Early Hepatocellular Carcinoma Research Articles

Safety of local thermal ablation in hepatocellular carcinoma patients with cirrhosis and severe thrombocytopenia.

Generally, invasive treatment is contraindication for patients with severe thrombocytopenia, because it may increase risk of bleeding. However, many early hepatocellular carcinoma (HCC) patients with cirrhosis have platelet counts (PC) less than 50 × 109/L due to hypersplenism. These patients are often accompanied by hepatic insufficiency, which makes hepatectomy impossible, and local thermal ablation (LTA) has become a major treatment. The aim of our study is to investigate the correlation between severe thrombocytopenia and bleeding after LTA in HCC patients with cirrhosis, and evaluate risk factors of bleeding. 473 patients with cirrhosis who underwent LTA for HCC from 2016 to 2020 were enrolled, and 709 ablations were performed in total. Based on preoperative PC, cases were divided into three groups, namely,group A (PC > 50 × 109/L), group B (30 × 109/L < PC ≤ 50 × 109/L) and group C (PC ≤ 30 × 109/L). The incidence of bleeding after LTA was compared among the three groups. Logistic regression was used to explore the risk factors for bleeding after ablation. The overall incidence of bleeding complications was 4.4%, and no significant difference was observed between group A, B, and C (3.9% vs. 6.4% vs. 3.3%, P = 0.410). In multivariate analysis, tumor diameter (OR = 2.657 per 1cm, P < 0.001), and multiple lesions (≥ 3) (OR = 3.723, P = 0.006) were found to be independent predictors of bleeding after LTA. In small HCC patients with cirrhosis and hypersplenism, the PC range 30-50 × 109/L will not increase the risk of bleeding after LTA. Tumor diameter and number of lesions are independent predictors for bleeding after LTA in HCC patients.

Rational Design of a Tandem Activatable Fluorescent Probe for Differential Diagnosis and Therapeutic Assessment of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a formidable disease, distinguished by its high aggressiveness and dismal outcomes. Although leucine aminopeptidase (LAP) has been widely employed as a biomarker in biological imaging of HCC, it is still susceptible to interference from false-positive signals activated in injured liver tissues. In this study, based on the significant difference of GSH levels in alcohol-damaged liver tissues and tumor tissues, a dual-tandem activatable probe (PCLT) was designed for differential diagnosis and treatment guidance of HCC by near-infrared fluorescence (NIRF) imaging. This probe comprised a dual-locked hemicyanine dye decorated with a tetraethylene glycol chain and dual-recognition unit of glutathione (GSH) and LAP, which could be sequentially cleaved by GSH and LAP to restore its NIRF signal. PCLT excellently discriminated orthotopic HCC from ALI far earlier (7 days) than histological analysis (28 days) and exhibited higher specificity toward early orthotopic HCC than the single-locked probe (PCL). In addition, PCLT is capable of accurately delineating the tumor contour, assisting in surgical resection of HCC tumors under fluorescence visualization, and noninvasively assessing the antitumor effect of HCC chemotherapy during ferroptosis, thereby presenting promising clinical implications for clinical diagnosis and therapy of HCC.

Abstract B073: Leveraging micronuclei DNA from erythrocytes for early detection of hepatocellular carcinoma

Abstract Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer and accounts for ∼90% of cases globally. Detection of early-stage HCC is vital as it allows for potentially curative treatment, yet remains a significant challenge. Micronuclei (MN) are a hallmark of genomic instability. An increased frequency of MN is commonly observed in tumor cells as well as other somatic cells, including erythrocytes, in cancer patients. Here, we have established a technique (WO2021/228246 A1), for the isolation and analysis of micronuclei DNA (MN-DNA) in erythrocytes from peripheral blood. Significant changes in read densities at specific genomic locations within MN-DNA were identified in patients, termed as tumor- associated MN-DNA (taMN-DNA) features. This study evaluates the potential of these taMN- DNA features for early-stage HCC detection across human and murine model. Methods: To explore the potential of MN-DNA in cancer detection, we first collected 1-2 mL of whole blood from HDs (N = 53) and HCC patients (N = 53). MN-DNA was isolated and purified from erythrocytes, followed by whole-genome sequencing. Participants were randomly divided into training, test cohorts in an 8:2 ratio. We applied machine learning algorithms to leverage these features for cancer detection in the human model. Additionally, to investigate the formation of taMN-DNA features, we employed a well-established mouse model that mimics HCC development. Mice were injected with the genotoxic agent diethylnitrosamine (DEN) 2 weeks after birth, and developed malignant macroscopic liver nodules at approximately 40 weeks of age. Results: In the human cohort, we enrolled 106 participants, with more than half of the HCC cases were diagnosed at early-stage (stage 0-II). The cancer detection model utilizing taMN- DNA features achieved an overall accuracy of 86.3%, with a sensitivity of 81.8% and specificity of 90.9%. For early-stage, the model demonstrated sensitivities of 54.5% at a specificity of 90.9%. In the DEN-induced HCC mouse model, unsupervised hierarchical clustering based on these selected taMN-DNA features clearly separated WT and tumor mice into two distinct groups. Notably, mice that were not tumorigenic at 36 weeks post-treatment in the DEN-treated group fell into the WT group when classified by the same taMN-DNA features, indicating that the formation of taMN-DNA signatures is associated with the presence of tumors specifically. Conclusions: This pilot study highlights the potential of MN-DNA as a promising tool for early HCC detection. Leveraging these taMN-DNA features can accurately distinguish early-stage HCC patients from HDs with high sensitivity. In both human and murine models, there is a significant relationship between these signatures and tumor presence, suggesting that taMN- DNA features might reflect the diseased state across mammalian species. Research sponsor: Timing Biotech. Citation Format: Hui Lin, Haobo Sun, Xingyun Yao, Xiaoxiao Fan, Fei Meng, Honghao Liang, Xiaofei Gao. Leveraging micronuclei DNA from erythrocytes for early detection of hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B073.

Combined Bone Mineral Density (BMD) and Monocyte-to-Lymphocyte Ratio (MLR) Predicts Recurrence and Prognosis in Hepatocellular Carcinoma Patients Following Liver Resection.

Bone mineral density (BMD) and monocyte-to-lymphocyte ratio (MLR) were recently identified as novel risk factors for patients with several malignancies. The objective of this study was to validate the role of preoperative BMD/MLR as a potential prognostic biomarker in patients with hepatocellular carcinoma (HCC) undergoing liver resection. This investigation enrolled 442 adult patients diagnosed with HCC who underwent liver resection. The patients were classified into high- and low-BMD/MLR groups based on the median, and forward stepwise logistic regression was employed to identify independent predictors for early HCC recurrence. To mitigate the impact of confounding factors, a propensity score matching (PSM) analysis was conducted between patients in the high- and low-BMD/MLR groups. The Kaplan-Meier method was employed to assess and compare the disease-free survival (DFS) and overall survival (OS) between the two cohorts. The study categorized patients into high-BMD/MLR and low-BMD/MLR groups. Forward stepwise logistic regression analysis revealed that low BMD/MLR (P < 0.001), tumor size > 50 mm (P < 0.001), and AFP > 200 ug/L (P = 0.001) were significantly associated with the early recurrence of HCC. Moreover, the results suggested that DFS and OS were significantly shorter in the low-BMD/MLR group compared to the high-BMD/MLR group, both before and after PSM (P < 0.05). Preoperative BMD/MLR held promise as a prognostic biomarker for early recurrence and prognosis in patients with HCC who underwent liver resection. Furthermore, the integration of tumor size, AFP level, and BMD/MLR demonstrated a robust predictive capacity for early recurrence within this patient population.

Early detection of liver fibrosis in patients with Fontan circulation using multiparametric magnetic resonance imaging

Abstract Introduction Fontan procedure (FP), serving as the palliative intervention for complex congenital heart diseases characterized by single-ventricle physiology, precipitates a spectrum of late-stage complications. Fontan-associated liver disease (FALD) encompassing liver fibrosis (LF) which may progress to liver cirrhosis (LC) and thereby hepatocellular carcinoma (HCC) is among the most serious. Despite its importance, optimal surveillance of FALD remains undefined. Multiparametric Liver Multiscan (LMS) with corrected T1 (cT1) value emerges as a novel magnetic resonance (MRI) based non-invasive quantitative tool for liver inflammation and fibrosis evaluation. Aim of this study was to ascertain prevalence and severity of LF utilizing LMS, alongside identifying contributory risk factors for LF in adults post-FP. Material and methods Our cohort included 29 adult patients after FP who underwent LMS. Median age was 25y (20-43y) 54% were females. Liver morphology was assessed by ultrasound (USG) and MRI-based LMS protocol. Hepatic scoring systems, including the Aspartate Aminotransferase to Platelet Ratio Index (APRI), Fibrosis-4 (FIB-4) Index, and Model for End-Stage Liver Disease (MELD), were computed. Additionally, presence of fenestrations in the Fontan circulation, hemoglobin levels (Hb), and blood oxygen saturation both at rest and during exercise (SatO2%) were evaluated. Results Median cT1 was 914 (±207) ms, in 87% exceeding normal threshold . In those with elevated cT1, LF was undetected by USG in 38%. LC was identified in 27% of the cohort by USG. LC group exhibited significantly higher cT1 values (P&amp;lt;0.001) compared to non-LC group. cT1 value &amp;gt;933ms was associated with a sensitivity of 89% and a specificity of 80% for diagnosing LC (AUC 0.92). Significant correlation was found between cT1 values and Hb (P=0.01) and desaturation (SatO2 &amp;lt;90%/ interventional closure of fenestration, P=0.004). Conventional liver tests and hepatic scoring systems (APRI/FIB-4/MELD) did not predict cT1 nor LC. Conclusion Our study confirmed that LF is almost widely prevalentamong adult patients with single-chamber circulation. Risk factors for LF are systemic desaturation (SatO2 &amp;lt;90% or interventional closure of fenestration) and polyglobulia. However, reliable FALD surveillance remains challenging. Conventional liver assessments and scoring algorithms fall short in delineating the full scope of LF or LC. Consequently, the integration of non-invasive LMS into routine follow-up regimens is advocated, given its pronounced sensitivity for detecting subclinical FALD manifestations and predicting LC. The LMS-derived cT1 value &amp;gt;933ms is a critical predictor for LC, underscoring its importance in guiding further patient monitoring, treatment, and facilitating early HCC detection.

Identification of a pyroptosis-related long noncoding RNA signature for determining the prognosis and immune status of hepatocellular carcinoma patients.

Despite improvements in cancer screening and diagnosis, hepatocellular carcinoma (HCC) is still diagnosed at an advanced stage, and the prognosis is worse than that of early HCC patients. Therefore, better molecular markers and therapeutic targets in HCC are required. We investigated the predictive value of pyroptosis-related long noncoding RNAs (lncRNAs) in HCC and the effects of these lncRNAs on the immune microenvironment of HCC. RNA sequencing data of HCC patients were extracted from The Cancer Genome Atlas (TCGA) database to identify differentially expressed pyroptosis-related lncRNAs related to overall survival (OS). A model was established to verify the character of pyroptosis-associated lncRNAs in the tumor microenvironment, and their prognostic value was evaluated. A total of 721 PR lncRNAs were identified based on the analysis of the TCGA database. Univariate Cox analysis revealed 37 survival-related PRlncRNAs with prognostic values. As a result of least absolute shrinkage and selection operator (LASSO) regression analysis, 'ELFN-AS1', AC099850.3, AC073389.3, 'HPN-AS1', AC009283.1, and AL139289.1 showed prognostic value. Kaplan-Meier analysis indicated that the OS of the high-risk set was worse than those of the low-risk set in both the training and testing cohorts. Univariate and multivariate analyses revealed that the risk score was a better independent prognostic factor than the stage. The precision of the lncRNA signature was confirmed using receiver operating characteristic curve (ROC) analysis. Immuneand metabolism-related pathways were enriched in both the lowand high-risk groups. Gene set enrichment analysis suggested that the identified lncRNAs regulate HCC tumorigenesis and prognosis by modulating metabolism. Various algorithms were used to confirm the significant differences in immune cells between these 2 groups. These findings could contribute to the development and validation of favorable biomarkers, improve the prognosis and survival of HCC, and help in developed individualized treatment plans for HCC.

Aberrant fragmentomic features of circulating cell-free mitochondrial DNA enable early detection and prognosis prediction of hepatocellular carcinoma.

Early detection and effective prognosis prediction in patients with hepatocellular carcinoma (HCC) provides an avenue for survival improvement, yet more effective approaches are greatly needed. We sought to develop the detection and prognosis models with ultra-sensitivity and low cost based on fragmentomic features of circulating cell free mtDNA (ccf-mtDNA). Capture-based mtDNA sequencing was carried out in plasma cell-free DNA samples from 1168 participants, including 571 patients with HCC, 301 patients with chronic hepatitis B or liver cirrhosis (CHB/LC) and 296 healthy controls (HC). The systematic analysis revealed significantly aberrant fragmentomic features of ccf-mtDNA in HCC group when compared with CHB/LC and HC groups. Moreover, we constructed a random forest algorithm-based HCC detection model by utilizing ccf-mtDNA fragmentomic features. Both internal and two external validation cohorts demonstrated the excellent capacity of our model in distinguishing early HCC patients from HC and high-risk population with CHB/LC, with AUC exceeding 0.983 and 0.981, sensitivity over 89.6% and 89.61%, and specificity over 98.20% and 95.00%, respectively, greatly surpassing the performance of alpha-fetoprotein (AFP) and mtDNA copy number. We also developed a HCC prognosis prediction model by LASSO-Cox regression to select 20 fragmentomic features, which exhibited exceptional ability in predicting 1-year, 2-year and 3-year survival (AUC = 0.8333, 0.8145 and 0.7958 for validation cohort, respectively). We have developed and validated a high-performing and low-cost approach in a large clinical cohort based on aberrant ccf-mtDNA fragmentomic features with promising clinical translational application for the early detection and prognosis prediction of HCC patients.

Oncofetal MCB1 Is a Functional Biomarker for HCC Personalized Therapy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T-IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome-dependent manner. Patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs-resistant HCC with adeno-associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy.

Novel Biomarkers for Early Detection of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality globally. Most patients present with late diagnosis, leading to poor prognosis. This narrative review explores novel biomarkers for early HCC detection. We conducted a comprehensive literature review analyzing protein, circulating nucleic acid, metabolite, and quantitative proteomics-based biomarkers, evaluating the advantages and limitations of each approach. While established markers like alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin, and AFP-L3 remain relevant, promising candidates include circulating tumor DNA, microRNAs, long noncoding RNAs, extracellular vesicle, and metabolomic biomarkers. Multi-biomarker panels like the GALAD score, Oncoguard, and Helio liver test show promise for improved diagnostic accuracy. Non-invasive approaches like urine and gut microbiome analysis are also emerging possibilities. Integrating these novel biomarkers with current screening protocols holds significant potential for earlier HCC detection and improved patient outcomes. Future research should explore multi-biomarker panels, omics technologies, and artificial intelligence to further enhance early HCC diagnosis and management.

The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome.

Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4+ regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.

Study of role of melanoma-associated antigen D1 (MAGE-D1) in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) ranks as the fifth most common neoplasm and the third leading cause of cancer-related deaths worldwide. Current serum biomarkers for HCC surveillance and early diagnosis, particularly alpha-fetoprotein (AFP) the most commonly used marker, lack satisfactory sensitivity and specificity, highlighting an urgent need for more effective markers with higher accuracy for early HCC detection. The downregulation of melanoma-associated antigen D1 (MAGE-D1) transcription plays a crucial role in apoptosis and inhibits cancer cell proliferation when expressed ectopically. Moreover, reduced MAGE-D1 expression correlates with improved prognosis in many cancers. Therefore, this study aims to evaluate the diagnostic role of MAGE-D1 in HCC, proposing it as a novel biomarker for early diagnosis and monitoring of tumor progression. Serum MAGE-D1 expression was measured using RT-qPCR on 198 subjects, divided into three groups: 88 with HCC, 56 with chronic liver conditions, and 54 as healthy controls. With a sensitivity of 93.3% and a specificity of 97.5%, MAGED-1 shows strong potential as a diagnostic marker for HCC. The performance of serum MAGED-1 expression in discrimination between HCC and chronic liver condition revealed an area under the curve (AUC) of 0.939 using the cutoff (0.752) yielded a sensitivity of 90%, specificity of 85%, and an accuracy of 91%. Evaluation of the diagnostic significance of MAGED-1 demonstrated an AUC value of 0.726, with a sensitivity of 63.6% and a specificity of 73.5%. In conclusion, MAGED-1 might be a specific and sensitive biomarker for HCC, potentially improving the malignancy diagnosis and prognosis.

Prognostic implications of CK19 positivity in patients with early recurrent hepatocellular carcinoma after hepatic resection undergoing transarterial chemoembolization

BackgroundThis study aimed to compare the survival outcomes of transarterial chemoembolization (TACE) between patients with early recurrent hepatocellular carcinoma (rHCC) after hepatic resection, stratified by cytokeratin (CK) 19 expression.MethodsA retrospective analysis was conducted on 63 patients with early rHCC after hepatic resection who underwent TACE between January 2017 and December 2021. Patients were divided into two groups based on CK19 expression: CK19-negative (n=31) and CK19-positive (n=32). Overall survival (OS) and progression-free survival (PFS) were compared between the two groups using the Kaplan-Meier method and log-rank test. Cox regression analysis was performed to identify independent risk factors for OS and PFS.ResultsThe CK19-negative group demonstrated a significantly longer median OS compared to the CK19-positive group (635 days vs. 432 days, p=0.013). Similarly, the CK19-negative group had a longer median PFS than the CK19-positive group (291 days vs. 117 days, p=0.014). Multivariate Cox analysis identified Child-Pugh A grade, CK19-negative expression, and increased TACE sessions as protective factors for OS. No severe TACE-related adverse events were observed.ConclusionIn patients with early rHCC after hepatic resection, those with CK19-positive expression had poorer survival outcomes following TACE compared to CK19-negative patients. These findings suggest the need for additional therapies to improve survival in CK19-positive individuals.

Outcomes and Complications of Image-Guided Percutaneous Tumour Ablation for Hepatocellular Carcinoma at the Irish National Liver Transplant Centre.

Background: Image-guided tumour ablation is a minimally invasive treatment for early stage hepatocellular carcinoma (HCC). Our study reviews the complications and long term outcomes in patients treated at a tertiary referral centre. Methods: Retrospective study. All patients with HCC who underwent microwave ablation (MWA) or radiofrequency ablation (RFA) from 1st January 2014 to 31st December 2022 were identified. Treatment response of target lesion, complications, and survival were recorded. Results: One hundred seventy ablations were performed in 118 patients; 70% MWA, 30% RFA. Median radiological follow-up 21 months (range 3-107). Follow-up imaging was reported using LI-RADS and mRECIST. At first follow-up imaging, 94 patients had complete response (primary efficacy rate 80.3%) while 19.7% (n = 23) had residual disease. Fifteen of these had repeat ablation; 10 had complete response (secondary efficacy rate 85.6%). By end of study duration, 70.5% (n = 79) achieved sustained local complete response from single ablation without documented recurrence. 14.3% (n = 16) required more than one ablation of target lesion. Overall, 84.8% (n = 95) demonstrated long term local complete response to ablation. Complication occurred in 5.9% (n = 10); 40.0% Grade I, 40.0% Grade II, 10.0% Grade III, 10.0% Grade IV as per the CIRSE Classification. 1-, 3-, and 5-year overall survival (OS) rate was 97%, 68%, and 61% respectively. Mean OS was 5.3 years (median 4.7). No difference in OS (P = .7) or local progression free survival (P = .5) between patients treated with MWA versus RFA. Conclusion: This study demonstrates excellent long-term response to TA, with acceptable complication profile. No difference in survival between RFA versus MWA.

Cost-effectiveness of radiofrequency ablation versus percutaneous ethanol injection for early hepatocellular carcinoma in a resource-poor setting: a randomized trial.

This study assessed the cost-effectiveness of radiofrequency ablation compared with percutaneous ethanol injection in patients with early hepatocellular carcinoma in relation to the objective response rate and costs related to the procedure. This was a prospective single-center randomized trial. The primary outcome was cost-effectiveness. Secondary outcomes were the complete response rate according to the modified response evaluation criteria in solid tumors 60 days after randomization and the complication rate within 180 60 days. Fifty patients were placed into the following groups: percutaneous ethanol injection (n=23) and radiofrequency ablation (n=27). Fifty-four nodules were randomized (mean follow-up: 205.37 days). The estimated mean hospital cost was US$ 1854.11 and US$ 2770.96 for the Radiofrequency Ablation and Percutaneous Ethanol Injection Groups, respectively. The incremental cost-effectiveness ratio was US$ -2674.59, which is advantageous for radiofrequency ablation. After 60 d, 28 of 29 nodules in the Radiofrequency Ablation Group achieved complete response versus 12 of 22 in the Percutaneous Ethanol Injection Group (RD, 42.01 [95%CI= 20.55-63.24]; p<0.001). Only four early complications were observed among patients treated by percutaneous ethanol injection (p<0.05). Late complications occurred in two and one patient(s) in the Radiofrequency Ablation and Percutaneous Ethanol Injection Groups (p>0.05), respectively. Radiofrequency ablation was more cost-effective and achieved higher complete response and lower complication rates than the Percutaneous Ethanol Injection Group within this cohort. NCT06450613.

Abstract PR002: County-level food insecurity and hepatocellular carcinoma risk: A cross-sectional analysis

Abstract Background: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the sixth most common cancer and third leading cause of cancer deaths worldwide. Hepatitis B and/or C virus, alcohol use, and obesity are main drivers of HCC incidence and prognosis, with risk higher among Black and Hispanic individuals and those with lower socioeconomic status. HCC etiology recently shifted from viral to non-viral-related causes, with up to 40% of HCC cases unexplained by known risk factors. Food insecurity (FI) is associated with several known and emerging HCC risk factors, including poor diet quality, obesity, and diabetes. However, there is limited data on whether FI is in fact a social determinant of HCC risk. In this study, we conducted a county-level cross-sectional analysis to examine whether FI is associated with HCC risk in the United States. Methods: We used the Surveillance Epidemiology and End Results 22 database to obtain county-level counts of HCC cases from 2018-2021 stratified by age (20-64, ≥65 years), sex (female, male), and race and ethnicity (non-Hispanic White, non- Hispanic Black, non-Hispanic Asian or Pacific Islander, non-Hispanic American Indian or Alaska Native, and Hispanic). We obtained county-level FI rates for the years 2018-2021 from Feeding America’s Map the Meal Gap and calculated the average rate over these years. FI rates were calculated using imputation methods that consider state- and county-level sociodemographic variables associated with FI. We obtained additional county-level variables from the Behavior Risk Factor Surveillance System for the years 2018-2021. We used multi- level Poisson regression models with robust standard errors to estimate the association between FI and HCC risk. Models specified county population size as the offset term, and random effects for states and counties. We examined models adjusted for age, sex, race, and ethnicity (Model 1), and further adjusted for county-level binge drinking, smoking, obesity, and diabetes rates (Model 2). We tested multiplicative effect modification by individual-level factors. Results: We included 38,986 cases of HCC diagnosed in 1,085 counties. The mean county-level FI rate was 12.9% (standard deviation (SD)=3.6%). Overall, a 1-SD increase in FI was associated with a 9% increase in HCC risk in Model 1 (incidence rate ratio (IRR)=1.09, 95% CI=1.04-1.15) and a 5% increase in risk in Model 2 (IRR=1.05, 95% CI=1.02-1.09). When stratified by race and ethnicity, FI was only associated with HCC risk in non-Hispanic Whites in Model 2 (IRR=1.07, 95% CI=1.03-1.11; interaction p-value=.05). When stratified by age, FI was only associated with HCC risk in the &amp;lt;65 years group (IRR=1.13, 95% CI=1.08-1.18; interaction p-value &amp;lt;.001). The association did not differ by sex. Conclusion: This study provides some of the first data linking FI to increased HCC risk, in particular early onset HCC. If confirmed in other studies, these findings support the need for interventions that screen for, prevent, and address FI in populations at increased risk for HCC. Citation Format: Rebecca D. Kehm, Chrystelle L. Vilfranc, Jasmine A. McDonald, Hui Chen Wu. County-level food insecurity and hepatocellular carcinoma risk: A cross-sectional analysis [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr PR002.

Benefits and Harms of Hepatocellular Carcinoma Screening Outreach in Patients with Cirrhosis: A Multi-Center Randomized Clinical Trial.

The value of hepatocellular carcinoma (HCC) screening is defined by the balance of benefits from early tumor detection vs harms due to false positive results. We evaluated the value of a mailed outreach strategy for HCC screening in patients with cirrhosis. We conducted a multi-center pragmatic randomized clinical trial comparing mailed outreach for HCC screening (n = 1436) and usual care with visit-based screening (n = 1436) among patients with cirrhosis at three health systems from March 2018 to September 2021. Outcomes of interest were early-stage HCC detection (ie, screening benefit) and diagnostic evaluation for false positive or indeterminate results (ie, screening harm). Screening harm was categorized as mild, moderate, and severe based on number and type of diagnostic exams. All patients were included in intention-to-screen analyses. Of 125 patients diagnosed with HCC (67 outreach and 58 usual care), 71.2% were found at an early stage per the Milan Criteria. Early tumor detection did not significantly differ between the outreach and usual care arms (64.2% vs 79.3%, p = .06). The proportion of patients with physical harms also did not differ between the outreach and usual care arms (10.8% vs 10.7%, p = .95) with 5.9% in both arms having mild harms, 4.0% and 3.8% respectively with moderate harms, and 0.9% and 1.0% respectively with severe harms. Most patients enrolled in HCC screening were detected at an early stage, and a minority experienced physical harms. A mailed outreach strategy did not significantly increase early HCC detection or physical harms compared to usual care. NCT02582918 and NCT03756051.

Ultrathin Gd-Oxide Nanosheet as Ultrasensitive Companion Diagnostic Tool for MR Imaging and Therapy of Submillimeter Microhepatocellular Carcinoma.

Early stage hepatocellular carcinoma (HCC) presents a formidable challenge in clinical settings due to its asymptomatic progression and the limitations of current imaging techniques in detecting micro-HCC lesions. Addressing this critical issue, we introduce a novel ultrathin gadolinium-oxide (Gd-oxide) nanosheet-based platform with heightened sensitivity for high-field MRI and as a therapeutic agent for HCC. Synthesized via a digestive ripening process, these Gd-oxide nanosheets exhibit an exceptional acid-responsive profile. The integration of the ultrathin Gd-oxide with an acid-responsive polymer creates an ultrasensitive high-field MRI probe, enabling the visualization of submillimeter-sized tumors with superior sensitivity. Our research underscores the ultrasensitive probe's efficacy in the treatment of orthotopic HCC. Notably, the ultrasensitive probe functions dually as a companion diagnostic tool, facilitating simultaneous imaging and therapy with real-time treatment monitoring capabilities. In conclusion, this study showcases an innovative companion diagnostic tool that holds promise for the early detection and effective treatment of micro-HCC.

Differences in Prediagnostic Serum Metabolomic and Lipidomic Profiles Between Cirrhosis Patients with and without Incident Hepatocellular Carcinoma.

Early detection of hepatocellular carcinoma (HCC) is crucial for improving patient outcomes, but we lack robust clinical biomarkers. This study aimed to identify a metabolite and/or lipid panel for early HCC detection. We developed a high-resolution liquid chromatography mass spectrometry (LC-MS)-based profiling platform and evaluated differences in the global metabolome and lipidome between 28 pre-diagnostic serum samples from patients with cirrhosis who subsequently developed HCC (cases) and 30 samples from patients with cirrhosis and no HCC (controls). We linked differentially expressed metabolites and lipids to their associated genes, proteins, and transcriptomic signatures in publicly available datasets. We used machine learning models to identify a minimal panel to distinguish between cases and controls. Among cases compared with controls, 124 metabolites and 246 lipids were upregulated, while 208 metabolites and 73 lipids were downregulated. The top upregulated metabolites were glycoursodeoxycholic acid, 5-methyltetrahydrofolic acid, octanoyl-coenzyme A, and glycocholic acid. Elevated lipids comprised glycerol lipids, cardiolipin, and phosphatidylethanolamine, whereas suppressed lipids included oxidized phosphatidylcholine and lysophospholipids. There was an overlap between differentially expressed metabolites and lipids and previously published transcriptomic signatures, illustrating an association with liver disease severity. A panel of 12 metabolites that distinguished between cases and controls with an area under the receiver operating curve of 0.98 for the support vector machine (interquartile range, 0.9-1). Using prediagnostic serum samples, we identified a promising metabolites panel that accurately identifies patients with cirrhosis who progressed to HCC. Further validation of this panel is required.

Five miRNAs identified in fucosylated extracellular vesicles as non-invasive diagnostic signatures for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer that presents significant challenges for early detection. This study introduces the GlyExo-Capture method for isolating fucosylated extracellular vesicles (Fu-EVs) from serum. We analyze microRNA (miRNA) profiles from Fu-EVs in 88 HCC patients and 179 non-HCC controls using next-generation sequencing (NGS) and identify five miRNAs (hsa-let-7a, hsa-miR-21, hsa-miR-125a, hsa-miR-200a, and hsa-miR-150) as biomarkers for HCC diagnosis. The five-miRNA panel demonstrates exceptional HCC diagnostic performance, with a sensitivity of 0.90 and specificity of 0.92 in a combined cohort of 194 HCC and 412 non-HCC controls, significantly surpassing the performance of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP). Notably, the miRNA model achieves recall rates of 85.7% and 90.8% for stage 0 and stage A early-stage HCC, respectively, identifies 88.1% of AFP-negative HCC cases, and effectively differentiates HCC from other cancers. This study provides a high-throughput, rapid, and non-invasive approach for early HCC detection.

Development of an indirect ELISA to detect antigens using DNA origami nanoantenna labeled specific monoclonal antibodies

This research examines the development of an indirect ELISA to detect antigens using DNA origami nanoantenna-labeled specific monoclonal antibodies. Hepatocellular carcinoma (HCC) is one of the five most common cancers and the second leading cause of cancer-related death worldwide. More than 60% of cases are detected in the late stage, with the absence of specific symptoms in the early stage of the disease. Adding measurements of AFP (Alpha-Fetoprotein), TXN (Thioredoxin), and DCP (Des-γ-Carboxy Prothrombin) has the potential to improve the accuracy of diagnosing hepatocellular carcinoma. DNA origami technology is revolutionizing the forefront of cancer diagnostics, particularly for HCC. In this study, an indirect enzyme-linked immunosorbent assay (ELISA) method targeting the assessment of the effectiveness of specific monoclonal antibody-conjugated DNA origami particles was developed. The results of DNA origami folding into complex nanostructures and labeled biomarkers like AFP, DCP, and TXN have explored the high specificity and sensitivity for targeting HCC. We found the cut-off values for AFP, DCP, and TXN to be 0.132, 0.156, and 0.150, respectively. The coefficients of variation for samples remained consistently under 10%, indicating the method's high degree of stability and reproducibility. This innovation, combined with biomarkers, promised in early HCC detection, holds the potential to significantly enhance patient outcomes in the fight against liver cancer. The platform also has enormous potential for advancing personalized medicine.