Survival In Hepatocellular Carcinoma Research Articles

IFRD1 promotes tumor cells “low-cost” survival under glutamine starvation via inhibiting histone H1.0 nucleophagy

Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

The landscape of etiological patterns of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in Thailand.

Thailand is among countries with the highest global incidence and mortality rates of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). While viral hepatitis and liver fluke infections have been associated with HCC and iCCA, respectively, other environmental risk factors, overall risk factor commonality and combinatorial roles, and effects on survival have not been systematically examined. We conducted a TIGER-LC consortium-based population study covering all high-incidence areas of both malignancies across Thailand: 837 HCC, 1474 iCCA, and 1112 controls (2011-2019) were comprehensively queried on lifelong environmental exposures, lifestyle, and medical history. Multivariate logistic regression and Cox proportional hazards analyses were used to evaluate risk factors and associated survival patterns. Our models identified shared risk factors between HCC and iCCA, such as viral hepatitis infection, liver fluke infection, and diabetes, including novel and shared associations of agricultural pesticide exposure (OR range of 1.50; 95% CI: 1.06-2.11 to 2.91; 95% CI: 1.82-4.63) along with vulnerable sources of drinking water. Most patients had multiple risk factors, magnifying their risk considerably. Patients with lower risk levels had better survival in both HCC (HR 0.78; 95% CI: 0.64-0.96) and iCCA (HR 0.84; 95% CI: 0.70-0.99). Risk factor co-exposures and their common associations with HCC and iCCA in Thailand emphasize the importance for future prevention and control measures, especially in its large agricultural sector. The observed mortality patterns suggest ways to stratify patients for anticipated survivorship and develop plans to support medical care of longer-term survivors, including behavioral changes to reduce exposures.

CARMIL1 regulates liver cancer cell proliferation by activating the ERK/mTOR pathway through the TRIM27/p53 axis

Capping protein regulatory factor and myosin 1 linker 1 is termed CARMIL1. CARMIL1 is involved in several physiological processes; it forms an actin filament network and plasma membrane-bound cellular projection tissues and positively regulates the cellular components and tissues. CARMIL1 exhibits important biological functions in cancer; nonetheless, these functions have not been completely explored. We aimed to investigate the novel functions of CARMIL1 in liver cancer, particularly in cell proliferation. The cell counting kit-8, 5-ethynyl-2′-deoxyuridine, Component A experiments, and subcutaneous tumor formation model suggest that CARMIL1 is central to the proliferation of liver cancer cells both in vivo and in vitro. We extracted CARMIL1 samples from The Cancer Genome Atlas Program and analyzed its enrichment. CARMIL1 regulated the pathway activity by affecting the expression of star molecular proteins of the extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR). Moreover, it influenced the proliferation ability of liver cancer cells. Western blotting suggested that CARMIL1 downregulation could affect ERK and mTOR phosphorylation. Results of the co-immunoprecipitation demonstrated that CARMIL1 binds to tripartite motif (TRIM)27, which in turn binds to p53. Subsequently, CARMIL1 can regulate p53 stability and promote its degradation through TRIM27. Additionally, CARMIL1 inhibition enhanced the sensitivity of liver cancer cells to sorafenib. Tumor growth was significantly inhibited in the group treated with sorafenib and CARMIL1, compared with the group treated with CARMIL1 alone. Sorafenib is a first-line targeted chemotherapeutic drug for hepatocellular carcinoma treatment. It increases the long-term survival of hepatocellular carcinoma by 44%. In this study, downregulated CARMIL1 combined with sorafenib significantly reduced the tumor volume and weight of the mouse subcutaneous tumor model, indicating the potential possibility of combining CARMIL1 with sorafenib in hepatocellular carcinoma treatment. In summary, CARMIL1 promotes liver cancer cell proliferation by regulating the TRIM27/p53 axis and activating the ERK/mTOR pathway.

Optimizing predictions: improved performance of preoperative gadobenate-enhanced MRI hepatobiliary phase features in predicting vessels encapsulating tumor clusters in hepatocellular carcinoma-a multicenter study.

Vessels Encapsulating Tumor Clusters (VETC) are now recognized as independent indicators of recurrence and overall survival in hepatocellular carcinoma (HCC) patients. However, there has been limited investigation into predicting the VETC pattern using hepatobiliary phase (HBP) features from preoperative gadobenate-enhanced MRI. This study involved 252 HCC patients with confirmed VETC status from three different hospitals (Hospital 1: training set with 142 patients; Hospital 2: test set with 64 patients; Hospital 3: validation set with 46 patients). Independent predictive factors for VETC status were determined through univariate and multivariate logistic analyses. Subsequently, these factors were used to construct two distinct VETC prediction models. Model 1 included all independent predictive factors, while Model 2 excluded HBP features. The performance of both models was assessed using the Area Under the Curve (AUC), Decision Curve Analysis, and Calibration Curve. Prediction accuracy between the two models was compared using Net Reclassification Improvement (NRI) and Integrated Discriminant Improvement (IDI). CA199, IBIL, shape, peritumoral hyperintensity on HBP, and arterial peritumoral enhancement were independent predictors of VETC. Model 1 showed robust predictive performance, with AUCs of 0.836 (training), 0.811 (test), and 0.802 (validation). Model 2 exhibited moderate performance, with AUCs of 0.813, 0.773, and 0.783 in the respective sets. Calibration and decision curves for both models indicated consistent predictions between predicted and actual VETC, benefiting HCC patients. NRI showed Model 1 increased by 0.326, 0.389, and 0.478 in the training, test, and validation sets compared to Model 2. IDI indicated Model 1 increased by 0.036, 0.028, and 0.025 in the training, test, and validation sets compared to Model 2. HBP features from preoperative gadobenate-enhanced MRI can enhance the predictive performance of VETC in HCC.

A novel risk scoring system predicts overall survival of hepatocellular carcinoma using Cox proportional hazards machine learning method

BackgroundRobust and practical prognosis prediction models for hepatocellular carcinoma (HCC) patients play crucial roles in personalized precision medicine. Material and MethodsWe recruited two independent HCC cohorts (discovery cohort and validation cohort), totally consisting of 222 HCC patients undergone surgical resection. We quantified the expressions of immune-related proteins (CD8, CD68, CD163, PD-1 and PD-L1) in paired HCC tissues and non-tumor liver tissues from these HCC patients using immunohistochemistry (mIHC) assays. We constructed the HCC prognosis prediction model using five different machine learning methods based on the patients in the discovery cohort, such as Cox proportional hazards (CoxPH). ResultsWe identified 19 features that were associated with overall survival of HCC patients in the discovery cohort (p < 0.1), such as immune-related features CD68+ and CD8+ cell infiltration. We constructed five HCC prognosis prediction models using five different machine learning methods. Among the five different machine learning models, the CoxPH model achieved the best performance (area under the curve [AUC], 0.839; C-index, 0.779). According to the risk score from CoxPH model, we divided HCC patients into high-risk group/low-risk group. In both discovery cohort and validation cohort, the patients in low-risk group showed longer overall survival compared with those in high-risk group (p = 1.8 × 10-7 and 3.4 × 10-5, respectively). Moreover, our novel scoring system efficiently predicted the 6, 12, and 18 months survival rate of HCC patients with AUC > 0.75 in both discovery cohort and validation cohort. In addition, we found that the scoring system could also distinguish the patients with high/low risks of relapse in both discovery cohort and validation cohort (p = 0.00015 and 0.00012). ConclusionThe novel CoxPH-based risk scoring model on clinical, laboratory-testing and immune-related features showed high prediction efficiencies for overall survival and recurrence of HCCs undergone surgical resection. Our results may be helpful to optimize clinical follow-up or therapeutic interventions.

Identification and Validation of Basement Membrane Related LncRNA Signatures as a Novel Prognostic Model for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a significant cancer with limited treatments and a poor prognosis, with the basement membrane (BM) playing a crucial role in its initiation and growth. This study utilized data from The Cancer Genome Atlas and the Gene Expression Omnibus (GEO) databases to identify basement membrane-related genes differentially expressed in HCC. Through gene co-expression analysis, BM-associated long non-coding RNAs (lncRNAs) were discovered. LncRNAs related to HCC survival were selected via univariate analysis, and a prognostic model was constructed using LASSO regression and multivariate analysis. This model effectively classified HCC patients into high and low-risk groups, uncovering significant differences in prognosis, immune response, mutation, and drug sensitivity. Six BM-related lncRNAs (GSEC, MIR4435-2HG, AC092614.1, AC127521.1, LINC02580, and AC008050.1) were validated in normal and HCC cell lines, and the key role of AC092614.1 in regulating proliferation, migration, and invasion of HCC cells in vitro was explored. This research emphasizes the prognostic and therapeutic relevance of BM-related lncRNAs in HCC, highlighting AC092614.1's role in disease progression and as a potential target for targeted therapy.

Surgical treatment improves overall survival of hepatocellular carcinoma with extrahepatic metastases after conversion therapy: a multicenter retrospective study

Systemic therapy is typically the primary treatment choice for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. Some patients may achieve partial response (PR) or complete response (CR) with systemic treatment, leading to the possibility of their primary tumor becoming resectable. This study aimed to investigate whether these patients could achieve longer survival through surgical resection of their primary tumor. We retrospectively collected data from 150 HCC patients with extrahepatic metastases treated at 15 different centers from January 1st, 2015, to November 30th, 2022. We evaluated their overall survival (OS) and progress-free survival (PFS) and analyzed risk factors impacting both OS and PFS were analyzed. Patients who received surgical treatment had longer OS compared to those who did not (median OS 16.5 months vs. 11.3 months). However, there was no significant difference in progression-free survival between the two groups. Portal vein invasion (P = 0.025) was identified as a risk factor for poor prognosis in patients, while effective first-line treatment (P = 0.039) and surgical treatment (P = 0.005) were protective factors. No factors showed statistical significance in the analysis of PFS. Effective first-line treatment (P = 0.027) and surgical treatment (P = 0.006) were both independent protective factors for prolonging patient prognosis, while portal vein invasion was an independent risk factor (P = 0.044). HCC patients with extrahepatic metastases who achieve PR/CR with conversion therapy may experience longer OS through surgical treatment. This study is the first to analyze the clinical outcomes of patients receiving surgical treatment for HCC with extrahepatic metastases.

Chemoembolization for Hepatocellular Carcinoma Including Contrast Agent-Enhanced CT: Response Assessment Model on Radiomics and Artificial Intelligence

Purpose: The aim of this study was to assess the efficacy of an artificial intelligence (AI) algorithm that uses radiomics data to assess recurrence and predict survival in hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE). Methods: A total of 57 patients with treatment-naïve HCC or recurrent HCC who were eligible for TACE were prospectively enrolled in this study as test data. A total of 100 patients with treatment-naïve HCC or recurrent HCC who were eligible for TACE were retrospectively acquired for training data. Radiomic features were extracted from contrast-enhanced, liver computed tomography (CT) scans obtained before and after TACE. An AI algorithm was trained using the retrospective data and validated using the prospective test data to assess treatment outcomes. Results: This study evaluated 107 radiomic features and 5 clinical characteristics as potential predictors of progression-free survival and overall survival. The C-index was 0.582 as the graph of the cumulative hazard function, predicted by the variable configuration by using 112 radiomics features. The time-dependent AUROC was 0.6 ± 0.06 (mean ± SD). Among the selected radiomics features and clinical characteristics, baseline_glszm_SizeZoneNonUniformity, baseline_ glszm_ZoneVariance and tumor size had excellent performance as predictors of HCC response to TACE with AUROC of 0.853, 0.814 and 0.827, respectively. Conclusions: A radiomics-based AI model is capable of evaluating treatment outcomes for HCC treated with TACE.

Curative effect of percutaneous microwave ablation therapy on hepatocellular carcinoma survival: a 15-year real-world study

Objective: To evaluate the long-term efficacy of percutaneous microwave ablation (MWA) therapy for hepatocellular carcinoma. Methods: 2054 cases with Barcelona Clinic Liver Cancer (BCLC) stage 0~B at the Fifth Medical Center of the Chinese People's Liberation Army General Hospital from January 2006 to September 2020 were retrospectively collected. All patients were followed up for at least 2 years. The primary endpoint of overall survival and secondary endpoints (tumor-related survival, disease-free survival, and postoperative complications) of patients treated with ultrasound-guided percutaneous MWA were analyzed. Kaplan-Meier method was used for stratified survival rate analysis. Fine-and-Gray competing risk model was used to analyze overall survival. Results: A total of 5 503 HCC nodules [mean tumor diameter (2.6±1.6) cm] underwent 3 908 MWAs between January 2006 and September 2020, with a median follow-up time of 45.6 (24.0 -79.2) months.The technical effectiveness rate of 5 375 tumor nodules was 97.5%. The overall survival rates at 5, 10, and 15-years were 61.6%, 38.8%, and 27.0%, respectively. The tumor-specific survival rates were 67.1%, 47.2%, and 37.7%, respectively. The free tumor survival rates were 25.8%, 15.7%, and 9.9%, respectively. The incidence rate of severe complications was 2.8% (108/3 908). Further analysis showed that the technical effectiveness and survival rate over the passing three time periods from January 2006-2010, 2011-2015, and 2016-September 2020 were significantly increased, with P < 0.001, especially for liver cancer 3.1~5.0 cm (P < 0.001). Conclusion: Microwave ablation therapy is a safe and effective method for BCLC stage 0-B, with significantly enhanced technical efficacy and survival rate over time.

Increased prevalence but decreased survival of nonviral hepatocellular carcinoma compared to viral hepatocellular carcinoma in recent ten years

Due to the comprehensive hepatitis B virus vaccination program in Taiwan since 1986, the development of antiviral therapy for chronic hepatitis B and chronic hepatitis C infection and covered by National health insurance. Besides, the increased prevalence of nonalcoholic fatty liver disease (NAFLD) and currently, approved therapy for NAFLD remain developing. The etiology of liver-related diseases such as cirrhosis and hepatocellular carcinoma required reinterpretation. This study aimed to analyze the incidence and outcome of hepatocellular carcinoma (HCC) due to viral (hepatitis B and hepatitis C) infection compared to that of nonviral etiology. We retrospectively analyzed patients with HCC from January 2011 to December 2020 from the cancer registry at our institution. Viral-related hepatitis was defined as hepatitis B surface antigen positivity or anti-hepatitis C virus (HCV) antibody positivity. A total of 2748 patients with HCC were enrolled, of which 2188 had viral-related HCC and 560 had nonviral-related HCC. In viral HCC group, the median age at diagnosis was significantly lower (65 years versus 71 years, p < 0.001), and the prevalence of early-stage HCC, including stage 0 and stage A Barcelona Clinic Liver Cancer, was significantly higher (52.9% versus 33.6%, p < 0.001). In nonviral HCC group, alcohol use was more common (39.9% versus 30.1%, p < 0.001), the prevalence of type 2 diabetes mellitus (T2DM) was higher (54.5% versus 35.1%, p < 0.001), and obesity was common (25.0% versus 20.5%, p = 0.026). The prevalence of nonviral HCC increased significantly from 19.2 to 19.3% and 23.0% in the last 10 years (p = 0.046). Overall survival was better in the viral HCC group (5.95 years versus 4.00 years, p < 0.001). In the early stage of HCC, overall survival was still better in the viral HCC group (p < 0.001). The prevalence of nonviral HCC has significantly increased in the last ten years. The overall survival was significantly lower in the nonviral HCC, perhaps because the rate of early HCC detection is lower in nonviral HCC and anti-viral therapy. To detect nonviral HCC early, we should evaluate liver fibrosis in high-risk groups (including people with obesity or T2DM with NAFLD/NASH and alcoholic liver disease) and regular follow-up for those with liver fibrosis, regardless of cirrhosis.

Drug research and development and unmet needs for advanced-stage hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is a global health challenge. Radical surgical resection is the most effective method to achieve long-term survival for HCC. Regrettably, the vast majority of HCC patients lose the opportunity for radical resection at the time of diagnosis due to advanced tumors or poor liver reserve capacity. HCC is resistant to conventional chemotherapy, and in the past, there have been no definite and effective systemic therapeutic drugs. Fortunately, over the last decade, the research and development of molecular targeted therapy and immunotherapy drugs for HCC have made rapid progress, and a variety of drugs and combination therapy regimens have been successively approved for clinical use. However, the overall therapeutic effect is still not ideal and needs further improvement.

Transarterial chemoembolization with 125I seed insertion for multifocal hepatocellular carcinoma.

A common treatment strategy for individuals with multifocal hepatocellular carcinoma (HCC) who are not candidates for surgical resection is transarterial chemoembolization (TACE). Combining TACE with 125I seed insertion (ISI) may offer a means of enhancing therapeutic efficacy. The purpose of this study was to compare the therapeutic efficacy of TACE administered with and without ISI for the treatment of multifocal HCC. The data from the two centers were analyzed retrospectively. The present study involved 85 consecutive patients with multifocal HCC who underwent TACE between January 2018 and December 2021. Of these patients, 43 were in the combined group, receiving TACE with ISI, and 42 were in the TACE-only group, receiving TACE without ISI. Comparisons of treatment outcomes were made between these groups. No significant differences in baseline data were observed between these groups of patients. Higher rates of complete (60.5% vs. 33.3%, P = 0.016) and total (93.0% vs. 61.9%, P = 0.001) responses were evident in the combined group compared to the TACE-only group. Median progression-free survival (PFS, 13 vs. 10 months, P = 0.014) and overall survival (OS, 22 vs. 17 months, P = 0.035) were also significantly longer in the combined group than in the TACE-only group. Using a Cox regression analysis, risk variables associated with shorter PFS and OS included Child-Pugh B status (P = 0.027 and 0.004) and only TACE treatment (P = 0.011 and 0.022). In summary, these findings suggest that, as compared to TACE alone, combining TACE and ISI can enhance HCC patients' treatment outcomes and survival.

Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

The Performance of a Survival Nomogram and Albumin-Bilirubin Grade as Prognostic Tools in Advanced Hepatocellular Carcinoma Treated with FOLFOX4.

The ability of the survival nomogram developed in the EACH study and albumin-bilirubin (ALBI) grade to predict the survival of advanced hepatocellular carcinoma (HCC) patients receiving oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) remains unvalidated. Here, we comprehensively evaluated these prognostic tools. The survival nomogram and ALBI grade of each patient were assessed, and the area under the receiver operating curve (AUROC) and Harrell's C-index for the risk classification model were calculated. Overall, 76 HCC patients who received FOLFOX4 between August 2017 and June 2023 were included. The survival nomogram classified patients into low-, intermediate-, and high-risk groups, with a median overall survival (OS) of 9.82, 10.64, and 3.70 months, respectively (p = 0.23). The AUROC was 0.621 and Harrell's C-index was 0.589. However, the ALBI grade categorized all patients into grade 1, 2, and 3, with a median OS of 9.82, 6.83, and 1.58 months, respectively (p = 0.00024). The AUROC was 0.663 and Harrell's C-index was 0.663. The ALBI grade can be a potential prognostic tool. However, the survival nomogram does not provide clear discrimination. Therefore, FOLFOX4 should be an option for patients with ALBI grade 1 who cannot receive immunotherapy or targeted therapy. Additional prospective studies with a larger cohort are warranted to validate the survival nomogram and ALBI grade as prognostic tools.

Retraction: The Significance of Notch1 Compared with Notch3 in High Metastasis and Poor Overall Survival in Hepatocellular Carcinoma.

Retraction: The Significance of Notch1 Compared with Notch3 in High Metastasis and Poor Overall Survival in Hepatocellular Carcinoma.

Pan-cancer analysis of SLC2A family genes as prognostic biomarkers and therapeutic targets

BackgroundThe major facilitator superfamily glucose transporters (GLUTs), encoded by solute carrier 2A (SLC2A) genes, mediate the transmembrane movement and uptake of glucose. To satisfy the improved energy demands, glycolysis flux is increased in cancers compared with healthy tissues. Multiple diseases, including cancer, have been associated with GLUTs. Nevertheless, not much research has been done on the functions of SLC2As in pan-cancer prognosis or their clinical treatment potential. MethodsThe SLC2A family genes' level of expression and prognostic values were analyzed in relation to pan-cancer. We then examined the association among SLC2As expression and TME, Stemness score, clinical characteristics, immune subtypes, and drug sensitivity. We merged bioinformatics analysis techniques with up-to-date public databases. Additionally, SLC2As from the KOBAS database were subjected to enrichment analysis. ResultsWe discovered that SLC2As' gene expression differed significantly between normal tissues and many malignancies. A number of tumors from various databases demonstrate a relationship between prognosis and SLC2A family gene expression. For instance, SLC2A2 and SLC2A5 were associated with the overall survival (OS) of hepatocellular carcinoma. SLC2A1 was associated with the OS of lung adenocarcinoma and pancreatic adenocarcinoma. Moreover, the SLC2A family gene expression is significantly correlated with the pan-cancer stromal and immune scores, and the RNA and DNA stemness scores. Furthermore, we found that the majority of SLC2As had a strong correlation with the tumor stages in KIRC. The immunological subtypes and all members of the SLC2A gene family exhibited a substantial correlation. Moreover, pathways containing insulin resistance and adipocytokine signaling pathway may influence the progression of some cancers. Finally, there is a significant positive or negative connection between drug sensitivity and SLC2A1 expression. ConclusionOur research highlights the significant promise of SLC2As as prognostic indicators and offers insightful approaches for upcoming exploration of SLC2As as putative therapeutic targets in malignancies.

Predicting survival of patients with advanced hepatocellular carcinoma receiving combination targeted immunotherapy: an evaluation of volumetric imaging parameters.

To evaluate the potential of volumetric imaging in predicting survival of advanced hepatocellular carcinoma (HCC) patients receiving immunotherapy. Retrospective analysis included 40 patients with advanced HCC who received targeted immunotherapy. Baseline and follow-up contrast-enhanced abdominal computed tomography (CT) scans were analyzed. The largest tumor was chosen as the index lesion. Viable tumor volume (qViable) and percentage tumor viability (%Viability) were calculated. Response Evaluation Criteria in Solid Tumors (RECIST) and Tumor volume change after treatment (qRECIST) were measured. Associations with overall survival (OS) were assessed. Cox regression analysis assessed the association between variables and overall survival (OS). A new prognostic stratification system was attempted to categorize patients based on significant predictors of OS. Patients with a baseline %viability > 69% and %viability reduction ≥ 8% were classified as better prognosis. Patients were stratified into better, intermediate and worse prognosis groups based on baseline %viability > 69% and ≥ 8% %viability reduction (better prognosis); baseline %viability ≤ 69% and < 8% %viability reduction (worse prognosis); remainder were intermediate prognosis. Patients with baseline %Viability > 69% and %Viability reduction ≥ 8% showed significantly higher OS. Multivariate analysis confirmed %Viability and %Viability reduction as significant predictors of OS. A prognostic stratification system using these parameters stratified patients into better, intermediate and worse prognosis groups, with the better prognosis showing highest OS. Most patients (97.5%) had stable disease by RECIST while the prognostic model re-classified 47.5% as better prognosis, 37.5% intermediate prognosis, and 15% worse prognosis. Volumetric parameters of %Viability and %Viability reduction predict OS in HCC patients undergoing immunotherapy.

Lysosome-Related Genes and RNF19B as Prognostic Markers for Survival and Immunotherapy Efficacy in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) poses a considerable worldwide health concern due to its associated high risk of death. The heterogeneity of HCC poses challenges in developing practical risk stratification tools and identifying prognostic markers for personalized targeted treatments. Recently, lysosomes were shown to be crucial contributors to numerous cellular activities, including tumor initiation and regulating immune responses. Here, we aimed to construct a reliable prognostic signature based on lysosome-related genes and determine its association with the immune microenvironment. We comprehensively analyzed lysosome-related genes in HCC to investigate their influence on patient survival and the tumor immune microenvironment. A prognostic signature comprising 14 genes associated with lysosomes was created to estimate the survival outcomes of individuals with HCC. Additionally, we verified the prognostic importance of Ring Finger Protein 19B (RNF19B) in HCC patients through multiplex immunohistochemistry analysis. Our constructed lysosome-related prediction model could significantly discriminate between HCC patients with good and poor survival outcomes (P < 0.05). We also found that elevated RNF19B expression was linked to unfavorable prognostic outcomes and showed a connection with specific clinicopathological characteristics. Moreover, it was observed that RNF19B could facilitate the transformation of macrophages into M2-polarized macrophages and showed a significant positive correlation with PD-1 and CTLA-4. In summary, our study proposes that the expression of lysosome-related genes is associated with the immune microenvironment, serving as a predictor for HCC patients' survival. Meanwhile, RNF19B was identified as a novel prognostic marker for predicting OS and immunotherapy effects in HCC patients.

Abstract 3723: Hepatic arterial infusion chemotherapy prolongs patient survival in HCC after atezolizumab and bevacizumab failure

Abstract Background: Atezolizumab/bevacizumab is the first-line chemotherapy for unresectable hepatocellular carcinoma (HCC) patients. In our institute, if the patient is not feasible for or cannot afford the first-line systemic chemotherapy, hepatic artery infusion chemotherapy (HAIC) is proposed and used for treatment The purpose of the study was to compare the prognosis of HAIC treatment in newly diagnosed patients and patients who received HAIC after atezolizumab-bevacizumab treatment failure. Methods: We retrospectively assessed 49 HCC patients who were treated with HAIC between January 2022 and August 2023. 35 patients were treated with HAIC at initial diagnosis and 14 patients were treated with HAIC after the first line chemotherapy Atezolizumab-bevacizumab combination chemotherapy. We evaluated tumor response, progression free survival (PFS), disease control rate (DCR) and overall survival (OS). Results: There was a no significant difference in OS and PFS between HCC patients who were treated with HAIC at initial diagnosis and those who were treated after atezolizumab bevacizumab treatment failure. (P value = 0.0770, 0.6993 respectively) In addition, there was no significant difference in the treatment responses. (P=0.4330) Our analysis of the objective response rate (ORR) and disease control rate (DCR) also revealed no significant difference between the two treatment groups. (P=0.247 and 0.829 respectively). Conclusion: There was no significant difference between the OS and PFS of advanced HCC patients who were treated with HAIC at initial diagnosis and those who were treated with HAIC after atezolizumab bevacizumab treatment failure. Hepatic arterial infusion chemotherapy may prolong patient survival in HCC after atezolizumab and bevacizumab failure. Citation Format: Pil Soo Sung. Hepatic arterial infusion chemotherapy prolongs patient survival in HCC after atezolizumab and bevacizumab failure [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 3723.

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.