Survival In Hepatocellular Carcinoma Research Articles

Abstract 7035: Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics

Abstract As the fifth leading cause of cancer-related mortality, liver cancer imposes a global burden. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with a five-year overall survival rate of less than 20% for advanced-stage cases. Even the most advanced immunotherapy for HCC has disparate response rates in each patient with HCC, which has led to efforts to unravel the underlying factors in the progression of HCC using bioinformatic approaches. In recent decades, numerous studies have explored T-cell subtypes with tissue-specific residency, suggesting their early protective functions and therapeutic potential within tumor microenvironment (TME). This study aimed to understand inter-individual and intercellular TME through single-cell RNA sequencing (scRNA-seq) and single-cell TCR sequencing (scTCR-seq) in five recurrent/non-recurrent HCC patients. We identified tumor-associated tissue-resident memory T (TA-TRM) cells and investigated the heterogeneous characteristics of two TRM clusters (CD69+ and CD103+). Whereas CD69+ TA-TRM showed high expression of genes associated with immunological activation, CD103+ TA-TRM exhibited upregulation of genes related to proliferation capacity. To validate the unique molecular patterns, we analyzed an independent HCC dataset (GSE140228) and observed high concordance of significant core marker genes for TA-TRM clusters between the two datasets. Moreover, we assessed the association of gene expression in TA-TRM cells with overall and recurrence-free survival by conducting survival analysis in two independent large-scale cohorts. The cross-validation approach was applied to estimate risk scores for patients with primary HCC tumors in The Cancer Genome Atlas (TCGA), and the trained model was evaluated using the International Cancer Genome Consortium (ICGC) data. The result of calculating the risk scores clearly indicates that TA-TRM cells are associated with survival in HCC. Therefore, our study characterized two distinct subtypes of TA-TRM cells in HCC, delineated their unique molecular signatures, and established their relevance to survival outcomes. The findings can potentially enhance the understanding of the roles of TA-TRM cells in the context of HCC. Citation Format: Mi-So Park, Hyunbin Cho, Hyeree Kim, Woong-Yang Park, Yong-Han Paik, Yeup Yoon, Wonseok Kang, Hong-Hee Won. Characterization of tissue-resident memory T cells in hepatocellular carcinoma through single-cell multi-omics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7035.

Abstract 5734: Polymeric delivery with dual drug payloads for hepatocellular carcinoma (HCC) therapy

Abstract Background: The long-term survival of hepatocellular carcinoma (HCC) patients is hampered by high recurrence and drug resistance. Targeting sonic hedgehog (SHH) pathways can overcome drug resistance in HCC. In this study, we co-loaded SHH inhibitor, cyclopamine (CPA) and paclitaxel (PTX) in a novel polymeric nanomicellar drug delivery system (M-CPA/PTX), to overcome the drug resistance in HCC tumor models. Method: The combinational effect in vitro was studied by treating HCC with CPA and PTX. The combinational index was calculated using CalcuSyn Biosoft software to determine the additive or synergistic effect of the combination. Three formulations (F0, F5, and F16) were selected for further testing based on formulation optimization using central composition design (CCD). The storage stability of M-CPA/PTXs at room temperature and 4 °C was evaluated by measuring the changes in micelle size, PDI, and encapsulation efficiency (EE) over pre-determined periods. In the pharmacokinetics (PK) study, nude mice were IP-injected with 5 mg/kg of PTX equivalent F0 and F16. Additionally, the toxicity of F0 was investigated using healthy Sprague Dawley rats, in which rats were intravenously injected with a single F0 dose of 1, 2, and 4 mg/kg/drug of M-CPA/PTX. Results: Combinational effect study suggested that CPA and PTX, demonstrated synergistic effect in Hep3B and HepG2 cells compared to the mono-treatment, thus overcoming resistance. F0, F5, and F16 exhibited particle sizes of 75.27 ± 1.06, 54.63 ± 0.85, and 70.63 ± 3.39 nm, respectively. The release kinetics of both drugs from these micelles displayed significantly slow-release profiles from the micelles, with less than 10% cumulative release within 24 hours in plasma. The stability study indicated that both drugs' micelle size and EE were not appreciably changed over 6 weeks at room temperature and 4 °C. Notably, the biodistribution studies showed that F16 achieved significantly greater accumulations of CPA in the liver, kidney, and spleen compared to F0 (P < 0.05). Additionally, the maximal tolerable dose of F0 in rats was 4 mg/kg/drug for the M-CPA/PTX combination, which did not result in treatment-related mortality. Conclusion: The combination of CPA and PTX offered promising synergistic effects on HCC treatment. F0, F5, and F16 were developed and characterized with the desired physicochemical properties and demonstrated controlled release characteristics for both payloads, suggesting their potential for sustained drug delivery in HCC therapy. Enhanced liver accumulation of F16 suggested favorable biodistribution for the site of action. Lastly, the safe toxicity profile supports the first choice of F0 among other lead candidates for further pre-clinical efficacy studies. Citation Format: Lu Dai, Guodong Zhang, Fatima Dagher, Airong Li, Amir Mohammad Gholizadeh, Chun Li, Diana S- Chow. Polymeric delivery with dual drug payloads for hepatocellular carcinoma (HCC) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5734.

Autophagy inhibition potentiates energy restriction-induced cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) significantly contributes to cancer-related mortality due to the limited response of HCC to current anticancer therapies, thereby necessitating more effective treatment approaches. Energy restriction mimetic agents (ERMAs) have emerged as potential therapies in targeting the Warburg effect, a unique metabolic process in cancer cells. However, ERMAs exhibit limited efficacy when used as monotherapy. Additionally, ERMAs have been found to induce autophagy in cancer cells. The role of autophagy in cancer survival remains a subject of debate. Thus, it is crucial to ascertain whether ERMA-induced autophagy is a mechanism for cell survival or cell death in HCC. Our study aims to investigate the effect of autophagy inhibition on the survival of HCC cells treated with ERMAs while also examining the potential of combining an autophagy inhibitor such as spautin-1 with ERMAs to enhance HCC cell death. Our results suggest a cytoprotective role for ERMA-induced autophagy in HCC cells, as combining the autophagy inhibitor spautin-1 with ERMAs effectively suppressed ERMA-induced autophagy and synergistically enhanced their antitumor activity. The treatment combination promoted HCC death through apoptosis, cell cycle arrest, and inhibition of AKT and ERK activation, which are known to play a key role in cellular proliferation. Collectively, our findings highlight a potential strategy to combat HCC by combining energy restriction with autophagy inhibition.

A pyrimidine metabolism-related signature for prognostic and immunotherapeutic response prediction in hepatocellular carcinoma by integrating analyses.

Hepatocellular carcinoma (HCC), with discouraging morbidity and mortality, ranks as one of the most prevalent tumors worldwide. Pyrimidine metabolism is a critical process that regulates DNA and RNA synthesis in cells. It is imperative to investigate the significance of pyrimidine metabolism in liver cancer. Transcriptome and clinical data were downloaded from the TCGA database and the GEO database. The genes related to pyrimidine metabolism were sourced from the MSigDB. The pyrimidine metabolism-related signature (PMRS) was constructed through Cox regression and Lasso regression and then verified in the external validation set from the ICGC database. Functional enrichment, immune infiltration analysis, drug sensitivity, and Immunophenoscore (IPS) were further implemented to predict the response to immunotherapy. The role of PMRS in the malignant phenotype of hepatocellular carcinoma was explored by conducting a series of in vitro experiments. Our study developed a four-genes PMRS which demonstrates a substantial correlation with the prognosis of HCC patients, serving as an independent predictor in clinical practice. The result of risk-stratified analysis yielded evidence that low-risk patients experienced more favorable clinical outcomes. The nomogram exhibited remarkable prognostic predictive value. The subsequent results revealed that low-risk patients manifested a more promising response to immunotherapy. Moreover, the results of cell experiments demonstrated that the downregulation of DCK markedly inhibited the malignant phenotype of hepatocellular carcinoma. Our pyrimidine metabolism-centered prognostic signature accurately predicts overall survival, immune status, and treatment response in hepatocellular carcinoma (HCC) patients, offering innovative insights for precise diagnosis, personalized treatment, and improved prognosis.

Chinese herbal medicine decreases incidence of hepatocellular carcinoma in diabetes mellitus patients with regular insulin management.

Type 2 diabetes mellitus (DM) is an independent risk factor for hepatocellular carcinoma (HCC), while insulin is a potent mitogen. Identifying a new therapeutic modality for preventing insulin users from developing HCC is a critical goal for researchers. To investigate whether regular herbal medicine use can decrease HCC risk in DM patients with regular insulin control. We used data acquired from the Taiwanese National Health Insurance research database between 2000 and 2017. We identified patients with DM who were prescribed insulin for > 3 months. The herb user group was further defined as patients prescribed herbal medication for DM for > 3 months per annum during follow-up. We matched the herb users to nonusers at a 1:3 ratio according to age, sex, comorbidities and index year by propensity score matching. We analyzed HCC incidence, HCC survival rates, and the herbal prescriptions involved. We initially enrolled 657144 DM patients with regular insulin use from 2000 to 2017. Among these, 46849 patients had used a herbal treatment for DM, and 140547 patients were included as the matched control group. The baseline variables were similar between the herb users and nonusers. DM patients with regular herb use had a 12% decreased risk of HCC compared with the control group [adjusted hazard ratio (aHR) = 0.88, 95%CI = 0.80-0.97]. The cumulative incidence of HCC in the herb users was significantly lower than that of the nonusers. Patients with a herb use of > 5 years cumulatively exhibited a protective effect against development of HCC (aHR = 0.82, P < 0.05). Of patients who developed HCC, herb users exhibited a longer survival time than nonusers (aHR = 0.78, P = 0.0001). Additionally, we report the top 10 herbs and formulas in prescriptions and summarize the potential pharmacological effects of the constituents. Our analysis indicated that Astragalus propinquus (Huang Qi) plus Salvia miltiorrhiza Bunge (Dan Shen), and Astragalus propinquus (Huang Qi) plus Trichosanthes kirilowii Maxim. (Tian Hua Fen) were the most frequent combination of single herbs. Meanwhile, Ji Sheng Shen Qi Wan plus Dan Shen was the most frequent combination of herbs and formulas. This large-scale retrospective cohort study reveals that herbal medicine may decrease HCC risk by 12% in DM patients with regular insulin use.

Infiltrative Vessel Co-optive Growth Pattern Induced by IQGAP3 Overexpression Promotes Microvascular Invasion in Hepatocellular Carcinoma.

Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms. IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.

Comparative analysis of perioperative and long-term outcomes of patients with hepatocellular carcinoma: Nonalcoholic fatty liver disease versus viral hepatitis.

Despite the accumulating evidence regarding the oncological differences between nonalcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC) and viral infection-related HCC, the short- and long-term outcomes of surgical resection of NAFLD-related HCC remain unclear. While some reports indicate improved postoperative survival in NAFLD-related HCC, other studies suggest higher postoperative complications in these patients. Patients with NAFLD and those with hepatitis viral infection who underwent hepatectomy for HCC at our department were retrospectively analyzed. The clinical, surgical, pathological, and survival outcomes were compared between the two groups. Among the 1047 consecutive patients who underwent hepatectomy for HCC, 57 had NAFLD-related HCC (NAFLD group), and 727 had virus-related HCC (VH group). The body mass index and serum glycated hemoglobin levels were significantly higher in the NAFLD group than in the VH group. There were no significant differences in operative time and bleeding amount. Moreover, the morbidity and the length of postoperative hospital stays were similar across both groups. The pathological results showed that the tumor size was significantly larger in the NAFLD group than in the VH group. No significant differences between the groups in overall or recurrence-free survival were found. In a subgroup analysis with matched tumor diameters, patients in the NAFLD group had a better prognosis after hepatectomy than those in the VH group. Surgical outcomes after hepatectomy were comparable between the groups. Subgroup analysis reveals early detection and surgical intervention in NAFLD-HCC may improve prognosis.

Suppression of A-to-I RNA-editing enzyme ADAR1 sensitizes hepatocellular carcinoma cells to oxidative stress through regulating Keap1/Nrf2 pathway

BackgroundA-to-I RNA editing is an abundant post-transcriptional modification event in hepatocellular carcinoma (HCC). Evidence suggests that adenosine deaminases acting on RNA 1 (ADAR1) correlates to oxidative stress that is a crucial factor of HCC pathogenesis. The present study investigated the effect of ADAR1 on survival and oxidative stress of HCC, and underlying mechanisms.MethodsADAR1 expression was measured in fifty HCC and normal tissues via real-time quantitative PCR, and immunohistochemistry. For stable knockdown or overexpression of ADAR1, adeno-associated virus vectors carrying sh-ADAR1 or ADAR1 overexpression were transfected into HepG2 and SMMC-7721 cells. Transfected cells were exposed to oxidative stress agonist tBHP or sorafenib Bay 43-9006. Cell proliferation, apoptosis, and oxidative stress were measured, and tumor xenograft experiment was implemented.ResultsADAR1 was up-regulated in HCC and correlated to unfavorable clinical outcomes. ADAR1 deficiency attenuated proliferation of HCC cells and tumor growth and enhanced apoptosis. Moreover, its loss facilitated intracellular ROS accumulation, and elevated Keap1 and lowered Nrf2 expression. Intracellular GSH content and SOD activity were decreased and MDA content was increased in the absence of ADAR1. The opposite results were observed when ADAR1 was overexpressed. The effects of tBHP and Bay 43–9006 on survival, apoptosis, intracellular ROS accumulation, and Keap1/Nrf2 pathway were further exacerbated by simultaneous inhibition of ADAR1.ConclusionsThe current study unveils that ADAR1 is required for survival and oxidative stress of HCC cells, and targeting ADAR1 may sensitize HCC cells to oxidative stress via modulating Keap1/Nrf2 pathway.

Machine Learning-Based Assessment of Survival and Risk Factors in Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma for Optimized Patient Management.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with an incidence that is exponentially increasing. Hepatocellular carcinoma (HCC) is the most frequent primary tumor. There is an increasing relationship between these entities due to the potential risk of developing NAFLD-related HCC and the prevalence of NAFLD. There is limited evidence regarding prognostic factors at the diagnosis of HCC. This study compares the prognosis of HCC in patients with NAFLD against other etiologies. It also evaluates the prognostic factors at the diagnosis of these patients. For this purpose, a multicenter retrospective study was conducted involving a total of 191 patients. Out of the total, 29 presented NAFLD-related HCC. The extreme gradient boosting (XGB) method was employed to develop the reference predictive model. Patients with NAFLD-related HCC showed a worse prognosis compared to other potential etiologies of HCC. Among the variables with the worst prognosis, alcohol consumption in NAFLD patients had the greatest weight within the developed predictive model. In comparison with other studied methods, XGB obtained the highest values for the analyzed metrics. In conclusion, patients with NAFLD-related HCC and alcohol consumption, obesity, cirrhosis, and clinically significant portal hypertension (CSPH) exhibited a worse prognosis than other patients. XGB developed a highly efficient predictive model for the assessment of these patients.

Three-dimensional morphology scoring of hepatocellular carcinoma stratifies prognosis and immune infiltration

BackgroundThe morphological attributes could serve as pivotal indicators precipitating early recurrence and dismal overall survival in hepatocellular carcinoma (HCC), and quantifying morphological features may better stratify the prognosis of HCC. ObjectiveTo develop a radiomics approach based on 3D tumor morphology features for predicting the prognosis of HCC and identifying differentially expressed genes related to morphology to guide HCC treatment. Materials and methodsRetrospective study of 357 HCC patients. Radiomic features were extracted from MRI tumor regions; 14 morphology-related features predicted early HCC recurrence and patient stratification via LASSO-Cox modeling. Overall survival (OS) and recurrence-free survival (RFS) were analyzed. RNA sequencing from the Cancer Imaging Archive (TCIA) examined drug sensitivity and stratified HCC using morphological immunity genes, validating recurrence and prognosis. ResultsPatients were split into training (n = 225), test (n = 132), and 50 TCIA dataset cohorts. Two features (Maximum2DdiameterColumn, Sphericity) in Cox regression stratified patients into high/low-risk Morphological Radiological Score (Morph-RS) groups. Significant OS and RFS were seen across all sets. Differentially expressed genes focused on T cell receptor signaling; low-risk group had higher T cells (P = 0.039), B cells (P = 0.041), NK cells (P = 0.018). SN-38, GSK2126458 might treat high-risk morphology. Morphology-immune genes stratified HCC, showing significant RFS/OS differences. ConclusionTumor Morph-RS effectively stratifies HCC patients' recurrence and prognosis. Limited immune infiltration seen in Morph-RS high-risk groups signifies the potential of employing tumor morphology as a potent visual biomarker for diagnosing and managing HCC.

Multitask deep learning for prediction of microvascular invasion and recurrence-free survival in hepatocellular carcinoma based on MRI images.

Accurate preoperative prediction of microvascular invasion (MVI) and recurrence-free survival (RFS) is vital for personalised hepatocellular carcinoma (HCC) management. We developed a multitask deep learning model to predict MVI and RFS using preoperative MRI scans. Utilising a retrospective dataset of 725 HCC patients from seven institutions, we developed and validated a multitask deep learning model focused on predicting MVI and RFS. The model employs a transformer architecture to extract critical features from preoperative MRI scans. It was trained on a set of 234 patients and internally validated on a set of 58 patients. External validation was performed using three independent sets (n = 212, 111, 110). The multitask deep learning model yielded high MVI prediction accuracy, with AUC values of 0.918 for the training set and 0.800 for the internal test set. In external test sets, AUC values were 0.837, 0.815 and 0.800. Radiologists' sensitivity and inter-rater agreement for MVI prediction improved significantly when integrated with the model. For RFS, the model achieved C-index values of 0.763 in the training set and ranged between 0.628 and 0.728 in external test sets. Notably, PA-TACE improved RFS only in patients predicted to have high MVI risk and low survival scores (p < .001). Our deep learning model allows accurate MVI and survival prediction in HCC patients. Prospective studies are warranted to assess the clinical utility of this model in guiding personalised treatment in conjunction with clinical criteria.

Prognostic and clinicopathological significance of systemic inflammation response index in patients with hepatocellular carcinoma: a systematic review and meta-analysis.

It is unclear whether the systemic inflammation response index (SIRI) can predict the prognosis of patients with hepatocellular carcinoma (HCC). Consequently, the present study focused on systematically identifying the relationship between SIRI and the prognosis of patients with HCC through a meta-analysis. Systematic and comprehensive studies were retrieved from PubMed, Web of Science, Embase, and the Cochrane Library from their inception to August 10, 2023. The role of SIRI in predicting overall survival (OS) and progression-free survival (PFS) in HCC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Odds ratios (ORs) and 95% CIs were pooled to analyze the correlations between SIRI and the clinicopathological features of HCC. Ten articles involving 2,439 patients were included. An elevated SIRI was significantly associated with dismal OS (HR=1.75, 95% CI=1.52-2.01, p<0.001) and inferior PFS (HR=1.66, 95% CI=1.34-2.05, p<0.001) in patients with HCC. Additionally, according to the combined results, the increased SIRI was significantly related to multiple tumor numbers (OR=1.42, 95% CI=1.09-1.85, p=0.009) and maximum tumor diameter >5cm (OR=3.06, 95% CI=1.76-5.30, p<0.001). However, the SIRI did not show any significant relationship with sex, alpha-fetoprotein content, Child-Pugh class, or hepatitis B virus infection. According to our results, elevated SIRI significantly predicted OS and PFS in patients with HCC. Moreover, the SIRI was significantly associated with tumor aggressiveness. https://inplasy.com/inplasy-2023-9-0003/, identifier INPLASY202390003.

Identification of immune cell-related prognostic genes characterized by a distinct microenvironment in hepatocellular carcinoma.

The development and progression of hepatocellular carcinoma (HCC) have been reported to be associated with immune-related genes and the tumor microenvironment. Nevertheless, there are not enough prognostic biomarkers and models available for clinical use. Based on seven prognostic genes, this study calculated overall survival in patients with HCC using a prognostic survival model and revealed the immune status of the tumor microenvironment (TME). To develop a novel immune cell-related prognostic model of HCC and depict the basic profile of the immune response in HCC. We obtained clinical information and gene expression data of HCC from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. TCGA and ICGC datasets were used for screening prognostic genes along with developing and validating a seven-gene prognostic survival model by weighted gene coexpression network analysis and least absolute shrinkage and selection operator regression with Cox regression. The relative analysis of tumor mutation burden (TMB), TME cell infiltration, immune checkpoints, immune therapy, and functional pathways was also performed based on prognostic genes. Seven prognostic genes were identified for signature construction. Survival receiver operating characteristic curve analysis showed the good performance of survival prediction. TMB could be regarded as an independent factor in HCC survival prediction. There was a significant difference in stromal score, immune score, and estimate score between the high-risk and low-risk groups stratified based on the risk score derived from the seven-gene prognostic model. Several immune checkpoints, including VTCN1 and TNFSF9, were found to be associated with the seven prognostic genes and risk score. Different combinations of checkpoint blockade targeting inhibitory CTLA4 and PD1 receptors and potential chemotherapy drugs hold great promise for specific HCC therapies. Potential pathways, such as cell cycle regulation and metabolism of some amino acids, were also identified and analyzed. The novel seven-gene (CYTH3, ENG, HTRA3, PDZD4, SAMD14, PGF, and PLN) prognostic model showed high predictive efficiency. The TMB analysis based on the seven genes could depict the basic profile of the immune response in HCC, which might be worthy of clinical application.

Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma

BackgroundThe increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials.MethodsWe systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival.ResultsThirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75).ConclusionsOne-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.

Elevated expression of HIGD1A drives hepatocellular carcinoma progression by regulating polyamine metabolism through c-Myc–ODC1 nexus

BackgroundHypoxia contributes to cancer progression through various molecular mechanisms and hepatocellular carcinoma (HCC) is one of the most hypoxic malignancies. Hypoxia-inducible gene domain protein-1a (HIGD1A) is typically induced via epigenetic regulation and promotes tumor cell survival during hypoxia. However, the role of HIGD1A in HCC remains unknown.MethodsHIGD1A expression was determined in 24 pairs of human HCC samples and para-tumorous tissues. Loss-of-function experiments were conducted both in vivo and in vitro to explore the role of HIGD1A in HCC proliferation and metastasis.ResultsIncreased HIGD1A expression was found in HCC tissues and cell lines, which was induced by hypoxia or low-glucose condition. Moreover, HIGD1A knockdown in HCC cells arrested the cell cycle at the G2/M phase and promoted hypoxia-induced cell apoptosis, resulting in great inhibition of cell proliferation, migration, and invasion, as well as tumor xenograft formation. Interestingly, these anti-tumor effects were not observed in normal hepatocyte cell line L02. Further, HIGD1A knockdown suppressed the expression of ornithine decarboxylase 1 (ODC1), a rate-limiting enzyme of polyamine metabolism under c-Myc regulation. HIGD1A was found to bind with the c-Myc promoter region, and its knockdown decreased the levels of polyamine metabolites. Consistently, the inhibitory effect on HCC phenotype by HIGD1A silencing could be reversed by overexpression of c-Myc or supplementation of polyamines.ConclusionsOur results demonstrated that HIGD1A activated c-Myc–ODC1 nexus to regulate polyamine synthesis and to promote HCC survival and malignant phenotype, implying that HIGD1A might represent a novel therapeutic target for HCC.

Signature construction and molecular subtype identification based on liver-specific genes for prediction of prognosis, immune activity, and anti-cancer drug sensitivity in hepatocellular carcinoma

BackgroundLiver specific genes (LSGs) are crucial for hepatocyte differentiation and maintaining normal liver function. A deep understanding of LSGs and their heterogeneity in hepatocellular carcinoma (HCC) is necessary to provide clues for HCC diagnosis, prognosis, and treatment.MethodsThe bulk and single-cell RNA-seq data of HCC were downloaded from TCGA, ICGC, and GEO databases. Through unsupervised cluster analysis, LSGs-based HCC subtypes were identified in TCGA-HCC samples. The prognostic effects of the subtypes were investigated with survival analyses. With GSVA and Wilcoxon test, the LSGs score, stemness score, aging score, immune score and stromal score of the samples were estimated and compared. The HCC subtype-specific genes were identified. The subtypes and their differences were validated in ICGC-HCC samples. LASSO regression analysis was used for key gene selection and risk model construction for HCC overall survival. The model performance was estimated and validated. The key genes were validated for their heterogeneities in HCC cell lines with quantitative real-time PCR and at single-cell level. Their dysregulations were investigated at protein level. Their correlations with HCC response to anti-cancer drugs were estimated in HCC cell lines.ResultsWe identified three LSGs-based HCC subtypes with different prognosis, tumor stemness, and aging level. The C1 subtype with low LSGs score and high immune score presented a poor survival, while the C2 subtype with high LSGs score and immune score indicated an enduring survival. Although no significant survival difference between C2 and C3 HCCs was shown, the C2 HCCs presented higher immune score and stroma score. The HCC subtypes and their differences were confirmed in ICGC-HCC dataset. A five-gene prognostic signature for HCC survival was constructed. Its good performance was shown in both the training and validation datasets. The five genes presented significant heterogeneities in different HCC cell lines and hepatocyte subclusters. Their dysregulations were confirmed at protein level. Furthermore, their significant associations with HCC sensitivities to anti-cancer drugs were shown.ConclusionsLSGs-based HCC subtype classification and the five-gene risk model might provide useful clues not only for HCC stratification and risk prediction, but also for the development of more personalized therapies for effective HCC treatment.

Diagnostic and Prognostic Value of Methyltransferase Like 13 in Hepatocellular Carcinoma Based on Bioinformatics Analysis.

Hepatocellular carcinoma (HCC) is one of the cancers with the highest incidence and mortality rates. This study aims to explore the diagnostic and prognostic utility of methyltransferase like 13 (METTL13) in patients with HCC via bioinformatics analysis. We obtained mRNA data of HCC from the database of the Cancer Genome Atlas (TCGA), drawing survival curve by R 4.2.1 software. Cox regression analysis was conducted based on tumor stage and METTL13 expression. The GSE114564 dataset was chosen from the Gene Expression Omnibus. The differences in serum METTL13 levels between the groups of early HCC (eHCC) and non-cancer controls were evaluated. Using a receiver operating characteristic curve, we calculated the area under the curve (AUC) of serum METTL13 for diagnosing eHCC. A total of 225 cases with HCC were screened from TCGA, and 29 cases were normal controls. The results showed that the METTL13 expression in the HCC group was higher than that in the normal controls (P <.001). The univariate [hazard ratio (HR) = 1.895, P = .006] and multivariate Cox regression (HR = 1.702, P = .037) analyses showed that high METTL13 expression reduced overall survival in HCC. Serum METTL13 levels were higher in the eHCC group than in the non-cancer controls (P = .008). The optimum AUC for predicting eHCC by serum METTL13 was 0.7091. Serum METTL13 has a moderate diagnostic value for eHCC. High METTL13 expression is correlated with a worse prognosis in patients with HCC. Methyltransferase like 13 possesses the potential to be a novel biomarker for HCC.

Development of a novel lncRNA-derived immune gene score using machine learning-based ensembles for predicting the survival of HCC

BackgroundLong noncoding RNAs (lncRNAs) are implicated in the tumor immunology of hepatocellular carcinoma (HCC). MethodsHCC mRNA and lncRNA expression profiles were used to extract immune-related genes with the ImmPort database, and immune-related lncRNAs with the ImmLnc algorithm. The MOVICS package was used to cluster immune-related mRNA, immune-related lncRNA, gene mutation and methylation data on HCC from the TCGA. GEO and ICGC datasets were used to validate the model. Data from single-cell sequencing was used to determine the expression of genes from the model in various immune cell types. ResultsWith this model, the area under the curve (AUC) for 1-, 3- and 5-year survival of HCC patients was 0.862, 0.869 and 0.912, respectively. Single-cell sequencing showed EREG was significantly expressed in a variety of immune cell types. Knockdown of the EREG target gene resulted in significant anti-apoptosis, pro-proliferation and pro-migration effects in HepG2 and HUH7 cells. Moreover, serum and liver tissue EREG levels in HCC patients were significantly higher than those of healthy control patients. ConclusionWe built a prognostic model with good accuracy for predicting HCC patient survival. EREG is a potential immunotherapeutic target and a promising prognostic biomarker.

Advanced lung cancer inflammation index predicts overall survival of hepatocellular carcinoma after hepatectomy.

Limited data are available regarding ALI's clinical relevance and prognostic value in patients with hepatocellular carcinoma (HCC) after hepatectomy. HCC patients who received hepatectomy at the Meizhou People's Hospital from May 2011 to February 2022 were enrolled in the study cohort. The ALI was calculated as follows: ALI = BMI (kg/m2) × ALB (g/dL)/(absolute neutrophil count/absolute lymphocyte count). The primary outcome was overall survival (OS). The secondary outcome was cancer-specific survival (CSS). Univariate and multivariate Cox regression analyses were performed, followed by nomogram construction and decision curve analysis (DCA). 425 HCC patients were enrolled for analyses. Lower preoperative ALI was significantly correlated with incomplete tumor capsule and advanced tumor stage. Lower preoperative ALI was an adverse independent prognostic factor for OS (HR: 1.512, 95% CI: 1.122-2.039, P 0.007) and CSS (HR: 1.754, 95% CI: 1.262-2.438, P <0.001) in HCC patients. The nomogram plot was built based on three (including age, TNM stage, and ALI) and two (including TNM stage and ALI) independent prognostic factors for OS and CSS, respectively. Further analyses indicated that the nomogram had better predictive value and some net benefit than the traditional TNM stage alone, especially in long-term OS. Our study further indicated that ALI could be a prognostic marker for OS and CSS in HCC patients after hepatectomy, especially in long-term OS.

Most deprived Louisiana census tracts have higher hepatocellular carcinoma incidence and worse survival.

Liver cancer incidence increased in the US from 1975 through 2015 with heterogeneous rates across subpopulations. Upstream or distal area-level factors impact liver cancer risks. The aim of this study was to examine the association between area-level deprivation and hepatocellular carcinoma (HCC) incidence and survival. We also explored the association between area deprivation and treatment modalities. Louisiana Tumor Registry identified 4,151 adult patients diagnosed with malignant HCC from 2011 to 2020 and linked residential address to census tract (CT)-level Area Deprivation Index (ADI) categorized into quartiles (Q1 = least deprived). ANOVA examined the association between ADI quartile and CT age-adjusted incidence rate (AAIR) per 100,000. Chi-square tested the distribution of demographic and clinical characteristics across ADI quartiles. Kaplan-Meier and proportional hazard models evaluated survival by deprivation quartile. Among the 1,084 CTs with incident HCC, the average (SD) AAIR was 8.02 (7.05) HCC cases per 100,000 population. ADI was observed to be associated with incidence, and the mean (SD) AAIR increased from 5.80 (4.75) in Q1 to 9.26 (7.88) in Q4. ADI was also associated with receipt of surgery (p < 0.01) and radiation (p < 0.01) but not chemotherapy (p = 0.15). However, among those who received chemotherapy, people living in the least deprived areas began treatment approximately 10 days sooner than those living in other quartiles. Q4 patients experienced the worst survival with a median of 247 (95% CI 211-290) days vs. Q1 patients with a median of 474 (95% CI 407-547) days (p < 0.0001). Q4 had marginally poorer survival (HR 1.20, 1.05-1.37) than Q1 but the association became non-significant (HR 1.12, 0.96-1.30) when adjusted for rurality, liquor store density, sex, race/ethnicity, age, insurance, BMI, stage, hepatitis diagnosis, and comorbidities. Increasing neighborhood (CT) deprivation (ADI) was observed to be associated with increased HCC incidence and poorer HCC survival. However, the association with poorer survival becomes attenuated after adjusting for putative confounders.