Advanced-stage Hepatocellular Carcinoma Research Articles

Artificial Intelligence and Machine Learning in Hepatocellular Carcinoma Screening, Diagnosis and Treatment - A Comprehensive Systematic Review

Background: Medical image analysis plays a crucial role in the screening, monitoring, diagnosis, and prognosis of diseases. Hepatocellular Carcinoma (HCC) often remain asymptomatic in their early stages. Timely identification and intervention are crucial to prevent the progression to decompensated liver diseases and advanced-stage HCC, minimizing morbidity and mortality. Methodology: This study examined twenty relevant research articles that met the inclusion criteria. Utilizing the PRISMA criteria, a systematic search was conducted on PubMed/MEDLINE and Google Scholar for studies on HCC screening employing Artificial Intelligence (AI) and Machine Learning (ML). The search focused on the keywords "artificial intelligence" and "hepatocellular carcinoma," with inclusion criteria specifying studies in the English language published in and after 2020. Exclusions were made for histology, animal research, and investigations conducted before 2020. Titles and abstracts were thoroughly reviewed, and any discrepancies were discussed. Results: The comprehensive review reveals the transformative impact of AI and ML on HCC screening, diagnosis, and therapy. ML models demonstrated effectiveness in early HCC diagnosis, distinguishing hepatic lesions, predicting treatment responses, and assessing recurrence risks across various techniques. Integration of mass spectrometry-based technologies, advanced imaging, and real-world data significantly improved diagnostic accuracy and clinical decision support. AI models exhibited diagnostic expertise with potential applications in therapy suggestions, personalized surveillance, and prognostic evaluations. However, further validation and seamless integration into clinical practice are essential for realizing their full potential. Conclusion: This systematic study underscores the progress made in the application of AI and ML in HCC screening, diagnosis, and treatment. Numerous studies highlight the capability of AI and ML systems to enhance hepatocellular carcinoma diagnosis, predict outcomes, and optimize therapy. The enduring and versatile nature of these technologies points towards a revolutionary future in personalized and efficient HCC management.

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.

Serum ApoB/ApoA1 ratio in patients with CHB and the occurrence of HBV related cirrhosis and HBV related hepatocellular carcinoma

Clinical research has suggested that chronic HBV infection exerts a certain effect on the occurrence of cardiovascular disease by regulating cholesterol metabolism in liver cells. High serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio plays a certain role in the above regulation, and it serves as a risk factor for cardiovascular disease. However, whether the ApoB/ApoA1 ratio is correlated with chronic HBV infection and its disease progression remains unclear. In accordance with the inclusion and exclusion criteria, all 378 participants administrated at Renmin Hospital of Wuhan University from March 2021 to March 2022, fell into Healthy Control (HC) group (50 participants), Hepatocellular carcinoma (HCC) group (107 patients), liver cirrhosis (LC) group (64 patients), chronic hepatitis B (CHB) group (62 patients), chronic hepatitis C (CHC) group (46 patients) and Hepatitis E Virus (HEV) group (49 patients). Serum ApoA1 and ApoB concentrations were measured at admission, and the ApoB/ApoA1 ratio was determined. The levels of laboratory parameters in the respective group were compared and ApoB/ApoA1 ratios in HCC patients and LC patients with different severity were further analyzed. ROC curves were plotted to analyze the early diagnostic ability of ApoB/ApoA1 ratio for HBV-associated HCC. Logistic regression and restricted cubic spline analysis were used to explore the correlation between ApoB/ApoA1 ratio and LC and HCC risk. A comparison was drawn in terms of ApoB/ApoA1 ratio between the groups, and the result was expressed in descending sequence: HEV group > CHB group > LC group > HCC group > CHC group > HC group, early-stage HCC < middle-stage HCC < advanced-stage HCC, Class A LC < Class B LC < Class C LC. Serum ApoB/ApoA1 ratio combined diagnosis with AFP exhibited the capability of increasing the detection efficacy and specificity of AFP for HCC and AFP-negative HCC. The incidence of LC and HCC in the respective logistic regression model showed a negative correlation with the serum ApoB/ApoA1 ratio in CHB patients (P < 0.05). After all confounding factors covered in this study were regulated, the result of the restricted cubic spline analysis suggested that in a certain range, serum ApoB/ApoA1 ratio showed an inverse correlation with the prevalence of LC or HCC in CHB patients. Serum ApoB/ApoA1 ratio in CHB patients may be conducive to identifying high-risk patients for HCC or LC, such that LC and HCC can be early diagnosed and treated.

Conversion therapy for advanced hepatocellular carcinoma in the era of precision medicine: Current status, challenges and opportunities.

Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.

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.

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.

Identification of key molecules in the formation of portal vein tumor thrombus in hepatocellular carcinoma based on single cell transcriptomics and in vitro experiments.

The presence of portal vein tumor thrombus (PVTT) is a significant indicator of advanced-stage hepatocellular carcinoma (HCC). Unfortunately, the prediction of PVTT occurrence remains challenging, and there is a lack of comprehensive research exploring the underlying mechanisms of PVTT formation and its association with immune infiltration. Our approach involved analyzing single-cell sequencing data, applying high dimensional weighted gene co-expression network analysis (hdWGCNA), and identifying key genes associated with PVTT development. Furthermore, we constructed competing endogenous RNA (ceRNA) networks and employed weighted gene co-expression network analysis (WGCNA), as well as three machine-learning techniques, to identify the upstream regulatory microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) of the crucial mRNAs. We employed fuzzy clustering of time series gene expression data (Mfuzz), gene set variation analysis (GSVA), and cell communication analysis to uncover significant signaling pathways involved in the activation of these important mRNAs during PVTT development. In addition, we conducted immune infiltration analysis, survival typing, and drug sensitivity analysis using The Cancer Genome Atlas (TCGA) cohort to gain insights into the two patient groups under study. Through the implementation of hdWGCNA, we identified 110 genes that was closely associated with PVTT. Among these genes, TMEM165 emerged as a crucial candidate, and we further investigated its significance using COX regression analysis. Furthermore, through machine learning techniques and survival analysis, we successfully identified the upstream regulatory miRNA (hsa-miR-148a) and lncRNA (LINC00909) that targeted TMEM165. These findings shed light on the complex regulatory network surrounding TMEM165 in the context of PVTT. Moreover, we conducted CIBERSORT analysis, which unveiled correlations between TMEM165 and immune infiltration in HCC patients. Specifically, TMEM165 exhibited associations with various immune cell populations, including memory B cells and CD8+ T cells. Additionally, we observed implications for immune function, particularly in relation to immune checkpoints, within the context of HCC. The regulatory axis involving TMEM165, hsa-miR-148a, and LINC00909 emerges as a crucial determinant in the development of PVTT in HCC patients, and it holds significant implications for prognosis. Furthermore, alterations in the TMEM165/hsa-miR-148a/LINC00909 regulatory axis exhibit a strong correlation with immune infiltration within the HCC tumor microenvironment, leading to immune dysfunction and potential failure of immunotherapy.

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.

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.

Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma.

Liver cancer, specifically hepatocellular carcinoma (HCC), is the sixth most common cancer and the third leading cause of cancer mortality worldwide. The development of effective systemic therapies, particularly those involving immune-checkpoint inhibitors (ICIs), has substantially improved the outcomes of patients with advanced-stage HCC. Approximately 30% of patients are diagnosed with earlystage disease andcurrently receive potentially curative therapies, such as resection, liver transplantation or local ablation, which result in median overall survival durations beyond 60 months. Nonetheless, up to 70% of these patients will have disease recurrence within 5 years of resection or local ablation. To date, the results of randomized clinical trials testing adjuvant therapy in patients with HCC have been negative. This major unmet need has been addressed with the IMbrave 050 trial, demonstrating a recurrence-free survival benefit in patients with a high risk of relapse after resection or local ablation who received adjuvant atezolizumab plus bevacizumab. In parallel, studies testing neoadjuvant ICIs alone or in combination in patients with earlystage disease have also reported efficacy. In this Review, we provide a comprehensive overview of the current approaches to manage patients with earlystage HCC. We also describe the tumour immune microenvironment and the mechanisms of action of ICIs and cancer vaccines in this setting. Finally, we summarize the available evidence from phase II/III trials of neoadjuvant and adjuvant approaches and discuss emerging clinical trials, identification of biomarkers and clinical trial design considerations for future studies.

Transcatheter arterial chemoembolization combined with PD-1 inhibitors and Lenvatinib for hepatocellular carcinoma with portal vein tumor thrombus.

Hepatocellular carcinoma (HCC) patients complicated with portal vein tumor thrombus (PVTT) exhibit poor prognoses and treatment responses. To investigate efficacies and safety of the combination of PD-1 inhibitor, transcatheter arterial chemoembolization (TACE) and Lenvatinib in HCC subjects comorbid with PVTT. From January 2019 to December 2020, HCC patients with PVTT types I-IV were retrospectively enrolled at Beijing Ditan Hospital. They were distributed to either the PTL or TACE/Lenvatinib (TL) group. The median progression-free survival (mPFS) was set as the primary endpoint, while parameters like median overall survival, objective response rate, disease control rate (DCR), and toxicity level served as secondary endpoints. Forty-one eligible patients were finally recruited for this study and divided into the PTL (n = 18) and TL (n = 23) groups. For a median follow-up of 21.8 months, the DCRs were 88.9% and 60.9% in the PTL and TL groups (P = 0.046), res-pectively. Moreover, mPFS indicated significant improvement (HR = 0.25; P < 0.001) in PTL-treated patients (5.4 months) compared to TL-treated (2.7 months) patients. There were no treatment-related deaths or differences in adverse events in either group. A triplet regimen of PTL was safe and well-tolerated as well as exhibited favorable efficacy over the TL regimen for advanced-stage HCC patients with PVTT types I-IV.

Correlation of Soluble Programmed Death Ligand-1 (sPD-L1) with Alpha-Fetoprotein Levels as a Predictor of Prognosis in Hepatocellular Carcinoma Patients

Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and one of the leading causes of cancer death worldwide. Chronic hepatitis B virus infection is the most common etiology of HCC. Programmed death ligand-1 (PD-L1) is a protein that is overexpressed on the surface of tumor cells, which can be detected in serum (sPD-L1). Elevated sPD-L1 concentrations in the plasma of cancer patients are associated with poor prognosis in HCC patients, as indicated by increased AFP levels. There have been no previous studies examining the correlation of sPD-L1 levels with AFP in HCC patients. The aim of the study was to determine the correlation of sPD-L1 and AFP as predictors of prognosis in HCC patients.&#x0D; Methods: The research is an observational study with a cross-sectional design to see the correlation of sPD-L 1 with serum alpha-fetoprotein levels in HCC patients at Dr. Mohammad Hoesin General Hospital Palembang starts from April to July 2023. Measurement of sPD-L1 levels and serum AFP levels is carried out using ELISA examination.&#x0D; Results: Of the 28 subjects studied, HCC patients were more commonly found in men (89.29%) aged 18-60 years (75%). sPD-L1 and AFP values were found to be increased in the advanced stages of HCC. The sPD-L1 value is directly proportional to the serum AFP value.&#x0D; Conclusion: There is a strong positive correlation between sPD-L1 levels and serum AFP levels caused by hepatitis B in HCC patients, so the higher the sPD-L1, the higher the serum AFP levels.

Engaging stimulatory immune checkpoint interactions in the tumour immune microenvironment of primary liver cancers - how to push the gas after having released the brake.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the first and second most common primary liver cancer (PLC). For decades, systemic therapies consisting of tyrosine kinase inhibitors (TKIs) or chemotherapy have formed the cornerstone of treating advanced-stage HCC and CCA, respectively. More recently, immunotherapy using immune checkpoint inhibition (ICI) has shown anti-tumour reactivity in some patients. The combination regimen of anti-PD-L1 and anti-VEGF antibodies has been approved as new first-line treatment of advanced-stage HCC. Furthermore, gemcibatine plus cisplatin (GEMCIS) with an anti-PD-L1 antibody is awaiting global approval for the treatment of advanced-stage CCA. As effective anti-tumour reactivity using ICI is achieved in a minor subset of both HCC and CCA patients only, alternative immune strategies to sensitise the tumour microenvironment of PLC are waited for. Here we discuss immune checkpoint stimulation (ICS) as additional tool to enhance anti-tumour reactivity. Up-to-date information on the clinical application of ICS in onco-immunology is provided. This review provides a rationale of the application of next-generation ICS either alone or in combination regimen to potentially enhance anti-tumour reactivity in PLC patients.

Radioembolization plus Immune Checkpoint Inhibitor Therapy Compared with Radioembolization plus Tyrosine Kinase Inhibitor Therapy for the Treatment of Hepatocellular Carcinoma

PurposeTo investigate if combination therapy with immune checkpoint inhibitor (ICI) and yttrium-90 (90Y) radioembolization results in superior outcomes than those yielded by tyrosine kinase inhibitor (TKI) therapy and 90Y for the treatment of intermediate- to advanced-stage hepatocellular carcinoma (HCC). MethodsA retrospective review of patients presented at an institutional multidisciplinary liver tumor board between January 1, 2012 and August 1, 2023 was conducted. In total, 44 patients with HCC who underwent 90Y 4 weeks within initiation of ICI or TKI therapy were included. Propensity score matching was conducted to account for baseline demographic differences. Kaplan–Meier analysis was used to compare median progression-free survival (PFS) and overall survival (OS), and univariate statistics identified disease response and control rate differences. Duration of imaging response was defined as number of months between the first scan after therapy and the first scan showing progression as defined by modified Response Evaluation Criteria in Solid Tumors (mRECIST) or immune Response Evaluation Criteria in Solid Tumors (iRECIST). Adverse events were analyzed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. ResultsPatients in the 90Y+ICI therapy group had better objective response rates (ORRs) (89.5% vs 36.8%; P < .001) and disease control rates (DCRs) (94.7% vs 63.2%; P < .001) by mRECIST and iRECIST (ORR: 78.9% vs 36.8%; P < .001; DCR: 94.7% vs 63.2%; P < .001). Median PFS (8.3 vs 4.1 months; P = .37) and OS (15.8 vs 14.3 months; P = .52) were not statistically different. Twelve patients (63.1%) in the 90Y+TKI group did not complete systemic therapy owing to adverse effects compared with 1 patient (5.3%) in the 90Y+ICI group (P < .001). Grade 3/4 adverse events were not statistically different (90Y+TKI: 21.1%; 90Y+ICI: 5.3%; P = .150). ConclusionsPatients with HCC who received 90Y+ICI had better imaging response and fewer regimen-altering adverse events than those who received 90Y+TKI. No significant combination therapy adverse events were attributable to radioembolization.

Low SAA4 gene expression is associated with advanced HCC stage and a poor prognosis

At present, although there are tumor markers for hepatocellular carcinoma (HCC), markers with better predictive efficiency are needed. SAA4 gene expression in liver tumor and paracancerous tissues was analyzed using The Cancer Genome Atlas database. The differentially expressed genes (DEGs) were analyzed and visualized by heatmap and volcano plot. Survival analysis was performed based on SAA4 expression. SAA4 expression was compared in patients grouped based on clinicopathological features, and gene set enrichment analysis (GSEA) was conducted. Immunohistochemical staining was used to verify the SAA4 protein staining intensity from The Human Protein Atlas database and our center’s samples. The diagnostic value of SAA4 for HCC was evaluated by receiver operating characteristic curves. SAA4 was expressed at low levels in HCC tissues, and low SAA4 expression was associated with a poor prognosis in HCC. In addition, SAA4 expression decreased with HCC progression. There were 188 upregulated DEGs and 1551 downregulated DEGs between the high and low SAA4 expression groups. Complement and coagulation cascades, fatty acid metabolism, and ECM receptor interaction were significantly enriched in the GSEA. SAA4 had good predictive efficacy for HCC and even early HCC and was superior to AFP. In general, low SAA4 expression was associated with advanced HCC stage and a poor prognosis. In addition, SAA4 may be helpful for the diagnosis of early HCC and may become a novel tumor marker with good predictive power for HCC.

Hepatocellular Carcinoma in Ceará: Epidemiology and Treatment in a Reference Liver Transplant Center in Northeast Brazil

Hepatocellular carcinoma remains a significant worldwide malignancy and an important cause of cancer-related death. The incidence is increasing globally. In Latin America, there is no consistent data on the epidemiology of hepatocellular carcinoma. However, Brazil is considered a country with an intermediate incidence of this liver neoplasm. In the state of Ceará, situated in the northeast region of Brazil, there are no consistent clinical and epidemiologic data on the actual incidence and the treatment of hepatocellular carcinoma. The purpose of this article is to describe epidemiologic characteristics and treatment forms of patients with hepatocellular carcinoma who were treated in a Liver Transplant Center. A retrospective observational study was conducted using the database from the register of 299 patients with hepatocellular carcinoma between June 2004 and February 2022. Only patients born in Ceará were included. Therefore, most patients were eligible, based on the Milan Criteria, to undergo liver transplantation with a Model End Stage Liver Disease score of 12.48 ± 4.66 points, and the waiting list time was approximately 7 months with 8.7% hepatocellular carcinoma recurrence after liver transplant. A total of 38.5 % of cases were outside the Milan criteria at the time of cancer diagnosis, and transarterial chemoembolization was the main treatment choice. In conclusion, the diagnosis of hepatocellular carcinoma in Ceará mainly occurs in male patients with hepatitis C or alcoholism, with a mean age of 61.55 years and a previous diagnosis of liver disease. Liver transplantation was the best curative therapeutic form in patients with cirrhosis and hepatocellular carcinoma in Ceará, where a significant number of patients were diagnosed with intermediate and advanced-stage hepatocellular carcinoma, so public health policies are important for the screening and monitoring of liver disease.

Response to atezolizumab plus bevacizumab specific for lung and lymph node metastases affects survival of patients with HCC.

Tumour microenvironment heterogeneity among different organs can influence immunotherapy responses. Here, we evaluated the impact of differential organ-specific responses on survival in patients with advanced-stage hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Atezo/Bev). We retrospectively analysed 366 consecutive patients with advanced-stage HCC treated with Atezo/Bev as first-line systemic treatment. Therapeutic response was assessed using RECIST v1.1. Patients were divided into an intention-to-treat (ITT) group (patients treated with ≥1 dose of Atezo/Bev) and a per-protocol (PP) analysis group (patients with at least one measurable lesion irrespective of location treated with ≥3 doses of Atezo/Bev). Overall response and organ-specific response at initial and best response were evaluated in the PP group. Responders were defined as patients achieving complete remission or partial response. Initial progressors were defined as patients with progressive disease after three doses of Atezo/Bev. The ITT and PP groups comprised 324 and 236 patients, respectively. In the PP group, the organ-specific response rate of lung and lymph node (LN) metastases at both initial and best responses were higher than those of intrahepatic lesions and macrovascular tumour thrombosis. Lung and LN-specific response rates were 21.1% and 23.5%, respectively, at initial response, and 24.7% and 31.4%, respectively, at best response. Both initial pulmonary and lymphatic progressors (adjusted hazard ratios [95% confidence intervals], 6.37 [2.10-19.3], and 8.36 [2.16-32.4], respectively) were independently associated with survival regardless of intrahepatic response. The response of metastatic HCC to the Atezo/Bev regimen may be used to determine whether to continue treatment or switch to second-line treatment at an early phase of therapy.

A single-center, real-world experience of atezolizumab plus bevacizumab as first-line therapy in patients with unresectable hepatocellular carcinoma, including patients with advanced cirrhosis.

445 Background: Atezolizumab plus bevacizumab (A+B) is approved by the Food and Drug Administration (FDA) for treatment of advanced stage hepatocellular carcinoma (HCC) as first line systemic therapy following results of the IMBRAVE150 trial. Since its approval, limited real-world data is available. The benefit of this treatment in patients with advanced cirrhosis is still unclear, especially in patients with Child Pugh (CP) B cirrhosis. We aim to supplement the trial data with real world outcomes of individuals with unresectable HCC treated with (A+B) in the first line setting including patients with advanced cirrhosis. Methods: This was a single-center, retrospective analysis of patients with advanced HCC treated with A+B as first line systemic therapy between May 2020-January 2023. Patient characteristics, HCC stage, treatment information, adverse events and survival data were collected. Outcomes evaluated included progression free survival (PFS), overall survival (OS), overall response rate (ORR) using RECIST 1.1 and adverse events (AE) rate according to CTCAE v5. R v4.2.1 was used for analysis. Results: We identified a total of 41 patients with advanced stage HCC who received A+B as first line systemic therapy. The median age at diagnosis was 69 years (range 42 – 85). 34(83%) of the patients were males. 8(20%) of the patients were African American. 7(17%) patients had CP B cirrhosis. Median PFS on A+B among all patients was 10.82 months (95% CI: 5.38 – 16.26). Median OS from time of A+B initiation was 14.01 months (95% CI: 10.67 – 17.34). Median OS and PFS were significantly shorter among CP B patients, 6.84(95% CI: NE – 19.36, p = 0.003) and 6.8(95% CI: NE -19.33, p = 0.016) respectively. Hazard ratio (HR) for death from any cause among CP B patients was 4.87(95% CI: 1.35 – 17.48, p &lt;0.01) compared to others. ORR was 31.42%. 10/23(39.13%) patients with CP A had overall response, while 1/7(14.28%) patients with CP B had overall response. AE of any grade was observed in 30(73.2%) patients.10(24.4%) patients had grade 3 or more events, 2(28.5%) among CP B patients. 1(14.2%) had GI bleed among CP B patients, while 4(9.7) patients had GI bleed overall. Common adverse events included fatigue (26.8%), anorexia (26.8%), aspartate aminotransferase (AST) elevation (14.6%), proteinuria (17%), rash (21.9%). Conclusions: Efficacy profile of A+B appears to be sustained in the real world. While the efficacy is inferior in CP B liver disease, A+B remains a viable option for these patients with limited treatment options and acceptable tolerability. Our study adds to the body of evidence for real world data with A+B.

Recent Progress in Systemic Therapy for Advanced Hepatocellular Carcinoma.

Patients with advanced hepatocellular carcinoma (HCC) have several systemic treatment options. There are many known risk factors for HCC, and although some, such as hepatitis C, are now treatable, others are not. For example, metabolic dysfunction-related chronic liver disease is increasing in incidence and has no specific treatment. Underlying liver disease, drug resistance, and an increasing number of treatment options without specific biomarkers are all challenges in selecting the best treatment for each patient. Conventional chemotherapy is almost never used for advanced-stage disease, which instead is treated with immunotherapy, tyrosine kinase inhibitors, and VEGF inhibitors. Immune checkpoint inhibitors targeting various receptors have been or are currently undergoing clinical evaluation. Ongoing trials with three-drug regimens may be the future of advanced-stage HCC treatment. Other immune-modulatory approaches of chimeric antigen receptor-modified T cells, bispecific antibodies, cytokine-induced killer cells, natural killer cells, and vaccines are in early-stage clinical trials. Targeted therapies remain limited for HCC but represent an area of potential growth. As we shift away from first-line sorafenib for advanced HCC, clinical trial control arms should comprise a standard treatment other than sorafenib, one that is a better comparator for advancing therapies.

Stem Cell Growth Factor-β as a Predictive Biomarker of Response to Chemotherapy and Prognosis in Patients with Advanced-Stage Hepatocellular Carcinoma: A Retrospective Study.

In this retrospective study, we investigated the potential application of serum stem cell growth factor beta (SCGF-β) as a biomarker for predicting the therapeutic response and prognosis in patients with hepatocellular carcinoma (HCC) undergoing atezolizumab and bevacizumab (Atz/Bev) combination therapy. Pre- and post-treatment serum SCGF-β levels were measured and analyzed in relation to treatment outcomes and overall survival (OS). Pretreatment SCGF-β levels were associated with treatment response. Patients with SCGF-β levels exceeding the 163,295 pg/mL cutoff experienced significantly reduced OS, with a median OS of 12.03 months, compared to 28.87 months in those with SCGF-β levels at or below this threshold. These findings suggest that SCGF-β can serve as a predictive marker for clinical outcomes in HCC treatment, highlighting the need for prospective studies to further validate these results and clarify the mechanisms underlying SCGF-β-related therapeutic resistance.