Anti HCV activity and expression inhibition of HCC markers by protein extract from Iberis gibraltarica / Atividade anti-HCV e inibição da expressão de marcadores HCC por extrato de proteína de Iberis gibraltarica

Hepatitis C virus infection (HCV) is the foremost reason of progressive hepatic fibrosis and cirrhosis, with an elevated risk of hepatocellular carcinoma (HCC) development. Medicinal plants have been used for human health benefits for several years, but their therapeutic potential needs to be explored. The main objective of this study was to figure out the in vitro antiviral and anticancer characteristics of total crude protein of Iberis gibraltarica against HCV and HCC. Total crude protein of Iberis gibraltarica was isolated and quantified. The level of cytotoxicity was measured against the HepG2 cell line and it shows no significant cytotoxicity at the concentration of 504µg/ml. The anti-HCV effect was determined by absolute quantification via real time RT-PCR method and viral titer was reduced up to 66% in a dose dependent manner against the total protein of Iberis gibraltarica. The anticancer potential of Iberis gibraltarica was also examined through mRNA expression studies of AFP and GPC3 genes against the total protein of Iberis gibraltarica-treated HepG2 cells. The results show up to 90% of the down-regulation expression of AFP and GPC3. The obtained results indicate the therapeutic potential of total protein of Iberis gibraltarica against HCV and hepatocellular carcinoma in vitro.

A infecção pelo vírus da hepatite C (HCV) é a principal causa de fibrose hepática progressiva e cirrose, com risco elevado de desenvolvimento de carcinoma hepatocelular (HCC). As plantas medicinais vêm sendo utilizadas para benefícios à saúde humana há vários anos, mas seu potencial terapêutico precisa ser explorado. O principal objetivo deste estudo foi descobrir as características antivirais e anticancerígenas in vitro da proteína bruta total de Iberis gibraltarica contra HCV e HCC. A proteína bruta total de Iberis gibraltarica foi isolada e quantificada. O nível de citotoxicidade foi medido contra a linha celular HepG2 e não apresenta citotoxicidade significativa na concentração de 504µg/ml. O efeito anti-HCV foi determinado por quantificação absoluta através do método RT-PCR em tempo real e o título viral foi reduzido em até 66% de forma dose-dependente contra a proteína total de Iberis gibraltarica. O potencial anticancerígeno de Iberis gibraltarica também foi examinado através de estudos de expressão de mRNA dos genes AFP e GPC3 contra a proteína total de células HepG2 tratadas com Iberis gibraltarica. Os resultados mostram até 90% da expressão de regulação negativa de AFP e GPC3. Os resultados obtidos indicam o potencial terapêutico da proteína total de Iberis gibraltarica contra HCV e carcinoma hepatocelular in vitro.

Lobelia chinensis Lour inhibits the progression of hepatocellular carcinoma via the regulation of the PTEN/AKT signaling pathway in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Lobelia chinensis Lour. (LCL) is a common herb used for clearing heat and detoxifying, and it has antitumor activity. Quercetin is one of its important components, which may play an important role in the treatment of hepatocellular carcinoma (HCC). AIM OF THE STUDY: To study the active ingredients of LCL, their mechanism of action on HCC, and lay the foundations for the development of new drugs for the treatment of HCC. MATERIALS AND METHODS: Network pharmacology was used to examine the probable active ingredients and mechanisms of action of LCL in HCC treatment. Based on an oral bioavailability of ≥30% and a drug-likeness index of ≥0.18, relevant compounds were selected from the Traditional Chinese Medicine Systems Pharmacology database and TCM Database@Taiwan. HCC-related targets were identified using gene cards and the Online Mendelian Inheritance in Man (OMIM) database. A Venn diagram was created to assess the relationship between the intersection of disease and medication targets by creating a protein-protein interaction network, and the hub targets were selected by topology. Gene Ontology enrichment analyses were performed using the DAVID tool. Finally, in vivo and in vitro experiments (qRT-PCR, western blotting, hematoxylin and eosin staining, transwell assays, scratch tests, and flow cytometry assays) verified that LCL demonstrated notable therapeutic effects on HCC. RESULTS: In total, 16 bioactive LCL compounds met the screening criteria. The 30 most important LCL therapeutic target genes were identified. Of these, AKT1 and MAPK1 were the most important target genes, and the AKT signaling pathway was identified as the key pathway. Transwell and scratch assays showed that LCL prevented cell migration, and flow cytometry tests revealed that the LCL-treated group showed a considerably higher rate of apoptosis than the control group. LCL reduced tumor formation in mice in vivo, and Western blot analysis of tumor tissues treated with LCL indicated variations in PTEN, p-MAPK and p-AKT1 levels. The results show that LCL may inhibit the progression of HCC through the PTEN/AKT signaling pathway to achieve the goal of treating HCC. CONCLUSION: LCL is a broad-spectrum anticancer agent. These findings reveal potential treatment targets and strategies for preventing the spread of cancer, which could aid in screening potential traditional Chinese medicine for anticancer and clarifying their mechanisms.

Based on network pharmacology and experiments to explore the underlying mechanism of Mahonia bealei (Fortune) Carrière for treating alcoholic hepatocellular carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Mahonia bealei (Fortune) Carrière (M. bealei) is a traditional medicine widely used by the Hmong community in Guizhou. It possesses diverse biological activities and shows promise in cancer treatment; however, contemporary pharmacological research in this area is lacking. AIMS OF THE STUDY: This study aimed to investigate the effects and underlying mechanisms of M. bealei on alcoholic hepatocellular carcinoma (HCC). MATERIALS AND METHODS: We initially employed the LC-MS/MS method to identify the compounds present in M. bealei serum. Subsequently, its potential targets were predicted using public databases. Bioinformatics and network pharmacology approaches, such as univariate Cox regression and random forest (RF) algorithms, were utilized to identify differentially expressed genes (DEGs) associated with the prognosis of alcoholic HCC. Survival curve and receiver operating characteristic (ROC) analyses were conducted using alcoholic HCC-related data from TCGA and GEO to determine the diagnostic value of the identified DEGs. Molecular docking using the CDOCKER approach based on CHARMm was performed to validate the affinity between the predictive compounds and targets. Additionally, we evaluated the impact of M. bealei on cell proliferation, migration, and conducted western blot assays. RESULTS: The LC-MS/MS approach identified 17 therapeutic components and predicted 483 component-related targets, of which 63 overlapped with alcoholic HCC targets and were considered potential therapeutic targets. GO and KEGG pathway analysis revealed significant associations between the 63 overlapping targets and alcoholic HCC progression. Through various approaches in the Cytoscape 3.9.0 software, we confirmed 9 hub genes (CDK1, CXCR4, DNMT1, ESR1, KIT, PDGFRB, SERPINE1, TOP2A, and TYMS) as core targets. TOP2A and CDK1 genes were identified as advantageous for diagnosing alcoholic HCC using univariate Cox regression, RF, survival curve, and ROC analysis. Molecular docking analysis demonstrated strong binding affinity between key bioactive components cyclamic acid, perfluoroalkyl carboxylic acid, perfluorosulfonic acid, alpha-linolenic acid, adenosine receptor antagonist (CGS 15943), and Prodigiosin and TOP2A and CDK1. In vitro experiments confirmed that M. bealei significantly suppressed cell proliferation and migration of HepG2 cells, while downregulating TOP2A and CDK1 expression. CONCLUSION: This study highlights the potential of M. bealei as a natural medicine for the treatment of alcoholic HCC. Six compounds (cyclamic acid, perfluoroalkylic carboxylic acids, perfluorosulfonic acid, alpha-linolenic acid, adenosine receptor antagonist (CGS 15943), and Prodigiosin) present in M. bealei serum may exhibit therapeutic effects against alcoholic HCC by downregulating CDK1 and TOP2A expression levels in vitro.

Enhancing NKT cell-mediated immunity against hepatocellular carcinoma: Role of XYXD in promoting primary bile acid synthesis and improving gut microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: 'Xiayuxue decoction' (XYXD) is a traditional Chinese medicine compound, composing of three natural medicines: Rheum officinale Baill., Prunus persica (L.) Batsch and Eupolyphaga sinensis Walker. It is derived from the famous traditional Chinese medical classics 'Jingui Yaolue' and has been used for thousands of years. In the Guidelines for the Diagnosis and Treatment of Primary liver Cancer issued by China's Health Commission, XYXD was applied in the treatment of primary liver cancer. AIM OF THE STUDY: To clarify the pharmacodynamic material basis and mechanism of XYXD in the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Firstly, the active components of XYXD and its distribution in vivo were identified by Ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Then, the effective components and mechanism of XYXD against HCC were explored by network pharmacology combined with cell experiments in vitro. Furthermore, the anti-HCC effect of XYXD was determined by animal experiments in vivo. Metagenomic sequencing was used to detect its effect in gut microbiota, and targeted metabolism was used to detect the changes of bile acids in the liver. Finally, the related targets of NKT cell immune function activation were detected by RT-qPCR and Elisa. RESULTS: A total of 113 active ingredients in XYXD were identified, and the distribution of active ingredients in blood, liver, tumor, cecum, intestinal contents and feces was clarified. The circulation process and active ingredient group of XYXD were preliminarily clarified. In addition, we found five anti-HCC active ingredients in XYXD through network pharmacology combined with cell experiments in vitro, among which aloe emodin had the most significant effect, and predicted the potential mechanism of XYXD against HCC through NKT cell pathway. Moreover, the inhibitory effect of XYXD on liver tumor growth was clarified by animal experiments in vivo. The mechanism was mainly to promote the production of bile salt hydrolase (BSH) by increasing the abundance of Bacteroides and Lactobacillus, BSH converts conjugated bile acids into primary bile acids, and reduces the conversion of primary bile acids to secondary bile acids by reducing the abundance of Eubacterium, thereby increasing the content of primary bile acids. Primary bile acids trigger NKT cells in the liver to produce interferon-γ to exert anti-HCC immune effects. CONCLUSION: This study found that the traditional Chinese herbal formula XYXD can trigger the immune effect of NKT cells against HCC by regulating the interaction between gut microbiota and bile acids.

miR-17-5p slows progression of hepatocellular carcinoma by downregulating TGFBR2

Objective Downregulation of miR-17-5p has been reported in several cancers, but whether and how miR-17-5p is downregulated in hepatocellular carcinoma (HCC) is unknown. Here, we examined whether miR-17-5p is downregulated in HCC and whether that affects expression of its target gene encoding transforming growth factor β receptor 2 (TGFβR). Methods We screened for potential microRNAs (miRNAs) involved in HCC by analyzing published transcriptomes from HCC patients. Expression of miR-17-5p was measured in HCC cell lines and in tissues from HCC patients using quantitative real-time PCR. The in vitro effects of miR-17-5p on HCC cells were assessed by EdU proliferation assay, CCK-8 cell proliferation assay, colony-formation assay, transwell migration/invasion assay, wound healing assay, and flow cytometry. Effects of miR-17-5p were evaluated in vivo using mice with subcutaneous tumors. Effects of the miRNA on the epithelial–mesenchymal transition (EMT) were assessed, while its effects on TGFβR2 expression were analyzed using bioinformatics and a dual luciferase reporter assay. Results Patients with low miR-17-5p expression showed lower rates of overall and recurrence-free survival than patients with high miR-17-5p expression, and multivariate Cox regression identified low miR-17-5p expression as an independent predictor of poor overall survival in HCC patients. In vitro, miR-17-5p significantly inhibited HCC cell proliferation, migration, invasion, and the EMT, while promoting apoptosis. In vivo, it slowed the development of tumors. These protective effects of miR-17-5p were associated with downregulation of TGFβR2. Conclusion The miRNA miR-17-5p can negatively regulate the expression of TGFβR2 and inhibit the EMT, thereby slowing tumor growth in HCC, suggesting a potential therapeutic approach against HCC (AU)

Extracellular Vesicles in Hepatocellular Carcinoma: Progress and Challenges in the Translation from the Laboratory to Clinic.

Extracellular vesicles (EVs) play critical roles in intercellular communication by transporting bioactive cargo to recipient cells. EVs have been implicated in a range of physiological and pathological processes, including tumor progression, metastasis, immune modulation, and drug resistance. The objective of this review is to present a thorough overview of recent studies focusing on EVs in hepatocellular carcinoma (HCC), with an emphasis on their potential utility as diagnostic biomarkers as well as therapeutic agents. Initially, we explore the utility of EVs as diagnostic biomarkers for HCC, followed by a discussion of their potential as carriers of therapeutic payloads. Additionally, we delve into the emerging field of therapeutic EVs for modulating tumor immune responses. Through this review, our ultimate aim is to provide a comprehensive understanding of the opportunities and challenges in the clinical translation of EV research in the domain of HCC.

Bioactivity-Guided Synthesis: In Silico and In Vitro Studies of ß-Glucosidase Inhibitors to Cope with Hepatic Cytotoxicity.

The major cause of hyperglycemia can generally be attributed to ß-glucosidase as per its involvement in non-alcoholic fatty liver disease. This clinical condition leads to liver carcinoma (HepG2 cancer). The phthalimides and phthalamic acid classes possess inhibitory potential against glucosidase, forming the basis for designing new phthalimide and phthalamic acid analogs to test their ability as potent inhibitors of ß-glucosidase. The study also covers in silico (molecular docking and MD simulations) and in vitro (ß-glucosidase and HepG2 cancer cell line assays) analyses. The phthalimide and phthalamic acid derivatives were synthesized, followed by spectroscopic characterization. The mechanistic complexities associated with ß-glucosidase inhibition were identified via the docking of the synthesized compounds inside the active site of the protein, and the results were analyzed in terms of the best binding energy and appropriate docking pose. The top-ranked compounds were subjected to extensive MD simulation studies to understand the mode of interaction of the synthesized compounds and binding energies, as well as the contribution of individual residues towards binding affinities. Lower RMSD/RMSF values were observed for 2c and 3c, respectively, in the active site, confirming more stabilized, ligand-bound complexes when compared to the free state. An anisotropic network model was used to unravel the role of loop fluctuation in the context of ligand binding and the dynamics that are distinct to the bound and free states, supported by a 3D surface plot. An in vitro study revealed that 1c (IC50 = 1.26 µM) is far better than standard acarbose (2.15 µM), confirming the potential of this compound against the target protein. Given the appreciable potential of the candidate compounds against ß-glucosidase, the synthesized compounds were further tested for their cytotoxic activity against hepatic carcinoma on HepG2 cancer cell lines. The cytotoxicity profile of the synthesized compounds was performed against HepG2 cancer cell lines. The resultant IC50 value (0.048 µM) for 3c is better than the standard (thalidomide: IC50 0.053 µM). The results promise the hypothesis that the synthesized compounds might become potential drug candidates, given the fact that the ß-glucosidase inhibition of 1c is 40% better than the standard, whereas compound 3c holds more anti-tumor activity (greater than 9%) against the HepG2 cell line than the known drug.

European Society for Organ Transplantation Consensus Statement on Biomarkers in Liver Transplantation.

Currently, one-year survival following liver transplantation (LT) exceeds 90% in large international registries, and LT is considered definitive treatment for patients with end-stage liver disease and liver cancer. Recurrence of disease, including hepatocellular carcinoma (HCC), significantly hampers post-LT outcomes. An optimal approach to immunosuppression (IS), including safe weaning, may benefit patients by mitigating the effect on recurrent diseases, as well as reducing adverse events associated with over-/under-IS, including chronic kidney disease (CKD). Prediction of these outcome measures-disease recurrence, CKD, and immune status-has long been based on relatively inaccurate clinical models. To address the utility of new biomarkers in predicting these outcomes in the post-LT setting, the European Society of Organ Transplantation (ESOT) and International Liver Transplant Society (ILTS) convened a working group of experts to review literature pertaining to primary disease recurrence, development of CKD, and safe weaning of IS. Summaries of evidence were presented to the group of panelists and juries to develop guidelines, which were discussed and voted in-person at the Consensus Conference in Prague November 2022. The consensus findings and recommendations of the Liver Working Group on new biomarkers in LT, clinical applicability, and future needs are presented in this article.

Establishment of nucleic acid sensing pathways-based model in predicting response to immunotherapy and targeted drug in hepatitis virus-related hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) accounts for 80% of liver cancers, while 70%-80% of HCC developed from chronic liver disease with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as the major etiology. Immunotherapy is assuming a role as a pillar of HCC treatment, but the remarkable immune-mediated responses are restricted in a minority of patients. Nucleic acid sensing (NAS) pathways are the central pathway of the innate immune system and antiviral immune response to viral infection, but their role in hepatitis virus-related HCC remains undetermined. In our study, we performed a comprehensive bioinformatics analysis based on transcriptomic data of hepatitis virus related-HCC tissues collected from multiple public data sets. Two subgroups were validated based on NAS-related genes in virus-related HCC patients, which were defined as NAS-activated subgroups and NAS-suppressed subgroups based on the expression of NAS-related genes. On this basis, a NAS-related risk score (NASRS) predictive model was established for risk stratification and prognosis prediction in the hepatitis virus-related HCC (TCGA-LIHC and ICGC cohorts). The predictive values of the NASRS in prognosis and immunotherapy were also verified in multiple data sets. A nomogram was also established to facilitate the clinical use of NASRS and demonstrate its effectiveness through different approaches. Additionally, six potential drugs binding to the core target of the NAS signature were predicted via molecular docking strategy. We subsequently evaluated the cytotoxic capabilities of potential drug in vitro and in vivo. Based on these results, we conclude that the NASRS model could serve as a power prognostic biomarker and predict responses to immunotherapy, which is meaningful in clinical decision-making of hepatitis virus-related HCC patients.

A novel formula used for predicting hepatocellular carcinoma after the achievement of sustained virologic response by direct-acting antivirals in patients with chronic hepatitis C.

Although eliminating HCV can prevent hepatocellular carcinoma (HCC), some patients develop HCC even after obtaining sustained virologic response (SVR). Previously, we developed a new formula to predict advanced liver fibrosis. This study aimed to clarify the usefulness of this formula for predicting HCC after achieving SVR. Among 351 consecutive patients who had been treated with direct-acting antivirals, 299 were included in this study. New formula scores were used as a marker for predicting liver fibrosis and as a predictive model for HCC incidence. The participants were 172 men and 127 women with a median age of 68 years. The median new formula score was -1.291. The cumulative HCC incidence rates were 4.3%, 9.7%, and 12.5% at 1, 3, and 5 years, respectively. The cumulative incidence of HCC was significantly higher in patients with a history of HCC than in those without treatment history of HCC (P = 2.52×10-26). Multivariate analysis revealed that male (HR = 6.584, 95% CI = 1.291-33.573, P = 0.023) and new formula score (HR = 1.741, 95% CI = 1.041-2.911, P = 0.035) were independent factors associated with the development of HCC in patients without a treatment history of HCC. The optimal cutoff value for predicting the development of HCC was -0.214. The cumulative incidence rates of HCC in patients with new formula scores ≥-0.214 were 5.4%, 15.3%, and 15.3% at 1, 3, and 5 years, respectively, whereas the incidence rates of HCC in patients with new formula scores <-0.214 were 0.0%, 0.6%, and 4.8%, respectively (P = 2.12×10-4). In conclusion, this study demonstrated the usefulness of new formula scores as a predictor of HCC after achieving SVR, especially in patients without past treatment history of treatment for HCC.

FAT4 expression in peripheral blood mononuclear cells is associated with prognosis and immune cell infiltration in hepatocellular carcinoma.

Peripheral blood mononuclear cell (PBMC) genes reflect the host immune status and could be suitable for evaluating the prognosis of patients with hepatocellular carcinoma (HCC), for which a reliable biomarker is unavailable and the host immune responses to cancer cells. This study aimed to investigate prognostically relevant genes in HCC PBMCs and assessed whether their expression represents tumor immune infiltration. Gene expression in PBMCs from patients with advanced or terminal HCC who had survived or died was examined. Correlations among FAT atypical cadherin 4 (FAT4) expression, cancer immune characteristics, and infiltrated immune cell gene marker sets were analyzed. FAT4 expression was lower in the PBMCs of patients with advanced or terminal HCC who had died than that in patients who survived. Kaplan-Meier analysis indicated that FAT4 downregulation was associated with a relatively poor prognosis while overexpression was positively correlated with immune cell infiltration, several immune cell markers, and immune checkpoint expression. Hsa-miR-93-5p represented the most probable upstream microRNA of FAT4. Thus, upregulated FAT4 in PBMCs and HCC tissues might indicate a favorable prognosis and increased immune cell infiltration, while miRNA-93-5p could be a modulator of FAT4 expression. Collectively, these findings suggest novel immunotherapy targets for HCC.

Recent advances in treatment strategies for hepatocellular carcinoma with portal vein cancer thrombus.

This is a review of current practices and advances in hepatocellular carcinoma (HCC) with portal vein cancer thrombus (PVTT). The treatment strategies of HCC with PVTT are non-uniform worldwide. Systemic treatment with molecularly targeted drugs and immune checkpoint inhibitors, such as sorafenib, lenflutinib, donafenib, atezolizumab plus bevacizumab, sintilimab plus IBI305, regorafenib, pembrolizumab and anti-Cytotoxic T Lymphocyte antigen 4 (CTLA-4) was recommended by guidelines, but with limited effectiveness for HCC patients with PVTT. More and more studies indicate that aggressive local or locoregional treatments, including liver resection, liver transplantation, radiation therapy, hepatic arterial infusion chemotherapy (HAIC), transarterial chemoembolization (TACE) and transarterial radioembolization (TARE) benefit for selected HCC patients with PVTT. In recent years, the comprehensive treatment of HCC has advanced greatly. This review aims to provide an insight into the treatment modalities available for HCC patients with PVTT.

A large-scale transcriptional analysis reveals herb-derived ginsenoside F2 suppressing hepatocellular carcinoma via inhibiting STAT3.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common type of cancer that shows great morbidity and mortality rates. However, there are limited available drugs to treat HCC. AIM: The present work focused on discovering the potential anti-HCC compounds from traditional Chinese medicine (TCM) by employing high-throughput sequencing-based high-throughput screening (HTS2) together with the liver cancer pathway-associated gene signature. METHODS: HTS2 assay was adopted for identifying herbs. Protein-protein interaction (PPI) network analysis and computer-aided drug design (CADD) were used to identify key targets and screen the candidate natural products of herbs. Molecular docking, network pharmacology analysis, western blotting, immunofluorescent staining, subcellular fractionation experiment, dual-luciferase reporter gene assay, surface plasmon resonance (SPR) as well as nuclear magnetic resonance (NMR) were performed to validate the ability of compound binding with key target and inhibiting its function. Moreover, cell viability, colony-forming, cell cycle assay and animal experiments were performed to examine the inhibitory effect of compound on HCC. RESULTS: We examined the perturbation of 578 herb extracts on the expression of 84 genes from the liver cancer pathway, and identified the top 20 herbs significantly reverting the gene expression of this pathway. Signal transducer and activator of transcription 3  (STAT3)  was identified as one of the key targets of the liver cancer pathway by PPI network analysis. Then, by analyzing compounds from top 20 herbs utilizing CADD, we found ginsenoside F2 (GF2) binds to STAT3 with high affinity, which was further validated by the results from molecular docking, SPR and NMR. Additionally, our results showed that GF2 suppresses the phosphorylation of Y705 of STAT3, inhibits its nuclear translocation, decreases its transcriptional activity and inhibits the growth of HCC in vitro and in vivo. CONCLUSION: Based on this large-scale transcriptional study, a number of anti-HCC herbs were identified. GF2, a compound derived from TCM, was found to be a chemical basis of these herbs in treating HCC. The present work also discovered that GF2 is a new STAT3 inhibitor, which is able to suppress HCC. As such, GF2 represents a new potential anti-HCC therapeutic strategy.

Longitudinal assessment of hepatocellular carcinoma response to stereotactic body radiation using gadoxetate-enhanced MRI: A case series.

PURPOSE: To describe the longitudinal response in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT) and who underwent liver transplant (LT) using gadoxetate-enhanced MRI. METHODS: Five men (median age 61y, range 57-64y) with 6 HCCs treated with SBRT (median dose 50 Gy) who subsequently underwent LT were included in this retrospective study. Patients underwent gadoxetate-enhanced MRI before and after SBRT over a period of 3-18 months. Response was assessed using RECIST1.1, mRECIST, LI-RADS and image subtraction, by 2 observers in consensus. Percentage of pathologic tumor necrosis was evaluated. RESULTS: LT was performed 278 days (IQR, 148-418d) after completion of SBRT and 48d after the last MRI. Histopathology demonstrated tumor necrosis of 48 ± 42% (range, 10-100%). Mean tumor size at baseline and last post-treatment MRIs pre-LT were 2.6 ± 0.8 cm and 2.4 ± 0.9 cm. Enhancing tumor component size at baseline MRI and last post-treatment MRI pre-LT were 1.6 ± 0.8 cm and 0.9 ± 1.0 cm. Responses assessed at the last LRI pre-LT were: partial response (PR, n = 3), stable disease (SD, n = 3) using RECIST1.1; complete response (CR, n = 2), partial response (PR, n = 2), stable disease (SD, n = 2) using mRECIST; and LR-TR viable (n = 4), LR-TR non-viable (n = 2) using LI-RADS. At the last MRI pre-LT, per-lesion features of arterial phase hyperenhancement (APHE, 4/6), portal venous washout (3/6) and capsule (3/6) were observed. 5/6 lesions displayed a hypointense perilesional halo on hepatobiliary phase with a mean delay of 3.1 months post-SBRT. CONCLUSIONS: This case-series showed decreased size, persistent APHE, and incomplete pathologic necrosis in most HCCs treated with SBRT undergoing transplant.

A radiomics signature associated with underlying gene expression pattern for the prediction of prognosis and treatment response in hepatocellular carcinoma.

PURPOSE: Identifying robust prognosis and treatment efficiency predictive biomarkers of hepatocellular carcinoma (HCC) is challenging. The purpose of this study is to develop a radiomics approach for predicting the overall survival (OS) based on pretreatment CT images and to explore the radiomic-associated key genes. METHODS: Patients with pathologically or clinically proven HCC from three data sets were retrospectively included in this study. The institute internal data that received transarterial chemoembolization (TACE) treatment was used as the training set to construct the radiomics signature to predict OS by the least absolute shrinkage and selection operator COX (LASSO-COX) regression algorithms. The model was externally tested in 41 patients from The Cancer Genome Atlas (TCGA) with available CT images. Area under the receiver operating characteristics curve (AUC) and the log-rank test were used for survival analysis based on high versus low radiomics score. RNA sequencing data of TCGA and Gene Expression Omnibus (GEO) public database were used for gene expression analysis. RESULTS: A total of 752 patients were divided into the Radiomics cohort (n = 267), the TCGA cohort (n = 338) and GEO cohort (n = 147). The rad-score divided patients into high and low risk groups, with significant survival differences (P < 0.0001 and P = 0.0055) in the training and external test set. The AUC for 5 years' OS were 0.730 and 0.695, respectively. Seven OS-related genes (SPP1, GJA5, GJA4, INMT, PDZD4, ALDOA and MAFG) were identified, all of which were related with TACE efficiency, except for MAFG (P greater than 0.05). CONCLUSIONS: CT-radiomics signature could effectively predict the prognosis and treatment response of HCC, which were also associated with the tumor microenvironment heterogeneity.

Comparing Long-Term survival benefits of hepatocellular carcinoma between thermal ablation monotherapy and combined therapy with transarterial Chemoembolization: A propensity score matched study.

PURPOSE: To compare the long-term survival benefits of hepatocellular carcinoma (HCC) in thermal ablation (TA) monotherapy and TA combined with transarterial chemoembolization (TACE) using propensity score matching (PSM). MATERIALS AND METHODS: Between 1 January 2015 and 28 February 2021, 432 consecutive patients (357 men, 75 women; age range, 20-87 years) with HCC (Barcelona Clinic Liver Cancer stage 0-B) underwent ultrasonography-guided percutaneous TA, which included radiofrequency ablation (n = 340) and microwave ablation (n = 92). The association between combined treatment of TACE prior to TA versus TA monotherapy and survival prognosis was evaluated, including (a) local tumor progression (LTP) by using a logistic regression model, and (b) disease-free survival (DFS) and (c) overall survival (OS) by using a Cox proportional hazards model according to propensity score matched data. RESULTS: After PSM, the final matched cohort consisted of 146 patients, with 73 receiving TA monotherapy and 73 receiving TA combined with TACE. The cumulative LTP rates did not show a significant difference between the two groups (P = 0.960). Neither the DFS nor OS rate was significantly different between the two groups (P = 0.070 and P = 0.680, respectively). The multivariate analysis identified two significant findings. Firstly, ultrasound echo, minimal ablative margin, and high risk of tumor burden score were found to be associated with LTP. Secondly, the type of TA, Child-Turcotte-Pugh grade, ablation time, and lymphocyte-monocyte ratio were identified as independent prognostic factors for OS. CONCLUSION: The differences in LTP, DFS, and OS rates of HCC patients were found to be statistically non-significant between TA monotherapy and TACE + TA groups. For HCC patients with BCLC stage 0-B, the combination treatment of TACE prior to TA may be not associated with long-term survival benefits relative to TA monotherapy.

Preoperative MRI features to predict vessels that encapsulate tumor clusters and microvascular invasion in hepatocellular carcinoma.

OBJECTIVE: To estimate the potential of preoperative MRI features in the prediction of the integration patterns of vessels that encapsulate tumor clusters (VETC) and microvascular invasion (MVI) (VM) patterns in hepatocellular carcinoma (HCC) patients after resection and to assess the prognostic value of VM patterns. MATERIALS AND METHODS: Patients who underwent surgical resection for HCC between July 2019 and July 2020 were retrospectively included in the training cohort and validation cohort. In the training cohort, patients were classified into VM-positive HCC (VM-HCC) and VM-negative HCC (non-VM HCC). Predictors associated with VM-HCC were determined by using logistic regression analyses and used to build a prediction model of VM-HCC. The model was tested in the validation cohort by area under the receiver operating characteristic curve (AUC) analysis. Prognostic factors associated with early recurrence of HCC were evaluated by use of Cox logistic regression analyses. RESULTS: Alpha-fetoprotein (AFP) level higher than 400 ng/mL (odds ratio [OR] = 8.0; 95% CI: 2.6-25.2; P < 0.001), non-smooth tumor margin (OR = 3.1; 95% CI: 1.4-6.0; P < 0.001) and peritumoral arterial enhancement (OR = 2.9; 95% CI: 1.4-6.2; P = 0.004) were independent predictors of VM-HCC. The AUCs of the prediction model for VM-HCC were 0.81 for the training cohort and 0.79 for the validation cohort. The high risk of VM-HCC predicted by the three preoperative predictors derived from the prediction model (hazard ratio [HR] 2.0; 95% CI: 1.3, 3.2; P = 0.003) were independently associated with early recurrence, while pathologically confirmed VM-HCC (HR 2.8; 95% CI: 1.6, 3.8; P < 0.001) and satellite nodules (HR 1.8; 95% CI: 1.1, 3.1; P = 0.025) were independently associated with early recurrence after surgical resection. CONCLUSION: The predictive model can be used to predict VM patterns. VM-HCC is associated with increased risk of early recurrence after surgical resection in HCC.

Remnant liver function is associated with long-term survival in patients with hepatocellular carcinoma undergoing hepatectomy.

It is important to assess the prognosis and intervene before and after surgery in patients with hepatocellular carcinoma. This study aims to elucidate the association of outcomes and residual liver function after hepatectomy. A total of 176 patients who underwent the initial resection for hepatocellular carcinoma between January 2011 and March 2021 at Jichi Medical University were included. Hepatic clearance of the remnant liver was measured using 99mTc-galactosyl serum albumin scintigraphy. The log-rank test was used to analyze survival using the Kaplan-Meier method. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival were calculated using Cox's proportional hazard model. In multivariate analysis, microvascular invasion, intraoperative blood loss, and hepatic clearance of the remnant liver were independently associated with overall survival. Hepatic clearance of the remnant liver was independently associated with recurrence free survival. This is the first report to show that lower residual liver function is associated with shorter survival in patients with hepatocellular carcinoma undergoing hepatectomy. Preoperative determination of remnant liver function may allow assessment of prognosis in patients planned to undergo resection of hepatocellular carcinoma. Preservation of liver functional reserve may be crucial for improved long-term outcomes after hepatectomy.

Long non-coding RNA CASC7 is a promising serum biomarker for hepatocellular carcinoma.

BACKGROUND: At present, a large number of studies have found that long non-coding RNAs (lncRNAs) can be used as biomarkers for diagnosis and monitoring prognosis of hepatocellular carcinoma (HCC). The expression of lncRNA cancer susceptibility candidate 7 (CASC7) in HCC has rarely been studied. The purpose of this study was to explore the expression of CASC7 and its correlation with clinical features, and to further analyze its diagnostic value in HCC. METHODS: Serum samples were collected from 80 patients with HCC, 80 patients with chronic hepatitis B (CHB), and 80 healthy people. The expression level of serum CASC7 was detected by droplet digital PCR. Appropriate parametric and nonparametric tests were used for data analysis. RESULTS: The results showed that the expression of CASC7 in serum of patients with HCC was significantly higher than that of patients with CHB (median: 8.8 versus 2.2 copies/µl, p < 0.001) and healthy controls (median: 8.8 versus 3.8 copies/µl, p < 0.001). High expression of serum CASC7 was significantly correlated with tumor number (p = 0.005), intrahepatic metastasis (IM) (p < 0.001), tumor size (p = 0.007) and tumor-node-metastasis (TNM) stage (p = 0.008). The area under the curve (AUC) of CASC7 to distinguish HCC patients from CHB patients and healthy controls was 0.808 (95% CI: 0.742-0.874) at the cut-off value of 7.24 copies/µl with 63.8% sensitivity and 95.2% specificity. CONCLUSIONS: This study suggested that CASC7 was significantly up-regulated in serum of patients with HCC and closely related to tumor number, IM, tumor size and TNM stage, which may serve as a promising diagnostic biomarker.

Hepatitis B reactivation in cancer patients receiving immune checkpoint inhibitors: a systematic review and meta-analysis.

BACKGROUND: Immunotherapy shows promise as a treatment option for various cancers. However, there is growing concern over potential complications from hepatitis B virus (HBV) reactivation after checkpoint blockade immunotherapy. Although most of the previous clinical trials on immune checkpoint inhibitors (ICIs) excluded patients with HBV, a few case reports and retrospective studies of HBV reactivation have been published. The aim of this study is to assess the risk of hepatitis B virus reactivation (HBVr) in patients receiving ICIs for advanced cancer. METHODS: English and Chinese language literature published prior to April 30, 2023, was searched in PubMed, EMBASE, Web of Science, Cochrane, SinoMed, CNKI and Wanfang Data for studies reporting HBVr rates in cancer patients treated with ICIs. A pooled risk estimate was calculated for HBVr rates with 95% confidence intervals (CI). RESULTS: Data from 34 studies including 7126 patients were retrieved and analyzed. The pooled HBVr rate in cancer patients treated with ICIs was 1.3% (I2 = 90.44%, 95% CI: 0.2-2.9%, P < 0.001). Subgroup analysis revealed that patients diagnosed with hepatocellular carcinoma (HCC), HBV carriers, and patients from Asian regions or in developing countries have a higher rate of HBVr. CONCLUSIONS: Our meta-analysis demonstrated a low risk of HBVr in patients treated with ICIs for advanced cancer. ICI treatment may be safely used in patients with existing HBV infection or chronic hepatitis B, accompanied by regular monitoring and appropriate antiviral prophylaxis if necessary.