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Activated Wnt/β-catenin pathway is a key genetic event in liver cancer development. Solute carrier (SLC) transporters are promising drug targets. Here, we identify SLC13A3 as a drug-targetable effector downstream of β-catenin in liver cancer. SLC13A3 expression is elevated in human liver cancer samples with gain of function (GOF) mutant CTNNB1, the gene encoding β-catenin. Activation of β-catenin up-regulates SLC13A3, leading to intracellular accumulation of endogenous SLC13A3 substrates. SLC13A3 is identified as a low-affinity transporter for glutathione (GSH). Silencing of SLC13A3 downregulates the leucine transporter SLC7A5 via c-MYC signaling, leading to leucine depletion and mTOR inactivation. Furthermore, silencing of SLC13A3 depletes GSH and induces autophagic ferroptosis in β-catenin-activated liver cancer cells. Importantly, both genetic inhibition of SLC13A3 and a small molecule SLC13A3 inhibitor suppress β-catenin-driven hepatocarcinogenesis in mice. Altogether, our study suggests that SLC13A3 could be a promising therapeutic target for treating human liver cancers with GOF CTNNB1 mutations., (© 2024. The Author(s).)

Background: Hepatocellular carcinoma (HCC) is one of the most common types of tumors. The influence of lipid metabolism disruption on the development of HCC has been demonstrated in published studies., Aim: To establish an HCC prognostic model for lipid metabolism-related long non-coding RNAs (LMR-lncRNAs) and conduct in-depth research on the specific role of novel LMR-lncRNAs in HCC., Methods: Correlation and differential expression analyses of The Cancer Genome Atlas data were used to identify differentially expressed LMR-lncRNAs. Quantitative real-time polymerase chain reaction analysis was used to evaluate the expression of LMR-lncRNAs. Nile red staining was employed to observe intracellular lipid levels. The interaction between RP11-817I4.1, miR-3120-3p, and ATP citrate lyase (ACLY) was validated through the performance of dual-luciferase reporter gene and RIP assays., Results: Three LMR-lncRNAs (negative regulator of antiviral response, RNA transmembrane and coiled-coil domain family 1 antisense RNA 1, and RP11-817I4.1) were identified as predictive markers for HCC patients and were utilized in the construction of risk models. Additionally, proliferation, migration, and invasion were reduced by RP11-817I4.1 knockdown. An increase in lipid levels in HCC cells was significantly induced by RP11-817I4.1 through the miR-3120-3p/ACLY axis., Conclusion: LMR-lncRNAs have the capacity to predict the clinical characteristics and prognoses of HCC patients, and the discovery of a novel LMR-lncRNAs, RP11-817I4.1, revealed its role in promoting lipid accumulation, thereby accelerating the onset and progression of HCC., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to disclose in this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Liver cancer is ranked as the sixth most prevalent from of malignancy globally and stands as the third primary contributor to cancer-related mortality. Metastasis is the main reason for liver cancer treatment failure and patient deaths. Speckle-type POZ protein (SPOP) serves as a crucial substrate junction protein within the cullin-RING E3 ligase complex, acting as a significant tumor suppressor in liver cancer. Nevertheless, the precise molecular mechanism underlying the role of SPOP in liver cancer metastasis remain elusive. In the current study, we identified cAMP response element binding 5 (CREB5) as a novel SPOP substrate in liver cancer. SPOP facilitates non-degradative K63-polyubiquitination of CREB5 on K432 site, consequently hindering its capacity to activate receptor tyrosine kinase MET. Moreover, liver cancer-associated SPOP mutant S119N disrupts the SPOP-CREB5 interactions and impairs the ubiquitination of CREB5.This disruption ultimately leads to the activation of the MET signaling pathway and enhances metastatic properties of hepatoma cells both in vitro and in vivo. In conclusion, our findings highlight the functional significance of the SPOP-CREB5-MET axis in liver cancer metastasis., Competing Interests: Declaration of competing interest The authors declare that there are no potential conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: To evaluate the predictive value of a combination model of Liver Imaging Reporting and Data System (LI-RADS)-based magnetic resonance imaging (MRI) and clinicopathologic features to identify atypical hepatocellular carcinoma (HCC) in LI-RADS category M (LR-M) observations., Methods: A total of 105 patients with HCC based on surgery or biopsy who underwent preoperative MRI were retrospectively reviewed in the training group from hospital-1 between December 2016 and November 2020. The LI-RADS-based MRI features and clinicopathologic data were compared between LR-M HCC and non-HCC groups. Univariate and least absolute shrinkage and selection operator regression analyses were used to select the features. Binary logistic regression analysis was then conducted to estimate potential predictors of atypical HCC. A predictive nomogram was established based on the combination of MRI and clinicopathologic features and further validated using an independent external set of data from hospital-2., Results: Of 113 observations from 105 patients (mean age, 61 years; 77 men) in the training set, 47 (41.59%) were classified as LR-M HCC. Following multivariate analysis, aspartate aminotransferase >40 U/L [odds ratio (OR): 4.65], alpha-fetoprotein >20 ng/mL (OR: 13.04), surface retraction (OR: 0.16), enhancing capsule (OR: 5.24), blood products in mass (OR: 8.2), and iso/hypoenhancement on delayed phase (OR: 10.26) were found to be independently correlated with LR-M HCC. The corresponding area under the curve for a combined model-based nomogram was 0.95 in the training patients (n = 113) and 0.90 in the validation cohort (n = 53)., Conclusion: The combined model incorporating clinicopathologic and MRI features demonstrated a satisfactory prediction result for LR-M HCC.

Hepatocellular carcinoma (HCC) is a common malignant tumor. At present, early diagnosis of HCC is difficult and therapeutic methods are limited. Radiomics can achieve accurate quantitative evaluation of the lesions without invasion, and has important value in the diagnosis and treatment of HCC. Radiomics features can predict the development of cancer in patients, serve as the basis for risk stratification of HCC patients, and help clinicians distinguish similar diseases, thus improving the diagnostic accuracy. Furthermore, the prediction of the treatment outcomes helps determine the treatment plan. Radiomics is also helpful in predicting the HCC recurrence, disease-free survival and overall survival. This review summarized the role of radiomics in the diagnosis, treatment and prognosis of HCC., (Copyright © 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance., Aim: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC., Methods: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively., Results: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone., Conclusion: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: To evaluate the efficacy and safety of Cidan Capsule combined with adjuvant transarterial chemoembolization (TACE) in patients with a high risk of early recurrence after curative resection of hepatocellular carcinoma (HCC)., Methods: A multicenter, randomized controlled trial was conducted in patients with high-risk recurrence factors after curative resection of HCC from 9 medical centers between July 2014 and July 2018. Totally 249 patients were randomly assigned to TACE with or without Cidan Capsule administration groups by stratified block in a 1:1 ratio. Postoperative adjuvant TACE was given 4-5 weeks after hepatic resection in both groups. Additionally, 125 patients in the TACE plus Cidan group were administrated Cidan Capsule (0.27 g/capsule, 5 capsules every time, 4 times a day) for 6 months with a 24-month follow-up. Primary endpoints included disease-free survival (DFS) and tumor recurrence rate (TRR). Secondary endpoint was overall survival (OS). Any drug-related adverse events (AEs) were observed and recorded., Results: As the data cutoff in July 9th, 2018, the median DFS was not reached in the TACE plus Cidan group and 234.0 days in the TACE group (hazard ratio, 0.420, 95% confidence interval, 0.290-0.608; P<0.01). The 1- and 2-year TRR in the TACE plus Cidan and TACE groups were 31.5%, 37.1%, and 60.8%, 63.4%, respectively (P<0.01). Median OS was not reached in both groups. The 1- and 2-year OS rates in TACE plus Cidan and TACE groups were 98.4%, 98.4%, and 89.5%, 87.9%, respectively (P<0.05). The most common grade 3-4 AEs included fatigue, abdominal pain, lumbar pain, and nausea. One serious AE was reported in 1 patient in the TACE plus Cidan group, the death was due to retroperitoneal mass hemorrhage and hemorrhagic shock, and was not related to study drug., Conclusions: Cidan Capsule in combination with TACE can reduce the incidence of early recurrence in HCC patients at high-risk of recurrence after radical hepatectomy and may be an appropriate option in postoperative anti-recurrence treatment. (Registration No. NCT02253511)., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

The roles of lamin A/C in adipocyte differentiation and skeletal muscle lipid metabolism are associated with familial partial lipodystrophy of Dunnigan (FPLD). We confirmed that LMNA knockdown (KD) in mouse adipose-derived mesenchymal stem cells (AD-MSCs) prevented adipocyte maturation. Importantly, in in vitro experiments, we discovered a significant increase in phosphorylated lamin A/C levels at serine 22 or 392 sites (pLamin A/C-S22/392) accompanying increased lipid synthesis in a liver cell line (7701 cells) and two hepatocellular carcinoma (HCC) cell lines (HepG2 and MHCC97-H cells). Moreover, HCC cells did not survive after LMNA knockout (KO) or even KD. Evidently, the functions of lamin A/C differ between the liver and adipose tissue. To date, the mechanism of hepatocyte lipid metabolism mediated by nuclear lamin A/C remains unclear. Our in-depth study aimed to identify the molecular connection between lamin A/C and pLamin A/C, hepatic lipid metabolism and liver cancer. Gain- and loss-of-function experiments were performed to investigate functional changes and the related molecular pathways in 7701 cells. Adenosine 5' monophosphate-activated protein kinase α (AMPKα) was activated when abnormalities in functional lamin A/C were observed following lamin A/C depletion or farnesyltransferase inhibitor (FTI) treatment. Active AMPKα directly phosphorylated acetyl-CoA-carboxylase 1 (ACC1) and subsequently inhibited lipid synthesis but induced glycolysis in both HCC cells and normal cells. According to the mass spectrometry analysis, lamin A/C potentially regulated AMPKα activation through its chaperone proteins, ATPase or ADP/ATP transporter 2. Lonafarnib (an FTI) combined with low-glucose conditions significantly decreased the proliferation of the two HCC cell lines more efficiently than lonafarnib alone by inhibiting glycolysis or the maturation of prelamin A.

Rationale and Objectives: Irreversible electroporation (IRE) is a promising non-thermal ablation technique for the treatment of patients with hepatocellular carcinoma. Early differentiation of the IRE zone from surrounding reversibly electroporated (RE) penumbra is vital for the evaluation of treatment response. In this study, an advanced statistical learning framework was developed by evaluating standard MRI data to differentiate IRE ablation zones, and to correlate with histological tumor biomarkers., Materials and Methods: Fourteen rabbits with VX2 liver tumors were scanned following IRE ablation and forty-six features were extracted from T1w and T2w MRI. Following identification of key imaging variables through two-step feature analysis, multivariable classification and regression models were generated for differentiation of IRE ablation zones, and correlation with histological markers reflecting viable tumor cells, microvessel density, and apoptosis rate. The performance of the multivariable models was assessed by measuring accuracy, receiver operating characteristics curve analysis, and Spearman correlation coefficients., Results: The classifiers integrating four radiomics features of T1w, T2w, and T1w+T2w MRI data distinguished IRE from RE zones with an accuracy of 97%, 80%, and 97%, respectively. Also, pixelwise classification models of T1w, T2w, and T1w+T2w MRI labeled each voxel with an accuracy of 82.8%, 66.5%, and 82.9%, respectively. Regression models obtained a strong correlation with behavior of viable tumor cells (0.62 ≤ r 2 ≤ 0.85, p < 0.01), apoptosis (0.40 ≤ r 2 ≤ 0.82, p < 0.01), and microvessel density (0.48 ≤ r 2 ≤ 0.58, p < 0.01)., Conclusion: MRI radiomics features provide descriptive power for early differentiation of IRE and RE zones while observing strong correlations among multivariable MRI regression models and histological tumor biomarkers., (Copyright © 2021 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Transcription factor 3 (TCF3) plays pivotal roles in embryonic development, stem cell maintenance and carcinogenesis. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. This study aimed to analyze the correlation between TCF3 expression and clinicopathological features of HCC, and further explore the underlying mechanism in HCC progression., Methods: The expression of TCF3 was collected from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) HCC datasets, and further confirmed by immunostaining and Western blotting assays. The correlation between TCF3 expression and the clinicopathological features was evaluated. Bioinformatical analysis and in vitro experiments were conducted to explore the potential role of TCF3 in HCC development., Results: Both the mRNA and protein levels of TCF3 were significantly higher in HCC tumor tissues compared to tumor adjacent tissues (P < 0.001 and P < 0.01). Analysis based on TCGA datasets showed that TCF3 was positively correlated with tumor clinical stage and grade, and patients with high TCF3 expression had shorter overall survival (P = 0.012), disease-specific survival (P = 0.022) and progression-free survival (P = 0.013). Similarly, the immunostaining results revealed that the high expression of TCF3 was closely correlated with tumor size (P = 0.001) and TNM stage (P = 0.002), and TCF3 was an independent risk factor of HCC. In vitro study exhibited that TCF3 knockdown dramatically suppressed cancer cell proliferation, and the underlying mechanism might be that the silencing of TCF3 reduced the expression of critical regulating proteins towards cell cycle and proteins involved in Wnt signaling pathways., Conclusions: TCF3 expression is significantly elevated in HCC and positively associated with the tumor size and TNM stage, as well as poor prognosis of HCC patients. The mechanism might be that TCF3 promotes cancer cell proliferation via activating Wnt signaling pathway., (Copyright © 2022. Published by Elsevier B.V.)

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2021. Published by Elsevier B.V.)

Background: Whether interferon (IFN)-α therapy is better than nucleos(t)ide analogs (NAs) in the prevention of adverse outcomes, including hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB) is still uncertain or controversial. This study aimed to compare the cumulative incidence of adverse outcomes in patients with CHB on IFN-α- and NA-based therapies., Methods: This was a retrospective study of patients with CHB on antivirals. Patients treated with IFN-α (IFN-α or peginterferon-α) with or without NAs were defined as the IFN-α group, and those only receiving NAs were defined as the NAs group. Propensity score matching (PSM) was used to minimize baseline bias. Cox regression models were performed to select possible factors related to adverse outcomes development., Results: All 1247 patients were divided into the IFN-α (n = 877) and NAs (n = 370) groups. 26patients (20 and 6 in the NAs and IFN-α groups) developed adverse outcomes (decompensated cirrhosis, liver failure, HCC, liver transplantation and deaths) during a median follow-up of 5.2 years. The cumulative adverse outcomes occurrence at 10 years was significantly lower in the IFN-α group than in the NAs group in all (1.1% vs. 11.9%, P <0.001) and treatment-naïve (1.1% vs. 12.4%, P <0.001) patients. Similar trends were observed after PSM and differentiation of cirrhosis. Multivariate analysis before and after PSM showed that IFN-α-based treatment was independently associated with a lower adverse outcomes incidence (before/after PSM: P = 0.001/P = 0.002). HCC risk stratification analyses revealed that the superiority of IFN-α in preventing HCC was more significant in patients with high-risk HCC., Conclusions: IFN-α-based therapy was superior to NAs in preventing adverse outcomes in patients with CHB regardless of cirrhosis, and in reducing HCC in those with a high risk of HCC., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Masson SAS.)

Rationale and Objectives: To investigate whether transcatheter intraarterial perfusion (TRIP) magnetic resonance imaging (MRI) can differentiate reversible electroporation (RE) zones from irreversible electroporation (IRE) zones immediately after IRE procedure in the rabbit liver., Materials and Methods: All studies were approved by the institutional animal care and use committee and performed in accordance with institutional guidelines. A total of 13 healthy New Zealand White rabbits were used. After selective catheterization of the hepatic artery under X-ray fluoroscopy, we acquired TRIP-MRI at 20 minutes post-IRE using 3 mL of 5% intraarterial gadopentetate dimeglumine. Semi-quantitative (peak enhancement, PE; time to peak, TTP; wash-in slope, WIS; areas under the time-intensity curve, AUT, over 30, 60, 90, 120, 150, and 180 seconds after the initiation of enhancement) and quantitative (K trans , v e , and v p ) TRIP-MRI parameters were calculated. The relationships between TRIP-MRI parameters and histological measurements and the differential ability of TRIP-MRI parameters was assessed., Results: PE, AUT 60 , AUT 90 , AUT 120 , AUT 150 , AUT 180 , K trans , and v e were significantly higher in RE zones than in IRE zones (all P < 0.05), and AUC for these parameters ranged from 0.91(95% CI, 0.80, 1.00) to 0.99 (95% CI, 0.98, 1.00). There was no significant difference in AUC between any two parameters (Z, 0-1.47; P, 0.14-1.00). Hepatocyte apoptosis strongly correlated with PE, AUT 60 , AUT 90 , AUT 120 , AUT 150 , AUT 180 , K trans , and v p (the absolute value r, 0.6-0.7, all P < 0.0001)., Conclusion: AUT 150 or AUT 180 could be a potential imaging biomarker to differentiate RE from IRE zones, and TRIP-MRI permits to differentiate RE from IRE zones immediately after IRE procedure in the rabbit liver., (Published by Elsevier Inc.)

Purpose: Irreversible electroporation (IRE) is a nonthermal tissue ablation technique that represents a promising treatment option for unresectable liver tumors, but the effectively treated zone cannot be reliably predicted. We investigate the potential benefit of transcatheter intra-arterial perfusion (TRIP) -MRI for the early noninvasive differentiation of IRE zone from surrounding reversibly electroporated (RE) zone., Methods: Seventeen rabbits with VX2 liver tumors were scanned with morphological and contrast-enhanced MRI sequences approximately 30 min after IRE tumor ablation. Quantitative TRIP-MRI perfusion parameters were evaluated in IRE zone and RE zone, defined according to histology. MRI and histology results were compared among zones using Wilcoxon rank-sum tests and correlations were evaluated by Pearson's correlation coefficient., Results: There were significant differences in area under the curve, time to peak, maximum and late enhancement, wash-in and wash-out rates in the tumor IRE zones compared with the boundary tumor RE zones and untreated tumors. Histology showed significantly fewer tumor cells, microvessels and significantly more apoptosis in tumor IRE zones compared with tumor RE zones (-51%, -66% and +185%, respectively) and untreated tumors (-60%, -67%, and +228%, respectively). A strong correlation was observed between MRI and histology measurements of IRE zones (r = 0.948) and RE zones (r = 0.951)., Conclusion: TRIP-MRI demonstrated the potential to detect immediate perfusion changes following IRE liver tumor ablation and effectively differentiate the IRE zone from the surrounding tumor RE zone., (© 2019 International Society for Magnetic Resonance in Medicine.)

Worldwide, hepatocellular carcinoma (HCC) remains a crucial medical problem. Precise and concise prognostic models are urgently needed because of the intricate gene variations among liver cancer cells. We conducted this study to identify a prognostic gene signature with biological significance. We applied two algorithms to generate differentially expressed genes (DEGs) between HCC and normal specimens in The Cancer Genome Atlas cohort (training set included) and performed enrichment analyses to expound on their biological significance. A protein-protein interactions network was established based on the STRING online tool. We then used Cytoscape to screen hub genes in crucial modules. A multigene signature was constructed by Cox regression analysis of hub genes to stratify the prognoses of HCC patients in the training set. The prognostic value of the multigene signature was externally validated in two other sets from Gene Expression Omnibus (GSE14520 and GSE76427), and its role in recurrence prediction was also investigated. A total of 2000 DEGs were obtained, including 1542 upregulated genes and 458 downregulated genes. Subsequently, we constructed a 14-gene signature on the basis of 56 hub genes, which was a good predictor of overall survival. The prognostic signature could be replicated in GSE14520 and GSE76427. Moreover, the 14-gene signature could be applied for recurrence prediction in the training set and GSE14520. In summary, the 14-gene signature extracted from hub genes was involved in some of the HCC-related signalling pathways; it not only served as a predictive signature for HCC outcome but could also be used to predict HCC recurrence., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective The purpose of this study was to produce an arginylglycylaspartic acid (RGD) peptide-modified ultra-small superparamagnetic iron oxide (Fe 3 O 4 ) nanoparticles (NPs) for targeted magnetic resonance (MR) imaging of hepatocellular carcinoma (HCC) cells and verify its utility as a T1 positive MRI imaging contrast agent in vitro and in vivo .Methods The carboxylated Fe 3 O 4 NPs stabilized with sodium citrate were conjugated with polyethylene glycol (PEG)-linked RGD nanoparticles to form a novel target contrast agent Fe 3 O 4 -PEG-RGD NPs. The specificity of Fe 3 O 4 -PEG-RGD to bind RGD receptor was investigated in vitro by HepG2 cellular uptake and cell MR imaging, and in vivo by MR imaging of subcutaneous HepG2 tumors of nude mice.Results The formed Fe 3 O 4 -PEG-RGD NPs displayed good biocompatibility, and the ultrahigh r1 relaxivity was 1.37 mM -1 S -1 . The synthesized Fe 3 O 4 -PEG-RGD NPs were demonstrated spherical-like with an approximate diameter of 2.7 nm in similar size. The targeting effect to HepG2 cells was confirmed by in vitro cellular uptake and cell MR imaging. The in vivo MR imaging of nude mice demonstrated that the MR signal intensity enhancement of HepG2 tumor in Fe 3 O 4 -PEG-RGD NPs treated mice was significantly higher than in mice treated with non-targeted Fe 3 O 4 -mPEG NPs at the same post-administration time point. Conclusion The results indicate that the Fe 3 O 4 -PEG-RGD particles have potential utility as T1 positive contrast agent in targeted MR imaging.

Gamma-glutamyl transpeptidase-to-platelet ratio (GPR) and fibrosis-4 (FIB-4) index have been reported to be useful predictors in predicting hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) patients. However, their predictive performances on HCC development have not been validated in elderly patients. Thus, the aim of this study was to evaluate the predictive values of the GPR and FIB-4 index on HCC in elderly CHB patients with in China.Between January 2007 and December 2016, 1011 CHB patients older than 60 years were enrolled in the study, and their data were retrospectively analyzed. Receiver-operating characteristic (ROC) curve analysis was used to determine the optimal cutoff points of GPR and the FIB-4 index. Cumulative HCC incidence rates were calculated by the Kaplan-Meier method and compared by the log-rank test. Univariate and multivariate analyses were performed to detect risk factors for HCC development. The prediction performances of GPR and FIB-4 index were compared based on time-dependent ROC analyses.After a median follow-up of 6.8 (interquartile range 3.9-8.4) years, 39 (3.9%) patients developed HCC. The ROC analysis of GPR and the FIB-4 index at the 5-year time point revealed that the optimal cutoff point was 0.23 for GPR and 4.15 for the FIB-4 index. When stratified by low and high GPR values and FIB-4 indices, the patients' subgroups showed significantly different cumulative incidences of HCC. The multivariate analysis revealed that high GPR (hazard ratio [HR] 4.224; 95% confidence interval [CI] 1.891-9.434, P < .001) was an independent risk factor for HCC development, whereas a high FIB-4 index was not (HR 0.470; 95% CI 0.212-1.043; P = .063). In the time-dependent ROC analysis, GPR showed higher area under curve (AUC) values than the FIB-4 index did at all time points and reached statistical significance at the 5-, 7-, and 10-year time points (GPR vs FIB-4 index, AUC 0.725 vs 0.549 at 5 years, P = .005; GPR vs FIB-4 index, AUC 0.733 vs 0.578 at 7 years, P = .001; GPR vs FIB-4 index, AUC 0.837 vs 0.475 at 10 years, P < .001).In conclusion, our study suggests GPR is superior to the FIB-4 index in predicting HCC development in elderly CHB patients in China.

Purpose: To evaluate the feasibility of diffusion-weighted imaging (DWI) in magnetic resonance imaging for quantitative measurement of responses following irreversible electroporation (IRE) in a rabbit liver tumor model., Materials and Methods: Twelve rabbits underwent ultrasound-guided VX2 tumor implantation in the left medial and left lateral liver lobes. The tumors in the left medial lobe were treated with IRE, whereas those in the left lateral lobe served as internal controls. DWI was performed before and immediately after IRE. Tumors were then harvested for histopathologic staining. The apparent diffusion coefficient (ADC) and change in ADC (ΔADC) were calculated based on DWI. Tumor apoptosis index (AI) was assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling. These measurements from DWI and histopathology were compared between untreated and treated tumors., Results: The ADC values, ΔADC, and AI showed statistically significant differences between treated and untreated tumors (P < .05 for all). ADC values were higher in treated tumors than in untreated tumors (1.08 × 10 -3 mm 2 /s ± 0.15 vs 0.88 × 10 -3 mm 2 /s ± 0.19; P = .042)., Conclusions: DWI can be used to quantitatively evaluate treatment response in liver tumors immediately after IRE., (Published by Elsevier Inc.)

Objective: To evaluate the dependability and accuracy of midkine (MK) in the diagnosis of hepatocellular carcinoma (HCC)., Methods: PubMed, EMBASE, Web of Science, China Biology Medicine disc and grey literature sources were searched from the date of database inception to January 2019. Two authors (B-H.Z. and B.L.) independently extracted the data and evaluated the study quality using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The sensitivity, specificity, positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were estimated using a bivariate model. Moreover, hierarchical summary receiver operating characteristic curves were generated. The diagnostic odds ratio (DOR) and area under the curve (AUC) were pooled using a univariate model., Results: Nine articles (11 studies) were included (1941 participants). The bivariate analysis revealed that the sensitivity and specificity of MK for HCC diagnosis were 0.85 (95% CI 0.78-0.91) and 0.83 (95% CI 0.76-0.88), respectively. We also found a LR+ of 5.05 (95% CI 3.33-7.40), a LR- of 0.18 (95% CI 0.11-0.28), a DOR of 31.74 (95% CI 13.98-72.09) and an AUC of 0.91 (95% CI 0.84-0.99). Subgroup analyses showed that MK provided the best efficiency for HCC diagnosis when the cutoff value was greater than 0.5 ng/mL., Conclusions: MK has an excellent diagnostic value for hepatocellular carcinoma., Competing Interests: The authors have declared that no competing interests exist.

Diol-type ginsenosides, such as protopanaxadiol (PPD), exhibit antioxidation, anti-inflammation, and antitumor effects. However, the antitumor effect of these ginsenosides and the mechanism of PPD remain unclear. In this work, the antitumor effects of several derivatives, including PPD, Rg5, Rg3, Rh2, and Rh3, were evaluated in five different cancer cell lines. PPD demonstrated the best inhibitory effects on the proliferation and migration of the five cancer cell lines, especially the hepatocellular carcinoma (HCC) cell lines. Therefore, the mechanism of action of PPD in HCC cells was elucidated. PPD inhibited the proliferation, migration, and invasion ability of HepG2 and PLC/PRF/5 cells in a dose-dependent manner. Western blot and immunofluorescence assay showed that PPD can alter the expression of epithelial-mesenchymal transition markers, increase E-cadherin expression, and decrease vimentin expression. Docking and biacore experiments revealed that STAT3 is the target protein of PPD, which formed hydrogen bonds with Gly583/Leu608/Tyr674 at the SH2 domain of STAT3. PPD inhibited the phosphorylation of STAT3 and its translocation from the cytosol to the nucleus, thereby inhibiting the expression of Twist1. PPD also inhibited tumor volume and tumor lung metastasis in PLC/PRF/5 xenograft model. In conclusion, PPD can inhibit the proliferation and metastasis of HCC cells through the STAT3/Twist1 pathway.

Background: The aim of this study was to compare radiofrequency ablation (RFA) with minimally invasive liver surgery (MIS) in the treatment of small hepatocellular carcinoma (SHCC) and to assess short-term and long-term clinical outcomes., Methods: PubMed, Embase, Cochrane Library, Web of science, and CBM were systematically searched for articles from inception to July 2018, comparing RFA and MIS in SHCC treatment. We evaluated overall survival (OS), disease-free survival (DFS), local recurrence, and complication rates, as well as hospitalization duration and operation times., Results: Six retrospective studies were analyzed, including a total of 597 patients, 313 treated with RFA and 284 treated with MIS. OS rates were significantly higher in patients treated with MIS at 3 years, when compared to RFA (OR 0.55; 95% CI 0.36 to 0.84). The 3-year DFS MIS rates were also superior to RFA (OR 0.63; 95% CI 0.41 to 0.98). In contrast, when compared to MIS, RFA demonstrated a significantly higher rate of local intrahepatic recurrences, (OR 2.24; 95% CI 1.47 to 3.42), and a lower incidence of postoperative complications (OR 0.34; 95% CI 0.22 to 0.53), as well as shorter operation times (OR - 145.31, 95% CI - 200.24 to - 90.38) and hospitalization duration (OR - 4.02,95% CI - 4.94 to - 3.10)., Conclusions: We found that MIS led to higher OS, DFS, and lower local recurrences in SHCC patients. Meanwhile, RFA treatments led to significantly lower complication rates, shorter operation times, and hospitalization duration. Considering long-term outcomes, MIS was found to be superior to RFA. However, RFA may be an alternative treatment for patients presenting a single SHCC nodule (≤ 3 cm), given its minimally invasive nature and its comparable long-term efficacy with MIS. Nevertheless, our findings should be explained with caution due to the low level of evidence obtained.

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.)

Posthepatectomy liver failure (PHLF) is the most leading cause of mortality following hepatectomy in patients with hepatocellular carcinoma (HCC). Platelet count was reported to be a simple but useful indicator of liver cirrhosis and function of spleen. Spleen stiffness (SS) was used to evaluate the morphological change of spleen and was reported to be related to liver cirrhosis and portal hypertension. However, the predictive value of platelet to spleen stiffness ratio (PSR) on PHLF remains unknown. A retrospective study was performed to analyze 158 patients with HCC following hepatectomy from August 2015 to February 2016. Univariate and multivariate analyses were performed to evaluate the value of each risk factor for predicting PHLF. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve. PHLF occured in 23 (14.6%) patients. PSR (P<0.001, odds ratio (OR) = 0.622, 95% confidence interval (CI) 0.493~0.784), hepatic inflow occlusion (HIO) (P = 0.003, OR = 1.044, 95% CI 1.015~1.075) and major hepatectomy (P = 0.019, OR = 5.967, 95% CI 1.346~26.443) were demonstrated to be the independent predictive factors for development of PHLF in a multivariate analysis. Results of the present study suggested PSR is a novel and non-invasive model for predicting PHLF in patients with HCC., Competing Interests: The authors have declared that no competing interests exist.

Aim: To investigate the impact of circadian rhythms on the outcomes of liver transplantation on patients suffering from hepatocellular carcinoma (HCC)., Methods: We retrospectively reviewed data of patients who underwent liver transplantation from 2012 to 2017 in our center. Based on the begin time of transplantation, these patients were separated into 2 groups: day group and night group. The intraoperative and postoperative clinical variables were analyzed to find out the impact of the circadian rhythms. Multivariate analysis was performed to examine strength associations between the begin time of operation and surgical outcomes., Results: A total of 147 patients were included in this study: 102 patients in the day group and 45 patients in the night group. Compared with the day group, patients in the night group had higher incidence of intraoperative massive hemorrhage (11.1% vs 2.0%, P = .048), more intraoperative blood loss (2168.00 ± 2324.20 mL vs 1405.88 ± 1037.69 mL, P = .040), and more requirement of red blood cells (RBC) suspension (8.59 ± 7.11 u vs 6.37 ± 5.78 u, P = .048). In addition, total operation time in the night group was longer than that in the day group (8.90 ± 1.65 hours vs 8.26 ± 1.69 hours, P = .034), as well as the cold ischemia time (9.35 ± 5.03 hours vs 7.21 ± 3.93 hours, P = .014). Furthermore, the night group had higher incidence of other intraoperative complications (13.3% vs 2.9%, P = .038), postoperative abdominal infection (20.0% vs 6.9%, P = .038), and more hospital cost (37,357.96 ± 6779.96 dollars vs 33,551.75 ± 11,683.38 dollars, P = .045). Moreover, patients in the night group needed longer time to restore hepatic function to normal (21.77 ± 10.91 days vs 17.54 ± 10.80 days, P = .033). Multivariate analysis showed that begin time of operation was the independent risk factor of longer operation time, more blood loss during operation, higher incidence of massive hemorrhage and other intraoperative complications, longer time for restoration of hepatic function to normal, higher incidence of abdominal infection at the early stage after transplantation, and more hospital cost (all P value ≤ .05)., Conclusion: Liver transplantation performed at night was associated with higher incidence of intraoperative and early postoperative complications, as well as higher hospital cost. And these worsened outcomes all could be explained by the influence that circadian rhythms had on patients or medical workers., (Copyright © 2019. Published by Elsevier Inc.)

Posthepatectomy liver failure (PHLF) is the main cause of perioperative death, and liver cirrhosis is one of the most important risk factors for PHLF. Spleen stiffness (SS) is a novel ultrasonic indicator for liver cirrhosis and portal hypertension, however, it is not clear that whether it has a significant influence on PHLF. Future remnant liver volume (FRLV) is a significant factor for liver regeneration after hepatectomy, spleen volume (SV) could also predict the degree of liver cirrhosis, and recent literatures reported that SV to FRLV ratio (SV/FRLV) could predict small for size syndrome (SFSS) in liver transplantation, however, the relationship between SV/FRLV and PHLF in patients receiving hepatectomy is not known. Systemic inflammatory response (SIR) plays a significant role in the pathogenesis and progression of liver cirrhosis, however, it is not very clear about the exact relationship between SIR and PHLF.We prospectively collected the medical data of consecutive patients diagnosed with hepatocellular carcinoma (HCC) who underwent hepatectomy from August 2015 to February 2016. Preoperative measurements of SS, liver stiffness (LS), SV, FRLV, and SIR were performed on all patients. A univariate analysis was performed to find the risk factors of PHLF and a multivariate analysis was used to identify independent risk factors. The predictive efficiency of the risk factors was evaluated by receiver operating characteristic (ROC) curve.Twenty three (23) (14.6%) patients developed PHLF. Univariate analysis found several variables significantly related to PHLF, they were as follows: tumor diameter (P = .01), cirrhosis (P = .001), neutrophil to lymphocyte ratio (NLR) (P = .018), LS (P = .001), SS (P = .001), SV/FRLV (P < .001), operation duration (P = .003), transfusion (P = .009), hepatic inflow occlusion (HIO) (P = .001). Finally, SV/FRLV (P < .001, hazard ratio (HR) = 26.356, 95% confidence interval (CI) 1.627-425.21), SS (P = .009, HR = 1.077, 95%CI 1.017-1.141), and HIO time (P = .002, HR = 1.043, 95%CI 1.014-1.072) were determined as the independent risk factors of PHLF by multivariate analysis.SS and SV/FRLV help to predict the development of PHLF in patients with hepatocellular carcinoma.

Liver cancer stem cells (CSCs) have important functions in tumorigenesis, progression, recurrence and drug resistance of hepatocellular carcinoma (HCC). lncARSR has been reported to play an important role in the maintenance and self-renewal of renal cancer stem cells, but its role in liver cancer stem cells (CSCs) remains obscure. Herein, we observed high expression of lncARSR in chemoresistant hepatocellular carcinomas (HCCs). A remarkable increase of lncARSR expression in EpCAM or CD133-positive liver CSCs as well as in CSC-enriched hepatoma spheres. Interference lncARSR suppressed liver CSC expansion by inhibiting the dedifferentiation of hepatoma cells and decreasing the self-renewal ability of liver CSCs. Mechanistically, we found STAT3 as the downstream of lncARSR in HCC cells. The special STAT3 inhibitor S3I-201 abolished the discrepancy in liver CSC proportion and the self-renewal capacity between lncARSR knockdown hepatoma cells and control cells, which further confirmed that STAT3 was required in lncARSR promoted liver CSCs expansion. More importantly, interference lncARSR HCC cells were more sensitive to sorafenib or cisplatin treatment. This maybe means that patients with low lncARSR levels benefited from cisplatin or sorafenib treatment, but patients with high lncARSR expression did not. Conclusion: lncARSR was upregulated in liver CSCs and could promote HCC cells dedifferentiation and liver CSCs expansion by targeting STAT3 signaling., (Copyright © 2018. Published by Elsevier B.V.)

There is little information regarding the predictive ability of albumin-bilirubin grades (ALBI) plus platelet-to-lymphocyte ratio (PLR) in patients with hepatocellular carcinoma (HCC) following liver resection. In this study, we aimed to evaluate the prognostic power of the ALBI-PLR score in patients with hepatitis B virus-related (HBV-related) HCC within Barcelona Clinic Liver Cancer (BCLC) stage A after liver resection.Around 475 patients were included in this study. Patients with preoperative ALBI grades 1, 2, or 3 were allocated a score of 0, 1, or 2, respectively. Patients with preoperative PLR >150 or ≤150 were allocated a score of 0 or 1, respectively. The ALBI-PLR score was the summary of the ALBI and PLR scores.During the follow-up period, 256 patients experienced recurrence, and 150 patients died. Multivariate analysis revealed tumor size, multiple tumors, positive HBV-DNA load, cirrhosis, and ALBI-PLR score as being independently associated with postoperative recurrence, whereas tumor size, high preoperative α-fetoprotein level, and ALBI-PLR score were independent risk factors for postoperative mortality. HCC patients with high ALBI-PLR score had poor recurrence-free and overall survival.The preoperative ALBI-PLR score is a surrogate marker for predicting HBV-related HCC patient's prognosis after liver resection. A high ALBI-PLR score is associated with a high incidence of postoperative recurrence and mortality.

Objective: To assess the value of hepatic resection by comparing it with transarterial chemoembolization for hepatocellular carcinoma beyond the Milan criteria with clinically relevant portal hypertension., Methods: A total of 363 patients and 193 propensity score-matched patients who had hepatocellular carcinoma beyond the Milan criteria with clinically relevant portal hypertension and underwent hepatic resection or transarterial chemoembolization were retrospectively analyzed. The short-term and long-term results were compared., Results: Postoperative complications and 30-day mortality were similar between the two groups. The hepatic resection provided a survival benefit over TACE at 1, 2, 3, and 5 years. Similar results were observed in the propensity score analysis. Five variables were identified as independent prognostic factors: treatment, AFP, Child-Pugh classification, tumor number and extension of disease in a multivariate analysis of the whole study population. In addition, only the tumor number was identified as an independent risk factor after propensity matching. The subgroup analysis demonstrated that the survival benefit of the hepatic resection can only be derived in a subset of patients with a single tumor., Conclusions: In a properly selected group of patients with hepatocellular carcinoma beyond the Milan criteria with clinically relevant portal hypertension, hepatic resection appears to be as safe as TACE and provides a significant survival benefit., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Objective: Albumin-bilirubin (ALBI) grade has been validated as a simple, evidence-based, and objective prognostic tool for patients with hepatocellular carcinoma (HCC). However, minimal information is available concerning postoperative ALBI grade changes in HCC. This study aimed to investigate the prognostic value of postoperative ALBI grade changes in patients with hepatitis B virus (HBV)-related HCC within the Milan criteria after liver resection., Methods: Patients with HBV-related HCC within the Milan criteria who underwent liver resection between 2010 and 2016 at West China Hospital were reviewed (N = 258). A change in ALBI grade was defined as first postoperative month ALBI grade-preoperative ALBI grade. If the value was >0, postoperative worsening of ALBI grade was considered; otherwise, stable ALBI grade was considered. Cox proportional hazard regression analyses were used to determine the factors that influence recurrence and survival., Results: During the follow-up, 130 patients experienced recurrence and 47 patients died. Multivariate analyses revealed that postoperative worsening of ALBI grade (HR 1.541, 95% CI 1.025-2.318, P = 0.038), microvascular invasion (MVI, HR 1.802, 95% CI 1.205-2.695, P = 0.004), and multiple tumors (HR 1.676, 95% CI 1.075-2.615, P = 0.023) were associated with postoperative recurrence, whereas MVI (HR 2.737, 95% CI 1.475-5.080, P = 0.001), postoperative worsening of ALBI grade (HR 2.268, 95% CI 1.227-4.189, P = 0.009), high alpha-fetoprotein level (HR 2.055, 95% CI 1.136-3.716, P = 0.017), and transfusion (HR 2.597, 95% CI 1.395-4.834, P = 0.003) negatively influenced long-term survival. Patients with postoperative worsening of ALBI grade exhibited increased incidence of recurrence and worse long-term survival., Conclusion: Postoperative worsening of ALBI grade was associated with increased recurrence and poorer overall survival for patients with HBV-related HCC within the Milan criteria. We should pay attention to liver function changes in HCC patients after liver resection.

Background: There is little information concerning futile liver resection for patients with Barcelona Clinic Liver Cancer (BCLC) stage B/C hepatocellular carcinoma (HCC). This study aimed to establish a predictive model of futile liver resection for patients with BCLC stage B/C HCC., Methods: The outcomes of 484 patients with BCLC stage B/C HCC who underwent liver resection at our centre between 2010 and 2016 were reviewed. Patients were randomised and divided 2:1 into training and validation sets. A novel risk-scoring model and prognostic nomogram were developed based on the results of multivariate analysis., Results: Fifty-seven futile operations were observed. Multivariate analyses revealed tumour numbers > 3, Vp4 portal vein tumour thrombosis (PVTT) and alpha-fetoprotein (AFP) > 400 ng/ml independently associated with futile liver resection. A risk-scoring model based on the above-mentioned factors was developed (predictive risk score = 1 × (if AFP > 400 ng/ml) + 2 × (if tumour number > 3) + 3 × (if with Vp4 PVTT)). The area under the receiver-operating characteristic curve of this model was 0.845, with a sensitivity of 60.0% and a specificity of 94.8%. A prognostic nomogram was also developed and achieved a C-index of 0.831. The validation studies optically supported these results., Conclusion: A risk-scoring model and predictive nomogram for futile liver resection were developed in the present study. T`he BCLC stage B/C HCC patients with a high risk obtained no benefit from liver resection.

The neutrophil-to-lymphocyte ratio (NLR) reflects the systematic inflammatory status, and the aspartate aminotransferase-to-alanine aminotransferase ratio (AAR) is a biomarker of liver fibrosis and cirrhosis. These values can be conveniently obtained from routine blood tests; however, their combined clinical utility has not been extensively studied in patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). This study aimed to investigate the prognostic value of NLR-AAR in patients with unresectable HCC undergoing TACE. Data for 760 patients with newly diagnosed HCC were retrospectively evaluated. The NLR-AAR was calculated as follows: patients in whom both the NLR and AAR were elevated according to the receiver operating characteristic (ROC) curve analysis were assigned a score of 2; patients showing an elevation in one or neither of these indicators were assigned a score of 1 or 0, respectively. Univariate and multivariate analyses were performed to identify the clinicopathological variables associated with overall survival. An ROC curve was also generated and the area under the curve (AUC) was calculated to evaluate the discriminatory ability of each index at 1, 3, and 5 years of follow-up, as well as overall. The NLR-AAR consistently had a greater AUC value at 1 year (0.669), 3 years (0.667), and 5 years (0.671) post-TACE compared with either NLR or AAR alone. The median survival times of patients with a NLR-AAR of 0, 1, and 2 were 31.0 (95% confidence interval [CI] 24.0-38.0), 15.0 (95% CI 11.2-18.8), and 5.0 (95% CI 4.0-5.9) months, respectively (P < .001). Multivariate analysis showed that the NLR-AAR, elevated total bilirubin level, and vascular invasion were independently associated with overall survival. NLR and AAR, when combined to produce an inflammation-based index and fibrosis score, is an independent marker of poor prognosis in patients with HCC receiving TACE.

For many malignancies, inflammation-based scores correlate with survival. The neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) are immunonutritional indices associated with postoperative outcomes in patients with hepatocellular carcinoma (HCC). We evaluated whether a combined preoperative NLR and PNI score was prognostically superior to either index alone in 793 patients with unresectable HCC after transarterial chemoembolization. Patient demographic, clinical, and pathological data were also collected and analysed. A receiver-operating characteristic (ROC) analysis was used to classify patients as follows: NLR-PNI 0 group (NLR ≤ 2.2 and PNI > 46), NLR-PNI 1 group (NLR > 2.2 or PNI ≤ 46) and NLR-PNI 2 group (NLR > 2.2 and PNI ≤ 46). Regarding 1-, 3-, and 5-year survival, the NLR-PNI score had superior discriminative abilities (i.e., higher area under the ROC curve), compared with either the NLR or PNI alone, and patients in the NLR-PNI 0, 1, and 2 groups had median survival times of 33 (95% confidence interval: 22.8-43.2), 14 (10.9-17.1), and 6 (9.9-14.1) months, respectively. In multivariate analyses, the Barcelona Clinic Liver Cancer, total bilirubin, vascular invasion, and NLR-PNI score adversely affected overall survival. In conclusion, the NLR-PNI score can improve the accuracy of prognoses for patients with unresectable HCC.

Recent studies have shown that radiofrequency (RF) ablation therapy is a safe, feasible, and effective procedure for hepatic hemangiomas, even huge hepatic hemangiomas. RF ablation has the following advantages in the treatment of hepatic hemangiomas: minimal invasiveness, definite efficacy, high safety, fast recovery, relatively simple operation, and wide applicability. It is necessary to formulate a widely accepted consensus among the experts in China who have extensive expertise and experience in the treatment of hepatic hemangiomas using RF ablation, which is important to standardize the application of RF ablation for the management of hepatic hemangiomas, regarding the selection of patients with suitable indications to receive RF ablation treatment, the technical details of the techniques, therapeutic effect evaluations, management of complications, etc . A final consensus by a Chinese panel of experts who have the expertise of using RF ablation to treat hepatic hemangiomas was reached by means of literature review, comprehensive discussion, and draft approval., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare.

Platelet, neutrophil, and lymphocyte ratio (PNLR) has its own unique role in influencing postoperative recurrence for patients with hepatocellular carcinoma (HCC). Surgical stress can change systemic inflammatory response of patients. Thus the aim of this study was to identify the prognostic value of changes of platelet times neutrophil to lymphocyte ratio in hepatitis B related HCC within Barcelona clinical liver cancer (BCLC) stage A.Data of patients with HCC within BCLC stage A were reviewed. Pre-, intra- and postoperative variables were retrospectively and statistically analyzed. The postoperative variable was calculated based on the data obtained on the first postoperative month following liver resection.A total of 556 patients were included in present study. During the follow-up period, 257 patients experienced recurrence and 150 patients died. Multivariate analyses suggested multiple tumors (hazard ratio [HR] = 2.409; 95% confidence interval [CI] = 1.649-3.518; P < .001), microvascular invasion (MVI) (HR = 1.585; 95% CI = 1.219-2.061; P = .001), and increased postoperative PNLR (HR = 1.900; 95% CI = 1.468-2.457; P < .001) independently associated with postoperative recurrence, whereas MVI (HR = 1.834; 95% CI = 1.324-2.542; P < .001), postoperative neutrophil to lymphocyte ratio (NLR) (HR = 1.151; 95% CI = 1.025-1.294; P = .018) and increased postoperative PNLR (HR = 2.433; 95% CI = 1.667-3.550; P < .001) contributed to postoperative mortality. The 5-year recurrence-free survival and overall survival rates of patients with increased postoperative PNLR (N = 285) versus those with decreased postoperative PNLR (N = 271) were 36.8% versus 61.5% and 47.6% versus 76.4% respectively (P < .001).Changes of PNLR was a powerful prognostic indicator of poor outcomes in patients with HCC within BCLC stage A. PNLR should be monitored in our postoperative follow-up.

Background: Increasing studies have suggested that surgical resection (SR) or liver transplantation (LT) could bring survival benefits for patients with hepacelluar carcinoma (HCC) beyond Milan criteria. This study compared the long-term survival of patients beyond the Milan criteria who received SR or LT., Material and Methods: A total of 461 HCC patients were retrospectively collected. Analysis was performed using propensity score matching (PSM), the Kaplan-Meier method and the Cox proportional hazards model., Results: Prognosis was significantly better for the LT group than the SR group before (P < 0.001) and after PSM(p = 0.003). In subgroup analysis, for patients with lower AFP level, the 1-, 3-, and 5-year OS rates for the two groups were significantly different (86.7, 71.9, and 71.9% for group LT vs. 75.8, 48.1, and 10.7% for group SR, P = 0.003). For patients with smaller tumor size, the 1-, 3-, and 5-year OS rates were 78.3, 66.7, and 66.7% for group LT, and 83.8, 42.6, and 18.6% for group SR, p = 0.009). Transplantation was a favorable factor associated with prognosis before and after propensity score matching (HR 2.643)., Conclusion: Our propensity model suggested that LT provided significantly better long-term survival than SR for HCC beyond Milan criteria before and after PSM., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Assessing the outcomes of surgeries for hepatocellular carcinoma (HCC) patients who exceed the Milan criteria is necessary. Some studies have demonstrated that preoperative or postoperative alpha fetoprotein (AFP) can predict HCC patients' prognoses., Methods: A total of 280 HCC patients who were positive for AFP and received curative resection were retrospectively analyzed. The patients were classified into three groups according to their preoperative and postoperative AFP levels (group A: normalized AFP; group B: AFP decreases >50%, but continued abnormality; and group C: AFP decreases <50%). Disease-free survival and overall survival rates were analyzed using the Kaplan-Meier method. The factors associated with AFP changes were evaluated by logistic regression., Results: AFP dynamic changes were independently associated with disease-free survival and overall survival rates. Group A had better 3- and 5-y survivals than groups B or C (58.7% and 39.5% versus 31.3% and 14.9% versus 17.1% and 8.8%, P < 0.001). Preoperative AFP, tumor differentiation, tumor diameter, microvascular invasion, and satellite nodules remained significant risk factors that were associated with AFP changes. Furthermore, in group A, the disappearances of AFP within and beyond 8 wk resulted in similar overall survival rates (P > 0.05). Among those with HCC recurrence, the patients treated with resurgery or radiofrequency ablation achieved the best recurrence to death survivals. Those treated with transcatheter arterial chemoembolization achieved the next best survivals., Conclusions: AFP changes predicted the prognoses of patients with HCC beyond the predictions of the Milan criteria. Preoperative AFP (>400 ng/mL), tumor differentiation, tumor diameter, and satellite nodules were the risk factors related to AFP normalization. The regular follow-up and early detection of recurrent HCCs that are suitable for curative therapies, such as resurgery and radiofrequency ablation, might improve the prognoses. Other therapies, such as transcatheter arterial chemoembolization, might also be effective., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The recurrence of patients with hepatocellular carcinoma (HCC) beyond the Milan criteria after liver resection (LR) is common. This study aimed to clarify whether LR plus postoperative adjuvant transcatheter arterial chemoembolization (TACE) could improve the outcomes of patients with HCC beyond the Milan criteria after LR., Methods: A total of 754 consecutive patients with HCC beyond the Milan criteria who received LR alone (n = 459) or LR + TACE (n = 295) were included. A propensity scoring matched model (PSM) was used to adjust for the baseline differences between the groups., Results: The 1, 3, and 5-y recurrence-free survival (76.7%, 40.4%, and 30.8%, respectively, for the LR-alone group versus 78.3%, 50.5%, and 46.2%, respectively, for the LR + TACE group; P = 0.004) and overall survival (94.1%, 58.3%, and 36.3%, respectively, for the LR-alone group versus 95.3%, 71.3%, and 54.9%, respectively, for the LR + TACE group; P < 0.001) rates of patients who underwent LR alone were much lower than in the LR + TACE group. Multivariate Cox proportional hazards regression analysis showed that LR alone was an independent risk factor for postoperative recurrence and poor long-term survival. After one-to-one PSM, 284 patients who underwent LR alone and 284 patients who underwent LR + TACE were selected for further analyses. Similar results were observed in the PSM model., Conclusions: This study showed that LR + TACE may be beneficial for patients with HCC beyond the Milan criteria. Postoperative adjuvant TACE should be considered to patients with HCC beyond the Milan criteria., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Little is known about the prognostic impact of cirrhosis on long-term survival of patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC) after hepatic resection. The aim of this study was to elucidate the long-term outcome of hepatectomy in cHCC-CC patients with cirrhosis., Methods: A total of 144 patients who underwent curative hepatectomy for cHCC-CC were divided into two groups: cirrhotic group (n = 91) and noncirrhotic group (n = 53). Long-term postoperative outcomes were compared between the two groups., Results: Patients with cirrhosis had worse preoperative liver function, higher frequency of HBV infection, and smaller tumor size in comparison to those without cirrhosis. The 5-year overall survival rate in cirrhotic group was significantly lower than that in non-cirrhotic group (34.5% versus 54.1%, P = 0.032). The cancer recurrence-related death rate was similar between the two groups (46.2% versus 39.6%, P = 0.446), while the hepatic insufficiency-related death rate was higher in cirrhotic group (12.1% versus 1.9%, P = 0.033). Multivariate analysis indicated that cirrhosis was an independent prognostic factor of poor overall survival (hazard ratio 2.072, 95% confidence interval 1.041-4.123; P = 0.038)., Conclusions: The presence of cirrhosis is significantly associated with poor prognosis in cHCC-CC patietns after surgical resection, possibly due to decreased liver function.

The optimal treatment (liver transplantation [LT] vs surgical resection [SR]) for early-stage hepatocellular carcinoma (HCC) remains controversial.A total of 209 SR patients and 129 LT patients were identified at our institution. After eliminating 27 patients with Child-Pugh C, the data from 209 SR patients and 102 LT patients were analyzed using a propensity score matching (PSM) model. Forty-six pairs were generated. A subgroup analysis was conducted based on the alpha-fetoprotein (AFP) level or platelet count (PLT). A survival analysis was performed using the Kaplan-Meier method.Gender, satellite lesions, and the treatment method were predictors of HCC recurrence. The Ishak score and treatment methods were associated with long-term survival after surgery. Before PSM, LT patients had a better prognosis than those treated by SR. Among HCC patients with childhood A/B cirrhosis, after PSM, SR achieved similar overall survival outcomes compared with LT. LT and SR resulted in comparable long-term survival for patients with or without thrombocytopenia. Patients with an AFP ≥ 400 ng/mL might achieve more survival benefits from LT.Our propensity score model provided evidence that, compared with transplantation, surgical resection could result in comparable long-term survival for resectable early-stage HCC patients, except for the AFP ≥ 400 ng/mL HCC subgroup. Surgical resection might not be a contraindication for early-stage HCC patients with thrombocytopenia due to their similar prognosis after transplantation., Competing Interests: The authors have no conflicts of interest to disclose.

Bortezomib (BTZ), a proteasome inhibitor, is the first proteasome inhibitor to be used in clinical practice. Here we investigated the mechanisms underlying acquired bortezomib resistance in hepatocellular carcinoma (HCC) cells. Using stepwise selection, we established two acquired bortezomib-resistant HCC cell lines, a bortezomib-resistant HepG2 cell line (HepG2/BTZ) and bortezomib-resistant HuH7 cell line (HuH7/BTZ). The 50% inhibitory concentration values of HepG2/BTZ and HuH7/BTZ were respectively 15- and 39-fold higher than those of parental cell lines. Sequence analysis of the bortezomib-binding pocket in the β5-subunit showed no mutation. However, bortezomib-resistant HCC cells had increased expression of β1 and β5 proteasome subunits. These alterations of proteasome expression were accompanied by a weak degree of proteasome inhibition in bortezomib-resistant cells than that in wild-type cells after bortezomib exposure. Furthermore, bortezomib-resistant HCC cells acquired resistance to apoptosis. Bortezomib up-regulated pro-apoptotic proteins of the Bcl-2 protein family, Bax and Noxa in wild-type HCC cells. However, in bortezomib-resistant HCC cells, resistance to apoptosis was accompanied by loss of the ability to stabilize and accumulate these proteins. Thus, increased expression and increased activity of proteasomes constitute an adaptive and auto regulatory feedback mechanism to allow cells to survive exposure bortezomib.

Long noncoding RNAs (lncRNAs) have been reported to play pivotal roles in a variety of cancers. However, lncRNAs involved in hepatocellular carcinoma (HCC) initiation and progression remain largely unclear. In this study, we identified an lncRNA gradually increased during hepatocarcinogenesis (lncRNA-GIHCG) using publicly available microarray data. Our results further revealed that GIHCG is upregulated in HCC tissues in comparison with adjacent non-tumor tissues. High GIHCG expression is correlated with large tumor size, microvascular invasion, advanced BCLC stage, and poor survival of HCC patients. Functional experiments showed that GIHCG promotes HCC cells proliferation, migration, and invasion in vitro, and promotes xenografts growth and metastasis in vivo. Mechanistically, we demonstrated that GIHCG physically associates with EZH2 and the promoter of miR-200b/a/429, recruits EZH2 and DNMT1 to the miR-200b/a/429 promoter regions, upregulates histone H3K27 trimethylation and DNA methylation levels on the miR-200b/a/429 promoter, and dramatically silences miR-200b/a/429 expression. Furthermore, the biological functions of GIHCG on HCC are dependent on the silencing of miR-200b/a/429. Collectively, our results demonstrated the roles and functional mechanisms of GIHCG in HCC, and indicated GIHCG may act as a prognostic biomarker and potential therapeutic target for HCC. KEY MESSAGE: lncRNA-GIHCG is upregulated in HCC and associated with poor survival of patients. GIHCG significantly promotes tumor growth and metastasis of HCC. GIHCG physically associates with EZH2. GIHCG upregulates H3K27me3 and DNA methylation levels on the miR-200b/a/429 promoter. GIHCG epigenetically silences miR-200b/a/429 expression.

Background: Combined hepatectomy and radiofrequency ablation (RFA) provides an additional treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) who are conventionally deemed unresectable. This study aimed to analyze the outcome of this combination therapy by comparing it with transarterial chemoembolization (TACE)., Methods: We retrospectively reviewed 51 patients with unresectable BCLC stage B HCC who had received the combination therapy. We compared the survival of these patients with that of 102 patients in the TACE group (control). Prognostic factors associated with worse survival in the combination group were analyzed., Results: No differences in tumor status and liver function were observed between the TACE group and combination group. The median survival time for the combination group and TACE group was 38 (6-54) and 17 (3-48) months, respectively (P<0.001). The combination group required longer hospitalization than the TACE group [8 (5-14) days vs 4 (2-9) days, P<0.001]. More than two ablations decreased the survival rate in the combination group., Conclusions: Combined hepatectomy and RFA yielded a better long-term outcome than TACE in patients with unresectable BCLC stage B HCC. Patients with a limited ablated size (≤2 cm), a limited number of ablations (≤2), and adequate surgical margin should be considered candidates for combination therapy.

Solitary large hepatocellular carcinomas (SLHCC) form a heterogeneous group of patients with different survival probabilities. The aim of our study was to develop a simple prognostic index for identifying prognostic subgroups of SLHCC patients.A retrospective analysis of clinical data from 268 patients with operable SLHCC was conducted to investigate prognostic factors and to construct a score system based on risk factors. A Cox proportional hazard regression analysis was used to evaluate the variables associated with prognosis. Survival analyses were performed using Kaplan-Meier survival curves.Three variables remained in the final multivariate model: platelet to lymphocyte ratio (PLR), microvascular invasion (MVI), and tumor size with hazard ratios equal to 1.004 (95% confidence interval: 1.001-1.006), 1.092 (1.044-1.142), and 2.233 (1.125-2.233), respectively. A score of 1 was assigned to each risk factor. Patient scores were determined based on these risk factors; thus, the scores ranged between 0 and 3. Ultimately, three categories (0, 1-2, 3) were defined. Patients with scores of 3 had a 5-year survival rate of 25.4%, whereas patients with a score of 0 had a 5-year survival rate of 52.1%. The prognosis significantly worsened as the score increased. Similar results were found among cirrhotic and noncirrhotic patients.Our simple prognostic index successfully predicts SLHCC survival.

An elevated preoperative aspartate aminotransferase (AST) to platelet ratio index (APRI) is reported to be a prognostic factor for patients with hepatocellular carcinoma (HCC) after treatment. However, delta APRI (ΔAPRI), which represents the change from preoperative to postoperative APRI, has received little attention. The present study was designed to evaluate the prognostic value of ΔAPRI in patients with small HCC after liver resection.A retrospective cohort study analyzing 244 patients with small HCC who had undergone liver resection was conducted. Medical data were retrieved from our prospectively maintained database. Patients were divided into 2 groups according to ΔAPRI as follows: group A (ΔAPRI ≥0.02) and group B (ΔAPRI <0.02). The association of demographic and clinical data, overall survival (OS), and recurrence-free survival (RFS) were statistically compared in the 2 groups, and a multivariate analysis was used to identify prognostic factors.The 1, 3, and 5-year OS of patients in group A were 94.2%, 79.5%, and 62.3%, respectively, and 95.1%, 87.9%, and 84.6%, respectively, for patients in group B (P = 0.001). The corresponding 1, 3, and 5-year RFS was 69.0%, 44.7 %, and 28.1%, and 77.4%, 57.0%, and 54.2% for patients in the 2 groups, respectively (P = 0.009). The results of a multivariate analysis indicated that ΔAPRI was an independent prognostic factor for both OS (P = 0.001, hazard ratio 3.115, 95% confidence interval 1.642-5.912) and RFS (P = 0.006, hazard ratio 1.689, 95% confidence interval 1.163-2.452).A positive ΔAPRI after liver resection predicts decreased OS and RFS in patients with small HCC., Competing Interests: The authors have no conflicts of interest to disclose.

Background: The anterior approach (AA) technique has been reported to provide better operative and survival outcomes compared with the conventional approach for large right hepatocellular carcinoma (HCC) resection. However, this technique runs the risk of massive retrograde bleeding from the right hepatic vein or middle hepatic vein at the deeper plane of parenchymal transection. This study was designed to evaluate the efficacy of AA combined with infrahepatic inferior vena cava (IVC) clamping on the perioperative outcomes in patients undergoing right hepatic resection for large HCC in randomized clinical trial settings., Methods: A total of 101 patients undergoing right hepatic resection for large HCC were randomized to receive AA combined with infrahepatic IVC clamping (group A, n = 50), or AA alone (group B, n = 51)., Results: The total blood loss (423 ± 154 vs 757 ± 338 mL; P = 0.001), blood loss during liver transection (272 ± 96 vs 563 ± 144 mL; P = 0.001), and intraoperative blood transfusion requirements (12.0% vs 29.4%; P = 0.031) were significantly less in group A patients compared with group B patients. There was no IVC clamping-associated morbidity in group A., Conclusion: AA combined with infrahepatic IVC clamping for large right HCC resection is a safe, feasible, and effective technique in reducing intraoperative blood loss., Competing Interests: The authors have no conflicts of interest to disclose.

Background: There is limited information concerning the postoperative prognostic nutritional index change (ΔPNI) in hepatocellular carcinoma (HCC). This study was designed to evaluate the prognostic value of ΔPNI in patients with small HCC who underwent liver resection., Methods: A retrospective cohort study was performed to analyze 243 patients with small HCC who underwent liver resection. Patients were divided into prognostic nutritional index (PNI)-increased group (n = 161) and PNI-decreased group (n = 82) according to postoperative PNI change. Clinical data, overall survival (OS), and recurrence-free survival (RFS) were statistically compared between the 2 groups, and a multivariate analysis was used to identify prognostic factors., Results: Multivariable analysis revealed that ΔPNI as independent predictors of OS and RFS in patients with small HCC after liver resection (P < .01 for both)., Conclusions: Decreased PNI, but not low preoperative PNI was an independent risk factor for OS and RFS in patients with small HCC who underwent liver resection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Microvascular invasion (MVI) is an important risk factor for survival of patients with hepatocellular carcinoma (HCC) after hepatectomy. However, its impact on patients with recurrent HCC who receive a second hepatectomy is unknown., Methods: We enrolled 167 patients with HCC who underwent a second hepatectomy because of intrahepatic recurrences. We compared the patients' demographic, tumor, and pathologic characteristics with 766 cases of original hepatectomy. We analyzed the possible risk factors for survival after the first and second hepatectomies and the influence of different MVI patterns on patients' survival after the second hepatectomy., Results: The median overall survival was comparable between the first and second hepatectomy groups, 34 (3-84) mo versus 27 (3-57) mo, P = 0.09. For patients who underwent a first hepatectomy, the presence of macro-VI or MVI, an early recurrence pattern, and a total tumor diameter >5 cm were independent risk factors. For survival after the second hepatectomy, MVI patterns that were positive-positive or negative-positive and a total recurrent tumor diameter >5 cm were significant risk factors for survival., Conclusions: A second hepatectomy provides satisfying survival for patients with intrahepatic recurrence of HCC after the initial operation. Different MVI patterns affect survival after the second hepatectomy. Because MVI represents the biological behavior of HCC, we place a high premium on the clinical value of MVI after each hepatectomy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The elevation of neutrophil-lymphocyte ratio (NLR) has adverse effects on the prognosis of patients with hepatocellular carcinoma (HCC) who have received liver transplantation (LT). The Hangzhou criteria are set for selecting HCC patients for LT. The present study aimed to establish a set of new criteria combining the NLR and Hangzhou criteria for selecting HCC patients for LT., Methods: Receiver operating characteristic (ROC) analysis was done to determine the optimal NLR threshold. Univariate and multivariate analyses were made to evaluate the factors affecting the outcomes of HCC patients after LT. We also proposed new criteria consisting of the elevated NLR and Hangzhou criteria. ROC analysis was carried out to validate the feasibility of the new criteria., Results: Three hundred and five HCC patients were included in this study. The mean follow-up time of these patients was 5.4 years. Of the 305 patients, 197 (64.6%) showed elevated NLRs (NLR > 4). The recurrence-free survival rates of the patients with elevated NLRs at 1, 3 and 5 years were lower than those of the patients with normal NLRs (NLR ≤ 4) (50.1%, 21.7% and 20.2% vs 80.5%, 58.7% and 56.4%, respectively; P < 0.001). The overall survival rate was lower in the patients with elevated NLR than in those with normal NLR at 1, 3 and 5 years (60.8%, 27.0% and 22.5% vs 78.4%, 51.1% and 47.8%, respectively; P < 0.001). Multivariate analysis demonstrated that an NLR > 4 (P = 0.034), total tumor size > 8 cm (P = 0.005), alpha-fetoprotein level > 400 μg/L (P = 0.007) and the presence of vascular invasion (P = 0.003) were independent predictors of HCC recurrence in post-transplant patients. We proposed a set of new criteria based on the elevated NLR and Hangzhou criteria. A ROC analysis demonstrated that the patients with scores ≥ 1 had an area under the curve of 0.764., Conclusion: The criteria combining the elevated NLR and Hangzhou criteria can be used to select patients with HCC for LT.