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Hepatocellular carcinoma (HCC) is a high-incidence, poor-prognosis malignancy worldwide, requiring new strategies for treatment. Ubiquitination, especially ubiquitination through E3 ubiquitin ligases, plays an indispensable role in the development and progression of HCC. E3 ubiquitin ligases are crucial enzymes in ubiquitination, controlling the degradation of specific substrate proteins and influencing various cellular functions, such as tumor cell proliferation, apoptosis, migration, and immune evasion. In this review, we systematically summarize the mechanisms of E3 ubiquitin ligases in HCC, with a focus on the significance of RING, HECT, and RBR types in HCC progression. The review also looks at the potential for targeting E3 ligases to modulate the tumor microenvironment (TME) and increase immunotherapy efficacy. Future studies will optimize HCC treatment by formulating specific inhibitors or approaches that will be based on gene therapy targeting E3 ligases in order to overcome resistance issues with present treatments and create optimism in the journey of treatment for HCC patients. [ABSTRACT FROM AUTHOR]

Although there have been remarkable advances in the treatment of hepatocellular carcinoma (HCC), the prognosis remains poor in those with advanced stage and more effective therapeutic options are urgently needed. Lenvatinib (Len), a multiple receptor tyrosine kinase inhibitor, is an emerging molecular targeted agent for HCC, whose immunomodulatory activities have been investigated. However, Len utilization is limited because of its low metabolic stability, poor bioavailability and dose-dependent toxicity, rendering its direct use insufficient for immune modulation. Stimuli-responsive nanoparticles, which are drug-targeted delivery platforms for on-demand drug release, facilitate deeper and uniform tumour penetration, providing alternative solutions to overcome current limitations. Ultrasound (US) exhibits superior tissue penetration abilities and can produce reactive oxygen species (ROS) at the tumour site to treat deeper tumours. In addition, US serves as an excellent and selective drug delivery mediator for tumour treatment. Herein, we designed US-triggered lenvatinib nanoparticles (Len-RNPs) for selective drug delivery that utilize US-triggered ROS to induce in situ oxidation reactions, resulting in nanoparticle disintegration. Len-RNPs mitigate the toxicity of Len and effectively trigger robust systemic anti-tumour immune responses in a H22 tumour model, resulting in a tumour suppression rate of 95.7%, with 60% of mice being cured. Our study elucidates a novel and precise strategy of combining Len and US therapy for enhanced HCC immunotherapy. [ABSTRACT FROM AUTHOR]

Objective: Long non-coding RNAs (lncRNAs) LINC02466 is an lncRNA newly linked to the adverse outcomes in primary liver cancer patients, and its crucial involvement in the disease's escalation. Decoding the specific role of LINC02466 in HCC progression is of great significance to provide a potential therapeutic target for HCC. Methods: RT-qPCR and Western Blot techniques was used to analyze the expression levels of LINC02466 in both malignant and surrounding healthy liver tissues. CCK8 assays and colony formation experiments indicates the LINC02466's effect on the proliferation rates of liver cancer cells. Flow cytometry was pivotal in revealing its significant influence on the cell cycle of these cells. Kaplan–Meier survival analysis with log-rank tests were employed. Results: The suppression of LINC02466 markedly reduces the stemness attributes of liver cancer cells, indicating a potential therapeutic target. LINC02466 overexpression significantly increased tumor growth rates and final volumes. Further research indicated that LINC02466 significantly influences liver cancer progression through regulating the mTOR signaling pathway. Conclusion: LINC02466 regulating cell proliferation, the cell cycle, and stemness characteristics via the mTOR pathway, suggesting LINC02466 as a potential therapeutic target for primary liver cancer. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods and Results Despite liver transplantation (LT) is considered the optimal treatment for hepatocellular carcinoma (HCC), particularly in patients with impaired liver function, the shortage of donors has forced the application of very restrictive criteria for selecting ideal candidates for whom LT can offer the best outcome. With the evolving LT landscape due to the advent of direct‐acting antivirals (DAAs) and the steady increase in donors, major efforts have been made to expand the transplant eligibility criteria for HCC. In addition, the emergence of immune checkpoint inhibitors (ICIs) for the treatment of HCC, with demonstrated efficacy in earlier stages, has revolutionized the therapeutic approach for these patients, and their integration in the setting of LT is challenging. Management of immunological compromise from ICIs, including the wash‐out period before LT and post‐LT immunosuppression adjustments, is crucial to balance the risk of graft rejection against HCC recurrence. Additionally, the effects of increased immunosuppression on non‐hepatic complications must be understood to prevent them from becoming obstacles to long‐term OS.In this review, we will evaluate the emerging evidence and its implications for the future of LT in HCC. Addressing these novel challenges and opportunities, while integrating the current clinical evidence with predictive algorithms, would ensure a fair balance between individual patient needs and the overall population benefit in the LT system. [ABSTRACT FROM AUTHOR]

Ferroptosis, a recently elucidated style of regulated cell death, has emerged as a significant area of investigation in cancer biology. Natural active compounds that have anti-cancer effects are promising candidates for cancer prevention. Iberverin, a natural compound derived from Brassica oleracea var. capitata, has been shown to exert anti-tumor activities in some cancers. However, its role in hepatocellular carcinoma (HCC) cells and the molecular mechanisms are still poorly understood. In this study, we proved that iberverin can induce intracellular reactive oxygen species (ROS) generation to inhibit cell proliferation and initiate ferroptotic cell death in HCC cells, which can be eradicated by the ferroptosis inhibitor ferrostatin-1 (Fer-1) or deferoxamine mesylate (DFO) and ROS scavenger (GSH or NAC). Mechanistically, iberverin treatment can simultaneously downregulate SLC7A11 mRNA level and degrade GPX4 through the ubiquitination pathway, leading to lipid peroxidation and ferroptotic cell death in HCC cells. Significantly, a low dose of iberverin can remarkably increase the sensitivity of HCC cells to ferroptosis induced by canonical ferroptosis inducers RSL3 and imidazole ketone erastin (IKE). This study uncovers a critical function of iberverin in preventing HCC through ferroptosis and provides a promising strategy for HCC treatment either via iberverin alone or in combination with canonical ferroptosis inducers in the future. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatocellular carcinoma (HCC) is a long-term complication of acute hepatic porphyria (AHP) inclusive of acute intermittent porphyria [AIP], variegate porphyria [VP], or hereditary coproporphyria [HCP]. Data on HCC risk in AHP patients are limited and heterogeneous. We performed this meta-analysis with aims to (a) determine incidence of HCC in AHP and specific subtypes of AHP and (b) examine high-risk groups for HCC. Methods: Data from studies reporting HCC development in AHP patients were pooled and reported per 100 person years with 95% confidence intervals (CI). Results: 12 observational (5 prospective) studies (11 Europe and 1 US) on 2735 patients (mean age 54.8 yrs., 62% females) with AHP (80% AIP) were analyzed. 115 HCC cases were observed with HCC incidence per 100 person years of 0.3 (0.2–0.5) in AHP, 0.4 (0.2–0.6) in AIP, 0.3 (0–0.4) in VP, and 0.2 (0.1–0.6) in HCP. The risk was 0.4 (0.2–0.6) in females, 0.3 (0.1–0.5) in males, 0.9 (0.1–1.7) in symptomatic, and 0.5 (0–1.6) in asymptomatic patients. Analyses were heterogeneous with publication bias. AHP patients with HCC were older females with a higher prevalence of cirrhosis, alcohol use, and viral hepatitis. Conclusions: The annual incidence of HCC in AHP patients is 0.3%, with higher risk in AIP, older females, symptomatic patients, and those with other risk factors of liver disease. Future studies pooling individual patient data and overcoming limitations of the current meta-analysis are needed as a basis for deriving a effective screening and surveillance approach for HCC in patients with AHP. [ABSTRACT FROM AUTHOR]

Background: Recent genome-wide association studies (GWASs) in liver diseases have generated some polygenic risk scores (PRSs), but their predictive effectiveness on hepatocellular carcinoma (HCC) risk assessment remains unclear. Methods: Here, we constructed a novel combined polygenic risk score and evaluated its increment to the well-established risk model. We used 15 HCC-associated genetic loci from two PRSs and FinnGen GWAS data to calculate a PRS-combined score and to fit the related PRS model in the UK Biobank cohort (N = 436,162). The PRS-combined score was further assessed for risk stratification for HCC integrating with the recommended clinical risk scores. Results: The PRS-combined model achieved a better AUC (0.657) than that of PRS-HFC (0.637) and PRS-cirrhosis (0.645). The top 20% of the PRS-combined distribution had a 3.25 increased risk of HCC vs. the middle decile (45–55%). At the population level, the addition of PRS-combined to the CLivD score significantly increased the C-statistic (from 0.716 to 0.746) and provided a remarkable improvement in reclassification (NRI = 0.088) at the 10-year risk threshold of 0.2%. In clinic, additional assessment of PRS-combined would reclassify 34,647 intermediate-risk participants as high genetic risk, corresponding to an increase of 63.92% (62/97) of the HCC events classified at high risk using the Fibrosis-4 alone. Conclusions: The PRS may enhance HCC risk prediction effectiveness in the general population and refine risk stratification of the conventional clinical indicator. [ABSTRACT FROM AUTHOR]

The crosstalk between tumor progression and ferroptosis is largely unknown. Here, we identify malate dehydrogenase 2 (MDH2) as a key regulator of ferroptosis. MDH2 deficiency inhibits the growth of hepatocellular carcinoma (HCC) cells and enhances their sensitivity to ferroptosis induced by RAS-selective lethal 3 (RSL3), a compound known to cause ferroptosis. MDH2 knock-down enhances RSL3-induced intracellular reactive oxygen species, free iron ions and lipid per-oxides levels, leading to HCC ferroptotic cell death which is rescued by ferrostatin-1 and iron chelator deferiprone. Importantly, the inhibition of HCC cell growth caused by MDH2 deficiency is partially rescued by ferroptosis blockade. Mechanistically, MDH2 resists RSL3-induced ferroptosis sensitivity dependent on glutathione peroxidase 4 (GPX4), an enzyme responsible for scavenging lipid peroxides, which is stabilized by MDH2 in HCC. The protein expressions of MDH2 and GPX4 are positively correlated with each other in HCC cell lines. Furthermore, through our UALCAN website analysis, we found that MDH2 and GPX4 are highly expressed in HCC samples. These findings reveal a critical mechanism by which HCC evades ferroptosis via MDH2-mediated stabilization of GPX4 to promote tumor progression and underscore the potential of MDH2 inhibition in combi-nation with ferroptosis inducers for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Ablative therapies for primary and secondary liver malignancies are increasingly adopted in current guidelines. Nevertheless, surgical resection remains the gold standard in most curative therapy settings. Extensive studies on mortality and morbidity after ablative treatment of the liver are missing. We investigated complications and mortality after ablative treatment in a large, unselected study cohort. Standardized patient and treatment data in 4374 percutaneous and angiographic ablative procedures of the liver from the DRG-based hospital reimbursement system (diagnosis-related groups) of an academic hospital in Germany were retrospectively evaluated. We analyzed descriptive patient data, length of stay (LOS), pre-existing medical conditions, previous gastrointestinal surgeries, severe complications, and occurrence of death. Treatment of secondary liver malignancies constituted over two-thirds of all procedures (71%, n = 3053). The mean LOS was 4.1 ± 3.5 days. Severe complications were documented in 1.4% and in-house death in 0.2% of cases, significantly more often after treatment with chemoembolization of primary liver malignancies (p = 0.003; p = 0.0001). Previous partial liver resection, partial bowel resection, and chronic renal failure were independent risk factors for the occurrence of severe complications. Severe complications and in-hospital death are rare in the treatment of primary and secondary liver malignancies with percutaneous and angiographic procedures. They are a viable alternative or addition to a surgical approach in treating liver lesions. [ABSTRACT FROM AUTHOR]

Purpose: To create and evaluate prediction models of local tumor recurrence after successful conventional transcatheter arterial chemoembolization (c-TACE) via radiomics analysis of lipiodol deposition using cone-beam computed tomography (CBCT) images obtained at the completion of TACE. Materials and Methods: A total of 103 hepatocellular carcinoma nodules in 71 patients, who achieved a complete response (CR) based on the modified Response Evaluation Criteria in Solid Tumors 1 month after TACE, were categorized into two groups: prolonged CR and recurrence groups. Three types of areas were segmented on CBCT: whole segment (WS), tumor segment (TS), and peritumor segment (PS). From each segment, 105 radiomic features were extracted. The nodules were randomly divided into training and test datasets at a ratio of 7:3. Following feature reduction for each segment, three models (clinical, radiomics, and clinical–radiomics models) were developed to predict recurrence based on logistic regression. Results: The clinical–radiomics model of WS showed the best performance, with the area under the curve values of 0.853 (95% confidence interval: 0.765–0.941) in training and 0.752 (0.580–0.924) in test dataset. In the analysis of radiomic feature importance of all models, among all radiomic features, glcm_MaximumProbability, shape_MeshVolume and shape_MajorAxisLength had negative coefficients. In contrast, shape_SurfaceVolumeRatio, shape_Elongation, glszm_SizeZoneNonUniformityNormalized, and gldm_GrayLevelNonUniformity had positive coefficients. Conclusion: In this study, a machine-learning model based on cone-beam CT images obtained at the completion of c-TACE was able to predict local tumor recurrence after successful c-TACE. Nonuniform lipiodol deposition and irregular shapes may increase the likelihood of recurrence. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. This study investigates the role and mechanisms of ADAM9 as a biomarker and potential therapeutic target in HCC. Utilizing RNA-sequencing data and clinicopathological characteristics from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we conducted survival and meta-analyses, functional enrichment, and immune infiltration studies. Additionally, we evaluated the effects of ADAM9 silencing on HCC cell proliferation, migration, and invasion through in vitro experiments. Our results demonstrate that high ADAM9 expression is associated with poor prognosis and increased immune infiltration in HCC patients. Furthermore, ADAM9 knockdown significantly inhibited tumor cell proliferation and migration. These findings indicate that ADAM9 is a promising prognostic biomarker and potential therapeutic target in HCC. In conclusion, ADAM9 could offer avenues for developing strategies to inhibit tumor progression and improve patient outcomes. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a malignancy known for its unfavorable prognosis. The dysregulation of the tumor microenvironment (TME) can affect the sensitivity to immunotherapy or chemotherapy, leading to treatment failure. The elucidation of PHLDA2's involvement in HCC is imperative, and the clinical value of PHLDA2 is also underestimated. Here, bioinformatics analysis was performed in multiple cohorts to explore the phenotype and mechanism through which PHLDA2 may affect the progression of HCC. Then, the expression and function of PHLDA2 were examined via the qRT-PCR, Western Blot, and MTT assays. Our findings indicate a substantial upregulation of PHLDA2 in HCC, correlated with a poorer prognosis. The methylation levels of PHLDA2 were found to be lower in HCC tissues compared to normal liver tissues. Besides, noteworthy associations were observed between PHLDA2 expression and immune infiltration in HCC. In addition, PHLDA2 upregulation is closely associated with stemness features and immunotherapy or chemotherapy resistance in HCC. In vitro experiments showed that sorafenib or cisplatin significantly up-regulated PHLDA2 mRNA levels, and PHLDA2 knockdown markedly decreased the sensitivity of HCC cells to chemotherapy drugs. Meanwhile, we found that TGF-β induced the expression of PHLDA2 in vitro. The GSEA and in vitro experiment indicated that PHLDA2 may promote the HCC progression via activating the AKT signaling pathway. Our study revealed the novel role of PHLDA2 as an independent prognostic factor, which plays an essential role in TME remodeling and treatment resistance in HCC. [ABSTRACT FROM AUTHOR]

Combination therapy of anti‐programmed cell death protein‐1 (PD‐1) antibodies and tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis for hepatocellular carcinoma (HCC), but many patients still have unsatisfactory outcomes. CD8 T cells are known to exert a pivotal function in the immune response against tumors. Nevertheless, most CD8 T cells in HCC tissues are in a state of exhaustion, losing the cytotoxic activity against malignant cells. Cytokines, mainly secreted by immune cells, play an important role in the occurrence and development of tumors. Here, we demonstrated the changes in exhausted CD8T cells during combination therapy by single‐cell RNA sequencing (scRNA‐seq) analysis on tumor samples before and after treatment. Combination therapy exerted a substantial impact on the exhausted CD8T cells, particularly in terms of cytokine expression. CCL5 was the most abundantly expressed cytokine in CD8T cells and exhausted CD8T cells, and its expression increased further after treatment. Subsequently, we discovered the CCL5/CCR5/CYP1A1 pathway through RNA sequencing (RNA‐seq) on CCL5‐stimulated Huh7 cells and verified through a series of experiments that this pathway can mediate the resistance of liver cancer cells to lenvatinib. Tissue experiments showed that after combination therapy, the CCL5/CCR5/CYP1A1 pathway was activated, which can benefit the residual tumor cells to survive treatment. Tumor‐bearing mouse experiments demonstrated that bergamottin (BGM), a competitive inhibitor of CYP1A1, can enhance the efficacy of both lenvatinib and combination therapy. Our research revealed one mechanism by which hepatoma cells can survive the combination therapy, providing a theoretical basis for the refined treatment of HCC. [ABSTRACT FROM AUTHOR]

Introduction: Pyroptosis is an inflammatory form of programmed cell death that plays a significant role in tumorigenesis. Cinobufotalin (CB), a bufadienolide extracted from toad venom, is associated with antitumor effects in various cancers, including liver cancer. However, the role of CB in pyroptosis and its underlying mechanisms have not been well characterized. Methods: MTT, Colony formation, EdU, Wound healing and Transwell migration and invasion assays were applied to determine the effects of CB on the proliferation, migration, and invasion ability of hepatocellular carcinoma (HCC) cells in vitro. The subcutaneous xenograft mouse model and pulmonary metastasis model were used to evaluate the effect of CB on HCC cells in vivo. PCR, western blot, immunohistochemistry, immunofluorescence, and ELISA were used to verify the expression of proliferation, migration, pyroptosis, and inflammation related molecules after CB treatment. Using si-RNA and inhibitors to interfere with NOX4 and HLRP3 expression to validate the key signaling pathways of pyroptosis induced by CB treatment. Results: In vivo experiments using nude mice with xenografted HCC cells and in vitro experiments with HCC cell lines demonstrated that CB treatment significantly inhibited the proliferation, migration, and invasiveness of HCC cells. CB treatment also showed dose-dependent activation of the NLRP3 inflammasome complex in HCC cells, leading to gasdermin D-induced pyroptosis. However, these effects were abrogated via the pretreatment of HCC cells with VX-765, a caspase-1 inhibitor. Additionally, CB increased the production of reactive oxygen species (ROS) and H2O2, along with upregulating NOX4 protein expression in HCC cells. Conversely, NOX4 silencing or pretreatment with VAS2870 (an NOX4 inhibitor) or NAC (an ROS scavenger) suppressed the activation of the NLRP3 inflammasome complex and pyroptosis in CB-treated HCC cells. Discussion: Our study demonstrated that CB suppressed the proliferation, migration, and invasiveness of HCC cells by inducing pyroptosis through the activation of the NOX4/NLRP3/GSDMD signaling pathway. Therefore, our results suggest that CB is a promising therapeutic agent for HCC. [ABSTRACT FROM AUTHOR]

Introduction: Pyroptosis is an inflammatory form of programmed cell death that plays a significant role in tumorigenesis. Cinobufotalin (CB), a bufadienolide extracted from toad venom, is associated with antitumor effects in various cancers, including liver cancer. However, the role of CB in pyroptosis and its underlying mechanisms have not been well characterized. Methods: MTT, Colony formation, EdU, Wound healing and Transwell migration and invasion assays were applied to determine the effects of CB on the proliferation, migration, and invasion ability of hepatocellular carcinoma (HCC) cells in vitro. The subcutaneous xenograft mouse model and pulmonary metastasis model were used to evaluate the effect of CB on HCC cells in vivo. PCR, western blot, immunohistochemistry, immunofluorescence, and ELISA were used to verify the expression of proliferation, migration, pyroptosis, and inflammation related molecules after CB treatment. Using si-RNA and inhibitors to interfere with NOX4 and HLRP3 expression to validate the key signaling pathways of pyroptosis induced by CB treatment. Results: In vivo experiments using nude mice with xenografted HCC cells and in vitro experiments with HCC cell lines demonstrated that CB treatment significantly inhibited the proliferation, migration, and invasiveness of HCC cells. CB treatment also showed dose-dependent activation of the NLRP3 inflammasome complex in HCC cells, leading to gasdermin D-induced pyroptosis. However, these effects were abrogated via the pretreatment of HCC cells with VX-765, a caspase-1 inhibitor. Additionally, CB increased the production of reactive oxygen species (ROS) and H2O2, along with upregulating NOX4 protein expression in HCC cells. Conversely, NOX4 silencing or pretreatment with VAS2870 (an NOX4 inhibitor) or NAC (an ROS scavenger) suppressed the activation of the NLRP3 inflammasome complex and pyroptosis in CB-treated HCC cells. Discussion: Our study demonstrated that CB suppressed the proliferation, migration, and invasiveness of HCC cells by inducing pyroptosis through the activation of the NOX4/NLRP3/GSDMD signaling pathway. Therefore, our results suggest that CB is a promising therapeutic agent for HCC. [ABSTRACT FROM AUTHOR]

Background and aims: Focal liver lesions (FLL) are one of the most common indications for hepatology and hepatobiliary surgery consultation. In this retrospective study, we aim to assess if contrast‐enhanced ultrasound (CEUS) can address diagnostic dilemmas in the evaluation of indeterminate liver lesions by identifying characteristics of indeterminate FLL on CEUS and correlating these with cross‐sectional imaging and pathology findings. Methods: We retrospectively reviewed all patients who underwent CEUS evaluation for liver lesions over a 28‐month period (Oct 2020 to Jan 2023) at the University of Kentucky. To assess the relationship between CEUS results and the corresponding CT, MRI, and/or pathologic findings, the McNemar–Bowker tests were performed. Results: Twenty‐nine patients were included (after two exclusions from a total n of 31). Mean age was 54 years, 62% were female, and 48% had underlying cirrhosis. Of the 29 patients with initial cross‐sectional imaging, the initial results showed malignancy or likely malignant lesion in 6 patients and benign or likely benign lesion in 6 patients. The remaining 17 patients had inconclusive/indeterminate results. CEUS clarified an "indeterminate" CT/MRI result 15 times out of 17 (88.2%), moving the diagnosis to "benign" 11 times while suggesting "malignant" only four times. When aggregating indeterminate cross‐sectional results with either benign or malignant categories suggested by CEUS, CEUS never reversed a benign CT/MRI diagnosis but often reversed a malignant CT/MRI diagnosis. Conclusion: CEUS provided a definitive diagnosis of indeterminate liver lesions in approximately 90% of patients and avoided the need for biopsy in most patients. In cases where the liver lesions were biopsied, CEUS accurately distinguished malignant versus benign lesions as confirmed by biopsy findings. CEUS, therefore, has the potential to provide a precise diagnosis for the majority of indeterminate lesions. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is associated with high mortality rate. This study investigated the status of lipid metabolism-related genes in HCC. Bulk transcriptomic and single-cell sequencing data for HCC were retrieved from public databases. The single-cell sequencing data was subjected to dimensionality reduction, which facilitated the annotation of distinct cell subpopulations and marker gene expression analysis within each subpopulation. Genes associated with lipid metabolism in liver cells were identified, and a machine-learning model was developed using the bulk transcriptomic data randomly partitioned into training and validation sets. The efficacy of the model was validated using these two sets. A multifactorial Cox analysis on the model genes combined with clinical features, led to the identification of age, HMGCS2, HNRNPU, and RAN as independent prognostic factors, which were included in the nomogram model construction and validation. A weighted gene co-expression analysis of all genes of the bulk transcriptome samples revealed the correlation between gene modules and risk score. Genes with cor > 0.4 in the highest-expressing module were selected for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes functional enrichment analysis. Immune-related analysis was conducted based on seven algorithms for immune cell infiltration prediction. For the genes in the nomogram model, the expression in clinical pathological factors was also analyzed. The drug sensitivity analysis offered a reference for the selection of targeting drugs. This investigation provides novel insights and a theoretical basis for the prognosis, treatment, and pharmaceutical advancements for patients diagnosed with HCC. [ABSTRACT FROM AUTHOR]

Aim: An ineffective immune response resulting from dysregulation of cytokine production might encourage viral persistence and cause chronic viral hepatitis to worsen. This study examined the relationship between alterations in interleukin-6 (IL-6) levels and the IL-6 − 174 G > C (rs1800795) polymorphism, as well as how this polymorphism affects the development and progression of chronic hepatitis brought on by hepatitis B (HBV) and hepatitis C (HCV) into hepatocellular carcinoma (HCC). Patients and methods: Whole blood samples from 126 Egyptian patients with HCC (111 with HCV and 15 with HBV), as well as 126 age- and sex-matched healthy individuals, were used to extract DNA. Using PCR-based allele-specific amplification (ASA), the existence of the IL-6 G-174C polymorphism was investigated. Additionally, each participant's serum IL-6 levels were determined using an enzyme-linked immunosorbent assay (ELISA). Results: The primary observations revealed that HCC patients had greater serum levels of IL-6 compared to the control groups (p < 0.001). Patients with the variant (CG and GG) genotype in the HCC group were found to have more disease severity indicated by higher levels of alpha-fetoprotein (AFP) and a higher ascites grade, as well as increased inflammatory activity as defined by higher levels of IL-6 and C-reactive protein (CRP) (p < 0.001 for both) in comparison to patients with the wild-type (CC) genotype (p < 0.001 and p = 0.002, respectively). Conclusion: The rs1800795 SNP in the IL-6 gene was associated with increased inflammatory activity and high levels of IL-6, indicating that this SNP may play a role in the development of HCC in Egyptian patients with chronic viral hepatitis. [ABSTRACT FROM AUTHOR]

Simple Summary: Diet is a fundamental determinant of health and longevity. This relationship is complex. Historically, among the most investigated variables have been quality and quantity of food. However, over the past 2 decades increasing attention has been devoted to dietary rhythms, including time of food consumption during the day and length of fasting intervals. In this respect, contrasting evidence has recently emerged in the literature regarding the effect of adequate intervals of fasting on the evolution of diet-related chronic liver diseases, including hepatocellular carcinoma. In this review, we briefly refer to this evidence and propose a hypothesis that may help reconcile apparently conflicting observations. Dietary rhythms have emerged as a relevant variable in the equation relating nutrition and health. Both experimental and epidemiological studies point to potential beneficial effects of adequate fasting intervals between meals on the evolution of chronic diseases associated with aging. Metabolic dysfunction-associated steatotic liver disease (MASLD) is eminently related to diet and unsurprisingly, diet-based approaches are a mainstay in countering its long-term clinical evolution, including the emergence of hepatocellular carcinoma (HCC). We briefly discuss current evidence linking fasting intervals, MASLD, and HCC and propose a working hypothesis to reconcile some of the apparently conflicting results. This hypothesis relates the beneficial effects of time-restricted eating schedules to the quantity and quality of food, and it is easily amenable to testing. [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the outcomes after stereotactic body radiotherapy (SBRT) for locally advanced primary liver cancer. Materials and methods: Patients with locally advanced liver cancer unsuitable for other loco-regional treatments were treated with SBRT with 50--60 Gy in 3--12 fractions in two consecutive prospective trials. Results: A total of 83 patients were included, of whom 14 were excluded, leaving 69 evaluable patients with 74 treated lesions. A total of 50 patients had hepatocellular carcinoma (HCC), and 11 patients had cholangiocarcinoma (CCC). Approximately 76% had a Child-Pugh (CP) score of A, while 54% had an albumin--bilirubin (ALBI) score of 1. With a median follow-up of 29 months, the median overall survival (OS) was 11 months, and the progression-free survival (PFS) was 18 months. The ALBI score was an important predictor of overall survival (HR 2.094, p = 0.001), which remained significant also in the multivariate analysis. Patients with an ALBI grade of ≥1 had an OS of 4 months versus 23 months in patients with an ALBI grade of 1 (p ≤ 0.001). The local control at 1 and 2 years was 91%. Thirteen patients developed grade ≥ 3 toxicities, of whom nine patients experienced liver toxicities. Patients with a higher ALBI score had a high risk for developing hepatic failure (OR 6.136, p = 0.006). Discussion: SBRT is a very effective treatment with low toxicity and should be considered as a local treatment option in patients with HCC and CCC. Patients with a higher ALBI grade are at risk for developing toxicities after SBRT and have a significantly lower survival rate. [ABSTRACT FROM AUTHOR]

The liver plays a crucrial role in detoxification, metabolism, and nutrient storage. Because liver cancer ranks among the top three leading causes of death globally, there is an urgent need for developing treatment strategies for liver cancer. Although traditional approaches such as radiation, chemotherapy, surgical removal, and transplantation are widely practiced, the number of patients with liver cancer continues to increase rapidly each year. Some novel therapeutics for liver cancer have been studied for many years. In the past decade, oncolytic therapy has emerged, in which viruses selectively infect and destroy cancer cells while sparing normal cells. However, oncolytic virotherapy for liver cancer remains relatively obscure due to the aggressive nature of the disease and the limited effectiveness of treatment. To keep pace with the latest developments in oncolytic tumor therapy for liver cancer, this review summarizes basic science studies and clinical trials conducted within 5 years, focusing on the efficacy and safety profiles of the five most commonly used oncolytic viruses: herpes simplex virus, adenovirus, influenza virus, vaccinia virus, and coxsackievirus. [ABSTRACT FROM AUTHOR]

The long-term benefits of direct-acting antiviral (DAA) therapy after achieving sustained virological response (SVR) remain uncertain in the Chinese population. This study evaluates the incidence of hepatocellular carcinoma (HCC), hepatic decompensation, and all-cause mortality among Chinese hepatitis C patients treated with DAAs. We included patients diagnosed since 2011 and followed them until November 1, 2022. The primary outcomes were HCC, hepatic decompensation, and mortality. Multivariable proportional hazards model was used to assess the impact of SVR and cirrhosis status. The cohort consisted of 1272 patients with SVR (92.1%) and 109 without SVR (7.9%), with a median follow-up of 61 months. The incidence of HCC was significantly lower in the SVR group (5.1 per 1000 person-years) compared to the no-SVR group (15.0 per 1000 person-years). Achieving SVR was associated with a significantly reduced risk of HCC (adjusted hazard ratio: 0.32; 95% CI 0.16–0.67). Cirrhosis was linked to an increased risk of developing HCC and hepatic decompensation. These findings highlight the importance of early DAA treatment, particularly for patients with cirrhosis. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the survival outcomes of transarterial chemoembolization (TACE) between patients with early recurrent hepatocellular carcinoma (rHCC) after hepatic resection, stratified by cytokeratin (CK) 19 expression. Methods: A retrospective analysis was conducted on 63 patients with early rHCC after hepatic resection who underwent TACE between January 2017 and December 2021. Patients were divided into two groups based on CK19 expression: CK19-negative (n=31) and CK19-positive (n=32). Overall survival (OS) and progression-free survival (PFS) were compared between the two groups using the Kaplan-Meier method and log-rank test. Cox regression analysis was performed to identify independent risk factors for OS and PFS. Results: The CK19-negative group demonstrated a significantly longer median OS compared to the CK19-positive group (635 days vs. 432 days, p=0.013). Similarly, the CK19-negative group had a longer median PFS than the CK19-positive group (291 days vs. 117 days, p=0.014). Multivariate Cox analysis identified Child-Pugh A grade, CK19-negative expression, and increased TACE sessions as protective factors for OS. No severe TACE-related adverse events were observed. Conclusion: In patients with early rHCC after hepatic resection, those with CK19-positive expression had poorer survival outcomes following TACE compared to CK19-negative patients. These findings suggest the need for additional therapies to improve survival in CK19-positive individuals. [ABSTRACT FROM AUTHOR]

Background and Aim: Hepatocellular carcinoma (HCC) diagnosis mainly relies on its pathognomonic radiological profile, obviating the need for biopsy. The project of incorporating artificial intelligence (AI) techniques in HCC aims to improve the performance of image recognition. Herein, we thoroughly analyze and evaluate proposed AI models in the field of HCC diagnosis. Methods: A comprehensive review of the literature was performed utilizing MEDLINE/PubMed and Web of Science databases with the end of search date being the 30th of September 2023. The MESH terms "Artificial Intelligence," "Liver Cancer," "Hepatocellular Carcinoma," "Machine Learning," and "Deep Learning" were searched in the title and/or abstract. All references of the obtained articles were also evaluated for any additional information. Results: Our search resulted in 183 studies meeting our inclusion criteria. Across all diagnostic modalities, reported area under the curve (AUC) of most developed models surpassed 0.900. A B‐mode US and a contrast‐enhanced US model achieved AUCs of 0.947 and 0.957, respectively. Regarding the more challenging task of HCC diagnosis, a 2021 deep learning model, trained with CT scans, classified hepatic malignant lesions with an AUC of 0.986. Finally, a MRI machine learning model developed in 2021 displayed an AUC of 0.975 when differentiating small HCCs from benign lesions, while another MRI‐based model achieved HCC diagnosis with an AUC of 0.970. Conclusions: AI tools may lead to significant improvement in diagnostic management of HCC. Many models fared better or comparable to experienced radiologists while proving capable of elevating radiologists' accuracy, demonstrating promising results for AI implementation in HCC‐related diagnostic tasks. [ABSTRACT FROM AUTHOR]

We assessed the impact of the COVID‐19 pandemic on hepatocellular carcinoma (HCC) surveillance among individuals with HCV diagnosed with cirrhosis in British Columbia (BC), Canada. We used data from the British Columbia Hepatitis Testers Cohort (BC‐HTC), including all individuals in the province tested for or diagnosed with HCV from 1 January 1990 to 31 December 2015, to assess HCC surveillance. To analyse the impact of the pandemic on HCC surveillance, we used pre‐policy (January 2018 to February 2020) and post‐policy (March to December 2020) periods. We conducted interrupted time series (ITS) analysis using a segmented linear regression model and included first‐order autocorrelation terms. From January 2018 to December 2020, 6546 HCC screenings were performed among 3429 individuals with HCV and cirrhosis. The ITS model showed an immediate decrease in HCC screenings in March and April 2020, with an overall level change of −71 screenings [95% confidence interval (CI): −105.9, −18.9]. We observed a significant decrease in HCC surveillance among study participants, regardless of HCV treatment status and age group, with the sharpest decrease among untreated HCV patients. A recovery of HCC surveillance followed this decline, reflected in an increasing trend of 7.8 screenings (95% CI: 0.6, 13.5) per month during the post‐policy period. There was no level or trend change in the number of individuals diagnosed with HCC. We observed a sharp decline in HCC surveillance among people living with HCV and cirrhosis in BC following the COVID‐19 pandemic control measures. HCC screening returned to pre‐pandemic levels by mid‐2020. [ABSTRACT FROM AUTHOR]

Immunotherapy has revolutionised the treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in combination with surgical or locoregional therapies for early-to intermediate-stage HCC have recently reported positive results, and other phase III trials in the same patient population are currently in progress. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarise key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Tumor recurrence after radiofrequency ablation (RFA) affects the survival rate of patients and limits its clinical application. Tumor recurrence around the ablation area may be related to the thermal injury of hepatocytes (HCs) around the tumor, but the specific mechanism is still unclear. Methods: A liver cancer thermal injury mouse model was established via RFA in the C57BL/6 mice. Primary HCs and Kupffer cells (KCs) were isolated and cultured to assess their sensitivity to thermal injury via the MTT assay. Flow cytometry was used to assess macrophage polarization. Furthermore, Western blotting and co-immunoprecipitation (co-IP) were utilized to evaluate the protein expression of intracellular signaling pathway. Finally, Transwell and wound healing assays was conducted to evaluate the invasion potential of liver cancer cells. Results: Our findings revealed that RFA-induced liver thermal injury promoted the upregulation and secretion of HMGB1 in HCs. HMGB1 had a protective effect on HCs thermal injury, potentially mediated through autophagy regulation. Heat-injured HCs release HMGB1, which activates the TREM1/JAK2/STAT3 signaling pathway in KCs, thus fostering an immunosuppressive tumor microenvironment (TME). Moreover, HMGB1 secretion by heat-injured HCs exacerbates the migration and invasion of HCC cells by influencing macrophage polarization. Conclusion: RFA-induced thermal injury triggers HMGB1 release from HCs, driving macrophage M2 polarization and increasing the invasion ability of liver cancer cells. These findings reveal a potential therapeutic target for combating liver cancer recurrence following thermal ablation. [ABSTRACT FROM AUTHOR]

The impact of RHBDF2 on the expression and potential function in many cancers is still unknown. Therefore, the expression and methylation modification of RHBDF2 were evaluated across TCGA cancers in this study. Moreover, two methods, COX regression and Kaplan-Meier, were utilized for analyses of the prognoses of RHBDF2 in patients. Besides, the association between RHBDF2 and immune microenvironment, mutation, tumor mutation burden and microsatellite instability was analyzed with Pearson correlation. We verified RHBDF2 expression in hepatocellular carcinoma (HCC) compared with normal cell and tissue samples, detected the effects of RHBDF2 knockdown on biological functions in HCC cells, and detected CD4, CD8 and CD68 expression in hepatocellular carcinoma tissues and paired normal tissues. Given these results, the significant mRNA overexpression and promoter hypomethylation of RHBDF2 in various tumor types was showed, and a clear relationship between RHBDF2 overexpression and unfavourable overall survival and progression-free survival was observed, including liver hepatocellular carcinoma (LIHC), glioma (GBMLGG) and pancreatic adenocarcinoma (PAAD). Additionally, hypomethylation of RHBDF2 can affect the overall survival in some tumors. Furthermore, a clear correlation between RHBDF2 and infiltration of immune cells, immune-related molecules, TMB and MSI was observed. Besides, RHBDF2 expression is upregulated in HCC cells and tissues, and RHBDF2 knockdown could decrease the cell adhesion ability of HCC cells. More importantly, the expression of CD4, CD8 and CD68 was higher in HCC tissues. Altogether, the research denoted that RHBDF2 can be a prognostic biomarker for cancers according to these results and participate in cell adhesion of HCC cells. [ABSTRACT FROM AUTHOR]

Background: Chronic liver diseases such as hepatic tumors can affect the brain through the liver–brain axis, leading to neurotransmitter dysregulation and behavioral changes. Cancer patients suffer from fatigue, which can be associated with sleep disturbances. Sleep is regulated via two interlocked mechanisms: homeostatic regulation and the circadian system. In mammals, the hypothalamic suprachiasmatic nucleus (SCN) is the key component of the circadian system. It generates circadian rhythms in physiology and behavior and controls their entrainment to the surrounding light/dark cycle. Neuron–glia interactions are crucial for the functional integrity of the SCN. Under pathological conditions, oxidative stress can compromise these interactions and thus circadian timekeeping and entrainment. To date, little is known about the impact of peripheral pathologies such as hepatocellular carcinoma (HCC) on SCN. Materials and Methods: In this study, HCC was induced in adult male mice. The key neuropeptides (vasoactive intestinal peptide: VIP, arginine vasopressin: AVP), an essential component of the molecular clockwork (Bmal1), markers for activity of neurons (c-Fos), astrocytes (GFAP), microglia (IBA1), as well as oxidative stress (8-OHdG) in the SCN were analyzed by immunohistochemistry at four different time points in HCC-bearing compared to control mice. Results: The immunoreactions for VIP, Bmal1, GFAP, IBA1, and 8-OHdG were increased in HCC mice compared to control mice, especially during the activity phase. In contrast, c-Fos was decreased in HCC mice, especially during the late inactive phase. Conclusions: Our data suggest that HCC affects the circadian system at the level of SCN. This involves an alteration of neuropeptides, neuronal activity, Bmal1, activation of glia cells, and oxidative stress in the SCN. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) has emerged as a prominent global health concern associated with high risk of metabolic syndrome, and has impacted a substantial segment of the population. The disease spectrum ranges from simple fatty liver to non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma (HCC) and is increasingly becoming a prevalent indication for liver transplantation. The existing therapeutic options for NAFLD, NASH, and HCC are limited, underscoring the urgent need for innovative treatment strategies. Insights into gene expression, particularly RNA modifications such as N6 methyladenosine (m6A), hold promising avenues for interventions. These modifications play integral roles in RNA metabolism and cellular functions, encompassing the entire NAFLD-NASH-HCC progression. This review will encompass recent insights on diverse RNA modifications, including m6A, pseudouridine (ψ), N1-methyladenosine (m1A), and 5-methylcytidine (m5C) across various RNA species. It will uncover their significance in crucial aspects such as steatosis, inflammation, fibrosis, and tumorigenesis. Furthermore, prospective research directions and therapeutic implications will be explored, advancing our comprehensive understanding of the intricate interconnected nature of these pathological conditions. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients. [ABSTRACT FROM AUTHOR]

Objective: To compare the detection rates of hepatic artery digital subtraction angiography (HA‐DSA) and magnetic resonance imaging (MRI) gadolinium diethylenetriaminepentaacetic acid (MRI‐Gd‐DTPA) and MRI gadolinium diethylenetriaminepentaacetic acid (MRI‐Gd‐EOB‐DTPA) for small (diameter ≤2 cm) hepatocellular carcinoma (HCC) lesions. Methods: A prospective analysis of patients admitted to the Tumor Hospital of Guangxi Medical University between January 1, 2015, and December 30, 2016, was conducted. The detection rates of the three methods were analyzed. The diameter of small HCC lesions detected using HA‐DSA and MRI‐Gd‐EOB‐DTPA were evaluated. The diagnostic value of HCC Barcelona staging for HA‐DSA was analyzed. Results: For 107 small lesions detected in 57 patients, the detection rates of HA‐DSA and MRI‐Gd‐DTPA were 86.0% (92/107) and 71.0% (76/107), respectively (p <.05). Of 77 small lesions detected in 42 patients using MRI‐Gd‐EOB‐DTPA and HA‐DSA, 67 were detected using HA‐DSA, all of which had a rich blood supply, and 72 were detected using MRI‐Gd‐EOB‐DTPA. The minimum diameter of lesions detected using MRI‐Gd‐EOB‐DTPA was approximately 0.4 cm, whereas that of lesions detected using HA‐DSA was approximately 0.5 cm. After HA‐DSA, a change in the Barcelona staging occurred in 33.3% (62/186) of cases but not after MRI‐Gd‐DTPA; HA‐DSA was significantly better than MRI‐Gd‐DTPA for staging (p =.03). Conclusion: HA‐DSA and MRI‐Gd‐EOB‐DTPA have high diagnostic values for the detection of small HCC lesions, which is helpful for accurate staging of HCC and provides the most valuable information for patient treatment and prognosis. [ABSTRACT FROM AUTHOR]

SEH1 like nucleoporin (SEH1L) is an important component of nuclear pore complex (NPC), which is crucial in the regulation of cell division. However, the interrelation between SEH1L expression and tumor progression is less studied. In this research, we performed a systematic bioinformatic analysis about SEH1L using TCGA, Timer 2.0, Cbioportal, UCLAN and CellMiner™ databases in pan-cancer. Besides, we further validated the bioinformatic results through in vitro and in vivo experiments in HCC, including transcriptome sequencing, real-time quantitative PCR (RT-qPCR), western blotting (WB), immunohistochemistry (IHC), cell proliferation assays, clone formation, EdU, transwell, flow cytometry and subcutaneous tumor model. Our results suggested that SEH1L was significantly up-regulated and related to poor prognosis in most cancers, and may serve as a potential biomarker. SEH1L could promote HCC progression in vitro and in vivo. Besides, the next generation sequencing suggested that 684 genes was significantly up-regulated and 678 genes was down-regulated after the knock down of SEH1L. SEH1L siliencing could activate ATF3/HMOX1/GPX4 axis, decrease mitochondrial membrane potential and GSH, but increase ROS and MDA, and these effects could be reversed by the knock down of ATF3. This study indicated that SEH1L siliencing could induce ferroptosis and suppresses hepatocellular carcinoma (HCC) progression via ATF3/HMOX1/GPX4 axis. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionThe risk of hepatocellular carcinoma (HCC) remains elevated in cirrhotic hepatitis C patients with sustained virological response (SVR) after DAA treatment. We assessed long-term HCC risk stratified by pretreatment liver stiffness measurement (LSM) and developed a risk score algorithm.This register-based nationwide cohort study of 7,227 DAA-treated patients with SVR evaluated annual HCC incidence rates (IRs) and cumulative incidences stratified by pretreatment LSM. The association between LSM and HCC risk was analyzed using multivariate Cox regression. A risk score algorithm was developed and internally validated in 2,664 individuals with LSM >9.5 kPa, assigning each patient a score based on risk factors, proportionally weighted by the association with HCC risk.During a median follow-up of 1.8 years (3.2 years for LSM ≥12.5 kPa), 92 patients (1.3%) developed HCC. The IRs for LSM 9.5–12.4, 12.5–19.9 and ≥20 kPa were 0.21, 0.99 and 2.20 HCC/100 PY, respectively, with no significant risk reduction during follow-up. The HRs (and 95% CI) for LSM 9.5–12.5, 12.5–19.9 and ≥20 kPa are 1.19 (0.43–3.28), 4.66 (2.17–10.01) and 10.53 (5.26–21.08), respectively. Risk score models including FIB-4, alcohol, diabetes, age and LSM effectively stratified patients with LSM >9.5 kPa into low-, intermediate- and high-risk groups, with a Harrell’s C of 0.799. Notably, 48% with LSM ≥9.5 kPa and 27% ≥12.5 kPa were classified as low-risk.Pretreatment LSM is associated with HCC risk, which remains stable during the initial five years post-SVR. The HCC risk score algorithm effectively identifies low-risk patients, who may not require HCC surveillance. [ABSTRACT FROM AUTHOR]

Background: Accurate detection of Hepatocellular carcinoma (HCC) feeding vessels during transcatheter arterial chemoembolization (TACE) is important for an effective treatment, while limiting non-target embolization. This study aimed to investigate the feasibility and accuracy of pre-TACE three dimensional (3D) CT angiography for tumor-feeding vessels detection compared to DSA. Methods: Sixty-nine consecutive patients referred for TACE from May 2022 to May 2023 were included. (3D) CT images were reconstructed from the pre-TACE diagnostic multiphasic contrast enhanced CT images and compared with non-selective digital subtraction angiography (DSA) images obtained during TACE for detection of HCC feeding vessels. A "Ground truth" made by consensus between observers after reviewing all available pre-TACE CT images, and DSA and CBCT images during TACE to detect the true feeding vessels was the gold standard. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), accuracy and ROC curve with AUC were calculated for each modality and compared. Results: A total of 136 active HCCs were detected in the 69 consecutive patients included in the study. 185 feeding arteries were detected by 3D CT and DSA and included in the analysis. 3D CT detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV and accuracy of 91%, 71%, 98%, 36%, and 90%, respectively, with mean AUC = 0.81. DSA detection of feeding arteries revealed mean sensitivity, specificity, PPV, NPV, and accuracy of 80%, 58%, 96.5%, 16.5% and 78%, respectively, with mean AUC = 0.69. Conclusions: Pre-TACE 3D CT angiography has shown promise in improving the detection of HCC feeding vessels compared to DSA. However, further studies are required to confirm these findings across different clinical settings and patient populations. Trial registration: This study was prospectively registered at Clinicaltrials.gov with ID NCT05304572; Date of registration: 2-4-2022. [ABSTRACT FROM AUTHOR]

Purpose: The Barcelona Clinic Liver Cancer (BCLC) staging schema is widely used for hepatocellular carcinoma (HCC) treatment. In the updated recommendations, HCC BCLC stage B can become candidates for transplantation. In contrast, hepatectomy is currently not recommended. Methods: This systematic review includes a multi-institutional meta-analysis of patient-level data. Survival, postoperative mortality, morbidity and patient selection criteria for liver resection and transplantation in BCLC stage B are explored. All clinical studies reporting HCC patients with BCLC stage B undergoing liver resection or transplantation were included. Results: A total of 31 studies with 3163 patients were included. Patient level data was available for 580 patients from 9 studies (423 after resection and 157 after transplantation). The overall survival following resection was 50 months and recurrence-free survival was 15 months. Overall survival after transplantation was not reached and recurrence-free survival was 45 months. The major complication rate after resection was 0.11 (95%-CI, 0.0-0.17) with the 90-day mortality rate of 0.03 (95%-CI, 0.03–0.08). Child-Pugh A (93%), minor resection (60%), alpha protein level less than 400 (64%) were common in resected patients. Resected patients were mostly outside the Milan criteria (99%) with mean tumour number of 2.9. Studies reporting liver transplantation in BCLC stage B were scarce. Conclusion: Liver resection can be performed safely in selected patients with HCC BCLC stage B, particularly if patients present with preserved liver function. No conclusion can done on liver transplantation due to scarcity of reported studies. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC), a prevalent primary malignant tumor, is notorious for its high mortality rate. Despite advancements in HCC treatment, patient outcomes remain suboptimal. This study endeavors to assess the potential prognostic significance of POLH-AS1 in HCC. Methods: In this research, we gathered RNA-Seq information from individuals with HCC in The Cancer Genome Atlas (TCGA). We analyzed the levels of POLH-AS1 expression in both HCC cells and tissues using statistical tests. Additionally, we examined various prognostic factors in HCC using advanced methodologies. Furthermore, we employed Spearman's rank correlation analysis to examine the association between POLH-AS1 expression and the tumor's immune microenvironment. Finally, the functional roles of POLH-AS1 in HCC were validated in two HCC cell lines (HEP3B and HEPG2). Results: Our analysis revealed elevated POLH-AS1 expression across various cancers, including HCC, with heightened expression correlating with HCC progression. Notably, POLH-AS1 expression emerged as a potential biomarker for HCC patient survival and prognosis. Mechanistically, we identified the involvement of POLH-AS1 in tumorigenesis pathways such as herpes simplex virus 1 infection, interactions with neuroactive receptors, and the cAMP signaling pathway. Lastly, inhibition of POLH-AS1 was discovered to hinder the proliferation, invasion and migration of HEP3B and HEPG2 HCC cells. Conclusions: POLH-AS1 emerges as a promising prognostic biomarker and therapeutic target for HCC, offering potential avenues for enhanced patient management and treatment strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) stands as a primary malignancy of the liver and represents a significant global health burden, particularly in regions where chronic hepatitis B and C infections prevail. Despite advancements in diagnostic techniques and therapeutic strategies, HCC continues to pose formidable challenges in clinical management due to its aggressive nature, frequent late-stage diagnosis, and metastasis to other organs. Although the incidence of metastasis to the diaphragm is low, this condition is one of few poor prognostic factors for HCC, making the early detection of diaphragm muscle involvement important in both primary and recurrent stages. The purpose of our study was to address two questions: (1) What symptoms or symptom clusters are reported among HCC patients with metastases to the diaphragm? (2) What risk factors for diaphragm muscle metastasis are present in HCC patients? Based on our findings, we conclude that the presence of hepatitis B and the localization of HCC cells in superior liver segments, particularly in the 8th liver segment, should be considered during the diagnostic process. Each patient in the reports presented with different symptoms, making it impossible to identify the leading symptom. The purpose of this study was to conduct a systematic review and meta-analysis of case reports presenting HCC spread to the diaphragm muscle and to determine possible risk factors for this condition. An extensive literature search was performed using the following electronic databases: MEDLINE, CINAHL, ScienceDirect, Google Scholar, and DOAJ. A total of 18 articles describing 27 hepatocellular carcinoma patients were included in this review. The presence of HCC cells in the superior liver segment is strongly associated with metastases to the diaphragm. Among the two types of diaphragm involvement by HCC cells, diaphragm infiltration occurs much more frequently than diaphragm adhesion. However, an HCC nodule in the 8th liver segment and a higher number of liver segments involved by HCC cells predispose patients to diaphragm adhesion. Hepatitis B is a risk factor for diaphragm metastases in recurrent HCC. The tumor diameter is not associated with HCC spread to the diaphragm muscle. We did not find specific symptoms reported by patients that could indicate HCC metastasis to the diaphragm muscle. The presence of hepatitis B and the localization of HCC cells in superior liver segments, especially in the 8th liver segment, should be take into consideration in the diagnostic process. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondria are important organelles in the human body, and they act as a source of chemical energy for different cellular processes. Multiple copies of mitochondria are normally detected in cells, and their copy number has also been reported to be aberrated in cancers, including liver cancer. Target-panel sequencing is frequently used in oncology studies, but the optimal pooling ratio of nuclear and mitochondrial probes has remained elusive. Therefore, it is necessary to determine the physiological mitochondrial DNA copy number in non-liver cancer subjects, which can serve as a useful reference for deciding the desirable ratio of nuclear and mitochondrial probes for a less biased target enrichment of nuclear and mitochondrial genomes and hence their even representation. In addition, it can also be used as a physiological basis that can distinguish normal physiological variations from the pathological conditions in liver cancer. Mitochondria generate energy to support cells. They are important organelles that engage in key biological pathways. The dysfunction of mitochondria can be linked to hepatocarcinogenesis, which has been actively explored in recent years. To investigate the mitochondrial dysfunction caused by genetic variations, target-panel sequencing is a flexible and promising strategy. However, the copy number of mitochondria generally exceeds nuclear DNA, which raises a concern that uneven target enrichment of mitochondrial DNA (mtDNA) and nuclear DNA (ncDNA) in target-panel sequencing would lead to an undesirably biased representation of them. To resolve this issue, we evaluated the optimal pooling of mtDNA probes and ncDNA probes by a series of dilutions of mtDNA probes in both genomic DNA (gDNA) and cell-free DNA (cfDNA) samples. The evaluation was based on read count, average sequencing depth and coverage of targeted regions. We determined that an mtDNA:ncDNA probe ratio of around 1:10 would offer a good balance of sequencing performance and cost effectiveness. Moreover, we estimated the median physiological mtDNA:ncDNA copy ratio as 38.1 and 2.9 in cfDNA and gDNA samples of non-liver cancer subjects, respectively, whereas they were 20.0 and 2.1 in the liver cancer patients. Taken together, this study revealed the appropriate pooling strategy of mtDNA probes and ncDNA probes in target-panel sequencing and suggested the normal range of physiological variation of the mtDNA:ncDNA copy ratio in non-liver cancer individuals. This can serve as a useful reference for future target-panel sequencing investigations of the mitochondrial genome in liver cancer. [ABSTRACT FROM AUTHOR]

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer‐related mortality and transarterial chemoembolisation (TACE) is an established technique to treat patients with intermediate‐stage HCC. The aim of this study was to generate accurate costing data on cTACE and DEB‐TACE in an Australian setting and assess whether one of the procedures offers favourable cost‐effectiveness. Methods: Costing study using data from all TACE procedures performed at a single centre between January 2018 and December 2022. Data were included from all direct and indirect costs including operative costs, wages, overheads, ward costs, transfusion, pathology, pharmacy and ward support. Cost‐effectiveness was assessed by dividing local costs by existing high‐quality data on quality‐adjusted life years (QALYs). Results: 64 TACE treatments were performed on 44 patients. Mean age was 66.5 years and 91% were male. Overall median total cost per patient for the entire TACE treatment regime was AUD$7380 (range AUD$3719–$20,258). However, 39% of patients received more than one treatment, and the median cost per individual treatment was AUD$5270 (range AUD$3533–$15,818). The difference in median cost between cTACE (AUD$4978) and DEB‐TACE (AUD$9202) was significant, P < 0.001. In calculating cost‐effectiveness, each cTACE treatment cost AUD$2489 per QALY gained, while each DEB‐TACE cost AUD$3834 per QALY gained. The incremental cost‐effectiveness ratio (ICER) for DEB‐TACE over cTACE was AUD$10,560 per QALY gained. Conclusion: Both cTACE and DEB‐TACE are low‐cost treatments in Australia. However, DEB‐TACE offers a solution with an ICER of AUD$10,560 per QALY gained which is below the Australian government willingness to pay threshold and thus is a more cost‐effective treatment. [ABSTRACT FROM AUTHOR]

Immunotherapies have significantly improved the prognosis of patients with advanced hepatocellular carcinoma (HCC), although more than 70% of patients still do not respond to this first‐line treatment. Many new combination strategies are currently being explored, which drastically increases the need for preclinical models that would allow large‐scale testing of new immunotherapies and their combinations. We developed several in ovo (in the egg) human liver cancer models, based on human tumor xenografts of different liver cancer cell lines on the chicken embryo's chorioallantoic membrane. We characterized the angiogenesis, as well as the collagen accumulation and tumor immune microenvironment, and tested atezolizumab (anti‐PD‐L1) plus bevacizumab (anti‐VEGF) treatment. Our results show the involvement of chicken immune cells in tumor growth, reproducing a classical non‐inflamed "cold" as well as inflamed "hot" tumor status, depending on the in ovo liver cancer model. The treatment by atezolizumab and bevacizumab was highly efficient in the "hot" tumor model PLC/PRF/5 in ovo with the reduction of tumor size by 76% (p ≤.0001) compared with the control, whereas the efficacy was limited in the "cold" Hep3B in ovo tumor. The contribution of the anti‐PD‐L1 blockade to the anti‐tumoral effect in the PLC/PRF/5 in ovo model was demonstrated by the efficacy of atezolizumab monotherapy (p =.0080, compared with the control). To conclude, our study provides a detailed characterization and rational arguments that could help to partially replace conventional laboratory animals with a more ethical model, suited to the current needs of preclinical research of new immunotherapies for liver cancer. [ABSTRACT FROM AUTHOR]

This study aims to evaluate and compare the predictive accuracy of Sonazoid-contrast-enhanced ultrasound (CEUS) and Gd-EOB-DTPA-enhanced MRI for detecting microvascular invasion (MVI) in hepatocellular carcinoma (HCC). In this single-center prospective study, we included 64 patients with histopathologically confirmed single HCC lesions. Based on post-operative pathologic data, patients were categorized into two groups: those with MVI (n = 21) and those without MVI (n = 43). The diagnostic efficacy of CEUS was compared with that of MRI in predicting MVI. Multifactorial analysis revealed that US features (tumor size > 4.35 cm, peritumoral enhancement, post-vascular ring enhancement, peak energy in the arterial phase of the difference between the margin area of HCC and distal liver parenchyma <−1.0 × 106 a.u), MRI features (rim enhancement, irregular tumor margin, and the halo sign) were all independent predictors of MVI (p < 0.05). The sensitivity and specificity of CEUS features in predicting MVI ranged from 61.9% to 86.4% and from 42.9% to 71.4%, respectively. For MRI features, the sensitivity and specificity ranged from 33.3% to 76.3% and from 54.7% to 90.5%, respectively. No statistically significant differences were observed in the area under the curve between CEUS and MRI (p > 0.05). Notably, peak energy of the difference showed the highest sensitivity at 86.4%, while the halo sign in MRI exhibited the highest specificity at 90.5%. Sonazoid-CEUS and Gd-EOB-DTPA-enhanced MRI demonstrate potential in predicting MVI in HCC lesions. Notably, CEUS showed higher sensitivity, whereas MRI displayed greater specificity in predicting MVI. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ever since the GALAD (gender-age-Lens culinaris agglutinin-reactive alpha-fetoprotein-alpha-fetoprotein-des-gamma-carboxy prothrombin) logistic regression model was established to diagnose hepatocellular carcinoma (HCC), there has been no high-level evidence that evaluates and summarizes it. OBJECTIVE: This meta-analysis was performed to assess the diagnostic ability of the GALAD model. METHODS: The following databases were systematically searched for original diagnostic studies on HCC: PubMed, Embase, Medline, the Web of Science, Cochrane Library, China National Knowledge Infrastructure Wanfang (China), Wiper and the Chinese BioMedical Literature Database. After screening the search results according to our criteria, the Quality Assessment of Diagnostic Accuracy Studies 2 tool was used to evaluate the methodologic qualities, and statistical software were used to output the statistics. RESULTS: Ultimately, 10 studies were included and analyzed. The results revealed the pooled sensitivity and specificity of the GALAD model to be 0.86 (95% confidence interval [CI]: 0.82, 0.90) and 0.90 (95% CI: 0.87, 0.92), respectively, for all-stage HCC. The area under the curve (AUC) was 0.94. For early-stage HCC, the pooled sensitivity and specificity of the GALAD model were 0.83 (95% CI: 0.78, 0.87) and 0.81 (95% CI: 0.78, 0.83), respectively. The AUC was 0.90. CONCLUSION: This meta-analysis confirmed that the GALAD model has excellent diagnostic performance for early-stage and all-stage HCC and can maintain high sensitivity and specificity in early-stage HCC. Therefore, the GALAD model is qualified for screening early-stage canceration from chronic liver disease. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most aggressive types of cancer. Although it has a high mortality rate, there is currently no effective treatment for HCC. Lenvatinib has traditionally been used as the first-line treatment for advanced HCC (aHCC); however, resistance to this therapy is common. It can be difficult to select effective second-line drugs to overcome lenvatinib resistance when treating aHCC. For patients with aHCC, poor treatment efficacy can result in patients missing the optimal treatment window and can lead to an irreversible situation. Lenalidomide has begun to be used to treat HCC; however, to the best of our knowledge, its efficacy in patients with lenvatinib-resistant HCC remains to be reported on in the literature. The present case report, to the best of our knowledge, describes the first case in the literature of a patient with lenvatinib-resistant aHCC who achieved a partial response after the treatment regimen was switched to lenalidomide. The present case report provides a promising novel route for the treatment of lenvatinib-resistant HCC. [ABSTRACT FROM AUTHOR]

The prediction of liver-related events (LRE) after sustained virological response (SVR) in HCV-advanced chronic liver disease (ACLD) patients is crucial. We aimed to evaluate incidence and risk factors of LRE in HCV-cirrhotic patients after SVR and to assess dynamic changes of liver stiffness in participants without LRE at the end of follow-up. We enrolled 575 consecutive patients with HCV-ACLD treated with DAAs and followed up for 5 years after SVR12. Overall, 98 (17%) patients developed any type of event, and HCC was the most frequent LRE. The incidence rate was 1.6 per 100 person-years (p/y) for both HCC and hepatic decompensation. Baseline LSM ≥ 20 kPa was the only independent predictor of hepatic decompensation, while LSM ≥ 20 kPa and male sex were independent predictors of HCC development. Among the 341 participants without LRE and with paired LSM, any LSM reduction was observed in 314 (92.1%), and half of them showed a decrease of LSM ≥ 20%. Among patients without LRE, 27.3% of participants without ≥20% LSM decrease at 2 years achieved the 5-year goal; in contrast, 31.6% of participants with ≥20% LSM decrease at 2 years lost it at 5 years. These findings provide evidence that baseline LSM is a tool to stratify patients at risk of developing LRE; the dynamic changes of LSM value suggest the need for monitoring this parameter over time. [ABSTRACT FROM AUTHOR]