Skeletal muscle quality predicts overall survival in advanced liver hepatocellular carcinoma treated with SIRT and sorafenib: A subanalysis of the SORAMIC trial.

BACKGROUND AND AIMS: Our purpose was to assess the impact of muscle quality on overall survival (OS) in patients with advanced HCC. METHODS: This is a subanalysis of the SORAMIC trial. Overall, 363 patients were included. The SIRT/Sorafenib treatment group comprised 182 patients and the sorafenib group 181 patients. Myosteatosis was defined as skeletal muscle density (SMD) < 41 HU for patients with a body mass index up to 24.9 kg/m2 and <33 HU for patients with a body mass index ≥25 kg/m2. Albumin-gauge score was calculated as follows: serum albumin (g/dL) × SMD (HU). To assess the impact of muscle quality on clinical variables and OS, a Cox regression model was used. Hazard ratios are presented together with 95 % confidence intervals (95 % CI). Kaplan-Meier curves were used for survival analysis. RESULTS: In the SIRT/sorafenib cohort, low albumin-gauge score was an independent predictor of worse OS, HR = 1.74, CI 95% (1.16-2.62), p = 0.01. In the sorafenib cohort, muscle quality parameters did not predict OS. In alcohol-induced HCC (n = 129), myosteatosis independently predicted OS, HR = 1.85, CI 95% (1.10; 3.12), p = 0.02. In viral-induced HCC (n = 99), parameters of muscle quality did not predict OS. In patients with NASH/Non-alcoholic fatty liver disease (NAFLD) induced HCC, albumin-gauge score was a strong independent predictor of worse OS in the subgroup undergoing combined treatment with SIRT and sorafenib, HR = 9.86, CI 95% (1.12; 86.5), p = 0.04. CONCLUSIONS: Myosteatosis predicts independently worse OS in patients with alcohol-induced HCC undergoing combined treatment with SIRT and sorafenib. In patients with NASH/NAFLD induced HCC undergoing treatment with SIRT and sorafenib, albumin-gauge score predicts independently worse OS. IMPACT AND IMPLICATIONS: Associations between parameters of muscle quality and OS are different in accordance to the treatment strategy and etiology of HCC. These findings highlight the prognostic potential of skeletal muscle quality in patients with advanced HCC.

Liver Transplantation Profile Among Teenagers in the United States.

PURPOSE: Indications for liver transplantation (LT) vary across age groups. We identified predictors of outcomes for teenage LT waitlisted candidates and recipients in the United States from 2008 to 2022. METHODS: The Scientific Registry of Transplant Recipients 2008-2022 provided data (clinical, sociodemographic, indications for LT, outcomes) for all teenagers (13-19 years) waitlisted for LT in the United States. Sociodemographic and clinical characteristics, including primary listing diagnoses, were evaluated and compared by age group (13-16 vs. 17-19 years) among waitlisted teenage candidates. RESULTS: There were 2,813 teenage LT candidates listed between 2008 and 2022. The most common LT indication was acute liver disease (23.5%), followed by biliary atresia or hypoplasia (11.9%), autoimmune hepatitis (11.1%), and primary sclerosing cholangitis (9.7%). In contrast, chronic viral hepatitis, metabolic dysfunction-associated steatotic liver disease, and alcohol-related liver disease (the most common indications in adults) did not exceed 1% each; 2.8% had hepatocellular carcinoma. Excluding the two most recent years, 67.2% of candidates received a transplant; mean time to transplant was 217.0 days (standard deviation 371.6). Independent predictors of receiving a transplant were a more recent calendar year, younger age, higher model for end-stage liver disease score, and an acute liver disease diagnosis (all p < .05). Among the LT group, 3-year survival was 90%, with an improving survival trend. Higher post-transplant mortality was associated with earlier years of transplantation, older age, having Medicaid, being retransplanted, and having hepatocellular carcinoma (adjusted hazard ratios >1, all p < .05). DISCUSSION: Indications for LT among US teenagers are different from adults or younger children. There is a trend toward improved post-transplant outcomes.

Clinical Utility of the aMAP Score for Predicting Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B.

This study aimed to evaluate the efficacy of the aMAP score and compare it with other risk scores for predicting hepatocellular carcinoma (HCC) development in Thai patients with chronic hepatitis B (CHB). We retrospectively analyzed patients with CHB between 1 January 2008 and 31 December 2019. Data on demographics, clinical parameters, cirrhosis status, HCC imaging, and alpha fetoprotein surveillance were collected to calculate the aMAP score (0-100) based on age, sex, albumin-bilirubin level, and platelet count. Of the 1060 patients analyzed, 789 were eligible, of whom 51 developed HCC. The cumulative HCC incidences in the low-, moderate-, and high-risk groups at 3, 5, and 10 years were significantly different (log-rank, p < 0.0001). The area under the receiver operating characteristic curves (AUROCs) of the aMAP scores for predicting HCC at 3, 5, and 10 years were 0.748, 0.777, and 0.784, respectively. Among the risk scores, the CU-HCC score had the highest AUROCs (0.823) for predicting 5-year HCC development. The aMAP score is a valuable tool for predicting HCC risk in Thai patients with CHB and can enhance surveillance strategies. However, its performance is inferior to that of the CU-HCC score, suggesting the need for new predictive tools for HCC surveillance.

The Negative Impact of Sarcopenia on Hepatocellular Carcinoma Treatment Outcomes.

INTRODUCTION: Hepatocellular carcinoma (HCC) represents a major global health concern, characterized by evolving etiological patterns and a range of treatment options. Among various prognostic factors, sarcopenia, characterized by loss of skeletal muscle mass, strength, and function, has emerged as a pivotal contributor to HCC outcomes. Focusing on liver transplantation, surgical resection, locoregional treatments, and systemic therapies, this review aims to analyze the impact of sarcopenia on HCC treatment outcomes, shedding light on an underexplored subject in the pursuit of more personalized management. METHODS: A comprehensive literature review was conducted by searching peer-reviewed articles on sarcopenia and treatment outcomes in patients with HCC from inception up to October 2023. RESULTS: Sarcopenia was found to be prevalent among HCC patients, exhibiting different occurrence, possibly attributable to diverse diagnostic criteria. Notably, despite variations in studies utilizing skeletal muscle indices, sarcopenia independently correlated with lower overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS) across surgical (both transplantation and resection), locoregional, and systemic therapies, including tyrosine-kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs). Moreover, a link between sarcopenia and increased rate and severity of adverse events, particularly in surgery and TKIs recipients, and larger tumor size at diagnosis was observed. While baseline sarcopenia negatively influenced treatment outcomes, alterations in muscle mass post-treatment emerged as primary determinants of reduced OS. CONCLUSIONS: Sarcopenia, either present before or after HCC treatment, negatively correlates with response to it, across all etiologies and therapeutic strategies. Although only a few studies have evaluated the impact of supervised physical activity training on muscle mass and OS after HCC treatment, it is crucial to evaluate the presence of sarcopenia before treatment initiation, to better stratify patients' prognosis, thus performing a more tailored approach, and identify therapies able to restore muscle mass in HCC patients. Conversely, the impact of sarcopenia on HCC recurrence and extrahepatic spread remains inadequately explored.

Preclinical Human and Murine Models of Hepatocellular Carcinoma (HCC).

Hepatocellular carcinoma (HCC) is the most frequent liver cancer, which account for more than 90 % of all liver cancer cases. It is the fifth leading cause of cancer globally and the second leading cause of cancer-related mortality in men. The availability of competent HCC preclinical models is fundamental to the success of mechanistic studies, molecular target identification, and drug testing. However, there are challenges associated with the use of these models. In this review, we provided updates on various cell lines, animals, and human HCC models, their specific preclinic use and associated potential challenges. Overall, the understanding of the merits and demerits of a particular HCC model will improve model selection for various preclinical studies.

Causal relationship between immune cells and hepatocellular carcinoma: a Mendelian randomisation study.

Background: Hepatocellular carcinoma (HCC), the predominant malignancy of the digestive tract, ranks as the third most common cause of cancer-related mortality globally, significantly impeding human health and lifespan. Emerging immunotherapeutic approaches have ignited fresh optimism for patient outcomes. This investigation probes the link between 731 immune cell phenotypes and HCC through Mendelian Randomization and single-cell sequencing, aiming to unearth viable drug targets and dissect HCC's etiology. Methods: We conducted an exhaustive two-sample Mendelian Randomization analysis to ascertain the causal links between immune cell features and HCC, utilizing publicly accessible genetic datasets to explore the causal connections of 731 immune cell traits with HCC susceptibility. The integrity, diversity, and potential horizontal pleiotropy of these findings were rigorously assessed through extensive sensitivity analyses. Furthermore, single-cell sequencing was employed to penetrate the pathogenic underpinnings of HCC. Results: Establishing a significance threshold of pval_Inverse.variance.weighted at 0.05, our study pinpointed five immune characteristics potentially elevating HCC risk: B cell % CD3- lymphocyte (TBNK panel), CD25 on IgD+ (B cell panel), HVEM on TD CD4+ (Maturation stages of T cell panel), CD14 on CD14+ CD16- monocyte (Monocyte panel), CD4 on CD39+ activated Treg ( Treg panel). Conversely, various cellular phenotypes tied to BAFF-R expression emerged as protective elements. Single-cell sequencing unveiled profound immune cell phenotype interactions, highlighting marked disparities in cell communication and metabolic activities. Conclusion: Leveraging MR and scRNA-seq techniques, our study elucidates potential associations between 731 immune cell phenotypes and HCC, offering a window into the molecular interplays among cellular phenotypes, and addressing the limitations of mono-antibody therapeutic targets.

Role of liver resection in the era of advanced systemic therapy for hepatocellular carcinoma.

The recent dramatic progress in systemic therapy for hepatocellular carcinoma (HCC) provides the possibility of a combination of surgery and systemic therapy including adjuvant, neoadjuvant, or conversion settings. Since the turn of the century, at least three negative studies have tested adjuvant therapies after curative resection or ablation, including uracil-tegafur, which is an oral chemotherapeutic drug, sorafenib, and peretinoin, which a synthetic retinoid that may induce the apoptosis and differentiation of liver cancer cells. Using more potent immuno-checkpoint inhibitors (ICIs), at least 4 phase III trials of adjuvant immunotherapy are ongoing: nivolumab, durvalumab/ bevacizumab, pembrolizumab, and atezolizumab+bevacizumab. Very recently, the last trial indicated a significantly better recurrence-free survival (RFS) for adjuvant atezolizumab+bevacizumab. Another promising combination of surgery and systemic therapy is neoadjuvant therapy for potentially resectable cases or a conversion strategy for oncologically unresectable cases. There are 2 neoadjuvant trials for technically or oncologically unresectable HCCs ongoing in Japan: the LENS-HCC trial using lenvatinib and the RACB study using atezolizumab+bevacizumab. A longer follow-up may be needed, but the overall survival (OS) in resected cases seems much higher than that in unresectable cases. Recently, the Japan Liver Cancer Association (JLCA) and the Japanese Society of HPB Surgery (JSHPBS) created a joint working group on "so-called borderline resectable HCC". They obtained a Japanese consensus on this issue that has been published on the websites of JLCA and JSHPBS. The definition of resectability or borderline resectability provides a common language regarding advanced HCC for investigators and is a useful tool for future clinical trials.

Prognostic value of CMTM6 protein in hepatocellular carcinoma involving the regulation of the immune microenvironment.

There have been notable irregularities in CMTM6 expression observed in hepatocellular carcinoma (HCC), with an evident correlation between CMTM6 dysregulation and patient prognosis. The cell cycle progression came to a halt at the G2/M phase. In-depth RNA-sequencing analysis of CMTM6 knockdown Hep3B cells revealed that the most prominent effect of CMTM6 perturbation was on the expression of CXCL8, a chemokine involved in immune responses, particularly through the interleukin-17F (IL-17F) signaling pathway. By carefully examining the RNA-sequencing data obtained from CMTM6 knockdown Hep3B cells and cross-referencing it with the TCGA-LIHC database, we were able to discern that CMTM6 and programmed death-ligand 1 (PD-L1) collaboratively partake in immune regulation within T cells. Furthermore, CMTM6 exerted an influential role in modulating the infiltration of CD4+ and CD8+ T cells in the HCC microenvironment, thereby impacting the overall immune response. Our investigation found that HCC cases characterized by an elevated co-expression of CMTM6 and PD-L1, along with augmented CD4+ T cell infiltration, demonstrated comparatively longer overall and progression-free survival rates when contrasted with those displaying lower CD4+ T cell infiltration.

Recent Advances in RNA Interference-Based Therapy for Hepatocellular Carcinoma: Emphasis on siRNA.

Even though RNA treatments were first proposed as a way to change aberrant signaling in cancer, research in this field is currently ongoing. The term "RNAi" refers to the use of several RNAi technologies, including ribozymes, riboswitches, Aptamers, small interfering RNA (siRNA), antisense oligonucleotides (ASOs), and CRISPR/Cas9 technology. The siRNA therapy has already achieved a remarkable feat by revolutionizing the treatment arena of cancers. Unlike small molecules and antibodies, which need administration every three months or even every two years, RNAi may be given every quarter to attain therapeutic results. In order to overcome complex challenges, delivering siRNAs to the targeted tissues and cells effectively and safely and improving the effectiveness of siRNAs in terms of their action, stability, specificity, and potential adverse consequences are required. In this context, the three primary techniques of siRNA therapies for hepatocellular carcinoma (HCC) are accomplished for inhibiting angiogenesis, decreasing cell proliferation, and promoting apoptosis, are discussed in this review. We also deliberate targeting issues, immunogenic reactions to siRNA therapy, and the difficulties with their intrinsic chemistry and transportation.

A study comparing the cost-effectiveness of conventional and drug-eluting transarterial chemoembolisation (cTACE and DEB-TACE) for the treatment of hepatocellular carcinoma in an Australian public hospital.

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.

Deubiquitination of CIB1 by USP14 promotes lenvatinib resistance via the PAK1-ERK1/2 axis in hepatocellular carcinoma.

Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo. Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC.

Emerging role of exosomal microRNA in liver cancer in the era of precision medicine; potential and challenges.

Exosomal microRNAs (miRNAs) have great potential in the fight against hepatocellular carcinoma (HCC), the fourth most common cause of cancer-related death worldwide. In this study, we explored the various applications of these small molecules while analyzing their complex roles in tumor development, metastasis, and changes in the tumor microenvironment. We also discussed the complex interactions that exist between exosomal miRNAs and other non-coding RNAs such as circular RNAs, and show how these interactions coordinate important biochemical pathways that propel the development of HCC. The possibility of targeting exosomal miRNAs for therapeutic intervention is paramount, even beyond their mechanistic significance. We also highlighted their growing potential as cutting-edge biomarkers that could lead to tailored treatment plans by enabling early identification, precise prognosis, and real-time treatment response monitoring. This thorough analysis revealed an intricate network of exosomal miRNAs lead to HCC progression. Finally, strategies for purification and isolation of exosomes and advanced biosensing techniques for detection of exosomal miRNAs are also discussed. Overall, this comprehensive review sheds light on the complex web of exosomal miRNAs in HCC, offering valuable insights for future advancements in diagnosis, prognosis, and ultimately, improved outcomes for patients battling this deadly disease.

Recurrence of Hepatocellular Carcinoma in Patients with Low Albumin-Bilirubin Grade in TACE Combined with Ablation: A Random Forest Cox Predictive Model.

Purpose: The aim of our study was to investigate the relationship between albumin-bilirubin (ALBI) grade and recurrence in patients who underwent TACE sequential ablation. We developed and validated a nomogram to predict low levels of ALBI patients' recurrence. Patients and Methods: A total of 880 patients undergoing TACE combined ablation at Beijing Youan Hospital from January 2014 to December 2021 were retrospectively enrolled, including 415 patients with L-ALBI (≤-2.6) and 465 patients with high levels (>-2.6) of ALBI (H-ALBI). L-ALBI patients were randomized in a 7:3 ratio into the training cohort (N=289) and validation cohort (N=126). Multivariate Cox regression followed by random survival forest was carried out to identify independent risk factors for prediction nomogram construction. An examination of nomogram accuracy was performed using the C-index, receiver operating characteristic (ROC), calibration curves, and decision curve analysis (DCA) curves. According to the nomogram, the patients were divided into low-risk, intermediate-risk, and high-risk groups. Kaplan-Meier (KM) curves were applied to compare the difference in recurrence-free survival (RFS) among the three groups. Results: The median RFS in L-ALBI patients was significantly longer than the H-ALBI patients (40.8m vs 20.1m, HR:1.71, 95% CI:1.44-2.04, P<0.0001). The nomogram was composed of five variables, such as age, Barcelona Clinic Liver Cancer (BCLC) stage, globulin, gamma-glutamyl transferase to lymphocyte ratio (GLR), and international normalized ratio (INR). The C-index (0.722 and 0.731) and 1-, 3-, and 5-year AUCs (0.725, 0.803, 0.870, and 0.764, 0.816, 0.798) of the training and validation cohorts proved the good predictive performance of the nomogram. Calibration curves and DCA curves demonstrated good consistency and good clinical utility. There were significant differences in RFS between the low-risk, intermediate-risk, and high-risk groups (P<0.0001). Conclusion: L-ALBI Patients who underwent TACE combined ablation had better recurrence-free survival than patients with H-ALBI. The nomogram developed and validated in our study had good predictive ability in recurrence for L-ALBI patients.

DPF2 overexpression correlates with immune infiltration and dismal prognosis in hepatocellular carcinoma.

Background: Double plant homeodomain finger 2 (DPF2), belonging to the d4 family of structural domains, has been associated with various human malignancies. However, its impact on hepatocellular carcinoma (HCC) remains unclear. The objective of this study is to elucidate the role of DPF2 in the diagnosis and prognosis of HCC. Methods: DPF2 gene expression in HCC and adjacent tissues was analyzed using Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, validated by immunohistochemical staining of Guangxi specimens and data from the Human Protein Atlas (HPA). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to identify DPF2's potential pathways and functions in HCC. DPF2's mutation and methylation statuses were assessed via cBioPortal and MethSurv. The association between DPF2 and immune infiltration was investigated by TIMER. The prognostic value of DPF2 in HCC was established through Kaplan-Meier and Cox regression analyses. Results: DPF2 levels were significantly higher in HCC than normal tissues (p<0.001), correlating with more severe HCC features (p<0.05). Higher DPF2 expression predicted poorer overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). DPF2 involvement was noted in critical signaling pathways including the cell cycle and Wnt. It also correlated with T helper cells, Th2 cells, and immune checkpoints like CTLA-4, PD-1, and PD-L1. Conclusion: High DPF2 expression, associated with poor HCC prognosis, may disrupt tumor immune balance and promote immune evasion. DPF2 could potentially be utilized as a biomarker for diagnosing and prognosticating hepatocellular carcinoma.

Beyond Occam's Razor: Concurrent Non-functional Pituitary Macroadenoma and Metastatic Hepatocellular Carcinoma in a Patient With Functional Cure of Hepatitis B.

Occam's razor, the principle of parsimony, is frequently employed in medicine to derive a single diagnosis from a patient's myriad symptoms. Conversely, Hickam's dictum, which embraces the principle of plenitude by considering multiple diagnoses for a patient's presentation, is often underutilized or not as widely recognized as Occam's razor. The application of Hickam's dictum is particularly crucial when evaluating nonspecific symptoms such as fatigue, which can manifest in various diseases. This report describes the case of a 72-year-old man with a history of functional cure for hepatitis B who presented with chronic fatigue and hyponatremia. Initially, he was diagnosed with non-functional pituitary macroadenoma and panhypopituitarism. Two months following pituitary surgery, the onset of dyspepsia and the recurrence of fatigue revealed metastatic tumors in the liver, stomach, pancreas, left adrenal gland, and peri-pancreatic lymph nodes. A liver biopsy confirmed the diagnosis of hepatocellular carcinoma. This case highlights the importance of considering multiple, potentially co-existing conditions based on the patient's symptoms and risk factors to complete the thorough diagnoses. Additionally, it emphasizes the need to remain vigilant regarding the risk of liver cancer in patients with a history of chronic hepatitis B infection, irrespective of a functional cure.

Risk Factors and Nomogram Model for Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients with Low-Level Viremia.

Background and aim: Patients with chronic hepatitis B patients (CHB) with low-level viremia (LLV) are not necessarily at low risk of developing hepatocellular carcinoma (HCC). The question of whether CHB patients with LLV require immediate antiviral agent (AVT) or long-term AVT remains controversial. The study aims to investigate the risk of HCC development and the risk factors in CHB patients with LLV and construct a nomogram model predicting the risk of HCC. Methods: We conducted a retrospective cohort study that enrolled 16,895 CHB patients from January 2008 to December 2020. The patients were divided into three groups for comparison: the LLV group, maintained virological response (MVR) group and HBV-DNA>2000 group. The cumulative incidence of progression to HCC was assessed. Cox regression analysis was performed to determine the final risk factors, and a nomogram model was constructed. The 10-fold Cross-Validation method was utilized for internal validation. Results: A total of 408 new cases of HCC occurred during the average follow-up period of 5.78 years. The 3, 5, and 10-year cumulative HCC risks in the LLV group were 3.56%, 4.96%, and 9.51%, respectively. There was a significant difference in the cumulative risk of HCC between the HBV-DNA level > 2000 IU/mL and LLV groups (p = 0.049). Independent risk factors for HCC development in LLV group included male gender, age, presence of cirrhosis, and platelets count. The Area Under the Curve (AUC) values for the 3-year and 5-year prediction from our HCC risk prediction model were 0.75 and 0.76, respectively. Conclusion: Patients with LLV and MVR are still at risk for developing HCC. The nomogram established for CHB patient with LLV, incorporating identified significant risk factors, serves as an effective tool for predicting HCC-free outcomes. This nomogram model provides valuable information for determining appropriate surveillance strategies and prescribing AVT.

Data Independent Acquisition Mass Spectrometry Enhanced Personalized Glycosylation Profiling of Haptoglobin in Hepatocellular Carcinoma.

Aberrant glycosylation has gained significant interest for biomarker discovery. However, low detectability, complex glycan structures, and heterogeneity present challenges in glycoprotein assay development. Using haptoglobin (Hp) as a model, we developed an integrated platform combining functionalized magnetic nanoparticles and zwitterionic hydrophilic interaction liquid chromatography (ZIC-HILIC) for highly specific glycopeptide enrichment, followed by a data-independent acquisition (DIA) strategy to establish a deep cancer-specific Hp-glycosylation profile in hepatitis B virus (HBV, n = 5) and hepatocellular carcinoma (HCC, n = 5) patients. The DIA strategy established one of the deepest Hp-glycosylation landscapes (1029 glycopeptides, 130 glycans) across serum samples, including 54 glycopeptides exclusively detected in HCC patients. Additionally, single-shot DIA searches against a DIA-based spectral library outperformed the DDA approach by 2-3-fold glycopeptide coverage across patients. Among the four N-glycan sites on Hp (N-184, N-207, N-211, N-241), the total glycan type distribution revealed significantly enhanced detection of combined fucosylated-sialylated glycans, which were the most dominant glycoforms identified in HCC patients. Quantitation analysis revealed 48 glycopeptides significantly enriched in HCC (p < 0.05), including a hybrid monosialylated triantennary glycopeptide on the N-184 site with nearly none-to-all elevation to differentiate HCC from the HBV group (HCC/HBV ratio: 2462 ± 766, p < 0.05). In summary, DIA-MS presents an unbiased and comprehensive alternative for targeted glycoproteomics to guide discovery and validation of glyco-biomarkers.

Suppression of CTC1 inhibits hepatocellular carcinoma cell growth and enhances RHPS4 cytotoxicity.

BACKGROUND: Although DNA repair mechanisms function to maintain genomic integrity, in cancer cells these mechanisms may negatively affect treatment efficiency. The strategy of targeting cancer cells via inhibiting DNA damage repair has been successfully used in breast and ovarian cancer using PARP inhibitors. Unfortunately, such strategies have not yet yielded results in liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a treatment-resistant malignancy. Despite the development of guided therapies, treatment regimens for advanced HCC patients still fall short of the current need and significant problems such as cancer relapse with resistance still exist. In this paper, we targeted telomeric replication protein CTC1, which is responsible for telomere maintenance. METHODS: CTC expression was analyzed using tumor and matched-tissue RNA-sequencing data from TCGA and GTEx. In HCC cell lines, q-RT-PCR and Western blotting were used to detect CTC1 expression. The knock-down of CTC1 was achieved using lentiviral plasmids. The effects of CTC1 silencing on HCC cells were analyzed by flow cytometry, MTT, spheroid and colony formation assays. RESULTS: CTC1 is significantly downregulated in HCC tumor samples. However, CTC1 protein levels were higher in sorafenib-resistant cell lines compared to the parental groups. CTC1 inhibition reduced cell proliferation in sorafenib-resistant HCC cell lines and diminished their spheroid and colony forming capacities. Moreover, these cells were more sensitive to single and combined drug treatment with G4 stabilizer RHPS4 and sorafenib. CONCLUSION: Our results suggest that targeting CTC1 might be a viable option for combinational therapies designed for sorafenib resistant HCC patients.

A Case Presentation of Well-Differentiated Hepatocellular Carcinoma With No Sign of Liver Disease.

The type of liver cancer that occurs most frequently is hepatocellular carcinoma (HCC). The majority of cases of HCC are secondary to alcoholic cirrhosis or viral hepatitis. The presence of malignant cells with modest nuclear atypia that resemble normal hepatocytes and the lack of bare nuclei in the smears, which shows the neoplastic hepatocytes' capacity, are characteristics of a well-differentiated HCC plasma membrane to tolerate smearing. We present the case of an 83-year-old male patient with a well-differentiated HCC, who had no etiological factors and no signs of alcohol cirrhotic liver, or any symptoms of liver disease which are the main causes of the HCC.

Prognostic value of oxidative phosphorylation-related genes in hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the most prevalent malignancies worldwide. Recently, oxidative phosphorylation (OXPHOS) has received extensive concern as an emerging target in antitumor therapy. However, the OXPHOS-involved underlying genes and clinical utilization in HCC remain worth exploring. The present research aimed to create an OXPHOS-relevant signature in HCC. PATIENTS AND METHODS: In this study, the prognostic signature genes linked with OXPHOS were identified, and prognostic models were built using least absolute shrinkage and selection operator (LASSO) cox regression analysis. Furthermore, the combination study of immune microenvironment and signature genes looked into the involvement of immune cells in signature-based genes in HCC. Following that, chemotherapeutic drug sensitivity and immunotherapy analysis was implemented to predict clinical efficacy in HCC patients. Finally, clinical samples were collected to measure the expression of OXPHOS-related signature genes. RESULTS: Following a series of screens, six prognostic signature genes related with OXPHOS were identified: MRPS23, MPV17, MAPK3, IGF2BP2, CDK5, and IDH2, on which a risk model was built. The findings revealed a significant drop in the survival rate of HCC patients as their risk score increased. Meanwhile, independent prognostic study demonstrated that the risk score could accurately identify HCC patients. Immuno-microenvironmental correlation research suggested that the prognostic characteristics could serve as a reference index for both immunotherapy and chemotherapy. Finally, RT-qPCR exhibited a trend in signature gene expression that was consistent with the results. CONCLUSION: In this study, a total of six prognostic genes associated with OXPHOS were selected and a prognostic model was constructed, providing an essential reference for the study of OXPHOS in HCC.