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Background: Hepatocellular carcinoma (HCC) is a highly heterogeneous tumor and a primary cause of cancer-relevant deaths worldwide. The role of reactive oxygen species (ROS) in HCC development is less studied., Methods: Seurat package and CellMarker database were employed for single-cell RNA sequencing (scRNA-seq) analysis based on the GSE189175 dataset from Gene Expression Omnibus (GEO). DAVID and MsigDB database were utilized for pathway analysis. SCENIC analysis was performed to map a transcription factors (TFs) regulatory network. CellChat was used for cellular communication analysis., Results: Six major cell subpopulations were identified, among which hepatocytes accounted for the highest proportion in both cancer and adjacent tissues. The enrichment scores of the 50 hallmark gene sets showed that the ROS pathway was abnormally activated in HCC hepatocytes and positively correlated with energy metabolism-related pathways (glucose metabolism, lipid metabolism, amino acid metabolism, etc.). Then, the hepatocytes were divided into four subgroups. Noticeably, GPX4+  hepatocytes with the highest activity of the ROS pathway was related to a worse prognosis of HCC. Mechanism analysis revealed that JUND was involved in the positive regulation of the ROS pathway in GPX4+  hepatocytes. It was found that the interdependent ligand-receptor interaction between GPX4+  liver cells and immune cells facilitated the malignant development of HCC., Conclusion: ROS pathway was over-activated in the hepatocytes of HCC tissues. GPX4+  hepatocytes having the highest activity of the ROS pathway closely interacted with T cells and M2 macrophage cells. Molecular subtypes and risk score signature based on the ROS pathway and its potential target gene JUND are encouraged to be developed for improving the precision treatment of HCC., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

5-Methylcytosine (m5C) RNA modification is a highly abundant and important epigenetic modification in mammals. As an important RNA m5C methyltransferase, NOP2/Sun-domain family member 2 (NSUN2)-mediated m5C RNA modification plays an important role in the regulation of the biological functions in many cancers. However, little is known about the biological role of NSUN2 in hepatocellular carcinoma (HCC). In this study, we found that the expression of NSUN2 was significantly upregulated in HCC, and the HCC patients with higher expression of NSUN2 had a poorer prognosis than those with lower expression of NSUN2. NSUN2 could affect the tumor immune regulation of HCC in several ways. In vitro and in vivo experiments confirmed that NSUN2 knockdown significantly decreased the abilities of proliferation, colony formation, migration and invasion of HCC cells. The methylated RNA immunoprecipitation-sequencing (MeRIP-seq) showed NSUN2 knockdown significantly affected the abundance, distribution, and composition of m5C RNA modification in HCC cells. Functional enrichment analyses and in vitro experiments suggested that NSUN2 could promote the HCC cells to proliferate, migrate and invade by regulating Wnt signaling pathway. SARS2 were identified via the RNA immunoprecipitation-sequencing (RIP-Seq) and MeRIP-seq as downstream target of NSUN2, which may play an important role in tumor-promoting effect of NSUN2-mediated m5C RNA modification in HCC. In conclusion, NSUN2 promotes HCC progression by regulating Wnt signaling pathway and SARS2 in an m5C-dependent manner., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate All methods used in this study were performed in accordance with the relevant guidelines and regulations. All animal experiments in this study were carried out in accordance with the regulations of Experimental Animal Use and Welfare Committee of Zhengzhou University (approval number: ZZU-LAC2024060416)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatocellular carcinoma with cirrhosis promotes the advancement of malignancy and the development of fibrosis in normal liver tissues. Understanding the pathological mechanisms underlying the development of HCC with cirrhosis is important for developing effective therapeutic strategies. Herein, the RNA-sequencing (RNA-seq) data and corresponding clinical features of patients with HCC were extracted from The Cancer Genome Atlas (TCGA) database using the University of California Santa Cruz (UCSC) Xena platform. The enrichment degree of hallmarkers for each TCGA-LIHC cohort was quantified by ssGSEA algorithm. Weighted gene co-expression network analysis (WGCNA) revealed two gene module eigengenes (MEs) associated with cirrhosis, namely, MEbrown and MEgreen. Analysis of these modules using AUCell showed that MEbrown had higher enrichment scores in all immune cells, whereas MEgreen had higher enrichment scores in malignant cells. The CellChat package revealed that both immune and malignant cells contributed to the fibrotic activity of myofibroblasts through diverse signaling pathways. Additionally, spatial transcriptomic data showed that hepatocytes, proliferating hepatocytes, macrophages, and myofibroblasts were located in closer proximity in HCC tissues. These cells may potentially participate in the process of stimulating myofibroblast fibrotic activity, which may be related to the development of liver fibrosis. In summary, we made full use of multi-omics data to explore gene networks and cell types that may be involved in the development and progression of cirrhosis in HCC., (© 2024. The Author(s).)

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S-phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non-invasive manner. The classifier demonstrates remarkable performance in predicting intra-tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra-tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC-LT., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background & Aims: Liver fibrosis in patients with chronic hepatitis B can regress with successful antiviral therapy. However, the long-term clinical benefits of fibrosis regression have not been fully elucidated. This study investigated the association between biopsy-proven fibrosis regression by predominantly progressive, indeterminate, and predominantly regressive (P-I-R) score and liver-related events (LREs) in chronic hepatitis B patients., Methods: Patients with on-treatment liver biopsy and significant fibrosis/cirrhosis (Ishak stage ≥3) were included in this analysis. Fibrosis regression was evaluated according to the P-I-R score of the Beijing Classification. LREs were defined as decompensations, hepatocellular carcinoma, liver transplantation, or death. The Cox proportional hazards model was used to determine associations of fibrosis regression with LREs., Results: A total of 733 patients with Ishak stages 3/4 (n = 456; 62.2%) and cirrhosis (Ishak stages 5/6; n = 277; 37.8%) by on-treatment liver biopsy were enrolled. According to the P-I-R score, fibrosis regression, indeterminate, and progression were observed in 314 (42.8%), 230 (31.4%), and 189 (25.8%) patients, respectively. The 7-year cumulative incidence of LREs was 4.1%, 8.7%, and 18.1% in regression, indeterminate, and progression, respectively (log-rank, P < .001). Compared with patients with fibrosis progression, those with fibrosis regression had a lower risk of LREs (adjusted hazard ratio, 0.40; 95% CI, 0.16-0.99; P = .047), followed by the indeterminate group (adjusted hazard ratio, 0.86; 95% CI, 0.40-1.85; P = .691). Notably, this favorable association also was observed in patients with cirrhosis or low platelet counts (<150 × 10 9 /L)., Conclusions: Antiviral therapy-induced liver fibrosis regression assessed by P-I-R score is associated with reduced LREs. This shows the utility of histologic fibrosis regression assessed by on-treatment P-I-R score as a surrogate endpoint for clinical events in patients with hepatitis B virus-related fibrosis or early cirrhosis., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Fibroblast activation protein contributes to immunosuppression and resistance to immunotherapies. This study aimed to compare baseline 68 Ga-labeled fibroblast activation protein inhibitor ( 68 Ga-FAPI) PET/CT and 18 F-FDG PET/CT in response and survival prediction in unresectable hepatocellular carcinoma (uHCC) patients treated with the combination of programmed cell death 1 (PD-1) inhibitor and lenvatinib. Methods: In this prospective cohort study, 22 patients with uHCC who underwent baseline 18 F-FDG and 68 Ga-FAPI PET/CT and soon began taking a combination of PD-1 inhibitor and lenvatinib were recruited. Semiquantitative indices of baseline PET/CT were measured as 18 F-FDG SUV max , metabolic tumor volume, total lesion glycolysis, 68 Ga-FAPI SUV max , 68 Ga-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The primary endpoint was durable or nondurable clinical benefit after treatment, and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The overall response rate of the combination therapy was 41% (9/22). Fifty percent of patients had durable clinical benefit. Median PFS and OS were 4.8 and 14.4 mo, respectively. Patients with nondurable clinical benefit showed a significantly higher FTV and TLF than those with durable clinical benefit, whereas 18 F-FDG parameters overlapped. A higher 68 Ga-FAPI-avid tumor burden (FTV > 230.46 cm 3 or TLF > 961.74 SUV body weight ⋅cm 3 ) predicted both shorter PFS (4.0 vs. 13.5 mo, P = 0.016) and shorter OS (7.8 mo vs. not reached, P = 0.030). Patients with a higher metabolic tumor burden (metabolic tumor volume > 206.80 cm 3 or total lesion glycolysis > 693.53 SUV body weight ⋅cm 3 ) showed a shorter OS although the difference did not reach statistical significance ( P = 0.085). In multivariate analysis, a higher 68 Ga-FAPI-avid tumor burden (hazard ratio [HR], 3.88 [95% CI, 1.26-12.01]; P = 0.020) and macrovascular invasion (HR, 4.00 [95% CI, 1.06-15.14]; P = 0.039) independently predicted a shorter PFS, whereas a higher 68 Ga-FAPI-avid tumor burden (HR, 5.92 [95% CI, 1.19-29.42]; P = 0.035) and bone metastases (HR, 5.88 [95% CI, 1.33-25.93]; P = 0.022) independently predicted a shorter OS. Conclusion: Volumetric indices on baseline 68 Ga-FAPI PET/CT were potentially independent prognostic factors to predict durable clinical benefit, PFS, and OS in uHCC patients treated with a combination of PD-1 and lenvatinib. Baseline 68 Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in the digestive system with rapid progression and poor prognosis. Recent studies have shown that RPL27A could be used as a biomarker for a variety of cancers, but its role in HCC is not clear., Method: We analyzed the expression of RPL27A in the pan-cancer analysis and analyzed the relationship between the expression of RPL27A and the clinical features and prognosis of patients with HCC. We evaluated the expression difference of RPL27A in HCC tissues and paired normal adjacent tissues using immunohistochemistry. Furthermore, we analyzed the co-expression genes of RPL27A and used them to explore the possible mechanism of RPL27A and screen hub genes effecting HCC. In addition, we studied the role of RPL27A in immune infiltration and mutation., Results: We found that the expression level of RPL27A increased in a variety of cancers, including HCC. In HCC patients, the high expression of RPL27A was related to progression and poor prognosis as an independent predictor. We also constructed a protein interaction network through co-expression gene analysis of RPL27A and screened 9 hub genes. Enrichment analysis showed that co-expression genes were associated with ribosome pathway, viral replication, nuclear-transcribed mRNA catabolic process, and nonsense-mediated decay. We found that the expression level of RPL27A was closely related to TP53 mutation and immune infiltration in HCC., Conclusion: RPL27A might become a biomarker in the diagnosis, treatment, and follow-up of patients with HCC., (© 2023. The Author(s).)

Background: Liver transplantation (LT) is the "cure" therapy for patients with hepatocellular carcinoma (HCC). However, some patients encounter HCC recurrence after LT. Unfortunately, there is no effective methods to identify the LT patients who have high risk of HCC recurrence and would benefit from adjuvant targeted therapy. The present study aimed to establish a scoring system to predict HCC recurrence of HCC patients after LT among the Chinese population, and to evaluate whether these patients are suitable for adjuvant targeted therapy., Methods: Clinical data of HCC patients who underwent LT from March 2015 to June 2019 were retrospectively collected and analyzed., Results: A total of 201 patients were included in the study. The multivariate Cox analysis suggested that preoperative alpha-fetoprotein (AFP) > 200 µg/L (HR = 2.666, 95% CI: 1.515-4.690; P = 0.001), glutamyl transferase (GGT) > 96 U/L (HR = 1.807, 95% CI: 1.012-3.224; P = 0.045), and exceeding the Hangzhou criteria (HR = 2.129, 95% CI: 1.158-3.914; P = 0.015) were independent risk factors for poor disease-free survival (DFS) in patients with HCC who underwent LT. We established an AFP-GGT-Hangzhou (AGH) scoring system based on these factors, and divided cases into high-, moderate-, and low-risk groups. The differences in overall survival (OS) and disease-free survival (DFS) rates among the three groups were significant (P < 0.05). The efficacy of the AGH scoring system to predict DFS was better than that of the Hangzhou criteria, UCSF criteria, Milan criteria, and TNM stage. Only in the high-risk group, we found that lenvatinib significantly improved prognosis compared with that of the control group (P < 0.05)., Conclusions: The AGH scoring system provides a convenient and effective way to predict HCC recurrence after LT in HCC patients in China. Patients with a high-risk AGH score may benefit from lenvatinib adjuvant therapy after LT., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: Dynamic PET/CT scan of 68 Ga-FAPI-04 in patients with suspected malignant hepatic lesions were retrospectively analyzed to find the optimal acquisition time with better lesion detection rate., Methods: Twenty-two patients with lesions confirmed by CT or MRI were performed with dynamic 68 Ga-FAPI-04 PET/CT scan. Tracer uptake of lesions and normal organs at different time points were analyzed. Standardized uptake value (SUV) and tumor-to-background (TBR) were calculated based on the quantification of images., Results: SUV of normal organs decreased rapidly from 10 to 30 min and decreased gradually from 30 to 60 min. Besides, the uterus showed a particularly high uptake in all patients (12.62 ± 4.58 at 10 min p.i., 12.04 ± 3.99 at 30 min p.i., 10.92 ± 2.38 at 60 min p.i.). SUV of lesions decreased gradually, while TBR increased from 10- to 60-min post-injection. Visual analysis verified a comparable lesion detectability of 30 min and 60 min with images of 10 min showing a decreased lesion detection number., Conclusion: This study revealed that similar detection rates were achieved at both 30 and 60 min, suggesting a static scan at 30 min to be appropriate in the clinic. Besides, although with high lesion uptake, early 68 Ga-FAPI-04 PET imaging at 10 min after tracer injection could cause missed lesion detection., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The aim of this study was to compare and rank different targeted therapies or immunotherapies for advanced hepatocellular carcinoma based on efficacy., Methods: A systematic search of the PubMed, EMBASE, and Cochrane Library databases was conducted. All systematic treatment regimens that reported comparisons with sorafenib were included in this analysis. The primary outcome measures were overall survival (OS) and progression-free survival (PFS), and other outcome measures included the objective response rate (ORR) and safety analysis according to reported treatment-related adverse events., Results: A total of 29 RCTs involving 13376 patients were included in the analysis, including 10 single-agent therapies and 17 combination therapies. Compared with sorafenib, sintilimab plus IBI305 (HR: 0.57, 95% CI: 0.43-0.75), camrelizumab plus rivoceranib (HR: 0.62, 95% CI: 0.49-0.78), and atezolizumab plus bevacizumab (HR: 0.66, 95% CI: 0.52-0.83) ranked in the top three in terms of OS., Conclusions: PD-1/PD-L1 inhibitors combined with anti-vascular endothelial growth factor (anti-VEGF)-targeting drugs have shown better therapeutic effects in the systematic treatment of patients with advanced hepatocellular carcinoma, and the combination of targeted and immune therapy modes should be further developed.

Globally, liver cancer, which is one of the major cancers worldwide, has attracted the growing attention of technological researchers for its high mortality and limited treatment options. Hydrogels are soft 3D network materials containing a large number of hydrophilic monomers. By adding moieties such as nitrobenzyl groups to the network structure of a cross-linked nanocomposite hydrogel, the click reaction improves drug-release efficiency in vivo, which improves the survival rate and prolongs the survival time of liver cancer patients. The application of a nanocomposite hydrogel drug delivery system can not only enrich the drug concentration at the tumor site for a long time but also effectively prevents the distant metastasis of residual tumor cells. At present, a large number of researches have been working toward the construction of responsive nanocomposite hydrogel drug delivery systems, but there are few comprehensive articles to systematically summarize these discoveries. Here, this systematic review summarizes the synthesis methods and related applications of nanocomposite responsive hydrogels with actions to external or internal physiological stimuli. With different physical or chemical stimuli, the structural unit rearrangement and the controlled release of drugs can be used for responsive drug delivery in different states., (© 2022 Wiley-VCH GmbH.)

Bioactive materials have been extensively developed for the adjuvant therapy of cancer. However, few materials can meet the requirements for the postoperative resection of hepatocellular carcinoma (HCC) due to massive bleeding and high recurrence. In particular, combination therapy for HCC has been highly recommended in clinical practice, including surgical resection, interventional therapy, ablation therapy and chemotherapy. Herein, an injectable magnetic colloidal gel (MCG) was developed by controllable electrostatic attraction between clinically available magnetic montmorillonites and amphoteric gelatin nanoparticles. The optimized MCG exhibited an effective magnetic heating effect, remarkable rheological properties, and high gel network stability, realizing the synergistic treatment of postoperative HCC by stimuli-responsive drug delivery, hemostasis and magnetic hyperthermia. Furthermore, a minimal invasive MCG-induced interventional magnetic hyperthermia therapy (MHT) under ultrasound guidance was realized on hepatic tumor rabbits, providing an alternative therapeutics to treat the postoperative recurrence. Overall, MCG is a clinically available injectable formulation for adjuvant therapy after HCC surgical resection., (© 2022. The Author(s).)

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies with few effective treatment options all around the world. The efficacy of the arisen immune checkpoint therapy is still uncertain due to local immunosuppression. In order to further overcome T cell suppression in the tumor immune microenvironment while promoting the immune response of antigen-presenting cells, a biointerfacing antagonizing T-cell inhibitory nanoparticles (BAT NPs) has been developed by cloaking platelet membrane on the PLGA microsphere surface to load T-cell immunoglobulin domain and mucin domain-3 antibodies (anti-TIM-3) as well as PD-L1. Notably, in addition to activating the proliferation and migration of T cells, the contained anti-TIM-3 can cooperate with PD-L1 checkpoint blockade to exert therapeutic effects. Furthermore, the components of BAT NPs like anti-TIM-3 and platelet can act together for collagen deposition in tumor starvation treatment. Thus, a novel targeting therapeutic strategy that can effectively reverse the immune-inhibiting microenvironment is effectively applied to PD-L1 checkpoint combination therapy. Such therapeutic effect can subsequently activate the effector T lymphocytes and antigen presentation of dendritic cells as well as the polarization of M1-type macrophages. Last, the study presented the synergistic effect of immune therapeutic adjuvants and BAT NPs components in achieving tumor inhibition and prolonging tumor-burden survival., (© 2021 Wiley-VCH GmbH.)

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. The majority of patients with HCC are diagnosed with advanced-stage disease. Sorafenib is a frontline therapy drug approved by the Food and Drug Administration for advanced HCC. However, the poor aqueous solubility of sorafenib limits its applications. The present study aimed to overcome this limitation of sorafenib. Thus, bovine serum albumin (BSA)-based nanoparticles were developed to encapsulate hydrophobic sorafenib. The resultant sorafenib-loaded BSA nanoparticles (Sf-BSA-NPs) were thoroughly characterized for size distribution, encapsulation efficiency and morphology. Previous studies on HepG2 cells in vitro have demonstrated that Sf-BSA-NPs exhibit remarkable superiority to free sorafenib in cytocompatibility, cytotoxicity and proapoptotic effect. The results of the present study demonstrated that Sf-BSA-NPs were effective in improving aqueous solubility, and enhanced drug cytotoxicity, suggesting its therapeutic potential for HCC.

Transarterial chemoembolization (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC) patients. Although overall survival (OS) of TACE-treated patients has been evidently prolonged, not all unresectable HCC patients can benefit from TACE. Genome-wide association studies identified multiple HCC susceptibility single nucleotide polymorphisms (SNPs). However, it is still unclear how lncRNAs and their functional SNPs impact therapeutic responses of TACE. In the study, we hypothesized that the functional lncRNA H19 SNP(s) might impact H19 expression and, thus, prognosis of TACE-treated HCC patients. We found that the H19 rs3741219 SNP was significantly associated with OS of HCC patients received TACE. Cox proportional hazards model demonstrated that the rs3741219 CC genotype was associated with longer OS and a 37% decreased death risk compared with the TT carriers after TACE therapy (P = 0.001). Interestingly, the rs3741219 T-to-C change led to allelic down-regulation of lncRNA H19 expression via creating the binding sites of miR-146b-3p and miR-1539. Luciferase reporter gene assays indicated that miR-146b-3p and miR-1539 could markedly silence the rs3741219 C-allelic H19 expression but not lncRNA H19 with the T allele. Consistently, there was significantly reduced expression of lncRNA H19 in HCC and normal tissues of the C allele carriers compared with the H19 levels in patients with the T allele. Knock-down of lncRNA H19 significantly promoted the anti-viability efficiency of oxaliplatin (the main chemotherapy drug used in TACE) to HCC cells. In view of these results, we assume that lncRNA H19 might be a potential therapeutic target for unresectable HCC patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Aim: Post-hepatectomy liver failure (PHLF) remains the primary cause of in-hospital mortality after hepatectomy. Identifying predictors of PHLF is important to improve surgical safety. We sought to identify the predictive accuracy of two noninvasive markers, albumin-bilirubin (ALBI) and aspartate aminotransferase to platelet count ratio index (APRI), to predict PHLF among patients with hepatocellular carcinoma (HCC), and to build up an online prediction calculator., Methods: Patients who underwent resection for HCC between 2013 and 2016 at 6 Chinese hospitals were retrospectively analyzed. The independent predictors of PHLF were identified using univariate and multivariate analyses; derivative data were used to construct preoperative and postoperative nomogram models. Receiver operating characteristic (ROC) curves for the two predictive models, and ALBI, APRI, Child-Pugh, model for end-stage liver disease (MELD) scores were compared relative to predictive accuracy for PHLF., Results: Among the 767 patients in the analytic cohort, 102 (13.3%) experienced PHLF. Multivariable logistic regression analysis identified high ALBI grade (>-2.6) and high APRI grade (>1.5) as independent risk factors associated with PHLF in both the preoperative and postoperative models. Two nomogram predictive models and corresponding web-based calculators were subsequently constructed. The areas under the ROC curves for the postoperative and preoperative models, APRI, ALBI, MELD and Child-Pugh scores in predicting PHLF were 0.844, 0.789, 0.626, 0.609, 0.569, and 0.560, respectively., Conclusions: ALBI and APRI demonstrated more accurate ability to predict PHLF than Child-Pugh and MELD. Two online calculators that combined ALBI and APRI were proposed as useful preoperative and postoperative tools for individually predicting the occurrence of PHLF among patients with HCC., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: This study aimed to compare the performance of 68 Ga-labelled fibroblast activating protein inhibitor (FAPI) PET and 18 F-FDG PET for imaging of hepatic tumours., Methods: We prospectively assessed 20 patients with suspected intrahepatic lesions. Tumour radiological features, pathology, or follow-up examinations were assessed as ground truth in correlation with PET scans. Semiquantitative analysis was additionally performed by measuring the standardised uptake value (SUV). Tumour-to-liver background ratios (TBR) were calculated and compared between 68 Ga-FAPI PET and 18 F-FDG PET. FAPI expression was assessed by immunochemistry in samples obtained from 7 patients with hepatocellular carcinomas (HCC)/intrahepatic cholangiocarcinoma (ICC) or granulomas., Results: Primary intrahepatic tumours, including 16 HCC in 14 patients and 4 ICC in 3 patients with extrahepatic metastases, were determined by histology (n = 14) and clinical examinations (n = 3). Based on visual analysis, 17 patients presented elevated 68 Ga-FAPI uptake (sensitivity: 100%, specificity: 100%), while 7 patients presented 18 F-FDG avid tumours (sensitivity: 58.8%, specificity: 100%). 68 Ga-FAPI PET/CT identified 17 extrahepatic metastases vs. 13 in 18 F-FDG PET/CT in 2 ICC patients. Three benign liver nodules in three patients showed negligible uptake in dual-PET scans. The SUV max&#95;HCC  = 8.47 ± 4.06 and TBR max&#95;HCC  = 7.13 ± 5.52, and SUV max&#95;ICC  = 14.14 ± 2.20 TBR max&#95;ICC  = 26.46 ± 4.94 in 68 Ga-FAPI-04 PET/CT were significantly higher than the 18 F-FDG uptake presenting SUV max&#95;HCC  = 4.86 ± 3.58 and TBR max&#95;HCC  = 2.39 ± 2.21, and SUV max&#95;ICC  = 9.19 ± 3.60 and TBR max&#95;ICC  = 2.39 ± 2.21 (all p values < 0.05). ICC patients showed higher levels of FAPI uptake in the primary hepatic lesions compared to extrahepatic metastases, TBR max&#95;ICC  = 15.18 ± 5.80 (p = 0.04)., Conclusions: 68 Ga-FAPI PET-CT has superior potential in the detection of primary hepatic malignancy compared to 18 F-FDG.

Background: Repeat hepatectomy is a feasible treatment modality for intrahepatic recurrence after hepatectomy of hepatocellular carcinoma, yet the survival benefit remains ill-defined. The objective of the current study was to define long-term, oncologic outcomes after repeat hepatectomy among patients with early and late recurrence., Methods: Patients undergoing curative-intent repeat hepatectomy for recurrent hepatocellular carcinoma were identified using a multi-intuitional database. Early and late recurrence was defined by setting 1 year after initial hepatectomy as the cutoff value. Patient clinical characteristics, overall survival, and disease-free survival were compared among patients with early and late recurrence before and after propensity score matching., Results: Among all the patients, 81 had early recurrence and 129 had late recurrence from which 74 matched pairs were included in the propensity score matching analytic cohort. Before propensity score matching, 5-year overall survival and disease-free survival after resection of an early recurrence were 41.7% and 17.9%, respectively, which were worse compared with patients who had resection of a late recurrence (57.0% and 39.4%, both P < .01). After propensity score matching, 5-year overall survival and disease-free survival among patients with early recurrence were worse compared with patients with late recurrence (41.0% and 19.2% vs 64.3% and 43.2%, both P < .01). After adjustment for other confounding factors on multivariable Cox-regression analysis, early recurrence remained independently associated with decreased overall survival and disease-free survival (hazard ratio 2.22, 95% confidence interval 1.35-3.34, P = .001; hazard ratio 1.86, 95% confidence 1.26-2.74, P = .002)., Conclusion: Repeat hepatectomy for early recurrence was associated with worse overall survival and disease-free survival compared with late recurrence. These data may help inform patients and selection of patients being considered for repeat hepatectomy of recurrent hepatocellular carcinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Evidence-based decision-making is critical to optimize the benefits and mitigate futility associated with surgery for patients with malignancies. Untreated hepatocellular carcinoma (HCC) has a median survival of only 6 months. The objective was to develop and validate an individualized patient-specific tool to predict preoperatively the benefit of surgery to provide a survival benefit of at least 6 months following resection., Methods: Using an international multicenter database, patients who underwent curative-intent liver resection for HCC from 2008 to 2017 were identified. Using random assignment, two-thirds of patients were assigned to a training cohort with the remaining one-third assigned to the validation cohort. Independent predictors of postoperative death within 6 months after surgery for HCC were identified and used to construct a nomogram model with a corresponding online calculator. The predictive accuracy of the calculator was assessed using C-index and calibration curves., Results: Independent factors associated with death within 6 months of surgery included age, Child-Pugh grading, portal hypertension, alpha-fetoprotein level, tumor rupture, tumor size, tumor number and gross vascular invasion. A nomogram that incorporated these factors demonstrated excellent calibration and good performance in both the training and validation cohorts (C-indexes: 0.802 and 0.798). The nomogram also performed better than four other commonly-used HCC staging systems (C-indexes: 0.800 vs. 0.542-0.748)., Conclusions: An easy-to-use online prediction calculator was able to identify patients at highest risk of death within 6 months of surgery for HCC. The proposed online calculator may help guide surgical decision-making to avoid futile surgery for patients with HCC.

Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-related death worldwide. However, the clinical diagnosis and treatment modalities are still relatively limited, which urgently require the development of new effective technologies. Recently, nanotechnology has gained extensive attention in HCC surveillance, imaging and pathological diagnosis, and therapeutic strategies. Typically, nanomedicines have been focused on early HCC diagnosis and precise treatment of advanced HCC, which has developed and improved a variety of new technologies and agents for future clinical practice. Furthermore, strategies of facilitating drug release and delivery in current treatment processes such as ablation, systematic therapy, transcatheter arterial chemoembolization, molecular targeted therapy, and immune-modulating therapy have also been studied widely. This review summarizes the recent advances in this area according to current clinical HCC guidelines: 1) Nanoparticle-based HCC surveillance; 2) Nanotechnology for HCC diagnosis; 3) Therapeutic advances for HCC Management; 4) Limitations of applications in nanotechnology for HCC; 5) Conclusions and perspectives. Although there are still many limitations and difficulties to overcome, the investigations of nanomedicines are believed to show potential applications in clinical practice., (© 2021 Wiley-VCH GmbH.)

Background: Conventional therapeutic strategies for advanced hepatocellular carcinoma (HCC) remains a great challenge, therefore the alternative therapeutic modality for specific and efficient HCC suppression is urgently needed. Methods: In this work, HCC-derived extracellular vesicles (EVs) were applied as surface nanocarrier for sequential nanocatalysts GOD-ESIONs@EVs (GE@EVs) of tumor-specific and cascade nanocatalytic therapy against HCC. By enhancing the intracellular endocytosis through arginine-glycine-aspartic acid (RGD)-targeting effect and membrane fusion, sequential nanocatalysts led to more efficient treatment in the HCC tumor region in a shorter period of time. Results: Through glucose consumption as catalyzed by the loaded glucose oxidase (GOD) to overproduce hydrogen peroxide (H 2 O 2 ), highly toxic hydroxyl radicals were generated by Fenton-like reaction as catalyzed by ESIONs, which was achieved under the mildly acidic tumor microenvironment, enabling the stimuli of the apoptosis and necrosis of HCC cells. This strategy demonstrated the high active-targeting capability of GE@EVs into HCC, achieving highly efficient tumor suppression both in vitro and in vivo . In addition, the as-synthesized nanoreactor could act as a desirable nanoscale contrast agent for magnetic resonance imaging, which exhibited desirable imaging capability during the sequential nanocatalytic treatment. Conclusion: This application of surface-engineering EVs not only proves the high-performance catalytic therapeutic modality of GE@EVs for HCC, but also broadens the versatile bio-applications of EVs., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: 68 Ga-FAPI-04 is a rapidly evolving PET tracer for whole-body imaging in a variety of cancers. We aimed to evaluate the diagnostic performance of 68 Ga-FAPI-04 for detecting and characterizing hepatic nodules in patients with suspected carcinoma., Methods: Twenty-five patients showing suspicious hepatic lesions for malignancy underwent 68 Ga-FAPI-04 PET. The maximum and mean standardised uptake values (SUV max , SUV mean ) were measured for all detected lesions and normal hepatic tissues, respectively. The target-to-background ratio (TBR) was calculated by dividing the lesion SUV max with the SUV mean of non-tumour liver tissue. Lesion uptake value was correlated with the in vitro hepatic FAP expression determined by immunohistochemistry (IHC)., Results: In total, 17 patients who underwent surgery or biopsy were recruited for the final analysis. A total of 28 intrahepatic malignant lesions were detected in 16 patients; the mean SUV max was 8.36 ± 4.21 (range 2.21 to 15.86), and mean TBR was 13.15 ± 9.48 (range 2.79 to 38.12) in all detected lesions (n = 28). One benign patient showed negligible hepatic uptake (SUV max  = 0.47), whereas 75% of the primary intrahepatic hepatocellular carcinoma (HCC) lesions (n = 6) showed prominent FAP expression, 12.5% of the lesions (n = 1) showed moderate expression in stromal cells, and one showed negligible expression., Conclusions: 68 Ga-FAPI-04 showed high sensitivity in detecting hepatic malignancies, particularly in poorly differentiated forms with concordantly elevated FAP expression.

Background: Hepatocellular carcinoma (HCC) is a recognized sequalae of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. This study aimed to identify long-term survival and prognostic factors after curative resection for HCC among patients with chronic HCV infection., Methods: From a Chinese multicenter database, the data of consecutive patients with HCV infection undergoing curative liver resection for initial HCC between 2006 and 2015 were retrospectively reviewed. Postoperative 30-day mortality and morbidity, long-term overall survival (OS) and recurrence-free survival (RFS) were evaluated., Results: Among 382 HCC patients with HCV infection, 68 (18%) had concurrent HBV infection and 110 (29%) had portal hypertension. Postoperative 30-day morbidity and mortality rates were 45% and 2.9%, respectively. The 5-year OS and RFS rates were 45% and 34%, respectively. Multivariable Cox-regression analyses identified that concurrent HBV infection, presence of portal hypertension, largest tumor size > 5 cm, and macrovascular and microvascular invasion were independently associated with worse OS and RFS, while postoperative regular anti-HCV therapy was independently associated with better OS., Conclusion: Long-term prognosis after HCC resection among patients with HCV infection was worse in those with concurrent HBV infection and concomitant portal hypertension. Postoperative regular anti-HCV therapy was associated with better OS., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: To develop an easy-to-use model to predict the probability of perioperative blood transfusion (PBT) in patients undergoing liver resection for hepatocellular carcinoma (HCC)., Method: 878 patients from Eastern Hepatobiliary Surgery Hospital of Shanghai were enrolled in the training cohort, while 691 patients from Tongji Hospital of Wuhan and 364 patients from two hospitals from Europe and America served as the Eastern and Western external validation cohorts, respectively. Independent predictors of PBT were identified and used for the nomogram construction. The predictive performance of the model was assessed using the concordance index (C-index) and calibration plot, and externally validated using the two independent cohorts. This model was compared with four currently available prediction risk scores., Results: Eight preoperative variables were identified as independent predictors of PBT, which were incorporated into the new nomogram model, with a C-index of 0.833 and a well-fitted calibration plot. The nomogram performed well on the externally Eastern and Western validation cohorts (C-indexes: 0.786 and 0.777). The discriminatory ability of the nomogram was superior to the four currently available prediction scores (C-indexes: 0.833 vs. 0.671-0.770). The nomogram was programmed into an online calculator, which is available at http://www.asapcalculate.top/Cal3&#95;en.html., Conclusion: A nomogram model, using an easy-to-access website, can be used to calculate the PBT risk and identify which patients undergoing HCC resection are at high risks of PBT and can benefit most by using blood conservation techniques., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Survival after liver resection of hepatocellular carcinoma (HCC) remains poor because of a high incidence of recurrence. We sought to investigate risk factors, patterns, and long-term prognosis among patients with early and late recurrence after liver resection for hepatitis B virus (HBV)-associated HCC., Methods: Data of consecutive patients undergoing curative resection for HBV-associated HCC were analyzed. According to the time to recurrence after surgery, recurrence was divided into early (≤2 years) and late recurrence (>2 years). Characteristics, patterns of initial recurrence, and postrecurrence survival (PRS) were compared between patients with early and late recurrence. Risk factors of early and late recurrence and predictors of PRS were identified by univariable and multivariable Cox regression analyses., Results: Among 894 patients, 322 (36.0%) and 282 (31.5%) developed early and late recurrence, respectively. On multivariable analyses, preoperative HBV-DNA >10 4 copies/mL was associated with both early and late recurrence, whereas postoperative no/irregular antiviral therapy was associated with late recurrence. Compared with patients with late recurrence, patients with early recurrence had a lower proportion of intrahepatic-only recurrence (72.0% vs. 91.1%, p < .001), as well as a lower chance of receiving potentially curative treatments for recurrence (33.9% vs. 50.7%, p < .001) and a worse median PRS (19.1 vs. 37.5 months, p < .001). Multivariable analysis demonstrated that early recurrence was independently associated with worse PRS (hazard ratio, 1.361; 95% confidence interval, 1.094-1.692; p = .006)., Conclusion: Although risk factors associated with early recurrence and late recurrence were different, a high preoperative HBV-DNA load was an independent hepatitis-related risk for both early and late recurrence. Early recurrence was associated with worse postrecurrence survival among patients with recurrence., Implications for Practice: Liver resection is the main curative treatment for hepatocellular carcinoma (HCC), but postoperative survival remains poor because of high recurrence rates. This study investigated the risk factors and patterns of early and late recurrence and found that a high preoperative hepatitis B virus (HBV) DNA load was an independent hepatitis-related risk factor for both. Early recurrence was also independently associated with worse postrecurrence survival. These data may provide insights into different biological origin and behavior of early versus late recurrence after resection for HBV-associated HCC, which could be helpful to make individualized treatment decision for recurrent HCC, as well as strategies for surveillance recurrence after resection., (© AlphaMed Press 2020.)

Background: Aging of the population and prolonged life expectancy have significantly increased the number of elderly patients undergoing hepatectomy for hepatocellular carcinoma (HCC). However, potential benefits, especially long-term oncologic outcomes of hepatectomy for elderly patients with HCC remain unclear., Method: Patients treated with curative-intent hepatectomy for HCC in 8 Chinese hospitals were enrolled. Patients were divided into the elderly (≥70 years old) and younger (<70 years old) groups. Overall survival (OS), cancer-specific survival (CSS), and time-to-recurrence (TTR) were compared. Risk factors of CSS and TTR were evaluated by univariable and multivariable competing-risk regression analyses., Results: Of 2134 patients, 259 (12.1%) and 1875 (87.9%) were elderly and younger aged, respectively. Postoperative 30-day and 90-day mortality was comparable among elderly and younger patients. Compared with younger patients, the elderly had a worse 5-year OS (49.4% vs. 55.3%, P = 0.032), yet a better 5-year CCS (74.5% vs. 61.0%, P = 0.005) and a lower 5-year TTR (33.7% vs. 44.9%, P < 0.001), respectively. Multivariable analyses identified that elder age was independently associated with more favorable CSS (HR 0.74, 95%CI 0.58-0.90, P = 0.011) and TTR (0.69, 0.53-0.88, P < 0.001) but was not associated with OS (P = 0.136)., Conclusions: Age by itself is not a contraindication to surgery, and selected elderly patients with HCC can benefit from hepatectomy. Compared with younger patients, elderly patients have noninferior oncologic outcomes following hepatectomy for HCC., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical guidelines recommend surveillance in high-risk population to early detect hepatocellular carcinoma (HCC), when curative treatment such as liver resection can be applied. However, it is largely unknown whether surveillance would provide long-term survival benefits to these high-risk patients who have received curative liver resection for HCC., Methods: A prospectively maintained database on patients with chronic hepatitis B infection who underwent curative liver resection for HCC from 2003 to 2014 was reviewed. Patients' overall survival and recurrence were compared between the groups of patients whose HCCs were diagnosed by surveillance or non-surveillance, as well as between the groups of patients operated in the first (2003-2008) and second (2009-2014) 6-year periods., Results: Of 1075 chronic hepatitis B patients with HCC, 452 (42.0%) patients were diagnosed by preoperative surveillance. Compared with the non-surveillance group, the OS and RFS rates were significantly better in the surveillance group (both P < 0.001). Surveillance was associated with a 55% decrease in the overall survival risk and a 48% decrease in the recurrence risk (HR 0.45, 95% CI 0.38-0.53, and HR 0.52, 95% CI 0.44-0.61). Compared with the first period, a significant reduction of 12% and 19% in the overall death and recurrence risks, respectively, was observed in the second period (HR 0.88, 95% CI 0.78-0.97, and HR 0.81, 95% CI 0.70-0.95)., Conclusion: Surveillance for HCC was associated with favorable long-term overall and recurrence-free survival rates after curative liver resection of HCC in patients with chronic hepatitis B.

Background: A clear definition of "early recurrence" after hepatocellular carcinoma (HCC) resection is still lacking. This study aimed to determine the optimal cutoff between early and late HCC recurrence, and develop nomograms for pre- and postoperative prediction of early recurrence., Methods: Patients undergoing HCC resection were identified from a multi-institutional Chinese database. Minimum P-value approach was adopted to calculate optimal cut-off to define early recurrence. Pre- and postoperative risk factors for early recurrence were identified and further used for nomogram construction. The results were externally validated by a Western cohort., Results: Among 1501 patients identified, 539 (35.9%) were recurrence-free. The optimal length to distinguish between early (n = 340, 35.3%) and late recurrence (n = 622, 64.7%) was 8 months. Multivariable logistic regression analyses identified 5 preoperative and 8 postoperative factors for early recurrence, which were further incorporated into preoperative and postoperative nomograms (C-index: 0.785 and 0.834). The calibration plots for the probability of early recurrence fitted well. The nomogram performance was maintained using the validation dataset (C-index: 0.777 for preoperative prediction and 0.842 for postoperative prediction)., Conclusions: An interval of 8 months was the optimal threshold for defining early HCC recurrence. The two web-based nomograms have been published to allow accurate pre- and postoperative prediction of early recurrence. These may offer useful guidance for individual treatment or follow up for patients with resectable HCC., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

More than two-thirds of patients with hepatocellular carcinoma (HCC) cannot receive curative therapy and have poor survival due to late diagnosis and few prognostic directions. In our study, nontargeted and targeted metabolomics analyses were conducted by liquid chromatography-mass spectrometry to characterize metabolic features of HCC and identify diagnostic and prognostic biomarker candidate incorporating liver tissue and serum metabolites. A total of 552 subjects, including 432 with liver tissue and 120 with serum specimens, were recruited in China. In the discovery cohort, a series of 138 metabolites were identified to discriminate HCC tissues from matched nontumor tissues. Retinol presented with the highest area under the curve (AUC) of 0.991 and associated with Edmondson grade. In the validation cohort, all metabolites in retinol metabolism pathway were examined and the levels of retinol and retinal in tumor tissue and serum decreased in the order of normal to cirrhosis to HCC of Edmondson Grades I to IV. Retinol and retinal levels could also differentiate between HCC and cirrhosis, with AUCs of 0.996 and 0.994, respectively, in tissue and 0.812 and 0.744, respectively, in serum. The AUC of the combined retinol and retinal panel in serum was 0.852. Univariate and multivariate Cox regression identified this panel as an independent predictor for HCC and showed that low expression of retinol and retinal correlated with decreased survival time. In conclusion, the retinol metabolic signature had considerable diagnostic and prognostic value for identifying HCC patients who would benefit from prompt therapy and optimal prognostic direction., (© 2019 UICC.)

Background: Morbidity remains a common problem following hepatic resection. The aim of this study was to investigate the association between preoperative body mass index (BMI) and morbidity in patients undergoing liver resection for hepatocellular carcinoma (HCC)., Methods: Patients were divided into three groups according to preoperative BMI: low-BMI (≤18.4 kg/m 2 ), normal-BMI (18.5-24.9 kg/m 2 ) and high-BMI (≥25.0 kg/m 2 ). Baseline characteristics, operative variables, postoperative 30-day mortality and morbidity were compared. Univariable and multivariable analyses were performed to identify independent risk factors associated with postoperative morbidity., Results: Among 1324 patients, 108 (8.2%), 733 (55.4%), and 483 (36.5%) were low-BMI, normal-BMI, and high-BMI, respectively. There were no differences in postoperative 30-day mortality among patients based on BMI (P = 0.199). Postoperative 30-day morbidity was, however, higher in low-BMI and high-BMI patients versus patients with a normal-BMI (33.3% and 32.1% vs. 22.9%, P = 0.018 and P < 0.001, respectively). Following multivariable analysis low-BMI and high-BMI remained independently associated with an increased risk of postoperative morbidity (OR: 1.701, 95%CI: 1.060-2.729, P = 0.028, and OR: 1.491, 95%CI: 1.131-1.966, P = 0.005, respectively). Similar results were noted in the incidence of postoperative 30-day surgical site infection (SSI)., Conclusion: Compared with normal-BMI patients, low-BMI and high-BMI patients had higher postoperative morbidity, including a higher incidence of SSI after liver resection for HCC., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The incidence of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Higher perioperative risks may be anticipated due to underlying steatohepatitis, while long-term outcomes after liver resection are unknown. We sought to investigate outcomes after liver resection for NAFLD-HCC versus hepatitis B virus (HBV)-HCC using propensity score matching (PSM)., Methods: Consecutive patients who underwent liver resection for HCC between 2003 and 2014 were identified from a multicenter database. Patients with NAFLD-HCC were matched one-to-one to patients with HBV-HCC., Results: Among 1483 patients identified, 96 (6.5%) had NAFLD-HCC and 1387 (93.5%) had HBV-HCC. Patients with NAFLD-HCC were older (median age 57 vs. 50 years), more often overweight (50.0% vs. 37.5%), less often to have cirrhosis (30.2% vs. 72.5%) and liver dysfunction (Child-Pugh B: 4.2% vs. 10.7%), had larger tumor size (median 7.2 vs. 6.2 cm) yet had better tumor differentiation (27.1% vs. 17.6%) compared with patients with HBV-HCC (all P < 0.05). Perioperative mortality and morbidity were comparable between the two groups (1.0% vs. 1.4% and 20.8% vs. 23.2%, both P > 0.05). No differences were noted in median OS and RFS among patient with NAFLD-HCC versus HBV-HCC before or after PSM., Conclusion: While patients with NAFLD-HCC had different clinical characteristics than patients with HBV-HCC, liver resection resulted in similar perioperative outcomes and comparable OS and RFS among patients with NAFLD-HCC and HBV-HCC.

Background: Patients on oral antiviral (OAV) therapy remain at hepatocellular carcinoma (HCC) risk. Risk prediction tools distinguishing treated patients with residual HCC risk are limited. The aim of this study was to develop an accurate, precise, simple-to-use HCC risk score using routine clinical variables among a treated Asian cohort., Methods: Adult Asian chronic hepatitis B (CHB) patients on OAV were recruited from 25 centers in the United States and the Asia-Pacific region. Excluded persons were coinfected with hepatitis C, D, or human immunodeficiency virus, had HCC before or within 1 year of study entry, or their follow-up was <1 year. Patients were randomized to derivation and validation cohorts on a 2:1 ratio. Statistically significant predictors from multivariate modeling formed the Real-world Effectiveness from the Asia Pacific Rim Liver Consortium for HBV (REAL-B) score., Results: A total of 8048 patients were randomized to the derivation (n = 5365) or validation group (n = 2683). The REAL-B model included 7 variables (male gender, age, alcohol use, diabetes, baseline cirrhosis, platelet count, and alpha fetoprotein), and scores were categorized as follows: 0-3 low risk, 4-7 moderate risk, and 8-13 high risk. Area under receiver operating characteristics were >0.80 for HCC risk at 3, 5, and 10 years, and these were significantly higher than other risk models (p < .001)., Conclusions: The REAL-B score provides 3 distinct risk categories for HCC development in Asian CHB patients on OAV guiding HCC surveillance strategy., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The Barcelona Clinic Liver Cancer (BCLC) categorizes a patient with performance status (PS)-1 as advanced stage of hepatocellular carcinoma (HCC) and surgical resection is not recommended. In real-world clinical practice, PS-1 is often not a contraindication to surgery for HCC. The aim of current study was to define the impact of PS on the surgical outcomes of patients undergoing liver resection for HCC., Methods: 1,531 consecutive patients who underwent a curative-intent resection of HCC between 2005 and 2015 were identified using a multi-institutional database. After categorizing patients into PS-0 (n = 836) versus PS-1 (n = 695), perioperative mortality and morbidity, overall survival (OS) and recurrence-free survival (RFS) were compared., Results: Overall perioperative mortality and major morbidity among patients with PS-0 (n = 836) and PS-1 (n = 695) were similar (1.4% vs. 1.6%, P = 0.525 and 9.7% vs. 10.2%, P = 0.732, respectively). In contrast, median OS and RFS was worse among patients who had PS-1 versus PS-0 (34.0 vs. 107.6 months, and 20.5 vs. 60.6 months, both P < 0.001, respectively). On multivariable Cox-regression analyses, PS-1 was independently associated with worse OS (HR: 1.301, 95% CI: 1.111-1.523, P < 0.001) and RFS (HR: 1.184, 95% CI: 1.034-1.358, P = 0.007)., Conclusions: Patients with PS-1 versus PS-0 had comparable perioperative outcomes. However, patients with PS-1 had worse long-term outcomes as PS-1 was independently associated with worse OS and RFS. Routine exclusion of HCC patients with PS-1 from surgical resection as recommended by the BCLC guidelines is not warranted., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background and Aims: Surgical resection for hepatocellular carcinoma (HCC) is potentially curative, but long-term survival remains unsatisfactory. There is currently no effective neoadjuvant or adjuvant therapy for HCC. We sought to evaluate the impact of preoperative transcatheter arterial chemoembolization (TACE) on long-term prognosis after surgical resection of huge HCCs (≥ 10 cm)., Methods: Using a multicenter database, consecutive patients who underwent curative-intent resection for huge HCC without macrovascular invasion between 2004 and 2014 were identified. The association between preoperative TACE with perioperative outcomes, long-term overall survival (OS), and recurrence-free survival (RFS) was assessed before and after propensity score matching (PSM)., Results: Among the 377 enrolled patients, 88 patients (23.3%) received preoperative TACE. The incidence of perioperative mortality and morbidity was comparable among patients who did and did not undergo preoperative TACE (3.4% vs. 2.4%, p= 0.704, and 33.0% vs. 31.1%, p= 0.749, respectively). PSM analysis created 84 matched pairs of patients. In examining the entire cohort as well as the PSM cohort, median OS (overall cohort: 32.8 vs. 22.3 months, p= 0.035, and PSM only: 32.8 vs. 18.1 months, p= 0.023, respectively) and RFS (12.9 vs. 6.4 months, p= 0.016, and 12.9 vs. 4.1 months, p= 0.009, respectively) were better among patients who underwent preoperative TACE vs. patients who did not. After adjustment for other confounding factors on multivariable analyses, preoperative TACE remained independently associated with a favorable OS and RFS after the resection of huge HCC., Conclusion: Preoperative TACE did not increase perioperative morbidity or mortality, yet was associated with an improved OS and RFS after liver resection of huge HCC (≥ 10 cm).

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

Purpose: To compare the survival outcomes of neoadjuvant three-dimensional conformal radiotherapy (RT) followed by hepatectomy with hepatectomy alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT)., Patients and Methods: A randomized, multicenter controlled study was conducted from January 2016 to December 2017 in patients with resectable HCC and PVTT. Patients were randomly assigned to receive neoadjuvant RT followed by hepatectomy (n = 82) or hepatectomy alone (n = 82). The modified Response Evaluation Criteria in Solid Tumors (mRECIST) guidelines were used to evaluate the therapeutic effects of RT. The primary end point was overall survival. The expression of interleukin-6 (IL-6) in patients' serum before RT and in surgical specimens was correlated with response to RT., Results: In the neoadjuvant RT group, 17 patients (20.7%) had partial remission. The overall survival rates for the neoadjuvant RT group at 6, 12, 18, and 24 months were 89.0%, 75.2%, 43.9%, and 27.4%, respectively, compared with 81.7%, 43.1%, 16.7%, and 9.4% in the surgery-alone group ( P < .001). The corresponding disease-free survival rates were 56.9%, 33.0%, 20.3%, and 13.3% versus 42.1%, 14.9%, 5.0%, and 3.3% ( P < .001). On multivariable Cox regression analyses, neoadjuvant RT significantly reduced HCC-related mortality and HCC recurrence rates compared with surgery alone (hazard ratios, 0.35 [95% CI, 0.23 to 0.54; P < .001] and 0.45 [95% CI, 0.31 to 0.64; P < .001]). Increased expressions of IL-6 in pre-RT serum and tumor tissues were significantly associated with resistance to RT., Conclusion: For patients with resectable HCC and PVTT, neoadjuvant RT provided significantly better postoperative survival outcomes than surgery alone. IL-6 may predict response to RT in these patients.

Background: The resection margin (RM) status and microscopic vascular invasion (MVI) are known prognostic factors for hepatocellular carcinoma (HCC). An enhanced understanding of their impact on long-term prognosis is required to improve oncological outcomes., Methods: Using multi-institutional data, the different impact of the RM status (narrow, <1 cm, or wide, ≥1 cm) and MVI (positive or negative) on overall survival (OS) and recurrence-free survival (RFS) after curative liver resection of solitary HCC without macrovascular invasion was analyzed., Results: In 801 patients, 306 (38%) had a narrow RM and 352 (44%) had positive MVI. The median OS and RFS were 109.8 and 74.8 months in patients with wide RM & negative MVI, 93.5 and 53.1 months with wide RM & positive MVI, 79.2 and 41.6 months with narrow RM & negative MVI, and 69.2 and 37.5 months with narrow RM & positive MVI (both P < 0.01). On multivariable analyses, narrow RM & positive MVI had the highest hazard ratio with reduced OS and RFS (HR 2.96, 95% CI 2.11-4.17, and HR 3.15, 95% CI, 2.09-4.67, respectively)., Conclusions: Concomitant having narrow RM and positive MVI increases the risks of postoperative death and recurrence by about 2-fold in patients with solitary HCC., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Postoperative complications have a great impact on the postoperative course and oncological outcomes following major cancer surgery. Among them, infective complications play an important role. The aim of this study was to evaluate whether postoperative infective complications influence long-term survival after liver resection for hepatocellular carcinoma (HCC)., Methods: Patients who underwent resection with curative intent for HCC between July 2003 and June 2016 were identified from a multicentre database (8 institutions) and analysed retrospectively. Independent risk factors for postoperative infective complications were identified. After excluding patients who died 90 days or less after surgery, overall survival (OS) and recurrence-free survival (RFS) were compared between patients with and without postoperative infective complications within 30 days after resection., Results: Among 2442 patients identified, 332 (13·6 per cent) had postoperative infective complications. Age over 60 years, diabetes mellitus, obesity, cirrhosis, intraoperative blood transfusion, duration of surgery exceeding 180 min and major hepatectomy were identified as independent risk factors for postoperative infective complications. Univariable analysis revealed that median OS and RFS were poorer among patients with postoperative infective complications than among patients without (54·3 versus 86·8 months, and 22·6 versus 43·2 months, respectively; both P < 0·001). After adjustment for other prognostic factors, multivariable Cox regression analyses identified postoperative infective complications as independently associated with decreased OS (hazard ratio (HR) 1·20, 95 per cent c.i. 1·02 to 1·41; P = 0·027) and RFS (HR 1·19, 1·03 to 1·37; P = 0·021)., Conclusion: Postoperative infective complications decreased long-term OS and RFS in patients treated with liver resection for HCC., (© 2019 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Background: The long-term prognosis after liver resection for multinodular (≥3 nodules) hepatocellular carcinoma (HCC) is generally considered to be unfavorable. However, the role of liver resection for binodular HCC is less investigated., Subjects, Materials, and Methods: From a multicenter database, consecutive patients who underwent curative-intent liver resection for binodular HCC and without macrovascular invasion between 2003 and 2015 were retrospectively reviewed. Patients' clinical variables as well as perioperative and long-term survival outcomes were analyzed. Univariable and multivariable analyses were performed to identify the risk factors associated with overall survival (OS) and recurrence-free survival (RFS) after curative resection., Results: Of 263 enrolled patients, the perioperative 30-day mortality and morbidity rates were 1.5% and 28.5%. The 1-, 3-, and 5-year OS and RFS rates were 81.5%, 52.4%, and 39.1% and 57.1%, 35.8%, and 26.6%, respectively. Multivariable Cox-regression analyses identified preoperative alpha-fetoprotein level >400 μg/L, tumor size with a sum of two nodules >8 cm, tumor size ratio of large/small nodule >1.5 (asymmetrical proportion), unilateral hemiliver distribution of two nodules, distance of ≤3 cm between two nodules, and microvascular invasion in any nodule as independent risk factors associated with decreased OS and RFS., Conclusion: Liver resection was safe and feasible in patients with binodular HCC, with acceptable perioperative and long-term outcomes. Sum of two tumor sizes, size ratio and distribution, and distance between two nodules were independent risk factors associated with long-term survival outcomes after surgery. These results may guide clinicians to make individualized surgical decisions and estimate long-term prognosis for these patients., Implications for Practice: Liver resection was safe and feasible in patients with binodular hepatocellular carcinoma, with acceptable perioperative and long-term outcomes. The sum of two tumor sizes, the size ratio and distribution of the two nodules, and the distance between two nodules were independent risk factors associated with long-term overall survival and recurrence-free survival after liver resection. The results of this study may guide clinicians to make individualized surgical decisions, estimate long-term prognosis, and plan recurrence surveillance and adjuvant therapy for these patients., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Aim: To evaluate the diagnostic performance of serum AFU for early stage hepatocellular carcinoma (HCC). Methods: Concentration of AFU and AFP were measured in 512 patients. The performance was compared for AFU and AFP alone or in combination. Results: The area under the curve (AUC) for AFU was 0.68, with a sensitivity of 56.1% and specificity of 69.2% at the cut-off value of 24 U/l; whereas the AUC for AFP was 0.83, with a sensitivity of 58.2% and specificity of 85.2% at cut-off value of 20 ng/ml. The AUC of AFU alone or the combination with AFP were lower than that of AFP alone. Conclusion: AFU is a suboptimal biomarker for early detection of HCC.

Importance: Late recurrence (more than 2 years) after liver resection for hepatocellular carcinoma (HCC) is generally considered as a multicentric tumor or a de novo cancer., Objective: To investigate the risk factors, patterns, and outcomes of late recurrence after curative liver resection for HCC., Design, Setting, and Participants: This study was a multicenter retrospective analysis of patients who underwent curative liver resection for HCC at 6 hospitals in China from January 2001 to December 2015. Among 734 patients who were alive and free of recurrence at 2 years after resection, 303 patients developed late recurrence. Data were analyzed from June 2017 to February 2018., Interventions: Liver resection for HCC., Main Outcomes and Measures: Risk factors of late recurrence as well as patterns, treatments, and long-term outcomes of patients with late recurrence. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors of late recurrence., Results: Of the included 734 patients, 652 (88.8%) were male, and the mean (SD) age was 51.0 (10.3) years. At a median (interquartile range) follow-up of 78.0 (52.8-112.5) months, 303 patients (41.3%) developed late recurrence. Multivariate analysis revealed that male sex, cirrhosis, multiple tumors, satellite nodules, tumor size greater than 5 cm, and macroscopic and microscopic vascular invasion were independent risk factors of late recurrence. Of the 303 patients with late recurrence, 273 (90.1%) had only intrahepatic recurrence, 30 (9.9%) had both intrahepatic and extrahepatic recurrence, and none had only extrahepatic recurrence. Potentially curative treatments were given to 165 of 303 patients (54.5%) with late recurrence, which included reresection, transplant, and local ablation. Multivariate Cox regression analysis showed that regular surveillance for postoperative recurrence (hazard ratio [HR], 0.470; 95% CI, 0.310-0.713; P = .001), cirrhosis (HR, 1.381; 95% CI, 1.049-1.854; P = .02), portal hypertension (HR, 2.424; 95% CI, 1.644-3.574; P < .001), Child-Pugh grade of B or C (HR, 1.376; 95% CI, 1.153-1.674; P < .001), Barcelona Clinic Liver Cancer stage B (HR, 1.304; 95% CI, 1.007-1.708; P = .04) and stage C (HR, 2.037; 95% CI, 1.583-2.842; P < .001), and potentially curative treatment (HR, 0.443; 95% CI, 0.297-0.661; P < .001) were independent predictors of overall survival for patients with late recurrence., Conclusions and Relevance: Late recurrence after HCC resection was associated with sex, cirrhosis, and several aggressive tumor characteristics of the initial HCC. The patterns of late recurrence suggested surveillance for recurrence after 2 years of surgery should be targeted to the liver. Postoperative surveillance improved the chance of potentially curative treatments, with improved survival outcomes in patients with late recurrence.

Background: There is a striking sex difference in the incidence of hepatocellular carcinoma, with a strong predominance for men; however, the impact of sex on the incidence of recurrence after curative resection of hepatocellular carcinoma remains controversial. This study aimed to assess sex differences in the risks of recurrence and mortality for patients treated with curative resection of hepatocellular carcinoma., Methods: We retrospectively reviewed data from 1,435 hepatocellular carcinoma patients treated with curative resection (1,228 men and 207 women) between 2004 and 2014 at 5 institutions in China. Patients' baseline characteristics, operative variables, and rates of early recurrence (≤2 years after resection), late recurrence (>2 years after resection), and cancer-specific mortality were evaluated and compared. To clarify the true oncologic impact of sex, multivariable competing-risks regression analyses were performed to identify predictors associated with early and late recurrence, as well as cancer-specific mortality., Results: The early recurrence rates between men and women were similar (43.3% vs 42.0%, P = .728), but the late recurrence and rates of cancer-specific mortality in men were greater compared with women (17.2% vs 11.2%, P = .044; and 42.8% vs 34.3%, P = .022, respectively). Multivariable competing-risks regression analyses revealed no sex difference in early recurrence; however, men had greater late recurrence rate (hazard ratio, 1.752; 95% confidence interval, 1.145-2.682; P = .010) and rate of cancer-specific mortality (hazard ratio, 1.307; 95% confidence interval, 1.015-1.683; P = .038)., Conclusion: There was no difference in early recurrence rate (≤2 years after resection between men and women, but men had significantly greater late recurrence (>2 years) and rates of cancer-specific mortality after hepatocellular carcinoma resection than women., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Whether preoperative bodyweight is associated with long-term prognosis in patients after liver resection for hepatocellular carcinoma (HCC) is controversial. This study aimed to investigate the relationship of patient weight with long-term recurrence and overall survival (OS) after curative liver resection for HCC., Methods: Data for patients with HCC who underwent curative liver resection between 2000 and 2015 in five centres in China were analysed retrospectively in three groups according to their preoperative BMI: underweight (BMI 18·4 kg/m 2 or less), normal weight (BMI 18·5-24·9 kg/m 2 ) and overweight (BMI 25·0 kg/m 2 or above). Patients' baseline characteristics, operative variables and long-term survival outcomes were compared. Univariable and multivariable Cox regression analyses were performed to identify risk factors for OS and recurrence-free survival (RFS) after resection., Results: Of 1524 patients, 107 (7·0 per cent) were underweight, 891 (58·5 per cent) were of normal weight and 526 (34·5 per cent) were overweight. Univariable analyses showed that underweight and overweight patients had poorer OS (both P < 0·001) and RFS (both P < 0·001) than patients of normal weight. Multivariable Cox regression analysis also identified both underweight and overweight to be independent risk factors for OS (hazard ratio (HR) 1·22, 95 per cent c.i. 1·19 to 1·56, P = 0·019; and HR 1·57, 1·36 to 1·81, P < 0·001, respectively) and RFS (HR 1·28, 1·16 to 1·53, P = 0·028; and HR 1·34, 1·17 to 1·54, P < 0·001)., Conclusion: Underweight and overweight patients appear to have a worse prognosis than those of normal weight following liver resection for HCC., (© 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: Serum prealbumin is a sensitive and stable marker for nutritional status and liver function. Whether preoperative prealbumin level is associated with long-term prognosis in patients undergoing liver resection for hepatocellular carcinoma (HCC) is unclear., Methods: Patients who underwent liver resection for HCC between 2001 and 2014 at six institutions were enrolled. These patients were divided into the low and normal prealbumin groups using a cut-off value of 170 mg/L for preoperative prealbumin level. The overall survival (OS) and recurrence-free survival (RFS) were compared between them., Results: In 1483 patients, 437 (29%) had a low prealbumin level. The 3- and 5-year OS and RFS rates of patients in the low-prealbumin group were 57 and 31%, and 40 and 20%, respectively, which were significantly poorer than those in the normal-prealbumin group (76 and 43%, and 56 and 28%, respectively, both p < 0.001). Multivariable Cox-regression analyses revealed that preoperative prealbumin level was an independent predictor of OS (HR, 1.45, 95% CI: 1.24-1.70, p <0.001) and RFS (HR, 1.28, 95% CI: 1.10-1.48, p <0.001)., Conclusions: Preoperative prealbumin level could be used in predicting long-term prognosis for patients undergoing liver resection for HCC., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) worldwide. The aim of the study was to identify the incidence and predictive factors of actual 10-year survival following liver resection of HBV-related HCC., Methods: A Chinese multicenter database of patients undergoing curative hepatectomy of HBV-related HCC was reviewed. Patients who survived ≥ 10 years and patients who died < 10 years after surgery were compared and analyzed. Univariable and multivariable regression analyses were performed to identify predictive factors associated with 10-year survival., Results: Among all enrolled 1016 patients, the actuarial 10-year survival rate was 24.1%, while the actual 10-year survival rate was 16.6%. There were 169 patients who survived at least 10 years after surgery and 688 who died within 10 years from surgery. These patients constituted the study population of this study. Multivariable regression analysis revealed that cirrhosis, preoperative HBV viral load > 10 4  copies/mL, maximum tumor size > 5 cm, multiple tumors, macroscopic and microscopic vascular invasion, postoperative HBV reactivation, and early recurrence (< 2 years after surgery) were independent risk factors associated with actual 10-year survival, while postoperative antiviral therapy, regular recurrence surveillance, and curative treatments for initial recurrence were independent protective factors., Conclusions: The actual 10-year survival after curative resection of HBV-related HCC was calculated to be 16.6%. Postoperative antiviral therapy and regular recurrence surveillance were independent protective factors associated with actual 10-year survival after liver resection of HBV-related HCC.

Background and Aims: Metabolomics serves as an important tool in distinguishing changes in metabolic pathways and the diagnosis of human disease. Hepatocellular carcinoma (HCC) is a malignance present of heterogeneous metabolic disorder and lack of effective biomarker for surveillance and diagnosis. In this study, we searched for potential metabolite biomarkers of HCC using tissue and serum metabolomics approach., Methods: A total of 30 pairs of matched liver tissue samples from HCC patients and 90 serum samples (30 HCC patients, 30 liver cirrhosis patients, and 30 healthy individuals) were assessed. Metabolomics was performed through ultra performance liquid chromatography-mass spectrometry in conjunction with multivariate and univariate statistical analyses., Results: A total of six differential metabolites including chenodeoxycholic acid (CDCA), glycocholic acid (GCA), LPC20:5, LPE18:0, succinyladenosine and uridine were present in HCC tissue and serum samples. CDCA, LPC20:5, succinyladenosine and uridine were used to construct a diagnostic model based on logistic regression. The four-metabolite panel discriminated HCC from liver cirrhosis with an AUC score of 0.938, sensitivity of 93.3% and specificity of 86.7%. For all HCC and cirrhosis patients, the diagnostic accuracy increased to 96.7% and 90.0%, respectively., Conclusion: The combination of CDCA, LPC20:5, succinyladenosine and uridine can be used as a biomarker panel to improve HCC sensitivity and specificity. This panel significantly benefits HCC diagnostics and reveals new insight into HCC pathogenesis., (Copyright © 2018 Elsevier B.V. All rights reserved.)