Stage Hepatocellular Carcinoma Research Articles

Abstract 1281: Oncoprotein YB-1 modulation of Lyn-MAPK-NF-kB pathway, a potential therapeutic strategy combined with sorafenib for advanced stage HCC

Abstract The Y-Box Binding protein 1 (YB-1) is a 324 amino acid-long member of the Cold Shock Domain (CSD) protein superfamily. YB-1 interacts with micro RNAs and non-coding RNAs in the cytoplasm, acting as a regulator of mRNA translation. YB-1 translocation into the nucleus is circadian clock-dependent and leads to the upregulation of cyclin gene expression, among others. Another mechanism of nuclear translocation of YB-1 is mediated by phosphorylation of the Ser 102 residue in the CSD. The YB-1 oncoprotein acts as a transcription factor when bound to DNA, modulating the transcription of genes that regulate biological processes such as Multidrug Resistance Mutation 1 (MDR1). YB-1 is linked to poor prognosis in breast, prostate, and liver cancer. Despite advances in biomedicine, the incidence and mortality of hepatocellular carcinoma (HCC) remain high. Sorafenib, a tyrosine kinase Inhibitor (TKI), is the first-line treatment for advanced HCC. Sorafenib also inhibits downstream activation of NF-kB by inhibition of Lyn phosphorylation (Y397). However, it was observed in many patients that its sorafenib’s effectiveness is hampered by drug resistance, but the mechanism is still unclear. We have found that SK-HEP-1 HCC cells transfected with a YB-X-1 overexpression plasmid subsequently developed into a stable YB-1 overexpression cell line (SK-HEP-1+YB-1) displayed increased invasion, migration, proliferation, and colony formation property as compared to the vector control (SKHEP1+Vec). The SK-HEP-1+YB-1 cell line also showed increased IC50 for sorafenib and elevated phosphorylation of Lyn (Y397) and further activated NF-kB (S165/S176) phosphorylation. This indicates YB-1 may cause increased Sorafenib resistance in HCC by activating tyrosine kinases (TK), such as lyn, and simultaneous activation of NF-kB. The combination of YB-1 inhibition and sorafenib might provide a novel therapeutic strategy and improve the survival of patients with advanced-stage HCC. Citation Format: Ana G. Ayala Pazzi, Omar Karkoutly, Kristopher Ezell, Samantha Lopez, Kyle D. Doxtater, Elias George, Vijian Dhevan, Manish K. Tripathi. Oncoprotein YB-1 modulation of Lyn-MAPK-NF-kB pathway, a potential therapeutic strategy combined with sorafenib for advanced stage HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1281.

Interaction of peripheral CD4+CD25+CD127− Tregs with prolactin in HCV hepatocellular carcinoma: oncogenic or immunogenic mechanisms

Background and objectiveThere is little and conflicting data about the peripheral CD4+CD25+CD127− Tregs in patients with hepatocellular carcinoma (HCC) of various etiologies. The expressed membrane-bound transforming growth factor (mTGF-β1) on these Tregs is a marker of their suppressive function. Prolactin suppresses Tregs function in healthy subjects but enhances local Tregs in breast cancer. Our study is the first to assess the frequency and function of CD4+CD25+CD127−Tregs and their association with clinicopathological features and staging in HCV-related HCC and to determine whether prolactin acts as an oncogenic growth factor or participates in the regulation of the immune response mediated by peripheral Tregs. In patients with HCV- elated HCC, HCV-cirrhotic patients, and healthy subjects, we measured the frequency of peripheral traditional CD4+ CD25+ Tregs and well-characterized CD4+CD25+CD127−Tregs and their mTGF-β1 using flow cytometric analysis and measured serum prolactin level.ResultsThe frequency of CD4+ CD25+ and CD4+CD25+CD127− Tregs was comparable between HCC and cirrhotic patients and healthy subjects. Serum prolactin and mTGF-β1 on traditional and CD4+CD25+CD127− Tregs were significantly higher in HCC and cirrhotic patients than healthy subjects with an insignificant difference between HCC and cirrhotic patients. Roc curve analysis revealed that cutoff value for mTGF-β1 on Tregs ≥ 13.5% is a good specific (87%) but low sensitive (54%) test in discriminating HCC patients from healthy subjects. The frequency of Tregs and mTGF-β1 were not correlated to clinicopathological characteristics or staging of HCC. Prolactin was higher in the multifocal lesions and negatively correlated to expressed mTGFβ1. The expressed mTGF-β1 was positively correlated with hemoglobin and alanine transaminase. The traditional Tregs was positively correlated with hemoglobin and albumin.ConclusionmTGFβ1, as a marker for suppressive function of peripheral CD4 + CD25 + CD127-Tregs, has a diagnostic role in discriminating HCV-related HCC patient from healthy subjects, unfortunately not from HCV-related cirrhotic patients. Serum prolactin has an oncogenic role as it is correlated to multiple focal lesions. It also impedes the suppressive function of peripheral Tregs as an immunogenic role. mTGF-β1 is related to hemoglobin and hepatic inflammation.

Overall Survival Rates Become Similar Between Percutaneous Ablation and Hepatic Resection With Increasing Age Among Elderly Patients With Early Hepatocellular Carcinoma

This study aimed to investigate the efficacy and safety of percutaneous ablation versus hepatectomy in an elderly population with hepatocellular carcinoma (HCC).Retrospective data on patients aged ≥ 65 years with very-early/early stages of HCC (≤ 50 mm) were obtained from three centers in China. Inverse probability of treatment weighting analysis was performed after stratifying the patients by age (65 - 69, 70 - 74 and ≥ 75 years).Of the 1,145 patients, 561 and 584 underwent resection and ablation, respectively. For patients aged 65 - 69 and 70 - 74 years, resection resulted in significantly better overall survival (OS) than ablation (age 65 - 69, P < 0.001, hazard ratio (HR) = 0.27; age 70 - 74, P = 0.012, HR = 0.64). However, in patients aged ≥ 75 years, resection and ablation resulted in a similar OS (P = 0.44, HR = 0.84). An interactive effect existed between treatment and age (effect of treatment on OS, age 65 - 69 as the reference, for age 70 - 74, P = 0.039; for age ≥ 75, P = 0.002). The HCC-related death rate was higher in patients aged 65 - 69, and the liver/other cause-related death rate was higher in patients aged > 69. Multivariate analyses showed that the type of treatment, number of tumors, α-fetoprotein level, serum albumin level and associated diabetes mellitus were independent factors associated with OS, but not hypertension or heart diseases.With increasing patient age, the treatment outcomes of ablation become similar to those of resection. A higher liver/other cause-related death rate in very elderly patients may shorten the life expectancy, which may lead to the same OS regardless of whether resection or ablation is chosen.

Living donor liver transplantation for Barcelona clinic liver cancer (BCLC) intermediate-stage hepatocellular carcinoma.

Barcelona clinic liver cancer (BCLC) stage B (intermediate stage) hepatocellular carcinoma (HCC) is highly heterogeneous; thus, identifying the most effective treatment for individual patients represents a significant clinical challenge. However, transarterial chemoembolization (TACE) is the only recommended treatment option. Therefore, we aimed to investigate the patient characteristics and outcomes of living donor liver transplantation (LDLT) for BCLC stage B HCC. A total of 516 patients with BCLC stage B HCC who underwent LDLT (n=104) or did not undergo LDLT (non-LDLT; n=412) between 2004 to 2018 were analyzed by propensity score matching (PSM; 1:4) analysis. Factors influencing overall survival (OS) and recurrence were analyzed using Cox's proportional hazards models. Patients treated with LDLT achieved better OS than the non-LDLT group, including liver- and non-liver related survival (all P<0.001). Multivariate Cox regression analysis showed age >60 years (P=0.006), a neutrophil-lymphocyte ratio (NLR) >4 (P=0.016) and >3 locoregional therapies (LRT) before LDLT (P<0.001) were independent risk factors for HCC recurrence. In addition, age >60 years (P<0.001) and >3 LRT before LDLT (P=0.001) were independent risk factors for OS. Using a combination of age, NLR, and LRT before liver transplantation (LT), the patients can be divided into low-risk (none of risk), intermediate-risk (one of risk), and high risk (more than two of risk) groups. There were significant differences in the cumulative HCC recurrence (P<0.001) and mortality (P<0.001) rates among the three groups. LDLT may represent a valuable therapeutic option for selected patients with BCLC stage B HCC.

Six-Transmembrane Epithelial Antigen of Prostate 4: An Indicator of Prognosis and Tumor Immunity in Hepatocellular Carcinoma.

The six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been linked to tumor progression via its involvement in inflammatory responses, oxidative stress, and metabolism. However, STEAP4 has rarely been studied in hepatocellular carcinoma (HCC). We explored STEAP4 expression associated with tumor prognosis to understand its role in tumor biology in HCC. STEAP4 mRNA and protein expressions were primarily analyzed using bioinformatics tools based on The Cancer Genome Atlas database to understand the expression pattern, molecular mechanism, prognostic impact, and association with immune cell infiltration. We further investigated the association between STEAP4 protein expression and clinicopathological parameters and their predictive value in HCC patients using immunohistochemical staining of tissue microarrays. The expression of STEAP4 mRNA and protein in HCC tissues was significantly lower than in normal liver tissues. Reduced expression of STEAP4 was linked to advanced HCC stages, poor recurrence-free survival (RFS), and overall survival. Furthermore, reduced STEAP4 expression was a significant predictor of worse RFS in univariate and multivariate analyses in the immunohistochemical cohort. GO, KEGG, and GSEA analyses revealed that STEAP4 is related to numerous biological processes and pathways, including drug metabolism, DNA replication, RNA metabolism, and immune response. In terms of the immune system, the decreased level of STEAP4 was correlated with the immunosuppressive microenvironment. Our data indicated that reduced STEAP4 expression was significantly associated with tumor aggressiveness and poor prognosis, possibly because of its link to various biological processes and induction of HCC immune evasion. Therefore, STEAP4 expression may serve as a potential prognostic biomarker for cancer progression and immunity, as well as a therapeutic target in HCC.

Prognostic Impact of a Novel Albumin-Platelet Index as Selection Criterion for Hepatic Resection in Intermediate Stage Hepatocellular Carcinoma.

Hepatic resection for Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate-stage) hepatocellular carcinoma (HCC) is not recommended by BCLC treatment algorithms. We sought to develop a new prognostic model for determining appropriate treatment strategies in patients with intermediate-stage HCC. This single-center retrospective study included patients who underwent hepatic resection for HCC between 2000 and 2018. A total of 498 patients were classified according to the BCLC staging system (0, n=116; A, n=319; B, n=63). The predictive impact for surgical outcomes was evaluated using receiver operating characteristic (ROC) curves. Based on a survival outcome probability formula, a new predictive model was established. The preoperative albumin level and platelet count were the strongest diagnostic values in patients with intermediate-stage HCC (areas under the ROC curves, AUCs: 0.710 and 0.676, respectively). Logistic regression analysis provided the albumin-platelet index [API; 156.2×albumin (g/dl)+platelet count (×109/l)] was defined as a new prognostic model for the probability of poor survival. The optimal cutoff value (781.2; AUC 0.755) divided patients with BCLC-B into B1 (>781.2, n=27) and B2 (≤781.2, n=36) categories. Patients in substage B2 had a significantly worse prognosis than patients in other stages (p<0.0001), whereas there was no difference in prognosis between patients in substage B1 and those in other stages. The API stratifies prognosis in patients with intermediate-stage HCC. For subgroup B1, hepatic resection can be considered a radical treatment, even for intermediate-stage HCC.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Strategies and Biomarkers Predicting Response and/or Resistance.

In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies.

A Multidisciplinary Treatment Strategy With Conversion Surgery for Hepatocellular Carcinoma.

Sorafenib was previously the only targeted therapy for hepatocellular carcinoma (HCC). However, pharmaceutical therapy for HCC has undergone remarkable advances in recent years. Herein, we report cases of unresectable advanced HCC responding to pharmaceutical therapy resulting in improved prognosis through surgical intervention. Five patients with intermediate and advanced stage HCC treated with lenvatinib followed by hepatectomy between October 2019 and September 2022 were retrospectively reviewed. Patient characteristics, tumor factors, and treatment factors were compared. The median patient age was 66 (60-79) years, and all patients (100%) were male. The median follow-up period was 10.4 months. All five patients received lenvatinib treatment for more than 2 months before surgery. Three patients achieved partial responses and 2 patients had stable disease with modified RESIST in response to lenvatinib. Three patients had a partial pathological response (50% or more tumor necrosis). Four patients underwent R0 resection and 3 cases had no recurrence. Lenvatinib might be useful for intermediate and advanced HCC and long-term survival may be obtained by combining lenvatinib therapy with surgery.

Nucleoporin 107 is a prognostic biomarker in hepatocellular carcinoma associated with immune infiltration.

To assess the diagnostic value and clinical significance of nucleoporin 107 (NUP107) in hepatocellular carcinoma (HCC), and explore the possible mechanisms. The transcriptomic and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) and GEO databases. Tissue specimens were collected from HCC patients in the Guangxi area. According to the expression levels and prognostic characteristics of NUP107, ROC curves and nomogram models were constructed using the R package. NUP107 was highly expressed in 26 human cancers including HCC, and was associated with advanced HCC staging and worse prognosis. NUP107 showed satisfactory ability to predict the prognosis of HCC patients (AUC >0.8). Results of gene set enrichment analysis (GSEA) further showed that NUP107 was mainly associated with cell cycle-related pathways such as the cell cycle, DNA replication, G2M checkpoint, E2F target, and mitotic spindle. In addition, NUP107 was also associated with immune infiltration in HCC and showed significant positive correlation with immune checkpoints (PD-L1 and TIM-3).

Immunotherapies for advanced hepatocellular carcinoma.

Primary liver cancer is the second leading cause of tumor-related deaths in China, with hepatocellular carcinoma (HCC) accounting for 80%-90% of these. Since there is a lack of symptoms in the early stages of HCC, a large proportion of patients were identified with unresectable HCC when diagnosed. Due to the severe resistance to chemotherapy, patients with advanced HCC were traditionally treated with systematic therapy in the past decades, and the tyrosine kinase inhibitor (TKI) sorafenib has remained the only treatment option for advanced HCC since 2008. Immunotherapies, particularly immune checkpoint inhibitors (ICIs), have shown a strong anti-tumor effect and have been supported by several guidelines recently. ICIs, for example programmed cell death-1 (PD-1) inhibitors such as nivolumab and pembrolizumab, programmed cell death ligand 1 (PD-L1) inhibitors such as atezolizumab, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors such as ipilimumab, the ICI-based combination with TKIs, and VEGF-neutralizing antibody or systematic or local anti-tumor therapies, are being further studied in clinical trials. However, immune-related adverse events (irAEs) including cutaneous toxicity, gastrointestinal toxicity, and hepatotoxicity may lead to the termination of ICI treatment or even threaten patients' lives. This review aims to summarize currently available immunotherapies and introduce the irAEs and their managements in order to provide references for clinical application and further research.

Well-Ordered Au Nanoarray for Sensitive and Reproducible Detection of Hepatocellular Carcinoma-Associated miRNA via CHA-Assisted SERS/Fluorescence Dual-Mode Sensing.

Ultra-sensitive detection of cancer-related biomarkers in serum is of great significance for early diagnosis, treatment, prognosis, and staging of cancer. In this work, we proposed a surface-enhanced Raman scattering and fluorescence (SERS/FL) dual-mode biosensor for hepatocellular carcinoma (HCC)-related miRNA (miR-224) detection using the composition of well-arranged Au nanoarrays (Au NAs) substrate coupled with the target-catalyzed hairpin assembly (CHA) strategy. The hot spots densely and uniformly distributed on the Au array offers considerably enhanced and reproducible SERS signals, along with their wide and open surface to facilitate miR-224 adsorption. By this sensing strategy, the target miR-224 can be detected in a wide linear range (1 fM to 1 nM) with a limit of detection of 0.34 fM in the SERS mode and 0.39 fM in the FL mode. Meanwhile, this biosensor with exceptional specificity and anti-interference ability can discriminate target miR-224 from other interference miRNAs. Practical analysis of human blood samples also demonstrated considerable reliability and repeatability of our developed strategy. Furthermore, this biosensor can distinguish HCC cancer subjects from normal ones and monitor HCC patients before and after hepatectomy as well as guide the distinct Barcelona clinic liver cancer (BCLC) stages. Overall, benefiting from a well-arranged Au nanoarray, CHA amplification strategy, and SERS/metal enhanced fluorescence effect, this established biosensor opens new avenues for the early prediction, warning, monitoring, and staging of HCC.

Key therapeutic targets implicated at the early stage of hepatocellular carcinoma identified through machine-learning approaches

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer. Early-stage detection plays an essential role in making treatment decisions and identifying dominant molecular mechanisms. We utilized machine learning algorithms to find significant mRNAs and microRNAs (miRNAs) at the early and late stages of HCC. First, pre-processing approaches, including organization, nested cross-validation, cleaning, and normalization were applied. Next, the t-test/ANOVA methods and binary particle swarm optimization were used as a filter and wrapper method in the feature selection step, respectively. Then, classifiers, based on machine learning and deep learning algorithms were utilized to evaluate the discrimination power of selected features (mRNAs and miRNAs) in the classification step. Finally, the association rule mining algorithm was applied to selected features for identifying key mRNAs and miRNAs that can help decode dominant molecular mechanisms in HCC stages. The applied methods could identify key genes associated with the early (e.g., Vitronectin, thrombin-activatable fibrinolysis inhibitor, lactate dehydrogenase D (LDHD), miR-590) and late-stage (e.g., SPRY domain containing 4, regucalcin, miR-3199-1, miR-194-2, miR-4999) of HCC. This research could establish a clear picture of putative candidate genes, which could be the main actors at the early and late stages of HCC.

Efficacy of lenvatinib in intermediate stage and advanced hepatocellular carcinoma: Results of monotherapy and combination with locoregional treatment

Efficacy of lenvatinib in intermediate stage and advanced hepatocellular carcinoma: Results of monotherapy and combination with locoregional treatment

Identification of a novel plasma metabolite panel as diagnostic biomarker for hepatocellular carcinoma

Background and aimsMetabolic reprogramming is one of the hallmarks of cancer. Hepatocellular carcinoma (HCC) is one of the most lethal malignancy camcer, but the early diagnosis of HCC remains difficult. In this study, we searched for potential plasma metabolite biomarkers of HCC. MethodsA total of plasma samples of 104 HCC, 76 cirrhosis and 10 healthy subjects were assessed and validated through Gas chromatography-Mass spectrometry. Receiver-operating characteristic curves (ROC) combined with multivariate statistical analyses were used to assess the diagnostic performance of metabolites and combinations. Results10 metabolites in screening cohort were significantly changed in the plasma of HCC patients. Multivariate logistic regression analysis of candidate metabolites in validation cohort showed that N-formylglycine, oxoglutaric acid, citrulline and heptaethylene glycol could distinguish HCC from cirrhosis. The combination of these four metabolites showed a better performance than AFP with the Area Under the Curve (AUC), sensitivity, specificity as 0.940, 84.00%, 97.56%, respectively. In further, the panel of N-formylglycine, heptaethylene glycol and citrulline can more effectively discriminate early stage HCC from cirrhosis than AFP (AUC: 0.835 vs. 0.634). Finally, heptaethylene glycol could significantly inhibit the proliferation, migration and invasion of HCC cells in vitro. ConclusionThe combination of plasma N-formylglycine, oxoglutaric acid, citrulline, and heptaethylene glycol can be an efficient novel diagnostic biomarker for HCC.

Non-alcoholic fatty liver disease: current diagnostic opportunities at different stages of the disease and scientific developments in treatment. Review

Nonalcoholic fatty liver disease (NAFLD) is a widespread disease and a major challenge for health care systems worldwide. Disease severity and end‑stage disease vary considerably among patients, so there is a need to identify those at greatest risk of disease progression. NAFLD is often asymptomatic, but should be suspected in individuals with risk factors. Marked liver fibrosis is the strongest predictor of long‑term mortality in patients with NAFLD and is one of the risk factors for the development of hepatocellular carcinoma (HCC). Liver biopsies are the gold standard for diagnosing the stage of liver fibrosis. However, this is an invasive procedure that cannot be widely used in a daily clinical practice. Therefore, there is a constant search for non‑invasive and safe biomarkers.&#x0D; The purpose of this publication is to analyze and summarize the current research results of non‑invasive tests for fibrosis, as well as scientific developments in the NAFLD treatment, which can be widely used in daily clinical practice. Non‑invasive methods of diagnosing liver fibrosis can be divided into biochemical serum tests (serological) and morphological. Serum markers of fibrosis are studied based on participation in the mechanisms of fibrogenesis and fibrolysis. The authors outlined the effectiveness of different scales including different markers of fibrosis, but for widespread use in clinical practice, it is recommended to use simple and accessible tests and scales. One of the modern and safe instrumental diagnostic methods is transient elastography, which has excellent effectiveness for diagnosing liver fibrosis, predicting the development of HCC and other clinical stages. Two‑dimensional shear wave elastography is a new technique that provides real‑time imaging of stiffness. Further studies are needed to establish specific markers of liver fibrosis based on further clinical and molecular studies.&#x0D; Recommendations for patients’ lifestyle changing with individualized approach to the non‑drug treatment administration are stated to be important for curation of patients with NAFLD. If patients adhere to such recommendations, the overall benefit for NAFLD regression and health can be quite significant. However, due to the insufficient compliance of some patients with non‑drug treatment, a constant search for candidate molecules for NAFLD treatment is conducted. At the current stage, there are no approved recommendations for drug treatment, thus the research in this direction is ongoing. The article provides up‑to‑date information on the stages of studying the main existing molecules

Does size matter for resection of giant versus non-giant hepatocellular carcinoma? A meta-analysis.

Research on long-term survival after resection of giant (≥ 10 cm) and non-giant hepatocellular carcinoma (HCC) (< 10 cm) has produced conflicting results. This study aimed to investigate whether oncological outcomes and safety profiles of resection differ between giant and non-giant HCC. PubMed, MEDLINE, EMBASE, and Cochrane databases were searched. Studies designed to investigate the outcomes of giant vs non-giant HCC were included. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were postoperative complications and mortality rates. All studies were assessed for bias using the Newcastle-Ottawa Scale. 24 retrospective cohort studies involving 23747 patients (giant = 3326; non-giant = 20421) who underwent HCC resection were included. OS was reported in 24 studies, DFS in 17 studies, 30-d mortality rate in 18 studies, postoperative complications in 15 studies, and post-hepatectomy liver failure (PHLF) in six studies. The HR was significantly lower for non-giant HCC in both OS (HR 0.53, 95%CI: 0.50-0.55, P < 0.001) and DFS (HR 0.62, 95%CI: 0.58-0.84, P < 0.001). No significant difference was found for 30-d mortality rate (OR 0.73, 95%CI: 0.50-1.08, P = 0.116), postoperative complications (OR 0.81, 95%CI: 0.62-1.06, P = 0.140), and PHLF (OR 0.81, 95%CI: 0.62-1.06, P = 0.140). Resection of giant HCC is associated with poorer long-term outcomes. The safety profile of resection was similar in both groups; however, this may have been confounded by reporting bias. HCC staging systems should account for the size differences.

Abstract No. 126 Radioembolization Prior to Checkpoint Inhibitor Immunotherapy versus Radioembolization Post Checkpoint Inhibitor Immunotherapy for the Treatment of Intermediate and Advanced Stage Hepatocellular Carcinoma

Abstract No. 126 Radioembolization Prior to Checkpoint Inhibitor Immunotherapy versus Radioembolization Post Checkpoint Inhibitor Immunotherapy for the Treatment of Intermediate and Advanced Stage Hepatocellular Carcinoma

Discontinuing Hepatitis Activity Reduced Hepatocellular Carcinoma Recurrence after Primary Curative Therapy

Hepatocellular carcinoma (HCC) tends to recur after curative treatment. This study aimed to identify the clinical factors associated with HCC recurrence after initial curative therapy. We retrospectively included patients with early stage HCC Barcelona Clinic Liver Cancer (BCLC) stages 0 and A who received curative surgical resection or local ablation at three different Chang Gung Memorial Hospitals in Taiwan (527 patients from Linkou, 150 patients from Keelung, and 127 patients from Chiayi) from 2000 to 2009. Pretreatment clinical data were subjected to univariate and multivariate logistic analyses to identify the risk factors for HCC recurrence within five years after the primary curative treatment. Recurrence and survival rates were assessed using Kaplan-Meier curves and log-rank tests. Patients with a history of nucleoside analog or peg-interferon treatment for hepatitis B or hepatitis C infection had lower HCC recurrence rates than did those without such treatment. By contrast, alcohol drinking habits (p = 0.0049, hazard ratio (HR): 1.508, 95%CI: 1.133-2.009), a platelet count of < 14 × 104/μL (p = 0.003, HR: 1.533, 95%CI: 1.155-2.035), and a serum alanine aminotransferase level > 40 U/L (p = 0.0450, HR: 1.305, 95%CI: 1.006-1.694) were independent risk factors for HCC recurrence. The five-year HCC recurrence rates did not differ between patients who received either local radiofrequency ablation or surgical resection at BCLC stages 0 and A. Factors contributing to persistent hepatitis activity and advanced fibrosis precipitate tumor recurrence. Active intervention to discontinue liver injury or hepatitis could reduce HCC recurrence.

Treatment Patterns and Survival in Patients with Intermediate, Advanced, or Terminal Stage of Hepatocellular Carcinoma in France over the Period 2015-2017: A Real-Life Study

Background. The prognosis of patients with hepatocellular carcinoma (HCC) not eligible to curative treatment is poor. Little information is available on treatment modalities and outcomes of these patients in everyday practice. The aim of this analysis was to describe the characteristics of patients with a newly diagnosed intermediate, advanced, or terminal (IAT) stage of HCC (ICD-10: C220) between 2015 and 2017, either present at diagnosis of HCC or having occurred after disease progression; treatment patterns, HCC aetiologies, and the associated survival were determined using the nationwide claims database. Methods. Patients with HCC were identified using the ICD-10 code C220. IAT stages, defined according to the terminology used in the Barcelona Clinic Liver Cancer classification, were indirectly identified by the presence of at least one of the following treatments: transarterial chemoembolization (TACE), transarterial radioembolization (TARE), HCC systemic therapy, best supportive care (BSC), or an ICD-10 code of metastatic HCC. Treatment patterns were described with an algorithm based on a ranking of palliative treatments identified. Survival was analysed by using Kaplan-Meier curves. Results. 19,649 eligible patients were identified. Their mean age was 70.5 years (SD: 11.0), and 82.5% were males. For 68.8% of patients, the IAT stage was present at HCC diagnosis. On the whole population, 5,114 patients (26.0%) were treated initially with a TACE or TARE, and 4,681 (23.8%) received a targeted systemic therapy at any moment during follow-up with sorafenib in 99.5% of cases. About 7,628 patients (45.6%) received only BSC. Survival since the diagnosis of the AIT stage of HCC differed according to the type of the first received palliative treatment. Median overall survival was 23.8, 9.6, 7.4, and 1.0 months in patients initially receiving TACE, TARE, systemic therapy, and BSC only, respectively. Conclusion. Over the period 2015-2017, hepatocellular carcinoma was still often diagnosed in France at late-stage disease with a very poor prognosis.

Aberrantly Expressed MicroRNAs in Cancer-Associated Fibroblasts and Their Target Oncogenic Signatures in Hepatocellular Carcinoma

Cancer-associated fibroblasts (CAFs) contribute to tumor progression, and microRNAs (miRs) play an important role in regulating the tumor-promoting properties of CAFs. The objectives of this study were to clarify the specific miR expression profile in CAFs of hepatocellular carcinoma (HCC) and identify its target gene signatures. Small-RNA-sequencing data were generated from nine pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues, respectively. Bioinformatic analyses were performed to identify the HCC-CAF-specific miR expression profile and the target gene signatures of the deregulated miRs in CAFs. Clinical and immunological implications of the target gene signatures were evaluated in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA_LIHC) database using Cox regression and TIMER analysis. The expressions of hsa-miR-101-3p and hsa-miR-490-3p were significantly downregulated in HCC-CAFs. Their expression in HCC tissue gradually decreased as HCC stage progressed in the clinical staging analysis. Bioinformatic network analysis using miRWalks, miRDB, and miRTarBase databases pointed to TGFBR1 as a common target gene of hsa-miR-101-3p and hsa-miR-490-3p. TGFBR1 expression was negatively correlated with miR-101-3p and miR-490-3p expression in HCC tissues and was also decreased by ectopic miR-101-3p and miR-490-3p expression. HCC patients with TGFBR1 overexpression and downregulated hsa-miR-101-3p and hsa-miR-490-3p demonstrated a significantly poorer prognosis in TCGA_LIHC. TGFBR1 expression was positively correlated with the infiltration of myeloid-derived suppressor cells, regulatory T cells, and M2 macrophages in a TIMER analysis. In conclusion, hsa-miR-101-3p and hsa-miR-490-3p were substantially downregulated miRs in CAFs of HCC, and their common target gene was TGFBR1. The downregulation of hsa-miR-101-3p and hsa-miR-490-3p, as well as high TGFBR1 expression, was associated with poor clinical outcome in HCC patients. In addition, TGFBR1 expression was correlated with the infiltration of immunosuppressive immune cells.