Stage Hepatocellular Carcinoma Research Articles

Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a high mortality neoplasm which usually appears on a cirrhotic liver. The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis. Notwithstanding the current deployment of treatments with curative intent (liver resection/local ablation and liver transplantation) in early and intermediate stages, a high rate of HCC recurrence persists, underscoring a pivotal clinical challenge. Emergent systemic therapies (ST), particularly immunotherapy, have demonstrate promising outcomes in terms of increase overall survival, but they are currently bound to the advanced stage of HCC. This review provides a comprehensive analysis of the literature, encompassing studies up to March 10th, 2024, evaluating the impact of novel ST in the early and intermediate HCC stages, specially focusing on the findings of neoadjuvant and adjuvant regimens, aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent. We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent. Finally, we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Recurrence and Survival after Robotic vs. Laparoscopic Liver Resection in Very-Early to Early Stage (BCLC 0-A) Hepatocellular Carcinoma: A Retrospective Cohort Study with Propensity Score Matching

Abstract Background Robotic (RLR) and laparoscopic liver resection (LLR) provide similar short-term outcomes in hepatocellular carcinoma (HCC) of stage BCLC 0-A, but data on recurrence and survival are still lacking in populations with high prevalence of cirrhosis. Aims We investigated the outcomes of RLR vs. LLR for HCC in a cohort with high rate of cirrhosis. The primary endpoint was recurrence-free (RFS) and overall survival (OS); incidence, pattern, and treatment of recurrence were the secondary ones. Methods RLRs and LLRs for HCC of stage BCLC 0-A from two tertiary centers for liver surgery were retrospectively reviewed. Propensity score matching (PSM) was used to mitigate selection bias. Survival was estimated with Kaplan Meier method with Log rank. Results One-hundred-ninety-six patients underwent RLR (n=68) or LLR (n=128) for BCLC 0-A HCC. After 1:1 PSM, two groups (RLR=68; LLR=68) of patients with similar characteristics, liver function and HCC features were obtained: age (median) 71-year-old, males 73.5%, underlying cirrhosis 91.2% (Child A 96.8%, MELD <9 96%), portal hypertension 22.1%, single-HCC 90.4%. At a median follow-up of 29.0 months, 2- and 5-year RFS were 78.0 vs. 59.0% and 54.0 vs. 53.0% (p=0.107), while OS was 97.0 vs. 90.0% and 87.0 vs. 90.0% (p=0.951) for RLR vs. LLR respectively. Incidence of recurrence was similar (35.3 vs. 39.7%; p=0.723) and was mostly within the liver (29.4 vs. 30.9%; p=1.000) or within 2 years after hepatectomy (54.2 vs. 81.5%, p=0.116) in RLR vs. LLRs. Curative-intent treatment of recurrences did not differ (liver transplantation 19.6%, redo-resection 15.7%) except for a tendency to more redo-resections of recurrences after RLR (29.2 vs. 3.7%; p=0.062). Conclusion Oncologic outcomes of RLR were not inferior to those of LLR in selected HCC patients of stage BCLC 0-A with underlying cirrhosis. Both techniques guaranteed similar salvageability at HCC recurrence in our experience.

Immortalized hepatocyte-like cells: A competent hepatocyte model for studying clinical HCV isolate infection.

More than 58 million individuals worldwide are inflicted with chronic HCV. The disease carries a high risk of end stage liver disease, i.e., cirrhosis and hepatocellular carcinoma. Although direct-acting antiviral agents (DAAs) have revolutionized therapy, the emergence of drug-resistant strains has become a growing concern. Conventional cellular models, Huh7 and its derivatives were very permissive to only HCVcc (JFH-1), but not HCV clinical isolates. The lack of suitable host cells had hindered comprehensive research on patient-derived HCV. Here, we established a novel hepatocyte model for HCV culture to host clinically pan-genotype HCV strains. The immortalized hepatocyte-like cell line (imHC) derived from human mesenchymal stem cell carries HCV receptors and essential host factors. The imHC outperformed Huh7 as a host for HCV (JFH-1) and sustained the entire HCV life cycle of pan-genotypic clinical isolates. We analyzed the alteration of host markers (i.e., hepatic markers, cellular innate immune response, and cell apoptosis) in response to HCV infection. The imHC model uncovered the underlying mechanisms governing the action of IFN-α and the activation of sofosbuvir. The insights from HCV-cell culture model hold promise for understanding disease pathogenesis and novel anti-HCV development.

Diagnostic and prognostic performances of GALAD score in staging and 1-year mortality of hepatocellular carcinoma: A prospective study

BACKGROUND The GALAD score has improved early hepatocellular carcinoma (HCC) detection rate. The role of the GALAD score in staging and predicting tumor characteristics or clinical outcome of HCC remains of particular interest. AIM To determine the diagnostic/prognostic performances of the GALAD score at various phases of initial diagnosis, tumor features, and 1-year mortality of HCC and compare the performance of the GALAD score with those of other serum biomarkers. METHODS This prospective, diagnostic/prognostic study was conducted among patients with newly diagnosed HCC at the liver center of Vajira Hospital. Eligible patients had HCC staging allocation using the Barcelona Clinic Liver Cancer (BCLC) categorization. Demographics, HCC etiology, and HCC features were recorded. Biomarkers and the GALAD score were obtained at baseline. The performance of the GALAD score and biomarkers were prospectively assessed. RESULTS Exactly 115 individuals were diagnosed with HCC. The GALAD score increased with disease severity. Between BCLC-0/A and BCLC-B/C/D, the GALAD score predicted HCC staging with an area under the curve (AUC) of 0.868 (95%CI: 0.80–0.93). For identifying the curative HCC, the AUC of GALAD score was significantly higher than that of Alpha-fetoprotein (AFP) (0.753) and Lens culinaris agglutinin-reactive fraction of AFP-L3 (0.706), and as good as that of Protein induced by vitamin K absence-II (PIVKA-II) (0.897). For detecting aggressive features, the GALAD score gave an AUC of 0.839 (95%CI: 0.75–0.92) and significantly outperformed compared to that of AFP (0.761) and AFP-L3 (0.697), with a trend of superiority to that of PIVKA-II (0.772). The performance to predict 1-year mortality of GALAD score (AUC: 0.711, 95%CI: 0.60–0.82) was better than that of AFP (0.541) and as good as that of PIVKA-II (0.736). The optimal cutoff value of GALAD score was ≥ 6.83, with a specificity of 72.63% for exhibiting substantial reduction in the 1-year mortality. CONCLUSION The GALAD model can diagnose HCC at the curative stage, including the characteristic of advanced disease, more than that by AFP and AFP-L3, but not PIVKA-II. The GALAD score can be used to predict the 1-year mortality of HCC.

The Apparent Diffusion Coefficient of the Paraspinal and Psoas Muscles Are of Prognostic Relevance in Patients With Hepatocellular Carcinoma Undergoing Transarterial Radioembolization.

Transarterial radioembolization (TARE) is a treatment option for early or intermediate stage hepatocellular carcinoma (HCC). Sarcopenia is defined as loss of muscle strength and quality which can be estimated by imaging modalities and has been associated with prognosis and treatment response in HCC patients. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted imaging (DWI) can reflect the tissue composition and might be better to determine muscle changes of sarcopenia than the standard method of computed tomography (CT). The present study sought to elucidate ADC values of the abdominal wall muscles as a prognostic factor in patients undergoing TARE. A retrospective analysis was performed between 2016 and 2020. Overall, 52 patients, 9 women (17.3%) and 43 men (82.7%), with a mean age of 69±8.5 years were included into the analysis. In every case, the first pre-interventional magnetic resonance imaging (MRI) including DWI was used to measure the ADC values of paraspinal and psoas muscle. The 12-month survival after TARE was used as the primary study outcome. Overall, 40 patients (76.9%) of the patient cohort died within the 12-month observation period. Mean overall survival was 10.9 months after TARE for all patients. Mean ADC values for all muscles were 1.31±0.13×10-3mm2/s. The ADC values of the paraspinal muscles were statistically significantly higher compared to the ADC values of the psoas muscles (p=0.0031). A positive correlation was identified between mean ADC and the thrombocyte count (r=0.37, p=0.005) and serum bilirubin (r=-0.30, p=0.03). In the multivariate Cox regression analysis, the mean ADC values of all muscles were associated with the survival after 12 months (HR=0.98, 95% CI=0.97-0.99, p=0.04). ADC values of the abdominal wall muscles could be used as a prognostic biomarker in patients with HCC undergoing TARE. These preliminary results should be confirmed by further studies using external validation cohorts and other treatment modalities.

Low preoperative serum uric acid is associated with early acute kidney injury after living donor liver transplantation.

Liver transplantation is treatment option for patients with end stage liver disease and hepatocellular carcinoma. Renal function deterioration significantly impacts the survival rates of liver recipients, and serum uric acid (SUA) is associated with both acute and chronic renal function disorders. Thus, our study aimed to assess the relationship and predictive value of preoperative SUA level and postoperative acute kidney injury (AKI) in living donor liver transplantation (LDLT). We conducted a prospective observational study on 87 patients undergoing LDLT. Blood samples were collected immediately prior to LDLT, and renal function status was followed up for 3 consecutive days postoperatively. Low SUA levels (cutoff value 4.15 mg/dL) were associated with a high risk of early post-transplantation AKI. The area under the curve was 0.73 (sensitivity, 79.2%; specificity, 59.4%). Although not statistically significant, there were no deaths in the non-AKI group but two in the early AKI group secondary to liver graft dysfunction in addition to early AKI within the first month after LDLT. AKI after liver transplantation may lead to a deterioration of patient status and increased mortality rates. We determined low preoperative SUA levels as a possible risk factor for early postoperative AK.

Metabolomics biomarkers of hepatocellular carcinoma in a prospective cohort of patients with cirrhosis

Background & AimsThe effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited, due to inadequate risk stratification and suboptimal performance of the screening modalities. MethodsWe developed a multicenter prospective cohort of cirrhotic patients undergoing surveillance with MRI, and applied global untargeted metabolomics to 612 longitudinal serum samples from 203 patients. Among them, 37 developed HCC during follow-up. ResultsWe identified 150 metabolites with significant abundance changes in samples collected prior to HCC (Cases) compared to samples from patients who didn’t develop HCC (Controls). Tauro-conjugated bile acids and gamma-glutamyl amino acids were increased, while acyl-cholines and deoxycholate derivatives were decreased. Seven amino acids including serine and alanine, had strong associations with HCC risk, while strong protective effects were observed for N-acetylglycine and glycerophosphorylcholine. Machine learning using the 150 metabolites, age, gender, patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TMS6SF2) SNPs, identified 15 variables giving optimal performance. Among them, N-acetylglycine had the highest AUC in discriminating Cases and Controls. When restricting Cases to samples collected within 1 year prior to HCC (Cases-12M), additional metabolites including microbiota-derived metabolites were identified. The combination of the top 6 variables identified by machine learning (alpha-fetoprotein, 6-bromotryptophan, N-acetylglycine, salicyluric glucuronide, testosterone sulfate and age) had good performance in discriminating Cases-12M from Controls (AUC=0.88 [0.83-0.93]). Finally, 23 metabolites distinguished Cases with Liver Imaging Reporting and Data System (LI-RADS)-3 lesions from Controls with LI-RADS-3 lesions, with reduced abundance of acyl-cholines and glycerophosphorylcholine-related lysophospholipids in Cases-LR3. ConclusionsThis study identified N-acetylglycine, amino acids, bile acids and choline-derived metabolites as main biomarkers of HCC risk, and microbiota-derived metabolites as main contributors to HCC development. Impact and ImplicationsThe effectiveness of surveillance for hepatocellular carcinoma (HCC) in patients with cirrhosis is limited. There is an urgent need for improvement in risk stratification and new screening modalities, blood biomarkers in particular. Longitudinal collection of paired blood samples and MRI images from cirrhotic patients is particularly valuable in assessing how early blood and imaging markers become positive during the period when lesions are observed to obtain a diagnosis of HCC. We generated a multicenter prospective cohort of patients with cirrhosis under surveillance with contrast MRI, applied untargeted metabolomics on 612 serum samples from 203 patients and identified metabolites associated with risk of HCC development. Such biomarkers may significantly improve early stage HCC detection for cirrhotic patients undergoing HCC surveillance, a critical step to increasing curative treatment opportunities and reducing mortality.

Longitudinal analysis of liver transplant candidates for hepatocellular carcinoma in a single center.

Wailitst lost is an critical issue and we investigated the long-term effect of insufficient liver functional reserve at liver transplantation evaluation on waitlist outcomes in patients with hepatocellular carcinoma (HCC). Clinical data of patients with HCC waitlisted for liver transplantation were retrospectively collected from a single hospital cohort during the period from 2014 to 2021. Parameters of liver reserve, including cirrhosis, Child-Pugh grade, and Model for End-Stage Liver Disease (MELD) scores, were analyzed for patient survival, after adjustment for tumor factors. Of 292 eligible patients, 94.2% had cirrhosis, 55.8% had Child-Pugh grade B or C, and the median MELD score was 13.2. The median follow-up time was 2.2years, with a dropout rate of 62.7%. Eighty-nine candidates (30.5%) eventually received liver transplant, including 67 from live donors. The estimated 1-year mortality rate reached 40.6% in 203 patients who remained on the waitlist without receiving a transplant, of whom 143 died. Most deaths were attributed to liver failure (37.1%) and cancer death (35.7%). After we adjusted for tumor confounders, including alpha fetoprotein, primary HCC stage, tumor number at evaluation, and sequential cancer treatment before and while waiting, hazard ratios (HRs) for patient survival were 1.69 (95% confidence interval, 1.18-2.41) for cirrhotic stage B or C, 1.07 (1.04-1.10) for MELD scores, and 1.14 (1.04-1.25) for tumor size at transplant evaluation. Transplantation was a protective disease modifier with adjusted HR 0.22 (0.14-0.33). Insufficient liver functional reserve poses more risk than expected to liver transplant waitlist outcomes with HCC.

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.

A Machine Learning Algorithm Facilitates Prognosis Prediction and Treatment Selection for Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma.

Given its heterogeneity and diverse clinical outcomes, precise subclassification of BCLC-C hepatocellular carcinoma (HCC) is required for appropriately determining patient prognosis and selecting treatment. We recruited 2,626 patients with BCLC-C stage HCC from multiple centers, comprising training/test (n=1,693) and validation cohorts (n=933). The XGBoost was chosen for maximum performance among the machine learning (ML) models. Patients were categorized into low-/intermediate-/high-/very high-risk subgroups which were based on the estimated prognosis, and this subclassification was named the CLAssification via Machine learning of BCLC-C (CLAM-C). The areas under the receiver operating characteristic curve of the CLAM-C for predicting the 6-/12-/24-month survival of patients with BCLC-C were 0.800/0.831/0.715, respectively-significantly higher than those of the conventional models, which was consistent in the validation cohort. The four subgroups had significantly different median overall survivals, and this difference was maintained among various patient subgroups and treatment modalities. Immune-checkpoint inhibitors and transarterial therapies were associated with significantly better survival than tyrosine kinase inhibitors (TKIs) in the low- and intermediate-risk subgroups. In cases with first-line systemic therapy, the CLAM-C identified atezolizumab-bevacizumab as the best therapy particularly in the high-risk group. In cases with later-line systemic therapy, nivolumab had better survival than TKIs in the low-to-intermediate-risk subgroup, whereas TKIs had better survival in the high-to-very high-risk subgroup. ML modeling effectively subclassified patients with BCLC-C HCC, potentially aiding treatment allocation. Our study underscores the potential utilization of ML modeling in terms of prognostication and treatment allocation in patients with BCLC-C HCC.

Neoadjuvant tislelizumab plus stereotactic body radiotherapy and adjuvant tislelizumab in early-stage resectable hepatocellular carcinoma: the Notable-HCC phase 1b trial

Notable-HCC (NCT05185531) is a phase 1b trial, aiming to evaluate the safety and preliminary effectiveness of neoadjuvant PD-1 blockade plus stereotactic body radiotherapy (SBRT) in early-stage resectable hepatocellular carcinoma (HCC). Twenty patients with HCC of BCLC stage 0-A received 3×\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\ imes $$\\end{document} Gy SBRT and two cycles of tislelizumab, an anti-PD-1 monoclonal antibody before the curative HCC resection. Primary endpoints were the surgery delay, radiographic and pathological tumor response after the neoadjuvant therapy, safety and tolerability. During the neoadjuvant therapy, treatment-related adverse events (TRAEs) of grade 1-2 occurred in all 20 patients (100%), eight patients (40%) had grade 3 TRAEs, no grade 4 to 5 TRAE occurred, and all resolved without corticosteroids treatment. Per mRECIST, the objective response rate was 63.2% (12/19), with 3 complete response; the disease control rate was 100%. Two (10.5%) patients achieved complete pathological response. No surgery delay occurred. The neoadjuvant therapy did not increase the surgical difficulty or the incidence of complications. Secondary endpoints of disease-free survival and overall survival were not mature at the time of the analysis. Our pilot trial shows that neoadjuvant therapy with anti-PD-1 + SBRT is safe and promotes tumor responses in early-stage resectable HCC.

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.

Plasma Cell-Free Adenomatous Polyposis Coli Gene Promoter Methylation as a Prognostic Biomarker for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide. Lack of biomarkers for follow-up after treatment is a clinical challenge. DNA methylation has been proposed to be a potential biomarker in HCC. However, there is still lacking of evidence of its clinical use. This study aims to evaluate the value of using plasma Adenomatous Polyposis Coli promoter methylation level (APC-MET) as a potential biomarker in HCC treatment. A total of 96 patients with HCC at BCLC stage B underwent local tumor ablation treatment were prospectively included in this study. APC-MET was examined from the plasma of each patient before and 1 months after treatment. The prediction value of APC-MET for survival outcome and disease status after treatment were analyzed, and adjusted with alpha-fetoprotein and protein induced by vitamin K absence-II using cox regression analysis. Univariate cox regression analysis showed preoperative APC-MET >0 (HR, 2.9, 95% CI 1.05－8.05, p=0.041) and postoperative APC-MET >0 (HR, 3.47, 95% CI 1.16－10.4, p=0.026) were both predictors of death, and preoperative APC-MET >0 was a predictor of disease progression after treatment (HR, 2.04, 95% CI 1.21－3.44, p=0.007). In multivariate models, pre-op APC-MET >0 was a significant predictor of disease progression after adjusting with other two traditional biomarkers (HR, 1.82, 95% CI 1.05－3.17, p=0.034). Hypermethylation of APC promoter appears to be a potential biomarker that could predict patient survival and disease progression outcome in patients with intermediate stage HCC after local ablation treatment.

Abstract 1526: The distinct tumor microenvironment of advanced hepatocellular carcinoma with high PVR or high PD-L1 expression

Abstract Background: The combination of anti-PD-L1 and anti-VEGF has been the standard-of-care for advanced hepatocellular carcinoma (HCC), while additionally targeting TIGIT is under active investigation. We aimed to explore the expression and clinical significance of PVR (CD155), the ligand of TIGIT, within the tumor microenvironment (TME) of advanced HCC. Methods: All HCC tumor specimens were obtained at the advanced stage of HCC. Immunohistochemistry (IHC) was employed to evaluate membranous staining of PVR and PD-L1 of tumor specimens, and semiquantitative scores with IHC 0, 1, 2, or 3 were given if &amp;lt; 1%, ≥1% but &amp;lt; 5%, ≥5% but &amp;lt; 10%, or ≥10% of tumor cells (TCs) and tumor-infiltrating immune cells (ICs) were PVR or PD-L1 positive. Selected tumor specimens underwent immune gene expression profiling using the nCounter Analysis System (NanoString Technologies, Inc.) with the PanCancer Immune Profiling Panel. Results: The study enrolled 67 advanced HCC patients, with median age of 59.2 years (male:female = 57:10). Forty-eight (71.6%) of the patients were hepatitis B virus (HBV) surface antigen positive, and 23 (34.3%) had received sorafenib before the study. Thirteen (19.4%) and 18 (26.9%) tumor tissues showed positive PVR expressions (IHC scores ≥1) in TCs and ICs, respectively; Seventeen (25.4%) and 36 (53.7%) tumor tissues showed positive PD-L1 expressions in TCs and ICs, respectively. The expressions of PVR in TCs or ICs showed no association with clinical factors, such as sex, age, HBV infection, sorafenib treatment, or overall survival. Interestingly, in both TCs and ICs, the intensities of PVR and PD-L1 expression were inversely correlated for those with at least IHC scores ≥1 in either PVR or PD-L1 (TCs, n = 26, r = -0.6966, p &amp;lt; 0.0001; ICs, n = 46, r = -0.4548, p = 0.0015). Immune profiling of the selected tumor specimens showed that those with high PVR but low PD-L1 expressions had significantly lower CD8 T cells scores, lower cytotoxic cells scores, and lower CD8/Treg ratio than those with high PD-L1 but low PVR expressions. Conclusions: There was an inverse correlation observed between expressions of PVR and PD-L1 in the advanced HCC tissues. The TME of those with high PVR expression was distinct from those with high PD-L1 expression. These findings may have important clinical implications for developing combination immunotherapy in advanced HCC. (This work is supported by grants from the Ministry of Science and Technology, Taiwan, MOST 110-2314-B-002-204-MY3). Citation Format: Li-Chun Lu, Yi-Hsuan Lee, Tsung-hao Liu, Yu-Yun Shao, Ann-Lii Cheng, Chih-Hung Hsu. The distinct tumor microenvironment of advanced hepatocellular carcinoma with high PVR or high PD-L1 expression [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 1526.

Development and validation of nomograms to evaluate the survival outcome of HCC patients undergoing selective postoperative adjuvant TACE.

The objective of this study was to develop and validate a novel prognostic nomogram to evaluate the survival benefit of hepatocellular carcinoma (HCC) patients receiving postoperative adjuvant transarterial chemoembolization (PA-TACE). Clinical data of HCC patients who underwent hepatectomy at four medical centers were retrospectively analyzed, including those who received PA-TACE and those who did not. These two categories of patients were randomly allocated to the development and validation cohorts in a 7:3 ratio. A total of 1505 HCC patients who underwent hepatectomy were included in this study, comprising 723 patients who did not receive PA-TACE and 782 patients who received PA-TACE. Among them, patients who received PA-TACE experienced more adverse events, although these events were mild and manageable (Grade 1-2, all p < 0.05). Nomograms were constructed and validated for patients with and without PA-TACE using independent predictors that influenced disease-free survival (DFS) and overall survival (OS). These two nomograms had C-indices greater than 0.800 in the development cohort and exhibited good calibration and discrimination ability compared to six conventional HCC staging systems. Patients in the intermediate-to-high-risk group in the nomogram who received PA-TACE had higher DFS and OS (all p < 0.05). In addition, tumor recurrence was significantly controlled in the intermediate-to-high-risk group of patients who received PA-TACE, while there was no significant difference in the low-risk group of patients who received PA-TACE. The nomograms were developed and validated based on large-scale clinical data and can serve as online decision-making tools to predict survival benefits from PA-TACE in different subgroups of patients.

Intermediate-stage hepatocellular carcinoma: refining substaging or shifting paradigm?

This review explores the evolution of cancer staging, focusing on intermediate hepatocellular carcinoma (HCC), and the challenges faced by physicians. The Barcelona Clinic Liver Cancer (BCLC) staging system, introduced in 1999, was designed to address the limitations associated with providing accurate prognostic information for HCC and allocating specific treatments, to avoid overtreatment. However, criticism has emerged, particularly regarding the intermediate stage of HCC (BCLC-B) and its heterogeneous patient population. To overcome this limitation, various subclassification systems, such as the Bolondi and Kinki criteria, have been proposed. These systems are aimed at refining categorizations within the intermediate stage and have demonstrated varying degrees of success in predicting outcomes through external validation. This study discusses the shift in treatment paradigms, emphasizing the need for a more personalized approach rather than strictly adhering to cancer stages, without dismissing the relevance of staging systems. It assesses the available treatment options for intermediate-stage HCC, highlighting the importance of considering surgical and nonsurgical options alongside transarterial chemoembolization for optimal outcomes. In conclusion, the text advocates for a paradigm shift in staging systems prioritizing treatment suitability over cancer stage. This reflects the evolving landscape of HCC management, where a multidisciplinary approach is crucial for tailoring treatments to individual patients, ultimately aiming to improve overall survival.

The relationship between tumor-infiltrating neutrophils and clinical outcomes in patients with resectable hepatocellular carcinoma

BackgroundThe impact of tumor-infiltrating neutrophils (TINs) on clinical outcomes has been reported in various cancer types, but their role in hepatocellular carcinoma (HCC) has not been fully evaluated. The aim of this study was to investigate the prognostic values for TINs in HCC patients undergoing curative resection.MethodsWe assessed immune markers (CD3, CD4, CD8, CD66b) using immunohistochemistry in 115 patients who underwent curative resection for HCC. We analyzed the prognostic values for tumor-infiltrating immune cells, including neutrophils, and other clinicopathological factors.ResultsIn the Multivariate Cox analysis of overall survival (OS), alpha-fetoprotein (AFP) ≥ 100 ng/mL (hazard ratio (HR), 2.74, 95% confidence interval (CI), 1.17–6.44; P = 0.021) and Barcelona Clinic Liver Cancer (BCLC) B/C stage (HR, 3.98, 95% CI, 1.68–9.43; P = 0.020) were found to be independent poor prognostic factors in HCC patients undergoing resection. The presence of CD66b+TINs was observed in 66 (57.4%) patients. However, CD66b+TINs were not associated with recurrence-free survival and OS.ConclusionsOur study identified low CD66b+TINs in resectable HCC, and CD66b+ TINs did not have a significant role for the clinical outcomes of patients undergoing curative resection. The results suggest that TINs may play a role in more advanced stages of HCC.

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Alterations in serum metabolic profiles of early-stage hepatocellular carcinoma patients after radiofrequency ablation therapy

ObjectiveTo investigate the alterations in serum metabolic profiles and early-stage hepatocellular carcinoma (HCC) patient characteristics after radiofrequency ablation (RFA) therapy. This evaluation aimed to assess treatment effectiveness and identify potential novel approaches and targets for HCC treatment and prognosis monitoring. MethodsUntargeted metabolomics technology was employed to analyze serum metabolic profiles in healthy volunteer controls (NCs) and early stage HCC patients before and after RFA therapy. Additionally, Human Metabolome Database and Kyoto Encyclopedia of Genes and Genomes database were used to identify the differential metabolites (DMs) and metabolic pathways. Cystoscape was utilized to construct DM gene networks. Amino acid analyses were performed to validate our findings. ResultsWe identified 11, 14, and six DMs between the NC and HCC groups, HCC patients before and after RFA therapy, and post-RFA HCC and NC groups, respectively. The expression levels of these DMs, particularly those of amino acids and lipids, significantly changed. Compared with the NC group, higher levels of L-tyrosine, aspartate, and 18-oxo-oleate were observed in HCC patients, which were significantly reduced in patients after RFA therapy. Meanwhile, HCC patients after RFA therapy had increased levels of L-arginine, phosphatidic acid (20:3), and lysophosphatidyl choline (LPC) (20:4) compared to those before therapy, while their levels before therapy were lower than those of NC. Moreover, most metabolites in the post-RFA and NC groups showed no significant changes in expression, except for L-tyrosine and LPC (16:0). These metabolites could potentially serve as characteristic factors of early-stage HCC patients after RFA therapy. Joint pathway analysis revealed striking changes, mainly in phenylalanine, tyrosine, and tryptophan biosynthesis; alanine, aspartate, and glutamate metabolism; and arginine and aminoacyl-tRNA biosynthesis. Bioinformatics analysis of publicly available data preliminarily identified 187 DM-related metabolic enzymes. ConclusionOur study proposed novel targets for early-stage HCC treatment, laying the groundwork for improving treatment efficacy and prognosis of early-stage HCC patients.

Construction and Validation of a Novel Nomogram Predicting Recurrence in Alpha-Fetoprotein-Negative Hepatocellular Carcinoma Post-Surgery Using an Innovative Liver Function-Nutrition-Inflammation-Immune (LFNII) Score: A Bicentric Investigation.

We developed a nomogram based on the liver function, nutrition, inflammation, and immunity (LFNII) score to predict recurrence-free survival (RFS) post-resection in patients with hepatocellular carcinoma (HCC) exhibiting alpha-fetoprotein (AFP) negativity (AFP ≤20 ng/mL). Clinical data of 661 patients diagnosed with alpha-fetoprotein-negative hepatocellular carcinoma (AFP-NHCC) who underwent surgical resection at two medical centers between 2012 and 2021 were collected. A total of 462 and 199 patients served as the training and validation sets, respectively. Pre-operative blood markers were collected and analyzed for LFNII. The LFNII score was formulated using the least absolute shrinkage and selection operator Cox regression model. A nomogram model was developed using the training set to incorporate other relevant clinicopathological indicators and predict postoperative recurrence. Model discrimination was assessed using the receiver operating characteristic curve, calibration was evaluated using a calibration curve, and clinical applicability was assessed using clinical decision curve analysis. A comparison with liver cancer staging was performed using the nomogram model. Finally, a cohort study was conducted to validate our findings. We derived the LFNII scores from nine indicators. Elevated LFNII scores correlated with unfavorable clinicopathological features. The LFNII score area under the curve revealed superior predictive efficacy at 1-, 2-, and 5-year RFS intervals, with values of 0.675, 0.658, and 0.633, respectively. Multivariate Cox analysis revealed that a high LFNII score independently increased RFS risk in patients with AFP-NHCC. The C-index of the LFNII-nomogram model was 0.686 (95% confidence interval [CI], 0.651-0.721). The nomogram model's clinical application value surpassed that of standard HCC staging systems. The LFNII score-derived nomogram effectively predicted the RFS of patients with AFP-NHCC after curative resection.