Identify Hepatocellular Carcinoma Patients Research Articles

Inhibition of KIF20A enhances the immunotherapeutic effect of hepatocellular carcinoma by enhancing c-Myc ubiquitination

Immune therapy has significantly improved the prognosis of hepatocellular carcinoma (HCC) patients, yet its efficacy remains limited, underscoring the urgency to identify new therapeutic targets and biomarkers. Here, we investigated the pathological and physiological roles of KIF20A and assess its potential in enhancing HCC treatment efficacy when combined with PD-1 inhibitors. We initially assess KIF20A's oncogenic function using liver-specific KIF20A knockout (Kif20a CKO) mouse models and orthotopic xenografts. Subsequently, we establish a regulatory axis involving KIF20A, FBXW7, and c-Myc, validated through construction of c-Myc splicing mutants. Large-scale clinical immunohistochemistry (IHC) analyses confirm the pathological relevance of the KIF20A-FBXW7-c-Myc axis in HCC. We demonstrate that KIF20A overexpression correlates with poor prognosis in HCC by competitively inhibiting FBXW7-mediated degradation of c-Myc, thereby promoting glycolysis and enhancing tumor proliferation. Conversely, KIF20A downregulation suppresses these effects, impairing tumor growth through c-Myc downregulation. Notably, KIF20A inhibition attenuates c-Myc-induced MMR expression, associated with improved prognosis in HCC patients receiving PD-1 inhibitor therapy. Furthermore, in Kif20a CKO HCC mouse models, we observe synergistic effects between Kif20a knockout and anti-PD-1 antibodies, significantly enhancing immunotherapeutic efficacy against HCC. Our findings suggest that targeting the KIF20A-c-Myc axis could identify HCC patients likely to benefit from anti-PD-1 therapy. In conclusion, we propose that combining KIF20A inhibitors with anti-PD-1 treatment represents a promising therapeutic strategy for HCC, offering new avenues for clinical development and patient stratification.

Predictors of good outcomes in patients with hepatocellular carcinoma (HCC) treated with transarterial radioembolization (TARE).

e16219 Background: No reliable biomarkers or risk factors guide treatment selection in HCC patients. Management is typically institution-specific, and compliance with the available guidelines is low. Our retrospective review aims to identify HCC patients suitable for TARE. Methods: HCC patients treated with TARE between 1/1/2015 and 8/30/22 at Ohio State University were included in this study. Patient-related information was extracted from chart review. Various risk factors (related to HCC and TARE) were compared between good (GR) and poor (PR) responders (progression-free survival (PFS) ≤ vs. > median (m)), and good (GSv) and poor (PSv) survivors (overall survival (OS) ≤ vs. > m). Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 141 patients. The median age was 65 years (range 49-88), 80% were males and 80% were White (16% were African American and 4% were other). The median OS and PFS were 9 months (m) (95% confidence interval [CI], 5-22.5) and 4m (95% CI, 2-9), respectively. Compared to PSv (OS ≤ 9m, N = 71), the GSv group (OS > 9m, N = 70) had a high alcohol history (hx) (64% vs. 44%, p = 0.01); less baseline (BL) encephalopathy (Enc) (21% vs. 37%, p = 0.04) and post-TARE ascites (As) (31% vs. 63%, p = 0.001); were able to receive immune-checkpoint inhibitor (ICI) (44% vs. 6%, p < 0.001) before (6% vs. 1%) or after (39% vs. 10%) TARE. Other key BL features with a trend to significance (p = 0.06-0.08) were less BL cirrhosis (69% vs. 87%) and As (19% vs. 34%), hx of HCC treatment (systemic or local, 43% vs, 28%), and ability to get second TARE (19% vs. 8%). In worse survivors (PFS ≤ 5m, N = 40), post-TARE As (65% vs. 41%, p = 0.008) was significantly higher. Only 2/40 patients were able to get ICI (95% vs. 37%, p = 0.0002) in this group. Compared to PR, the GR group (PFS > 5m, N = 64) had a higher rate of diabetes mellitus (DM) (45% vs. 26%, p = 0.02) and less post-TARE As (34% vs. 58%, p = 0.004). BL and HCC-related factors prominently NOT featured in these comparisons were hepatitis (B or C) or smoking hx and macrovascular invasion. Conclusions: TARE suits patients with hx of alcohol use or DM, no BL Enc, As, or cirrhosis, and failed prior lines. Post-TARE As is poor prognostic markers. ICI use will improve the outcomes.

Predictors of good outcomes in patients with hepatocellular carcinoma (HCC) treated with transarterial radioembolization (TARE).

e16219 Background: No reliable biomarkers or risk factors guide treatment selection in HCC patients. Management is typically institution-specific, and compliance with the available guidelines is low. Our retrospective review aims to identify HCC patients suitable for TARE. Methods: HCC patients treated with TARE between 1/1/2015 and 8/30/22 at Ohio State University were included in this study. Patient-related information was extracted from chart review. Various risk factors (related to HCC and TARE) were compared between good (GR) and poor (PR) responders (progression-free survival (PFS) ≤ vs. > median (m)), and good (GSv) and poor (PSv) survivors (overall survival (OS) ≤ vs. > m). Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 141 patients. The median age was 65 years (range 49-88), 80% were males and 80% were White (16% were African American and 4% were other). The median OS and PFS were 9 months (m) (95% confidence interval [CI], 5-22.5) and 4m (95% CI, 2-9), respectively. Compared to PSv (OS ≤ 9m, N = 71), the GSv group (OS > 9m, N = 70) had a high alcohol history (hx) (64% vs. 44%, p = 0.01); less baseline (BL) encephalopathy (Enc) (21% vs. 37%, p = 0.04) and post-TARE ascites (As) (31% vs. 63%, p = 0.001); were able to receive immune-checkpoint inhibitor (ICI) (44% vs. 6%, p < 0.001) before (6% vs. 1%) or after (39% vs. 10%) TARE. Other key BL features with a trend to significance (p = 0.06-0.08) were less BL cirrhosis (69% vs. 87%) and As (19% vs. 34%), hx of HCC treatment (systemic or local, 43% vs, 28%), and ability to get second TARE (19% vs. 8%). In worse survivors (PFS ≤ 5m, N = 40), post-TARE As (65% vs. 41%, p = 0.008) was significantly higher. Only 2/40 patients were able to get ICI (95% vs. 37%, p = 0.0002) in this group. Compared to PR, the GR group (PFS > 5m, N = 64) had a higher rate of diabetes mellitus (DM) (45% vs. 26%, p = 0.02) and less post-TARE As (34% vs. 58%, p = 0.004). BL and HCC-related factors prominently NOT featured in these comparisons were hepatitis (B or C) or smoking hx and macrovascular invasion. Conclusions: TARE suits patients with hx of alcohol use or DM, no BL Enc, As, or cirrhosis, and failed prior lines. Post-TARE As is poor prognostic markers. ICI use will improve the outcomes.

Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).

e16212 Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p < 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p < 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p < 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p < 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).

Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).

e16212 Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p < 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p < 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p < 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p < 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).

Risk assessment in liver transplantation for hepatocellular carcinoma: long-term follow-up of a two-centre experience.

Liver transplantation (LT) is a well-established treatment for hepatocellular carcinoma (HCC), but there are ongoing debates regarding outcomes and selection. This study examines the experience of LT for HCC at a high-volume centre. A prospectively maintained database was used to identify HCC patients undergoing LT from 2000 to 2020 with more than or equal to 3-years follow-up. Data were obtained from the centre database and electronic medical records. The Metroticket 2.0 HCC-specific 5-year survival scale was calculated for each patient. Kaplan-Meier and Cox-regression analyses were employed assessing survival between groups based on Metroticket score and individual donor and recipient risk factors. Five hundred sixty-nine patients met criteria. Median follow-up was 96.2 months (8.12years; interquartile range 59.9-147.8). Three-year recurrence-free (RFS) and overall survival (OS) were 88.6% ( n =504) and 86.6% ( n =493). Five-year RFS and OS were 78.9% ( n =449) and 79.1% ( n =450). Median Metroticket 2.0 score was 0.9 (interquartile range 0.9-0.95). Tumour size greater than 3cm ( P =0.012), increasing tumour number on imaging ( P =0.001) and explant pathology ( P <0.001) was associated with recurrence. Transplant within Milan ( P <0.001) or UCSF criteria ( P <0.001) had lower recurrence rates. Increasing alpha-fetoprotein (AFP)-values were associated with more HCC recurrence ( P <0.001) and reduced OS ( P =0.008). Chemoembolization was predictive of recurrence in the overall population ( P =0.043) and in those outside-Milan criteria ( P =0.038). A receiver-operator curve using Metroticket 2.0 identified an optimal cut-off of projected survival greater than or equal to 87.5% for predicting recurrence. This cut-off was able to predict RFS ( P <0.001) in the total cohort and predict both, RFS ( P =0.007) and OS ( P =0.016) outside Milan. Receipt of donation after brain death (DBD) grafts (55/478, 13%) or living-donor grafts (3/22, 13.6%) experienced better survival rates compared to donation after cardiac death (DCD) grafts ( n =15/58, 25.6%, P =0.009). Donor age was associated with a higher HCC recurrence ( P =0.006). Both total ischaemia time (TIT) greater than 6hours ( P =0.016) and increasing TIT correlated with higher HCC recurrence ( P =0.027). The use of DCD grafts for outside-Milan candidates was associated with increased recurrence ( P =0.039) and reduced survival ( P =0.033). This large two-centre analysis confirms favourable outcomes after LT for HCC. Tumour size and number, pre-transplant AFP, and Milan criteria remain important recipient HCC-risk factors. A higher donor risk (i.e. donor age, DCD grafts, ischaemia time) was associated with poorer outcomes.

Abstract LB090: Predictive genomic biomarkers for atezolizumab plus bevacizumab combination immunotherapy response in liver cancer: Insights from the IMbrave150 trial

Abstract Introduction: Combination immunotherapy regimens, exemplified by atezolizumab plus bevacizumab or sintilimab paired with a bevacizumab biosimilar (IBI305), have become the established standard of care for individuals with inoperable hepatocellular carcinoma (HCC). Despite this advancement, the absence of clear predictive biomarkers and a comprehensive understanding of the mechanisms governing response and resistance to these combined therapies pose challenges. Our aim is to evaluate whether previously defined immune signature scores (ISS) from the TCGA pan-cancer study can identify HCC patients likely to derive enhanced benefit from the combination immunotherapy. Methods: We applied ISS predictor to gene expression data from IMbrave150 clinical trial in which HCC patients were treated with atezolizumab plus bevacizumab or sorafenib and stratify the patients into responders and non-responders (cutoff of 0.5). The significance of the stratification was assessed by multiple statistical approaches using Kaplan-Meier plots, the log-rank test, chi-square tests, and cox regression analysis. Results: In the IMBrave150 trial cohort, data on gene expression and outcomes were accessible for 247 patients who received atezolizumab plus bevacizumab, and 48 patients who received sorafenib. The high ISS demonstrated a significant association with enhanced PFS in the atezolizumab plus bevacizumab group (p=0.003), while no such association was observed in the sorafenib group (p=0.6). Similarly, in the high ISS subgroup, the combination therapy exhibited superior OS (p.0.001) and PFS (p=0.02) compared to sorafenib, but no discernible benefit was noted in the low ISS subgroup (both p&amp;gt;0.7). The OS hazard ratio for the combination versus sorafenib was 0.26 (95% CI 0.14-0.51, p&amp;lt;0.001) among high ISS patients, while it was not statistically significant in low ISS (HR 0.88, p=0.68). Interaction testing confirmed a notable interaction between ISS subtype and treatment benefit, particularly for OS (p=0.01). In the combination arm, the objective response rate was 45.6% in the high ISS group versus 22.8% in the low ISS group. Conclusions: Our study suggests that ISS may serve as a promising predictive biomarker for enhanced therapeutic outcomes in patients undergoing combination immunotherapy for HCC. The identification of such markers is crucial for refining patient stratification and personalized treatment approaches, thereby advancing the effectiveness of current standard-of-care regimens in both early and advanced stage HCC. Further validation studies are warranted to solidify the clinical utility of ISS and its integration into the decision-making process for HCC immunotherapy. Citation Format: Ju-Seog Lee, Sun Young Yim, Seung-Woo Baek, Sung Hwan Lee, BoHwa Sohn, Yun Seong Jeong, Sanghee Kang, Kena Park, Hyewon Park, Sunyoung S. Lee, Ahmed O. Kaseb, Ji Hoon Kim, In-Sun Chu. Predictive genomic biomarkers for atezolizumab plus bevacizumab combination immunotherapy response in liver cancer: Insights from the IMbrave150 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB090.

PD1 and TIM3 Expression is Associated with Very Early Hepatocellular Carcinoma Recurrence After Percutaneous Thermal Ablation.

Percutaneous thermal ablation (PTA) is a cornerstone in the management of early-stage hepatocellular carcinoma (HCC). However, intrahepatic distant recurrence (IDR) occurs in the majority of patients after PTA. The aim of this study was to evaluate the immune signature associated with very early IDR. Thirty-one patients (26 men, 5 women; mean age:72.4 ± 8.6; age range:57-86 years) who underwent PTA for HCC were included in this study. After PTA for HCC, patients were followed and later divided into two groups: a "very early recurrence" group in case of IDR within 12 months after PTA, and a "prolonged recurrence-free" group in case of no recurrence before 12 months of follow-up. Freshly harvested intratumoral and nontumoral liver tissues and peripheral blood were obtained before PTA and explored by multiparametric flow cytometry. The frequency of PD1+CD4+ T cells was higher in the early recurrence group than in the prolonged recurrence-free group in the peripheral blood (24.3%, IQR: 22.3-36.5 vs 14.0%, IQR: 11.5-16.4, p<0.0001), in the nontumoral liver (37.9%, IQR: 36.0-50.0 vs 22.5%, IQR: 18.0-29.9, p=0.0004), and in the tumor (37.6%, IQR: 32.3-39.3 vs 24.0%, IQR: 20.0-30.3, p=0.0137). Similarly, the frequency of TIM+CD8+ T cells was higher in the very early recurrence group in the peripheral blood (p=0.0021), non-tumoral liver (p=0.0012), and tumor (p=0.0239). The expression of immune checkpoint molecules, such as PD1 and TIM3 on T cells identified HCC patients at risk of very early IDR after PTA who would likely benefit from adjuvant immunotherapy. Thus, our study contributes to a better understanding of the potential association of PTA with adjuvant immunotherapies.

Multi-cohort validation study of a four-gene signature for risk stratification and treatment response prediction in hepatocellular carcinoma

BackgroundThe intricate molecular landscape of hepatocellular carcinoma (HCC) presents a significant challenge to achieving precise risk stratification through clinical genetic testing. At present, there is a paucity of robust gene signatures that could assist clinicians in making clinical decisions for patients with HCC. MethodsWe obtained gene expression profiles of patients with HCC from 20 independent cohorts available in public databases. A gene signature was developed by employing two machine learning algorithms. In addition to validating the signature with high-throughput data in public cohorts, we external validated the signature in 64 HCC cases by RT-PCR method. We compared genomic, transcriptomic and proteomic features between different subgroups. We also compared our signature to 130 gene signatures that have already been published. ResultsWe developed a novel four-gene signature, designated as HCC4, that demonstrates significant potential for the prediction of survival outcomes in more than 1300 patients with HCC. The HCC4 also has potential for predicting recurrence and tumor volume doubling time, assessing transcatheter arterial chemoembolization and immunotherapy responses, and non-invasive detection of HCC. The high HCC4 score group shows a higher frequency of mutations in genes TP53, RB1 and TSC1/2, as well as increased activity of cell-cycle, glycolysis and hypoxia signaling pathways, higher cancer stemness score, and lower lipid metabolism activity. In seven HCC cohorts, HCC4 exhibited a higher average C-index in predicting overall survival compared to the 130 signatures previously published. Drug screening indicated that patients with high HCC4 scores were more sensitive to agents targeting AURKA, TUBB, JMJD6 and KIFC1. ConclusionsOur findings demonstrated that HCC4 is a powerful tool for improving risk stratification and for identifying HCC patients who are most likely to benefit from TACE treatment, immunotherapy, and other experimental therapies.

Prediction model for hepatocellular carcinoma recurrence after hepatectomy: Machine learning-based development and interpretation study

BackgroundIdentifying patients with hepatocellular carcinoma (HCC) at high risk of recurrence after hepatectomy can help to implement timely interventional treatment. This study aimed to develop a machine learning (ML) model to predict the recurrence risk of HCC patients after hepatectomy. MethodsWe retrospectively collected 315 HCC patients who underwent radical hepatectomy at the Third Affiliated Hospital of Sun Yat-sen University from April 2013 to October 2017, and randomly divided them into the training and validation sets at a ratio of 7:3. According to the postoperative recurrence of HCC patients, the patients were divided into recurrence group and non-recurrence group, and univariate and multivariate logistic regression were performed for the two groups. We applied six machine learning algorithms to construct the prediction models and performed internal validation by 10-fold cross-validation. Shapley additive explanations (SHAP) method was applied to interpret the machine learning model. We also built a web calculator based on the best machine learning model to personalize the assessment of the recurrence risk of HCC patients after hepatectomy. ResultsA total of 13 variables were included in the machine learning models. The multilayer perceptron (MLP) machine learning model was proved to achieve optimal predictive value in test set (AUC = 0.680). The SHAP method displayed that γ-glutamyl transpeptidase (GGT), fibrinogen, neutrophil, aspartate aminotransferase (AST) and total bilirubin (TB) were the top 5 important factors for recurrence risk of HCC patients after hepatectomy. In addition, we further demonstrated the reliability of the model by analyzing two patients. Finally, we successfully constructed an online web prediction calculator based on the MLP machine learning model. ConclusionMLP was an optimal machine learning model for predicting the recurrence risk of HCC patients after hepatectomy. This predictive model can help identify HCC patients at high recurrence risk after hepatectomy to provide early and personalized treatment.

A Cuproptosis-Related LncRNA Risk Model for Predicting Prognosis and Immunotherapeutic Efficacy in Patients with Hepatocellular Carcinoma.

Cuproptosis is a novel programmed cell death pathway that is initiated by direct binding of copper to lipoylated tricarboxylic acid (TCA) cycle proteins. Recent studies have demonstrated that cuproptosis-related genes regulate tumorigenesis. However, the potential role and clinical significance of cuproptosis-related long noncoding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) have not been established. We performed a bioinformatics analyses of RNA-sequencing data of HCC patients extracted from The Cancer Genome Atlas (TCGA) dataset to identify and validate a cuproptosis-related lncRNA prognostic signature. Furthermore, we analyzed the clinical significance of the prognostic signature of cuproptosis-related lncRNA in predicting the immunotherapeutic efficacy and the status of the tumor immune microenvironment. The RNA-sequencing data, genomic mutations, and clinical information were downloaded for 374 HCC samples and 50 normal liver samples from TCGA-Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. Co-expression analysis of Gene-lncRNA pairs with 49 known cuproptosis-related prognostic genes was used to define cuproptosis-related prognostic lncRNAs. We performed the LASSO algorithm and univariate and multivariate Cox regression analysis, respectively, to gradually identify the prognostic risk models of cuproptosis-related lncRNA based on the TCGA-LIHC dataset. Subsequently, the predictive performance of the model was evaluated using receiver operation characteristic (ROC) curves, Kaplan-Meier survival curves, and prognostic nomogram. The analysis of gene-lncRNA co-expression with 49 known cuproptosis-related genes identified 1359 cuproptosis-related lncRNAs in the TCGA-LIHC data set. A prognostic model was constructed with nine cuproptosis-related prognostic lncRNAs (AC007998.3, AC003086.1, AC009974.2, IQCH-AS1, LINC0256 1, AC105345.1, ZFPM2-AS1, AL353708.1 and WAC-AS1) using LASSO regression and Cox regression analyses. Risk scores were calculated for all HCC patient samples based on the four cuproptosis-related lncRNA prognostic models. All HCC patients were divided into high-risk and low-risk subgroups according to a 1:1 ratio column. The Kaplan-Meier survival curve analysis showed that the overall survival rate (OS) of the high-risk group patients was significantly lower than that of the low-risk group. The principal component analysis (PCA) confirmed that the prognostic lncRNA model accurately distinguished between high- and low-risk HCC patients. Furthermore, regression analysis as well as ROC curves confirmed the prognostic value of the risk score. A nomogram with risk scores and other clinicopathological characteristics was constructed. The nomogram accurately predicted the probability of 1-, 3-, and 5-year OS in HCC patients. Tumor mutation burden (TMB) scores were higher for high-risk patients than for low-risk patients. HCC patients in the low-risk group showed lower TIDE scores and greater sensitivity to antitumor drugs than those in the high-risk group. Tumor immune responses and tumor immune cell infiltration were significantly different between the high-risk and low-risk groups of patients with HCC. Our study identified a 9-cuproptosis-related lncRNA signature that accurately predicted prognosis, immunotherapeutic efficacy, and the status of the tumor immune microenvironment in HCC patients. Therefore, this cuproptosis-related lncRNA risk model is a potential prognostic biometric feature in HCC and shows high clinical value in identifying HCC patients who are potentially responsive to immunotherapy.

FAIL-T (AFP, AST, tumor sIze, ALT, and Tumor number): a model to predict intermediate-stage HCC patients who are not good candidates for TACE.

Patients with un-resectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) are a diverse group with varying overall survival (OS). Despite the availability of several scoring systems for predicting OS, one of the unsolved problems is identifying patients who might not benefit from TACE. We aim to develop and validate a model for identifying HCC patients who would survive <6 months after their first TACE. Patients with un-resectable HCC, BCLC stage 0-B, who received TACE as their first and only treatment between 2007 and 2020 were included in this study. Before the first TACE, demographic data, laboratory data, and tumor characteristics were obtained. Eligible patients were randomly allocated in a 2:1 ratio to training and validation sets. The former was used for model development using stepwise multivariate logistic regression, and the model was validated in the latter set. A total of 317 patients were included in the study (210 for the training set and 107 for the validation set). The baseline characteristics of the two sets were comparable. The final model (FAIL-T) included AFP, AST, tumor sIze, ALT, and Tumor number. The FAIL-T model yielded AUROCs of 0.855 and 0.806 for predicting 6-month mortality after TACE in the training and validation sets, respectively, while the "six-and-twelve" score showed AUROCs of 0.751 (P < 0.001) in the training set and 0.729 (P = 0.099) in the validation sets for the same purpose. The final model is useful for predicting 6-month mortality in naive HCC patients undergoing TACE. HCC patients with high FAIL-T scores may not benefit from TACE, and other treatment options, if available, should be considered.

Serum Exosome-Derived piRNAs Could Be Promising Biomarkers for HCC Diagnosis.

Serum exosome-based liquid biopsy has significant advantages for screening and diagnosing hepatocellular carcinoma (HCC). P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are novel small silencing RNAs that have been identified to function in cancer-related signalling pathways. However, studies on the presence of piRNAs in serum exosomes from HCC patients and their diagnostic values in HCC are not well reported. Our aim is to validate serum exosome-derived piRNAs as the valuable component of liquid biopsy for diagnosing HCC. We used small RNA (sRNA) sequencing to profile piRNAs from serum exosomes and describe the base distribution characteristics of serum exosome-derived piRNAs. Serum exosomes from 125 HCC patients and 44 nontumor donors were included in this study. We found that piRNAs were components of serum exosomes from HCC patients. A total of 253 differentially expressed serum exosome-derived piRNAs were screened from HCC compared with the piRNAs from nontumor donors. Serum exosome-derived piRNAs from HCC displayed a distinctive base distribution. To further confirm the potential diagnostic value of serum exosome-derived piRNAs in HCC, we detected the levels of the top 5 upregulated piRNAs in our Chinese cohort. The training set and validation set both showed that all 5 piRNAs were dramatically increased in the serum exosomes from HCC compared with the piRNAs from non-tumour donors. The piRNAs could strongly identify HCC patients from non-tumour donors according to the area under the receiver operating characteristic (AUROC) model. Additionally, the piRNAs could also present significant values for the diagnosis of HCC with low tumour burden. piRNAs enriched the components of serum exosomes from HCC and could serve as promising biomarkers for HCC diagnosis.

Disparities in Hepatocellular Carcinoma Outcomes Among Subgroups of Asians and Pacific Islanders: A SEER Database Study.

Hepatocellular carcinoma (HCC) is highly prevalent in Asians and Pacific Islanders (API) but this heterogenous group is often aggregated into a single category, despite vast differences in culture, socioeconomic status, education, and access to care among subgroups. There remains a significant knowledge gap in HCC outcomes among different subgroups of API. The Surveillance, Epidemiology, and End Results (SEER) database was accessed, and site/ICD codes were used to identify HCC patients during 2010-2019 who were API ethnicity. Data collected: demographics, socioeconomic status, tumor characteristics, treatment, and survival. Subgroup analyses were performed among different Asian ethnicities in a secondary analysis. 8,249 patients were identified/subdivided into subgroups of Asian ethnicities and Other Pacific Islanders (NHOPI) groups. The median age was 65years for Asians and 62years for NHOPI (p < 0.01), and significant differences were found in income (p < 0.01). A higher proportion of NHOPI lived in rural areas compared to Asians (8.1 vs. 1.1%, p < 0.01). There were no statistically significant differences in tumor size, stage, pre-treatment AFP level, or surgical treatments between the two groups. However, Asians had higher overall median survival than NHOPI (20months v 12months, p < 0.01). Secondary analyses among different subgroups of Asian ethnicities revealed significant differences in tumor size and staging, surgical resection, transplant rates, and median survival. While API had similar tumor characteristics and treatment, Asians had much higher survival than NHOPI. Socioeconomic differences and access to care may contribute to these differences. This study also found significant survival disparities within API ethnicities.

The predictive value of PD-L1 expression in patients with advanced hepatocellular carcinoma treated with PD-1/PD-L1 inhibitors: A systematic review and meta-analysis.

Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have transformed the treatment landscape of advanced hepatocellular carcinoma (HCC), but consistent responses are not observed in all patients, and prognostic biomarkers to guide treatment decisions are lacking. We aimed to evaluate the predictive value of PD-L1 expression in advanced HCC patients treated with PD-1/PD-L1 inhibitors. A comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Studies comparing the objective response rate (ORR) and/or disease control rate (DCR) based on the tumor PD-L1 status of HCC were included. Eleven studies with 1,330 HCC patients treated with PD-1/PD-L1 inhibitors were included. Pooled odds ratio (OR) analysis demonstrated a significantly improved ORR in PD-L1-positive patients compared with PD-L1-negative patients (OR, 1.86, 95% CI, 1.35-2.55). Similar results were observed in the anti-PD-1 treatment (p < 0.001) and anti-PD-1/PD-L1 monotherapy (p < 0.001) subgroups. The pooled ORRs in the PD-L1-positive and PD-L1-negative groups were 26% (95% CI, 20%-32%) and 18% (95% CI, 13%-22%), respectively. For DCR, the pooled OR analysis showed no significant difference between PD-L1-positive patients and PD-L1-negative patients (66% [95% CI, 55%-76%] vs. 69% [95% CI, 62%-76%]; OR, 0.92, 95% CI, 0.59-1.44). The results were consistent across the drug target and combination treatment subgroups. Positive PD-L1 expression is associated with a better ORR in advanced HCC patients treated with anti-PD-1/PD-L1-based therapies. This feature can help to identify HCC patients who will benefit most from PD-1/PD-L1 inhibitors.

The investigation on the hypercoagulability of hepatocellular carcinoma‐related cerebral infarction with thromboelastography

To investigate the hypercoagulability of hepatocellular carcinoma (HCC)-related cerebral infarction (HCRCI) with thromboelastography (TEG). A multicenter prospective study was conducted in HCRCI patients, HCC patients without cerebral infarction, and acute cerebral infarction (ACI) patients without HCC between January 2016 and December 2019. TEG parameters and laboratory and clinical data were collected and compared among the three groups. To confirm the independent risk factors of HCRCI, multivariate analyses were conducted. Receiver operating characteristic (ROC) curves were utilized to evaluate the area under the curve (AUC) plotted by each independent risk factor. There were 38 patientsrecruited in the HCRCI group, and 152 patients were recruited to the HCC group and the ACI group. The levels of plasma neutrophil count, D-dimer, α-fetoprotein (AFP), carcinoembryonic antigen, and maximum amplitude (MA)-a parameter of TEG-were significantly higher in the HCRCI group than HCC and ACI groups. Multivariate logistic regression analysis showed that increased neutrophile count, D-dimer, AFP, and MA were independently associated with HCRCI. ROC curve analysis showed firstthat AUC of MA for HCRCI was .875, which was larger than the other risk factors, and second that the optimal cutoff value for MA was 61.35, with a sensitivity of 89.50% and specificity of 66.40%. It was suggested that TEG disclosed that the pathogenesis of HCRIC is exactly related to the hypercoagulability. And with a cutoff value of MA equaling to 61.35, TEG facilitatesclinicians to identify HCC patients at high risk of HCRIC.

Evaluating the benefit of surgical resection for hepatocellular carcinoma with multifocality or intrahepatic vascular invasion

BackgroundThe role of hepatectomy for hepatocellular carcinoma (HCC) with multifocality or intrahepatic vascular involvement remains ill-defined. Our objective was to evaluate benefits of surgical resection for patients with these high-risk features. MethodsThe National Cancer Database was used to identify HCC patients with vascular involvement and/or multifocality (T2/T3, N-/M−) from 2011 to 2015. Propensity score matching (k-nearest neighbors, no replacement, 1:1) grouped patients by treatment: surgical resection versus non-surgical modalities. Groups were matched using patient, clinical, and liver-specific characteristics. Median overall survival (OS) was calculated using Kaplan–Meier, and adjusted analyses were performed using shared frailty models. Results14,557 patients met inclusion criteria, including 1892 (9.4%) treated with surgical resection. Median cohort OS was 20.5 months. After adjustment, surgical resection was associated with survival advantage compared to non-surgical treatment (37.8 versus 15.7 months, log-rank P < .001; adjusted hazard ratio 0.49, 95% confidence interval, 0.45–0.54). Patients with minimal comorbidity, unifocal disease, and age <54 had highest probability of survival one year post-surgery. ConclusionsSurgical resection is associated with a survival advantage in HCC with multifocality and/or intrahepatic vascular involvement. The presence of these features should not contraindicate consideration of hepatectomy in suitable surgical candidates.

Beyond CPS for PD-L1 scoring: Genetic alterations that impact efficacy of immunotherapy in hepatocellular carcinoma (HCC).

592 Background: Tumor-agnostic approvals of immune checkpoint inhibitors (ICI) include deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) and high tumor mutational burden (TMB) while in cancer like metastatic gastroesophageal cancers, ICI use has been predicated on PD-L1 expression. ICI are increasingly used for metastatic HCC, but without required markers. We aimed to examine the genomic landscape of HCC in context of PD-L1 expression, and to determine clinical responses to ICI in this setting. Methods: Next-generation sequencing of DNA (592 or WES) and RNA (WTS) was tested at Caris Life Sciences (Phoenix, AZ). PD-L1 expression was tested by IHC (SP142) and compared as high (2+,5%), low (1-2,1%) and negative (0). dMMR/MSI-H was tested by IHC/NGS and TMB-High was defined as ³10 mutations/MB. QuantiSEQ was used to estimate the tumor microenvironment. X2/Fisher-Exact were used and significance was determined as P-value adjusted for multiple comparison ( Q &lt; 0.05). Real-world overall survival (rwOS) was obtained from insurance claims and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of ICI treatments. Results: Overall, 17.7% of HCC expressed PD-L1 by IHC; 79/1306 (6.1%) had high expression. The overall prevalence of dMMR/MSI-H was 0.2%; TMB was high in 5.1%. PD-L1 expression was not associated with MSI-H or high TMB. When comparing tumors that are PD-L1 high vs. negative vs. low, expression of several immuno-oncologic (IO) markers LAG3 (median TPM: 2.4, 0.8, 0.5), CTLA-4 (2.9, 1.2, 0.5), IDO1 (4.2, 1.3, 0.6) and others, as well as T-cell inflamed and IFNg scores all decreased significantly with PD-L1 (all q&lt;0.05), similar trends were seen with B cells, M1 macrophages, CD8+ T cells and T regs while opposite differences seen in NK cells (q&lt;0.05). Additionally, when PDL1-high tumors were compared to PDL1-negative, mutations in CTNNB1 trended lower (21% vs 35%) while amplifications of KRAS (4% vs 0%), PDCD1LG2 (4% vs 0%) and mutations in HNF1A (3% vs 0%), HOXB13 (6% vs 0%), STK11 (5% vs 0%) trended higher; when PDL1-low were compared to PDL1-negative, mutations in TP53 (45% vs 32%), ELF3 (3% vs 0%), TSC2 (6% vs 2%) and PIK3CA (5% vs 1%) and amplifications in BCL9 (2% vs 0%) and CCNE1 (2% vs 0%) trended higher. When investigating clinical outcome of a cohort of 908 HCC tumors, PD-L1 expression had no effect on prognosis, and was not associated with differences in TOT of ICI in HCC. Conclusions: Prevalence of dMMR/MSI-H and TMB-H is very low in HCC. PD-L1 is only expressed in &lt;20%. Even with a finding of strong association of expression of several established IO biomarkers with PD-L1 expression, it’s still not predictive of response to ICI. New biomarkers or molecular signatures need to be identified and validated to objectively identify HCC patients most likely to benefit from ICI treatment.

Comparison of liver-directed combined radiotherapy versus sorafenib in patients with locally advanced hepatocellular carcinoma with portal vein tumor thrombosis: An Asian Liver Radiotherapy Group Study.

565 Background: While systemic treatment is the mainstay for advanced hepatocellular carcinoma (HCC), numerous studies have highlighted the added value of local treatment. This study aimed to investigate the clinical efficacy of liver-directed combined radiotherapy (LD-CRT) compared to sorafenib, a recommended treatment until recently in locally advanced HCC presenting portal vein tumor thrombosis (PVTT) using a multinational patient cohort. Methods: We identified HCC patients presenting PVTT treated with either sorafenib or LD-CRT in 10 tertiary hospitals over Asia during 2005-2014. Propensity score matching (PSM) was performed to minimize the imbalance in patient and tumor characteristics of the two groups. The primary endpoint was overall survival (OS), and secondary endpoints were distant metastasis free survival (DMFS), local failure free survival (LFFS), and treatment related toxicity. Results: Total 1,035 patients including 360 patients in the sorafenib group and 675 patients in the LD-CRT group were enrolled. The majority of patients in the sorafenib group received 400 mg of sorafenib twice a day initially, and the dose was reduced to 50% or 25% if adverse reactions were noted. LD-CRT was given in liver-directed concurrent chemoradiotherapy in 502 (74.4%) patients, followed by transarterial chemoembolization plus radiotherapy in 149 (22.1%) patients. After PSM, 336 patients from each group were matched, and all features were well balanced between the two groups. At a median follow up of 28.8 months (interquartile range, 16.5-63.6), the median OS was 11.0 and 17.1 months for the sorafenib and LD-CRT groups, respectively ( p=0.001). In addition, LD-CRT group showed significantly improved DMFS and LFFS compared to the sorafenib group (median DMFS 14.9 vs 9.6 months, p=0.004, and median LFFS 15.7 vs 9.6 months, p=0.002). Conversion rate to curative surgery was significantly higher in the LD-CRT group (8.6% vs 0.9%, p=0.002). Those who underwent surgery had younger median age (54 vs 59, p=0.024), smaller median tumor size (6.5 cm vs 8.9 cm, p=0.012), and more unilateral disease (75.0% vs 43.8%, p&lt;0.001). OS and LFFS were significantly prolonged in patients who underwent surgical treatment. Grade 3 or higher toxicity was more frequently noted in the sorafenib group compared to the LD-CRT group (7.7% vs 0.7%, p&lt;0.001). Conclusions: Analysis of a propensity score matched multinational patient cohort revealed that liver-directed combined RT improved survival outcomes of locally advanced HCC patients presenting PVTT. While further prospective studies are warranted, we carefully suggest active multimodal local treatment for locally advanced HCC presenting PVTT.

A bile acid-related prognostic signature in hepatocellular carcinoma

Due to the high mortality of hepatocellular carcinoma (HCC), its prognostic models are urgently needed. Bile acid (BA) metabolic disturbance participates in hepatocarcinogenesis. We aim to develop a BA-related gene signature for HCC patients. Research data of HCC were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) online databases. After least absolute shrinkage and selection operator (LASSO) regression analysis, we developed a BA-related prognostic signature in TCGA cohort based on differentially expressed prognostic BA-related genes. Then, the predictive performance of the signature was evaluated and verified in TCGA and ICGC cohort respectively. We obtained the risk score of each HCC patient according to the model. The differences of immune status and drug sensitivity were compared in patients that were stratified based on risk score. The protein and mRNA levels of the modeling genes were validated in the Human Protein Atlas database and our cell lines, respectively. In TCGA cohort, we selected 4 BA-related genes to construct the first BA-related prognostic signature. The risk signature exhibited good discrimination and predictive ability, which was verified in ICGC cohort. Patients were classified into high- and low-risk groups according to their median scores. The occurrence of death increased with increasing risk score. Low-risk patients owned favorable overall survival. High-risk patients possessed high immune checkpoint expression and low IC50 values for sorafenib, cisplatin and doxorubicin. Real-time quantitative PCR and immunohistochemical results validate expression of modeling genes in the signature. We constructed the first BA-related gene signature, which might help to identify HCC patients with poor prognosis and guide individualized treatment.