic translocation of hnRNPC, enhanced the interaction between hnRNPC and DDR2 mRNA, subsequently promoted the expression of DDR2. Meanwhile, CEBPA-DT induced epithelial-mesenchymal transition (EMT) process through upregulation of Snail1 via facilitating nuclear translocation of β-catenin. Using DDR2 inhibitor, we revealed that the CEBPA-DT induced the interaction between DDR2 and β-catenin, thus promoting the nuclear translocation of β-catenin to activate transcription of Snail1, contributing to EMT and HCC metastasis., Conclusions: Our results suggested that CEBPA-DT promoted HCC metastasis through DDR2/β-catenin mediated activation of Snail1 via interaction with hnRNPC, indicating that the CEBPA-DT-hnRNPC-DDR2/β-catenin axis may be used as a potential therapeutic target for HCC treatment., (© 2022. The Author(s).)

Hepatocellular carcinoma (HCC) remains a global health challenge due to high recurrence and metastasis rates. The interferon regulatory factor (IRF) family plays an essential role in the tumour immune microenvironment. However, an IRF family-based score that can predict prognosis and response to immunotherapy in HCC patients has not been adequately investigated. Here, we comprehensively evaluated the expression landscape and prognostic significance of IRF family genes as well as their relationship with the immune microenvironment. We further screened IRF4-associated genes to construct a signature and explored their biological features. Then, we established an IRF4 risk score consisting of nine IRF4-associated genes. Importantly, we demonstrated significant differences in the prognostic stratification and immune characteristics of HCC patients with different IRF4 risk scores. The predictive capability of the IRF4 risk score was validated in different HCC subgroups and independent HCC cohorts. Moreover, immunohistochemical analysis of our HCC cohort revealed a positive correlation between IRF4 and PD-1 expression. In vitro experiments demonstrated that the overexpression of IRF4 inhibited the proliferation and migration capacity of HCC cells by restricting the JAK2/STAT3 signalling pathway and epithelial-mesenchymal transition. Overall, our study identified a novel IRF4 risk score that could serve as a robust prognostic biomarker and provide therapeutic benefits for immunotherapy in HCC patients, which may be helpful for clinical decision-making for HCC patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent studies have suggested that exploring the potential mechanisms regulating ferroptosis vulnerability may contribute to improving the systemic therapeutic efficacy in HCC. High-density lipoprotein-binding protein (HDLBP), the largest RNA-binding protein, is an important transporter that protects cells from overaccumulation of cholesterol, but few studies have elucidated the role of HDLBP in the regulation of ferroptosis vulnerability in HCC. Our study suggests that HDLBP was markedly elevated in HCC compared with noncancerous liver tissues and that this elevation inhibited the ferroptosis vulnerability of HCC. Further experiments revealed that HDLBP bound to and stabilized the long noncoding RNA lncFAL (ferroptosis-associated lncRNA), which is derived from the plexin B2 gene. Moreover, our study suggests that the splicing of lncFAL was increased by YTH N6-methyladenosine (m6A) RNA-binding protein 2 (YTHDF2) in a m6A-dependent manner. Although HDLBP or lncFAL could not regulate the GPX4 antioxidant signalling pathway, lncFAL reduced ferroptosis vulnerability by directly binding to ferroptosis suppressor protein 1 (FSP1) and competitively abolishing Trim69-dependent FSP1 polyubiquitination degradation. More importantly, FSP1 inhibition promoted the antitumour activity of ferroptosis inducers both in vitro and in vivo. Collectively, our results provide a clinically promising demonstration that HDLBP stabilizes lncFAL, which mediates a FSP1-dependent anti-ferroptosis mechanism in HCC. These results support the enormous potential of disrupting FSP1 as a promising therapeutic approach for HCC patients with high HDLBP or lncFAL expression., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Tumor metastasis is a major cause of cancer mortality. However, little is known regarding the regulation of abnormal cholesterol metabolism in hepatocellular carcinoma (HCC) metastasis. Here, we show that the expression of high-density lipoprotein binding protein (HDLBP), a lipid transporter, is clinically correlated with tumor metastasis in HCC patients. Moreover, HDLBP was required for cholesterol-induced HCC metastasis. We revealed that knockdown and overexpression of HDLBP significantly inhibited and enhanced, respectively, the metastasis, invasion and epithelial-mesenchymal transition (EMT) of HCC cells in vitro and in vivo. Mechanistically, coimmunoprecipitation and mass spectrometry screening uncovered BRAF as a protein target of HDLBP. HDLBP was found to promote EMT signaling in a BRAF-dependent manner. Furthermore, HDLBP interacts with BRAF and inhibits its ubiquitinated degradation by abrogating BRAF-ITCH interactions. Notably, further studies suggest that dabrafenib exhibited a greater metastasis-suppressive effect in HDLBP knockout HCC than isolated treatment. Overall, our findings imply that cholesterol-induced HDLBP contributes to the metastasis and invasion of HCC through BRAF-dependent EMT signaling and that HDLBP may be applied as a biomarker and therapeutic target for HCC., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Molecular targeted therapy has shown potential in hepatocellular carcinoma (HCC) patients, and immunotherapy applications are developing rapidly. However, clinical guidance for making individualized therapy decisions for HCC patients remains lacking. MDH (Medication Decision in HCC) gene signatures comprising 70 genes were screened using transcriptomic data from multikinase inhibitor (TKI)-resistant HCC cells and HCC patient-derived xenograft model (PDX) models. Four MDH subtypes with distinct biological and clinical characteristics were defined by unsupervised cluster analysis of HCC data from The Cancer Genome Atlas (TCGA) database. To facilitate individualized and reasonable clinical guidance for each HCC patient, we constructed the MDH score. Comprehensive analysis suggested high MDH scores were associated with TKI resistance, a high proportion of stromal cell infiltration and poor survival outcomes. We recommend concomitant stromal activity intervention and immunotherapy for this type of HCC. Moreover, low MDH scores indicate TKI sensitivity, and a combination of targeted and immunotherapy is recommended. The nomogram constructed by iteration least absolute shrinkage and selection operator (LASSO) Cox regression analysis successfully predicted 3- or 5-year survival outcomes and mortality risks of HCC patients. In conclusion, TKI resistance model-based MDH gene signatures provide novel insight into potential mechanisms of drug resistance and heterogeneity in HCC. Integrative analysis plus a simplified decision model may aid personalized treatment and prognostic assessment among HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yuan, Liu, Wu, Yan, Yang and Shi.)

Background: With the advancement of laparoscopic technology, more precise anatomical hepatectomies such as segmentectomy or even bi-segmentectomy have been recommended by updated expert consensus to treat a single small hepatocellular carcinoma (HCC) [1, 2]. Herein, we presented a video of laparoscopic anatomic bi-segmentectomy (S3 and S4b) using the Glisson's pedicle-first and intrahepatic anatomic markers approach., Methods: A 66-year-old male was referred for treatment of a single HCC adjacent to the Sagittal part of the left portal vein. The procedure was performed according to the following steps: (1) dissecting and transecting the Glisson's pedicle to S3 and S4b based on Laennec's capsule [3]; (2) identification of the ischemia boundary on the liver surface and confirming the presence of adequate surgical margins within the boundary, ensuing the integrity of segment 2 and 4a by the intraoperative ultrasonography meanwhile; (3) the left parenchymal transection was begun along the demarcation line, exposing the Glisson's pedicle to S2, left hepatic vein, and umbilical fissure vein; (4) the right parenchymal transection was performed to expose the V5, V4b, and V4a. And this operation was approved by the Institutional Review Board of the West China Hospital and written informed consent was obtained from patient of Sichuan University and written informed consent was obtained from patient. (5) The blood supply of residual liver surface was observed, and the integrity of segment 2 and 4a hepatic pedicle was ensured by intraoperative ultrasonography., Results: The operative time was 224 min and blood loss during operation was 50 ml. The histopathologic examination showed a solitary HCC, 4 cm in diameter, with negative surgical margin and no microvascular invasion. The patient had an uneventful postoperative recovery and was discharged on postoperative day 5., Conclusion: Laparoscopic bi-segmentectomy (S3 and S4b) using the Glisson's pedicle-first and intrahepatic anatomic markers approach is feasible and effective. Its advantages lie in obtaining the benefits of anatomical hepatectomy, while maximizing the postoperative functional hepatic reserve [4-6]., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The role of hepatic resection (HR) combined with radiofrequency ablation (RFA) versus HR alone remains unclear for patients with multifocal hepatocellular carcinomas (HCCs). The aim of this study was to assess the outcomes of selected patients with moderately advanced multifocal HCCs after HR combined with intraoperative RFA versus HR alone., Methods: A total of 304 selected patients with multifocal HCCs (three or fewer lesions, with the largest lesion > 4.5 cm and the residual lesion[s] ≤ 3 cm) who underwent HR plus RFA (HR+RFA group) or HR alone (HR group) were included. Propensity score matching (PSM) was used to adjust for baseline differences. Multivariable and subgroup analyses estimated the effects of clinical factors on survival., Results: Both overall survival (OS) and recurrence-free survival (RFS) were comparable between both groups before and after PSM. Subgroup analysis showed that HR was associated with better RFS than HR+RFA for those patients with two tumors, or with all lesions located in the same lobe or without microvascular invasion (MVI) [all p < 0.05]. Moreover, en bloc resection provided a higher RFS than separate resection for those with all lesions in the same lobe (p = 0.039)., Conclusion: For selected patients with moderately advanced multifocal HCCs, HR+RFA may offer similar OS and RFS as HR alone. However, HR may be more suitable for those with two tumors, or with all lesions in the same lobe or without MVI. Moreover, en bloc resection may be recommended for those with all lesions in the same lobe., (© 2022. Society of Surgical Oncology.)

Background: The feasibility and safety of using longer ischemic interval during intermittent Pringle maneuver for hepatectomy in patients with hepatocellular carcinoma are still unclear. The aim of this study was to compare the short-term outcomes of hepatectomy using intermittent Pringle maneuver with an ischemic interval of 25 minutes versus 15 minutes in hepatocellular carcinoma patients., Methods: A total of 344 patients with hepatocellular carcinoma undergoing hepatectomy were randomized to receive the intermittent Pringle maneuver with a 15-minute (n = 172) or 25-minute (n = 172) ischemic interval. Primary endpoint was transaminase-based postoperative hepatic injury, assessed by their peak values as well as area under the curve of the postoperative course of aminotransferases. Secondary endpoints included the intraoperative blood loss, transection speed, morbidity, mortality, and postoperative inflammatory reaction., Results: There were no significant differences between the 2 groups in the postoperative aminotransferase serum levels or their area under the curve values, but the 25-minute intermittent Pringle maneuver group was associated with significantly higher speed for liver transection (1.38 vs 1.23 cm 2 /min, P = .002) and a lower blood loss during transection (109 vs 166 mL, P < .001) than the 15-minute intermittent Pringle maneuver group. Postoperative complications, inflammatory cytokines serum levels, and 90-day mortality were comparable. Stratification analysis showed that the 25-minute intermittent Pringle maneuver did not aggravate the hepatic injury but resulted in a lower blood loss during transection and higher transection speed in hepatocellular carcinoma patient undergoing laparoscopic or open hepatectomy., Conclusion: Intermittent Pringle maneuver with a 25-minute ischemic interval can be applied safely and efficiently in open or laparoscopic hepatectomy in patients with hepatocellular carcinoma patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Laparoscopic segmentectomy, which maximizes the preservation of the functional hepatic reserve and the possibility for future repeat hepatectomy while ensuring adequate surgical margin, is a feasible alternative to hemihepatectomy for hepatocellular carcinoma (HCC) (Vigano et al. in Ann Surg 270(5):842-851, 2019, Ishizawa et al. in Ann Surg 256(6):959-964, 2012). Herein, we present a video of laparoscopic segmentectomy IV for HCC using hepatic round ligament approach combined with fluorescent negative staining method., Patient and Methods: A 44-year-old male with history of chronic hepatitis B virus (HBV) infection for 22 months was referred for treatment of a single HCC in segment IV. The procedure was performed according to the following steps: (1) lowering the hilar plate based on Laennec's capsule (Sugioka et al. in J Hepatobiliary Pancreat Sci 24(1):17-23, 2017) after cholecystectomy; (2) cutting the Glisson's pedicles to segment IV along the fissure for the round ligament; (3) the first parenchyma transection was along the falciform ligament, while cutting some deep pedicles to segment IV; (4) clamping the left Glisson's pedicle and using fluorescent negative staining method (Abo et al. in Eur J Surg Oncol 41(2):257-264, 2015, Funamizu et al. in J Hepatobiliary Pancreat Sci, 2021, Xu et al. in Surg Endosc 34(10):4683-4691, 2020); (5) the second parenchyma transection was performed along the boundary of negative fluorescence region to expose the middle hepatic vein (MHV) using a combination of cranial and caudal approaches., Results: The operative time was 190 min, and blood loss during operation was 80 mL. The histopathologic examination showed a solitary HCC, 2.5 cm in diameter, with negative surgical margin and no microvascular invasion. The patient had an uneventful postoperative recovery and was discharged on postoperative day 5., Conclusion: The round ligament approach combined with fluorescent negative staining method for laparoscopic anatomic segmentectomy IV is a feasible and effective technique., (© 2021. Society of Surgical Oncology.)

Introduction: Immunotherapy has become a new therapy for advanced hepatocellular carcinoma (HCC); however, its treatment results are considerably different. CD4+ T cells (CD4+) are the key to immunotherapy, but patients with HCC that have low CD4+ are rarely observed for clinical evidence. Hepatitis B virus-related HCC is often accompanied by cirrhosis and portal hypertension; therefore, CD4+ tend to be relatively low in number. TACE is the standard treatment for Barcelona Clinic Liver Cancer (BCLC)-B HCC, which may further reduce the number of CD4 + ., Methods: This retrospective cohort study further reduced CD4+ by including patients with human immunodeficiency virus (HIV) to observe the relationship between CD4+ and Chronic hepatitis B virus (CHB) induced HCC. A total of 170 BCLC-B HCC patients (42 HIV+) were included. Univariate and multivariate analyses, and artificial neural networks (ANNs) were used to evaluate the independent risk factors for the two-year survival., Results: The statistical analysis of the two-year survival rate showed that the main factors influencing survival were liver function and immune indices, including CD4+, platelet, alanine aminotransferase, aspartate aminotransferase, aspartate aminotransferase-to-platelet ratio index, and fibrosis-4 (FIB-4) (P < 0.05). Compared with that in other indices, in logistic and ANN multivariate analysis, CD4 + -to-FIB-4 ratio (CD4+/FIB-4) had the highest importance with 0.716 C-statistic and 145.93 cut-off value. In terms of overall survival rate, HIV infection was not a risk factor (P = 0.589); however, CD4+/FIB-4 ≤ 145.93 significantly affected patient prognosis (P = 0.002)., Conclusion: HIV infection does not affect the prognosis of BCLC-B HCC, but CD4+ have a significant predictive value. CD4+ played a vital role in HCC and this deserves the attention from physicians. Further, the CD4+/FIB-4 is a clinically valuable effective prognostic indicator for these patients., (© 2022. The Author(s).)

Background: An elevated preoperative aspartate aminotransferase-to-lymphocyte ratio index (ALRI) may predict poor survival in various cancers. However, the prognostic value of aminotransferase-to-lymphocyte ratio index (ALRI) in patients with hepatocellular carcinoma (HCC) remains to be determined., Materials and Methods: A retrospective cohort study was conducted among 983 patients with HCC in our hospital from February 2007 to March 2016. A propensity-score matching (PSM) was performed to correct the selection bias and confounding factors. The risk of death and recurrence was plotted over aminotransferase-to-lymphocyte ratio index (ALRI) using the locally weighted scatterplot smoothing (LOWESS)-smoothed fit curve. Time-dependent receiver operating characteristic (ROC) and Kaplan-Meier method analysis was utilized to the role of aminotransferase-to-lymphocyte ratio index (ALRI) in HCC. Multivariate analysis was conducted to identify independent prognostic factors associated with overall survival (OS) and recurrence-free survival (RFS)., Results: With the increase of aminotransferase-to-lymphocyte ratio index (ALRI), the risk of recurrence and death in HCC patients increases. In time-dependent ROC analysis, the AUC of aminotransferase-to-lymphocyte ratio index (ALRI) for predicting 1-, 3- and 5-year OS were 0.668 (95% CI: 0.596-0.740), 0.605 (95% CI: 0.560-0.649) and 0.613 (95% CI: 0.570-0.656), respective. The AUC of aminotransferase-to-lymphocyte ratio index (ALRI) for predicting 1-, 3- and 5-year RFS were 0.598 (95% CI: 0.555-0.641), 0.590 (95% CI: 0.552-0.628) and 0.604 (95% CI: 0.562-0.646), respectively. HCC patients with high aminotransferase-to-lymphocyte ratio index (ALRI) had a poor overall survival. Moreover, cox regression analysis revealed that aminotransferase-to-lymphocyte ratio index (ALRI) was an independent factor affecting the prognosis of HCC patients., Conclusions: Elevated preoperative aminotransferase-to-lymphocyte ratio index (ALRI) is a noninvasive, simple, and effective predictor in the prognosis of patients with HCC., (© 2020 John Wiley & Sons Australia, Ltd.)

Background: Postoperative oral antiviral treatment with nucleoside or nucleotide analogues can suppress viral replication and reduce tumour recurrence for patients with hepatitis b virus-related hepatocellular carcinoma (HBV-related HCC) after curative resection. However, the superior antiviral treatment is still unclear. We conducted this study to investigate the different effects of nucleotide and nucleoside analogues on the prognosis of HBV-related HCC after curative resection., Methods: From February 2007 to February 2016, 487 consecutive patients with newly diagnosed HCC according to the Milan criteria who underwent R0 resection were enrolled according to the inclusion and exclusion criteria. According to their postoperative antiviral treatment, they were divided into the nucleotide group (NtA, n = 111) and the nucleoside group (NsA, n = 376)., Results: The baseline characteristics, serologic parameters, tumour characteristics, and operative data of the 2 groups were comparable. Nucleotide analogue use significantly decreased HCC recurrence (P = 0.028) and HCC-related death (P = 0.004), with hazard ratios (HRs) of 0.685 (95% CI, 0.484 to 0.971, P = 0.033) and 0.507 (95% CI, 0.310 to 0.830, P = 0.004), respectively, in multivariate Cox analyses. After the study patients were stratified according to three variables, we found that nucleotide analogue use was significantly associated with increased disease-free and overall survival among patients with cirrhosis, HBeAg-negative patients, and patients with positive HBV-DNA., Conclusions: In patients with HBV-related HCC, nucleotide analogues but not nucleoside analogues significantly reduced HCC recurrence and improved overall survival after R0 hepatic resection.

Purpose: We assessed the efficacy and safety of camrelizumab [an anti-programmed death (PD-1) mAb] plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma (HCC)., Patients and Methods: This nonrandomized, open-label, multicenter, phase II study enrolled patients with advanced HCC who were treatment-naïve or refractory/intolerant to first-line targeted therapy. Patients received intravenous camrelizumab 200 mg (for bodyweight ≥50 kg) or 3 mg/kg (for bodyweight <50 kg) every 2 weeks plus oral apatinib 250 mg daily. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC) per RECIST v1.1., Results: Seventy patients in the first-line setting and 120 patients in the second-line setting were enrolled. As of January 10, 2020, the ORR was 34.3% [24/70; 95% confidence interval (CI), 23.3-46.6] in the first-line and 22.5% (27/120; 95% CI, 15.4-31.0) in the second-line cohort per IRC. Median progression-free survival in both cohorts was 5.7 months (95% CI, 5.4-7.4) and 5.5 months (95% CI, 3.7-5.6), respectively. The 12-month survival rate was 74.7% (95% CI, 62.5-83.5) and 68.2% (95% CI, 59.0-75.7), respectively. Grade ≥3 treatment-related adverse events (TRAE) were reported in 147 (77.4%) of 190 patients, with the most common being hypertension (34.2%). Serious TRAEs occurred in 55 (28.9%) patients. Two (1.1%) treatment-related deaths occurred., Conclusions: Camrelizumab combined with apatinib showed promising efficacy and manageable safety in patients with advanced HCC in both the first-line and second-line setting. It might represent a novel treatment option for these patients. See related commentary by Pinato et al., p. 908 ., (©2020 American Association for Cancer Research.)

Background: How much difference there is between hepatic resection (HR) combined with intraoperative radiofrequency ablation (RFA) and living donor liver transplantation (LDLT) in treatment of multifocal hepatocellular carcinomas (HCCs) remains unclear. This study compared outcomes for patients with multifocal HCCs meeting the University of California San Francisco (UCSF) criteria treated by LDLT or HR + RFA., Methods: A total of 126 consecutive Child-Pugh A patients with multifocal HCCs meeting the UCSF criteria, who underwent LDLT (n = 51) or HR + RFA (n = 75), were included. Propensity score (PS) matching was performed to adjust for baseline differences. Overall survival (OS) and recurrence-free survival (RFS) were calculated, and subgroup, multivariate and nomogram analyses were performed., Results: LDLT provided significantly better OS and RFS than did HR + RFA before and after PS matching and reduced the dropout rate on waiting list, but HR + RFA was more convenient, less invasive and less cost. Patients with all lesions located in the same lobe had better OS and RFS than those located in the different lobes after HR + RFA. Multivariate and nomogram analyses revealed that HR + RFA, alpha-fetoprotein ≥ 400 ng/mL, the major tumour size > 3 cm and microvascular invasion were independent predictors of poor prognosis., Conclusion: For Child-Pugh A patients with multiple HCCs meeting the UCSF criteria, LDLT may offer significantly better long-term results than did HR + RFA, and HR + RFA may still be considered as an acceptable curative therapy for those without considering transplantation or as a bridge treatment for a patient, with a plan for transplantation in the future.

The surgical treatment and transcatheter arterial chemoembolization (TACE) rate of human immunodeficiency virus (HIV)-infected hepatocellular carcinoma (HCC) patients is relatively low in West China. For various reasons, most patients do not receive timely surgical treatment. Upon transfer to an infectious disease centralized hospital, they were already classified in the Barcelona Clinic Liver Cancer (BCLC)-B stage. A total of 2249 BCLC-B HCC patients were analyzed. The eligible population was divided into three groups for analysis of survival and prognostic factors; These were 21 HIV infected (HIV+) HCC patients treated with TACE (TACE+), 1293 non-HIV-infected (HIV-) HCC patients treated with TACE, and 150 HIV- HCC patients who only receive medication (TACE-) as a second control group. After 1:2 matching, 1- and 2-year survival of HIV+ TACE+ and HIV- TACE+ groups was 64.3% and 76.5% (P = 0.453) and 45.5% vs. 50.0% (P = 0.790) respectively. We also compared one and two-year survival between HIV+ TACE+ and HIV- TACE-. One-year overall survival was 64.3% vs. 45.7% (P = 0.097) and 2-year survival was 45.5% vs. 7.1% (P = 0.004). Multivariate analysis showed that the most important prognostic factors for survival were serum alpha-fetoprotein (AFP) and Child-Pugh score and tumor size, while HIV status had no significant effect on prognosis statistically. CD4 levels below 200 may increase the risk of opportunistic infection after surgery, but after anti-infection and systematic supportive therapy, it has no effect on survival. HIV+ patients should have the same treatment opportunities as HIV- patients. If the patient's immune status permits, we suggest that early TACE treatment should be administered to BCLC-B HCC patients, regardless of HIV infection.

Background: Whether hepatic resection (HR) combined with radiofrequency ablation (RFA) or HR alone is the treatment of choice for early or moderately advanced multifocal hepatocellular carcinomas (HCCs) is a matter of debate. This study compared the short- and long-term outcomes of patients with multifocal tumors meeting the University of California San Francisco (UCSF) criteria after HR plus intraoperative RFA or HR alone., Methods: A total of 261 consecutive patients with multifocal HCCs meeting the UCSF criteria from January 2010 to January 2018, who underwent combined treatment (n = 51) or HR (n = 210), were included. Propensity score matching was performed to adjust for baseline differences. Overall survival (OS) and recurrence-free survival (RFS) were calculated, and subgroup analysis, along with univariate and multivariate analyses, were performed., Results: The 1-, 3-, and 5-year OS rates after combined treatment or HR alone were 86.3%, 66.6%, and 34.2%, and 92.8%, 67.1%, and 37%, respectively (p = 0.423); combined treatment provided similar RFS rates as HR at 1, 3, and 5 years (78.4%, 35.8% and 20.9% vs. 82.6%, 50.4% and 24.5%, respectively; p = 0.076). The propensity matching model showed similar results. Subgroup analysis showed that HR was associated with better RFS than HR plus RFA for patients with two tumors or major tumors ≤ 3 cm. Multivariate analysis revealed that portal hypertension and three tumors are independent risk factors., Conclusions: For multifocal HCC patients meeting the UCSF criteria, combined treatment may offer similar OS and RFS as HR; however, HR may be more suitable than combined treatment for patients with two tumors or major tumors ≤ 3 cm.

Aberrant expression of microRNAs (miRNAs) has been widely reported in many malignant tumors, and dysregulated miRNAs play an important role in the malignant progression of tumors. It has been reported that miR‑29c‑3p expression is dysregulated in tumors and promotes the development of tumors, especially in hepatocellular carcinoma (HCC). However, the specific mechanism of miR‑29c‑3p in HCC is not clear. The present study demonstrated that miR‑29c‑3p was expressed at low levels in HCC patients and cell lines and that its decreased expression was closely related to poor prognosis of HCC patients. Overexpression of miR‑29c‑3p could significantly inhibit the proliferation and migration of HCC cells in vitro and suppress the HCC tumor growth in vivo. The luciferase reporter assay demonstrated that miR‑29c‑3p directly bound to tripartite motif containing 31 (TRIM31) and suppressed TRIM31 expression. Finally, upregulation of TRIM31 could partially abolish the tumor suppressing roles of miR‑29c‑3p in HCC. Overall, miR‑29c‑3p, as a tumor suppressor gene, was revealed to inhibit the malignant progression of HCC by reducing the expression of TRIM31 and may be used as a potential therapeutic target for the precise treatment of HCC.

Background: The role of laparoscopically anatomical resection (LAR) for hepatocellular carcinoma (HCC) remains unclear due to the more demanding technique required in laparoscopy. This study is to analyze the clinical impact of LAR compared to laparoscopically non-anatomical resection (LNAR) for HCC., Methods: All patients received laparoscopic hepatectomy for HCC (diameter 5-10 cm) from January 2015 to December 2018 were retrospectively enrolled in this study. Patients were divided into LAR and LNAR groups. The perioperative and oncological outcomes were evaluated based on propensity score matching (PSM) method., Results: After PSM, 51 patients in each group were enrolled. The operative time in LAR group was longer (240 vs 195.0 min, p = 0.012) and blood loss was more (200.0 vs 150.0 mL, p = 0.030) than those of LNAR group, respectively. The total complication rates were comparable between them (21.6% vs 17.6%, p = 0.500). The 3-year overall survival rates were 59.4% in LAR group and 38.7% in LNAR group, respectively (p = 0.045). The 3-year disease-free survival rates were 52.3% in LAR group and 27.0% in LNAR group, respectively (p = 0.042)., Conclusion: LAR could be feasibly performed with comparable perioperative outcomes and contributed to improve long-term survival in patients with HCC (diameter 5-10 cm) when compared to LNAR., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The American Joint Committee on Cancer staging recently classified solitary hepatocellular carcinoma (HCC) ≤ 2 cm with or without vascular invasion as stage T1a. We aimed to discuss the risk factors of these stage T1a patients., Methods: Patients diagnosed with solitary HCC ≤2 cm from September 2008 to June 2015 were included in our study. Due to the small number of patients undergoing a non-curable approach and liver transplantation, patients undergoing liver resection (LR) and radiofrequency ablation (RFA) were included. In the comparison between LR and RFA, 1:1 propensity score matching (PSM) was used. The overall survival (OS) and disease-free survival (DFS) were predicted, and the Cox proportional hazard model was used to find the prognostic factors, described as hazard ratio (HR) and 95% confidence interval (CI)., Results: In total, 273 HCC patients were involved in our study, of whom 192 patients underwent LR and 81 patients underwent RFA. The proportion of Child-Pugh A patients was higher in the LR group (91.7%) versus the RFA group (76.5%) (P = 0.001), and the tumour size was slightly larger in the LR group, with a median size of 1.9 cm versus 1.7 cm in the RFA group (P = 0.001). No difference was found in OS between LR and RFA. However, RFA was the only risk factor for recurrence (HR 1.578, 95% CI 1.006-2.467, P = 0.047). A total of 80 pairs were compared after PSM, and there was no significant difference in OS or DFS between LR and RFA after PSM (P = 0.5434 or P = 0.1642, respectively). Child-Pugh stage B was the only risk factor for OS in the multivariate analysis after PSM (HR 2.289, 95% CI 1.089-4.812, P = 0.029)., Conclusion: RFA was comparable with LR in treating solitary HCC up to 2 cm but with a higher risk for recurrence due to the imbalanced pre-operative covariates. When the pre-operative factors were consistent, liver function was the only prognostic factor for long-term OS., (Copyright © 2019 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Background: The association between metabolic syndrome (MS), both in terms of its components and as a whole, and the risk of hepatocellular carcinoma (HCC) in subjects with hepatitis B virus (HBV) infection remains unclear, especially in mainland China., Methods: We prospectively included 6,564 individuals with HBV infection from an initial cohort of 105,397 civil servants. The multivariate-adjusted HR and 95% confidence interval (95% CI) were evaluated using Cox proportional hazards models to explore the potential connection between HCC risk and MS. Cumulative incidences were plotted using Kaplan-Meier curves., Results: After a 45,668.0 person-year follow-up (76.0 ± 30.8 months) of 6,564 subjects who were seropositive for hepatitis B surface antigen, 89 incident HCC cases were identified. MS as a whole was independently associated with a 2-fold increased HCC risk (HR, 2.25; 95% CI, 1.41-3.60) after adjusting for age (in 1-year increments), gender, cigarette smoking, alcohol consumption, liver cirrhosis, and elevated aspartate aminotransferase levels (≥40 U/L). Subjects with three or more factors and those with one or two factors had adjusted increased HCC risks of 2.12-fold (95% CI, 1.16-3.89) and 1.28-fold (95% CI, 0.74-2.22), respectively, in comparison with those without any metabolic factors. Central obesity and type 2 diabetes were associated with significantly increased HCC risk, whereas this association was not observed in obese subjects (body mass index ≥30 kg/m 2 ; 95% CI, 0.73-3.44)., Conclusions: MS as a whole, central obesity, and type 2 diabetes were independently associated with increased HCC risk in a population with HBV infection in mainland China., Impact: MS may be a risk factor for HCC., (©2019 American Association for Cancer Research.)

Background: The purpose of this research was to assess the feasibility of reconstructing the middle hepatic vein (MHV) with resected left portal vein during left hemihepatectomy., Methods: From January 2014 to January 2018, six patients received left hemihepatectomy combined with MHV reconstruction using the resected left portal vein in West China Hospital. We reviewed the clinical data including patient details, surgical technique, graft patency, and operative results., Results: All six patients underwent left hemihepatectomy for liver tumors located at left hepatocaval confluence. In these patients, MHV was resected due to tumor invading and reconstructed using the resected left portal vein as graft. The mean operating time was 316 min. Two patients developed complications: one experienced bile leakage and one experienced pleural effusion. No patient developed vascular graft complications. All the grafts remained unobstructed, and no local tumor recurrence occurred during the observation period of 13-41 months., Conclusions: Our results indicated that the left portal vein was a safe graft for hepatic vein reconstruction. In addition, left hemihepatectomy combined with middle hepatic vein resection and reconstruction using the left portal vein can be performed safely to treat liver tumors located at hepatocaval confluence.

The complete resection offers the best long-term survival for advanced hepatocellular carcinoma patients. ALPPS as a choice of resection, how is its outcome compared to one-stage resection, liver transplantation and TACE? This retrospective study included 20 ALPPS patients. To minimize the effect of confounding influences of measured covariates, PSM was performed. The overall survival (OS), morbidity, mortality and the increasing rate, KGR were analyzed. The OS in ALPPS group is 27.4 (±3.8 months) moths and the TACE group is 13.5(±1.2 months) (P < .001), LT group is 41.3 (±3.2 months) (P = .048), Resection group is 31.8 (±2.6 months) (P = .368). And the medium increasing volume is 209.5 cm (±61.5 cm) with the increasing ratio 52.4% (+26.9%). The ALPPS is a feasible treatment for HCC patients and it provides a better long-term survival than TACE and it is similar to Resection, less than LT.

Background: Few studies had been performed to concern the outcomes of pure laparoscopic Glissonian pedicle approach hepatectomy (LGAH) for hepatocellular carcinoma (HCC). The aim of this study was to compare the outcomes of LGAH versus open Glissonian pedicle approach hepatectomy (OGAH) for HCC, especially in patients with cirrhosis., Methods: Hepatocellular carcinoma patients who underwent pure LGAH and OGAH between January 2015 and July 2017 in our institution were retrospectively enrolled in this study. Propensity score matching (PSM) of patients in a ratio of 1:1 was conducted to adjust the known confounders. The perioperative and oncological outcomes were compared between the two groups after PSM., Results: Some 80 patients underwent pure LGAH and 134 had OGAH. After PSM, 67 patients in each group were well matched for analysis. Both the postoperative overall complication rates (13.4% vs. 29.9%, P = 0.021) and mean comprehensive complication index (2.63 vs. 7.40, P = 0.035) were significantly lower in the LGAH group than those in OGAH group. Although the operative time was longer in the LRH group (P < 0.001), the length of postoperative hospital stay was shorter in the LRH group (P = 0.024). Furthermore, both the 3-year overall survival rate (73.3% for LGAH vs. 77.8% for OGAH, P = 0.338) and 3-year disease-free survival rate (56.4% for LGAH vs. 62.5% for OGAH, P = 0.455) were not significantly different between the groups., Conclusion: Pure laparoscopic Glissonian approach may be a better alternative to open Glissonian approach in selected HCC patients, which provided fewer complications, shorter postoperative hospital stay and comparable oncological outcomes.

Background: Microvascluar invasion and satellite lesion (MS), important unfavourable pathological factors, significantly contribute to tumour recurrence and impair the prognosis in hepatocellular carcinoma. We aimed to construct a model for the prediction of MS in order to plan treatment better., Methods: A total of 1135 consecutive patients with hepatocellular carcinoma who received radical hepatectomy at West China Hospital were randomly assigned to a training set and a validation set. Multivariate analysis was preformed to identify independent risk factors of MS in the training set, and a nomogram was then constructed based on the risk factors. The concordance index (C-index) and a calibration curve were used to assess the predictive performance of the model., Results: The occurrence rate of MS was about 36.5%. Based on the multivariate analysis, the following six variables were incorporated into the nomogram: age (hazard ratio (HR): 0.531), alpha fetoprotein (HR: 1.327), neutrophil-to-lymphocyte ratio (>2.8, HR: 1.732), international normalized ratio (>1.07, HR: 1.702), tumour size (HR: 1.116) and tumour number (HR: 1.842). The model showed satisfactory discrimination abilities, with a C-index of 0.721 for the training set and 0.704 for the validation set. The receiver operating characteristic curve confirmed the predictive power. Meanwhile, the calibration curve presented a goodness of fit between prediction of the model and actual observations., Conclusions: The user-friendly model may be useful for prediction of the occurrence of MS and to plan treatment more rationally preoperatively., (© 2018 Royal Australasian College of Surgeons.)

Postoperative complication III-V is closely related with hepatectomy-related mortality for hepatocellular carcinoma (HCC) patients. The aim of the study was to investigate the relationship between CONUTS and postoperative complication III-V. 1334 HCC patients who underwent hepatectomy were divided into two groups: high CONUTS group (early postoperative CONUTS ≥ 8, n = 659) and low CONUTS group (early postoperative CONUTS < 8, n = 675). The characteristics and clinical outcomes were compared and analyzed. Risk factors for postoperative complication III-V were evaluated by univariate and multivariate analysis. early postoperative CONUTS showed a good prediction ability for postoperative complication III-V (AUROC = 0.653, P < 0.001), with the cut-off value of 8. The high CONUTS group had higher incidence of postoperative pulmonary complications (12.0% vs 7.9%, P = 0.011), bile leakage (2.6% vs 0.9%, P = 0.018), intra-abdominal hemorrhage (4.9% vs 1.6%, P = 0.001), postoperative liver failure Grade C (3.6% vs 1.0%, P = 0.002), complication III-V (15.6% vs 6.2%, P < 0.001), length of ICU stay > 48 hours (9.4% vs 4.1%, P < 0.001) and mortality in 90 days (2.6% vs 0.4%, P = 0.001), longer period of postoperative hospitalization (10 (8-13) vs 9 (7-11) days, P < 0.001). Multivariable analysis revealed that early postoperative CONUTS ≥ 8 (OR = 2.054, 95%CI = 1.371-3.078, P < 0.001) was independently associated with postoperative complication III-V. Early postoperative CONUTS ≥ 8 was identified as a novel risk factor for postoperative complication III-V, and should be further evaluated as a predictive marker for who are to undergo liver resection.

The outcomes following anterior approach (AA) hepatectomy in huge hepatocellular carcinoma (HCC) patients with diaphragmatic invasion (DI) remain unclear. This study compared the outcomes of single huge right HCC patients with and without DI after AA hepatectomy. A total of 203 consecutive patients with single huge right lobe HCC who underwent AA major hepatectomy were included. They were divided into group PDI (n = 53) and group ADI (n = 150) according to the presence or the absence of DI. Their short- and long-term outcomes were compared, and a subgroup analysis was performed. There were no significant differences regarding postoperative complications and 90-day mortality between the 2 groups. The overall survival (OS) and recurrence-free survival (RFS) rates were similar between the 2 groups. The subgroup analysis also showed that patients with tumor resection en bloc with part of the diaphragm had similar OS and RFS rates as those who underwent diaphragmatic resection after hepatectomy. Tumor diameter ≥ 15 cm, serum AFP level ≥ 400 ng/mL, and tumor grade of G4 and microvascular invasion are independent predictors of poor prognosis. For the single huge right lobe HCC patients with DI, AA major hepatectomy combined with diaphragmatic resection could offer similar OS and RFS as those without diaphragmatic invasion.

Geriatric nutritional risk index (GNRI) is a novel and useful screening tool for evaluating nutritional status in elderly in-patients. We aimed to investigate whether the preoperative GNRI could be a predictive factor for outcomes in patients over 65 years of age with a diagnosis of hepatocellular carcinoma (HCC). We retrospectively enrolled 261 consecutive HCC patients after hepatectomy and classified them into four risk groups based on the GNRI values: high risk (GNRI, <82), moderate risk (GNRI, 82-92), low risk (GNRI, 92-98), and normal (GNRI, >98). We found that the lower GNRI value was significantly associated with severe postoperative complications (P < 0.001) and liver failure (P < 0.001). By multivariate logistic regression analysis, high risk- and moderate risk GNRI groups were identified as independent risk factors for postoperative serve complications and liver failure. Multivariate Cox regression analysis revealed preoperative GNRI (P < 0.001) adversely affected overall survival. In conclusion, preoperative GNRI could predict severe postoperative complications included liver failure, and the lower GNRI value was associated with worse overall survival after hepatectomy in elderly HCC patients.