Metastatic Hepatocellular Carcinoma Patients Research Articles

Abstract 976: Detection of circulating tumor DNA predicts survival in advanced HCC patients treated with personalized therapeutic DNA cancer vaccine in combination with immune checkpoint blockade

Abstract Circulating tumor DNA (ctDNA) has enabled the non-invasive monitoring of molecular residual disease (MRD) which reflects therapeutic response/resistance prior to conventional imaging approaches. However, little is known about the applications of ctDNA in the neoantigen-targeted personalized cancer vaccine setting, potentially due to the limited sensitivity of current ctDNA assays. NeXT Personal®, an ultra-sensitive tumor-informed ctDNA assay was used to longitudinally track ctDNA in advanced hepatocellular carcinoma (HCC) patients treated with GNOS-PV02 (a personalized therapeutic DNA cancer vaccine) in combination with pembrolizumab. Advanced unresectable or metastatic HCC patients that progressed on, or were intolerant to, first-line TKI therapy were enrolled into the Phase 1b/2a GT-30 study [NCT04251117]. Whole exome/transcriptome tumor sequencing was used for the design of GNOS-PV02. Patients were treated with GNOS-PV02 (1mg; Q3W x 4, Q9W) and plasmid-encoded IL-12 (0.3mg; Q3W x 4, Q9W) in combination with pembrolizumab (200mg; Q3W). Clinical Response was evaluated by RECIST 1.1 at baseline and Q9W. The ctDNA analysis and tracking for progression was performed as an exploratory objective. Over 200 prospective baseline and on-treatment plasma samples from 31 patients were collected and analyzed using NeXT Personal. WGS was performed to identify up to ~1,800 selected tumor variants to create a personalized panel for MRD detection. NeXT Personal has been analytically validated to detection thresholds down to 1-3 parts per million (PPM) of ctDNA with >99.95% specificity. ctDNA was detected in 152 of 207 plasma samples with a dynamic range of 1.76 - 166,968 PPM. The limit of ctDNA detection ranged down to 1.05 PPM. 96% (24/25) of patients were baseline ctDNA+. The percentage change of ctDNA relative to baseline at week 9 (C4D1) significantly correlated with best overall response (CR/PR/SD vs. PD: p = 0.0076). The ctDNA change from baseline to week 9 was predictive of OS (P=0.008), with 31.2% 2-yr OS (95% CI: 13.2 - 73.7%) for molecular non-responders vs 100% 2-yr OS (95%CI: 100 - 100%) for molecular responders. In addition, the ctDNA levels at week 9 were predictive of best overall response (P = 0.017). ctDNA burden at week 9 was significantly correlated with overall survival (HR = 5.46, 95%CI: 1.79 - 16.65; P=0.003; C-index = 0.886). ctDNA clearance was observed in all 3 CR patients with a lead time of 483, 126 and 105 days compared with MRI. This ultra-sensitive ctDNA assay shows significant association between ctDNA change and clinical response and survival, and can be used to accurately predict clinical outcome. The convenience of non-invasive liquid biopsy and rapid availability of data could enable the use of ctDNA to allow real-time monitoring of personalized cancer immunotherapy. Citation Format: Jian Yan, Bailiang Li, Josette Northcott, Charles W. Abbott, Rachel M. Pyke, Renzo Perales-Linares, Neil Cooch, Sarah Rochestie, Joann Peters, Edward J. Gane, Mark Yarchoan, Thomas U. Marron, Sean M. Boyle, Ildiko Csiki, Richard Chen, Niranjan Y. Sardesai. Detection of circulating tumor DNA predicts survival in advanced HCC patients treated with personalized therapeutic DNA cancer vaccine in combination with immune checkpoint blockade [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 976.

The novel predictive nomograms for early death in metastatic hepatocellular carcinoma: A large cohort study.

Metastatic hepatocellular carcinoma (HCC) is an aggressive disease which usually have a poor prognosis. Early mortality and risk factors in patients with metastatic HCC are poorly understood. Our study sought to identify associated risk factors and develop the nomograms for predicting early death in metastatic HCC patients. The patients diagnosed with metastatic HCC were chosen from the surveillance, epidemiology, and end results database between 2010 and 2015. To identify significant independent risk factors for early death, both univariate and multivariate logistic regression models were used. We constructed a pragmatic nomogram and then evaluated by using receiver operating characteristic curves, calibration plots, and decision curve analysis. The prediction model included 2587 patients with metastatic HCC. Among them, 1550 experienced early death (died within 3 months of initial diagnosis) and 1437 died from cancer-specific causes. Multivariate logistic regression analysis found that grade, surgery, radiation, chemotherapy, alpha-fetoprotein levels, and lung metastasis were independent risk factors for both all-cause early death and cancer-specific early death. In addition, bone metastasis were independent risk factors for all-cause early death, T-stage and brain metastasis were also independent risk factors for cancer-specific early death. Then we used the relevant risk factors to developed the practical nomograms of all-cause and cancer-specific early deaths. The nomograms demonstrated good predictive power and clinical utility under receiver operating characteristic curves and decision curve analysis. We developed 2 novel comprehensive nomograms to predict early death among metastatic HCC patients. Nomograms may help oncologists develop better treatment strategies and implementation of individualized treatment plans.

Conditional survival probability of distant-metastatic hepatocellular carcinoma: A population-based study

BACKGROUND The prognosis of many patients with distant metastatic hepatocellular carcinoma (HCC) improved after they survived for several months. Compared with traditional survival analysis, conditional survival (CS) which takes into account changes in survival risk could be used to describe dynamic survival probabilities. AIM To evaluate CS of distant metastatic HCC patients. METHODS Patients diagnosed with distant metastatic HCC between 2010 and 2015 were extracted from the Surveillance, Epidemiology and End Results database. Univariate and multivariate Cox regression analysis were used to identify risk factors for overall survival (OS), while competing risk model was used to identify risk factors for cancer-specific survival (CSS). Six-month CS was used to calculate the probability of survival for an additional 6 mo at a specific time after initial diagnosis, and standardized difference (d) was used to evaluate the survival differences between subgroups. Nomograms were constructed to predict CS. RESULTS Positive -fetoprotein expression, higher T stage (T3 and T4), N1 stage, non-primary site surgery, non-chemotherapy, non-radiotherapy, and lung metastasis were independent risk factors for actual OS and CSS through univariate and multivariate analysis. Actual survival rates decreased over time, while CS rates gradually increased. As for the 6-month CS, the survival difference caused by chemotherapy and radiotherapy gradually disappeared over time, and the survival difference caused by lung metastasis reversed. Moreover, the influence of age and gender on survival gradually appeared. Nomograms were fitted for patients who have lived for 2, 4 and 6 mo to predict 6-month conditional OS and CSS, respectively. The area under the curve (AUC) of nomograms for conditional OS decreased as time passed, and the AUC for conditional CSS gradually increased. CONCLUSION CS for distant metastatic HCC patients substantially increased over time. With dynamic risk factors, nomograms constructed at a specific time could predict more accurate survival rates.

TrkB inhibition of DJ-1 degradation promotes the growth and maintenance of cancer stem cell characteristics in hepatocellular carcinoma

Although TrkB may be associated with the pathogenesis of various cancer by upregulation, how upregulation of TrkB led to tumor progression in hepatocellular carcinoma (HCC) and the signaling mechanisms by which TrkB induces motility, invasion, metastasis, drug resistance, and acquisition of self-renewal traits has remained unclear. Here, we demonstrated that TrkB was significantly upregulated in highly metastatic HCC cells and HCC patients. Also, the increased TrkB levels were significantly correlated with tumor stages and poor survival of HCC patients. Furthermore, the upregulated TrkB expression enhances the metastatic ability of HCC cells through reduced anoikis sensitivity, induced migration, and colony formation. Most strikingly, TrkB markedly enhances the activation of STAT3 by preventing DJ-1 degradation through the formation of the TrkB/DJ-1 complex. This signaling mechanism is responsible for triggering cellular traits of highly aggressive HCC. The activation of the EMT program of HCC via increasing DJ-1 stability by TrkB induces the gain of cancer stem cell states and chemoresistance via the upregulation of stem cells cell markers and ABC transporters. Also, TrkB-mediated inhibition of DJ-1 degradation promotes tumor formation and metastasizes to other organs in vivo. Our observations illustrate that TrkB is a prognostic and therapeutic targeting in promoting aggressiveness and metastasis of HCC.

Construction of a lipid metabolism-related risk model for hepatocellular carcinoma by single cell and machine learning analysis.

One of the most common cancers is hepatocellular carcinoma (HCC). Numerous studies have shown the relationship between abnormal lipid metabolism-related genes (LMRGs) and malignancies. In most studies, the single LMRG was studied and has limited clinical application value. This study aims to develop a novel LMRG prognostic model for HCC patients and to study its utility for predictive, preventive, and personalized medicine. We used the single-cell RNA sequencing (scRNA-seq) dataset and TCGA dataset of HCC samples and discovered differentially expressed LMRGs between primary and metastatic HCC patients. By using the least absolute selection and shrinkage operator (LASSO) regression machine learning algorithm, we constructed a risk prognosis model with six LMRGs (AKR1C1, CYP27A1, CYP2C9, GLB1, HMGCS2, and PLPP1). The risk prognosis model was further validated in an external cohort of ICGC. We also constructed a nomogram that could accurately predict overall survival in HCC patients based on cancer status and LMRGs. Further investigation of the association between the LMRG model and somatic tumor mutational burden (TMB), tumor immune infiltration, and biological function was performed. We found that the most frequent somatic mutations in the LMRG high-risk group were CTNNB1, TTN, TP53, ALB, MUC16, and PCLO. Moreover, naïve CD8+ T cells, common myeloid progenitors, endothelial cells, granulocyte-monocyte progenitors, hematopoietic stem cells, M2 macrophages, and plasmacytoid dendritic cells were significantly correlated with the LMRG high-risk group. Finally, gene set enrichment analysis showed that RNA degradation, spliceosome, and lysosome pathways were associated with the LMRG high-risk group. For the first time, we used scRNA-seq and bulk RNA-seq to construct an LMRG-related risk score model, which may provide insights into more effective treatment strategies for predictive, preventive, and personalized medicine of HCC patients.

Prognostic Impact of Metastatic Site in Patients Receiving First-Line Sorafenib Therapy for Advanced Hepatocellular Carcinoma.

Extrahepatic spread is a well-known negative prognostic factor in patients with advanced hepatocellular carcinoma (HCC). The prognostic role of different metastatic sites and their response rate to systemic treatment is still being debated. We considered 237 metastatic HCC patients treated with sorafenib as first-line therapy in five different Italian centers from 2010 to 2020. The most common metastatic sites were lymph nodes, lungs, bone and adrenal glands. In survival analysis, the presence of dissemination to lymph nodes (OS 7.1 vs. 10.2 months; p = 0.007) and lungs (OS 5.9 vs. 10.2 months; p < 0.001) were significantly related to worse survival rates compared with all other sites. In the subgroup analysis of patients with only a single metastatic site, this prognostic effect remained statistically significant. Palliative radiation therapy on bone metastases significantly prolonged survival in this cohort of patients (OS 19.4 vs. 6.5 months; p < 0.001). Furthermore, patients with lymph node and lung metastases had worse disease control rates (39.4% and 30.5%, respectively) and shorter radiological progression-free survival (3.4 and 3.1 months, respectively). In conclusion, some sites of an extrahepatic spread of HCC have a prognostic impact on survival in patients treated with sorafenib; in particular, lymph nodes and lung metastases have worse prognosis and treatment response rate.

An open-label, multi-center phase IIIb study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma (TREMENDOUS study).

TPS628 Background: Hepatocellular carcinoma (HCC) is of high incidence and mortality rate in China, with nearly half of them are diagnosed as advanced or metastatic stage at the initial diagnosis. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors and immune checkpoint inhibitors in combination with vascular endothelial growth factor. Recently, the phase III HIMALAYA trial investigated the STRIDE regimen, tremelimumab 300mg × 1 dose and durvalumab 1500mg every 4 weeks, compared to sorafenib in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved overall survival (OS) (16.4 mos vs 13.8mos, HR=0.78) and a well-tolerated safety profile (≥grade 3 treatment-related adverse events 25.8% vs 36.9% ). Notably, the HIMALAYA trial did not enroll subject from mainland China and excluded patients with class Child-Pugh B liver dysfunction or ECOG performance status (PS) 2. We hypothesize the STRIDE regimen will be safe and well tolerated in Chinese patients with locally advanced or metastatic HCC with Child-Pugh class A or B liver dysfunction or ECOG PS 0-2. In addition, the study will also assess efficacy and explore biomarkers. Methods: This will be an open label, multi-center phase IIIb study investigating the safety and efficacy of the STRIDE regimen in Chinese unresectable HCC patients without prior systemic therapy. Patients with Child-Pugh A liver dysfunction and ECOG PS 0-1 will be enrolled in cohort 1, while patients with Child-Pugh B liver dysfunction or ECOG PS 2 will be enrolled in cohort 2. Patients with main portal vein tumor thrombosis (Vp4), clinically significant ascites or hepatic encephalopathy, or active or prior documented gastrointestinal bleeding within 12 months will be excluded. We plan to enroll 300 patients with the primary endpoint of grade 3-5 adverse event (AE) rate by CTCAE v5.0 and adverse events of special interest (AESI). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), OS, OS rate at 6 months and 12 months. Patients of both cohorts will receive a single dose of tremelimumab 300 mg and durvalumab 1500 mg at Cycle 1 (Week 0), followed by durvalumab 1500 mg monotherapy every 4 weeks until confirmed disease progression or unacceptable toxicity. Archival or fresh tumor biopsy will be required at baseline. The trial is currently screening eligible subjects. Clinical trial information: CTR20222433 .

Prognostic Value of a CT Radiomics-Based Nomogram for the Overall Survival of Patients with Nonmetastatic BCLC Stage C Hepatocellular Carcinoma after Stereotactic Body Radiotherapy.

This study aimed to investigatie the feasibility of pretherapeutic CT radiomics-based nomograms to predict the overall survival (OS) of patients with nondistant metastatic Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) undergoing stereotactic body radiotherapy (SBRT). A retrospective review of 137 patients with nondistant metastatic BCLC-C HCC who underwent SBRT was made. Radiomics features distilled from pretherapeutic CT images were selected by the method of LASSO regression for radiomics signature construction. Then, the clinical model was constructed based on clinical characteristics. A radiomics nomogram was constructed using the radiomics score (Rad-score) and clinical characteristics to predict post-SBRT OS in BCLC-C HCC patients. An analysis of discriminatory ability and calibration was performed to confirm the efficacy of the radiomics nomogram. In order to construct the radiomic signature, seven significant features were selected. Patients were divided into low-risk (Rad-score < -0.03) and high-risk (Rad-score ≥ -0.03) groups based on the best Rad-score cutoff value. There were statistically significant differences in OS both in the training set (p < 0.0001) and the validation set (p=0.03) after stratification. The C-indexes of the radiomics nomogram were 0.77 (95% CI: 0.72-0.82) in the training set and 0.71 (95% CI: 0.61-0.81) in the validation set, which outperformed the clinical model and radiomics signature. An AUC of 0.76, 0.79, and 0.84 was reached for 6-, 12-, and 18-month survival predictions, respectively. The predictive nomogram that combines radiomic features with clinical characteristics has great prospects for application in the prediction of post-SBRT OS in nondistant metastatic BCLC-C HCC patients.

Golgi-protein 73 facilitates vimentin polymerization in hepatocellular carcinoma.

Golgi-protein 73 (GP73) is highly expressed in hepatocellular carcinoma (HCC) and, as a secretory protein, it has been proposed as a serum biomarker indicating progression of HCC. The underlying mechanism by which GP73 may promote HCC metastasis is still poorly understood. In this study, we discovered that GP73 interacted with vimentin to facilitate Serine/Threonine-protein phosphatase PP1-alpha (PP1A)-mediated dephosphorylation of vimentin at S56 and facilitated vimentin polymerization, which blocked vimentin degradation via TRIM56-mediated ubiquitin/proteasome-dependent pathway. Strikingly, Clomipramine, a 5-hydroxytryptamine receptor (5-HTR) agonist approved for the treatment of depression, impaired GP73-mediated vimentin polymerization to effectively inhibit metastasis of HCC with high GP73 expression, which provided a new strategy against HCC metastasis. Lastly, it was found that serum GP73 (sGP73) correlated positively with vimentin in primary tissues of HCC, suggesting that sGP73 might serve as a potential serum biomarker for companion diagnosis of HCC with highly expressed vimentin. In summary, this study reveals the process of GP73-mediated vimentin polymerization and proves that Clomipramine serves as a potential drug targeting vimentin for metastatic HCC patients with high sGP73 level.

ARFIP2 Regulates EMT and Autophagy in Hepatocellular Carcinoma in Part Through the PI3K/Akt Signalling Pathway.

ARFIP2, a canonical BAR domain-containing protein, is closely associated with regulating cargo exit from the Golgi. However, the potential biological functions of ARFIP2 in hepatocellular carcinoma (HCC) have not been well investigated. This study aimed to explore the critical role of ARFIP2 in HCC cells. The expression of proteins related to epithelial to mesenchymal transition (EMT) and cell autophagy in HCC cells and tissues was assayed by quantitative real-time PCR, Western blotting, immunohistochemistry and immunofluorescence staining. The ability of cells to proliferate, migrate and invade was detected by Cell Counting Kit-8, Transwell migration and invasion assays. In addition, the function of ARFIP2 in vivo was assessed using a tumour xenograft model. ARFIP2 expression is significantly upregulated in early recurrent and metastatic HCC patients and was positively correlated with a poor prognosis. ARFIP2 overexpression promoted cell proliferation, migration, and invasion by inducing EMT and inhibiting autophagy in vitro. Furthermore, the regulatory effects of ARFIP2 on autophagy and EMT were partially attributed to its regulation of the PI3K/AKT signalling pathway. The in vivo results also showed that ARFIP2 modulates HCC progression. Our results substantiate a novel mechanism by which ARFIP2 can regulate the activity/phosphorylation of Akt to promote EMT and inhibit autophagy in part via the PI3K/Akt signalling pathway. The ARFIP2/PI3K/Akt axis may be a potential diagnostic biomarker and therapeutic target for HCC.

LOXL3-promoted hepatocellular carcinoma progression via promotion of Snail1/USP4-mediated epithelial-mesenchymal transition.

Lysyl-oxidase-like 3 (LOXL3) was reported to be essential in epithelial-mesenchymal transition (EMT) of cancers. However, the role of LOXL3 in hepatocellular carcinoma (HCC) remained unclear. In this study, we explored clinical significance, biological functions, and regulatory mechanisms of LOXL3 in HCC. Our study found that LOXL3 expression was markedly associated with the tumor size and clinical stage of HCC, and it was highly expressed in tumor tissues of metastatic HCC patients. High expression of LOXL3 predicted a poor prognosis of HCC. TGF-β1 treatment elevated LOXL3 protein expression and cell invasion, and reduced cell apoptosis in HCC cell lines (SMMC-7721 and Huh-7), while downregulation of LOXL3 reversed the promotive effects of TGF-β1 treatment on LOXL3 protein expression and cell invasion, and the inhibitory effect on cell apoptosis. Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin-specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co-IP assays. Overexpression of USP4 reversed the inhibitory effect of LOXL3 silence on EMT in HCC cells through deubiquitinating and stabilizing the expression of Snail1. Moreover, LOXL3-promoted HCC EMT through Wnt/β-catenin/Snail1 signaling pathway. In vivo study revealed that silence of LOXL3-inhibited HCC tumor growth. In conclusion, LOXL3 silence inhibited HCC invasion and EMT through Snail1/USP4-mediated circulation loop and Wnt/β-catenin signaling pathway.

No significant relationship exists between tumor size and prognosis in distant metastatic hepatocellular carcinoma: a propensity score matching analysis based on SEER database

BackgroundPrevious studies have shown that tumor size has an impact on the prognosis of hepatocellular carcinoma (HCC). Whether tumor size is related to the prognosis of distant metastatic HCC is unclear. The purpose of this study was to investigate the effect of tumor size on the prognosis of distant metastatic HCC.MethodsData on patients with HCC were collected from the (SEER) database of surveillance, epidemiology and final results. Propensity score matching (PSM) was used to reduce confounding factors and comprehensively evaluate the clinicopathological features and prognosis of distant metastatic HCC.ResultsThere were 189 patients with distant metastatic HCC whose tumor size was ≤ 50 mm and 615 patients with a tumor size > 50 mm. The tumor sizes of distant metastatic HCC patients were associated with race, grade, surgical treatment, N and AFP. The Kaplan–Meier analysis showed that the mortality rate of patients with a tumor size > 50 mm was higher than that of patients with a tumor size ≤ 50 mm (p = 0.00062). However, there were no significant differences in mortality rates after adjusting for confounding variables by using propensity score matching (p = 0.23).ConclusionThis propensity score matching study provides the best data in support of the following assertions: tumor size is not an independent prognostic factor for distant metastatic HCC.

BTCRC-GI20-457: A phase II study of atezolizumab and bevacizumab in Child-Pugh B7 hepatocellular carcinoma (the AB7 Trial).

TPS493 Background: Both the incidence and death rate of hepatocellular carcinoma (HCC) are on the rise in the United States, and overall, the prognosis is grim. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors (TKIs) which have resulted in a median overall survival (OS) of less than a year. Combinations of immune checkpoint inhibitors (CPIs) with vascular endothelial growth factor (VEGFR) inhibitors are of interest given the known effects of VEGF in the tumor microenvironment, including promoting inhibitory immune cells, suppressing maturation of dendritic cells, decreasing cytotoxic T cell responses, and altering lymphocyte development and trafficking. The phase III IMbrave150 trial investigated the combination of atezolizumab (A) and bevacizumab (B) as compared to sorafenib (S) in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved OS (mOS: 19.2 mos AB vs 13.4 mos S), PFS (mPFS: 6.9 mos AB vs 4.3 mos S), and response rates (ORR: 29.8% AB vs 11.3% S), and a meaningful improvement in duration of response (mDOR: 18.1 mos AB vs 14.9 mos S). Notably, patients with class Child-Pugh B liver dysfunction were excluded from this study, although they are clinically abundant. We hypothesize the combination of AB will be safe and well tolerated in patients with locally advanced or metastatic HCC with Child-Pugh class B7 liver dysfunction. In addition, we expect efficacy will be similar to that demonstrated by the IMbrave150 study, and that ctDNA will correlate with, and possibly predict, clinical outcomes. Methods: This will be a single arm phase II study investigating the safety of the combination of AB in patients with previously untreated locally advanced or metastatic HCC with Child-Pugh B7 liver dysfunction. Patients must also be ECOG PS 0-1 and without clinically significant ascites or hepatic encephalopathy, untreated esophageal/gastric varices (assessed by EGD within the prior 6 months), or recent significant bleeding. We will enroll 50 patients with the primary endpoint of grade 3-5 treatment-related adverse event rate by CTCAE v5. Secondary endpoints include ORR, disease control rate (DCR), DOR, progression free survival (PFS), and OS. Correlative studies include tumor molecular signature by next generation sequencing (NGS) tissue analysis and ctDNA levels to correlate both with each other and with clinical benefit. Patients will receive A 1,200 mg IV and B 15 mg/kg IV every 3 weeks until disease progression or intolerable toxicity. Tumor imaging reassessment will occur every 3 cycles. Archival or fresh tumor biopsy will be required at baseline, and plasma for ctDNA will be collected with each imaging reassessment. The trial is being conducted at sites throughout the Big Ten Cancer Research Consortium (Big Ten CRC) and is currently screening eligible subjects (NCT04829383). Clinical trial information: NCT04829383.

ACADL Functions as a Tumor Suppressor in Hepatocellular Carcinoma Metastasis by Inhibiting Matrix Metalloproteinase 14.

High aggressiveness is the main reason for the poor prognosis of hepatocellular carcinoma (HCC) patients. However, its molecular mechanisms still remain largely unexplored. ACADL, a mitochondrial enzyme that facilitates the primary regulated step in mitochondrial fatty acid oxidation, plays a role in HCC growth inhibition. However, the function of ACADL in tumor metastasis is not well elucidated. We found that the reduced expression of ACADL is closely associated with the loss of tumor encapsulation, extrahepatic metastasis, and poor prognosis in HCC patients. Upregulation of ACADL significantly inhibited HCC migration and invasion ability. Whereas knockdown of ACADL markedly enhanced cell invasive capability. Expression of matrix metalloproteinase-14 (MMP14) was negatively associated with the content of ACADL in HCC specimens. MMP14-positive patients with a low expression of ACADL showed worse outcome. Treatment with MMP14 agonist reversed the inhibitory effect of ACADL on HCC metastasis. In addition, ACADL negatively regulated MMP14 expression by inhibiting the STAT3 signaling pathway, as the sustained activation of STAT3 effectively restored the level of MMP14 in ACADL-overexpressed cells. Collectively, these findings disclose that ACADL represses HCC metastasis via STAT3-MMP14 pathway. This study may propose a promising strategy for the precise treatment of metastatic HCC patients.

Socioeconomic and racial/ethnic disparities in receipt of palliative care among patients with metastatic hepatocellular carcinoma.

Patients with metastatic hepatocellular carcinoma (HCC) suffer symptoms of both end-stage liver disease and cancer. Palliative care (PC) enhances the quality of life via symptom control and even improves survival for some cancers. Our study characterized rates of PC utilization among metastatic HCC patients and determined factors associated with PC receipt. We conducted a retrospective review of adult National Cancer Database patients diagnosed with metastatic HCC between 2004 and 2016. Chi-square tests were used to analyze two cohorts: those who received PC and those who did not. Logistic regression was performed to assess the impact of clinicodemographic factors on the likelihood of receiving PC. PC utilization was low at just 17%. Later yearof diagnosis, insured status, and higher education level were associated with an increased likelihood of receiving PC. Treatment at academic centers or integrated network cancer programs increased the likelihood of receiving PC compared to treatment at a community center (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.03-1.33 and OR = 1.25, 95% CI = 1.07-1.45; respectively). Hispanics were significantly less likely to received PC than non-Hispanic Whites (OR = 0.73, 95% CI = 0.64-0.82). PC utilization among patients with metastatic HCC remains low. Targeted efforts should be enacted to increase the delivery of PC in this group.

Serum MiRNA-23a as a Diagnostic and Prognostic Biomarker of Hepatitis C Related Hepatocellular Carcinoma

Background: Micro-ribonucleic acids (MiRNAs) are small, non-coding RNA molecules which regulate gene expression. Several miRNAs including miR-23a were found to be frequently deregulated in hepatocellular carcinoma (HCC). Objective: This study aimed to evaluate serum miR-23a as a biomarker of hepatitis C related HCC. Methods: This study was conducted on 60 hepatitis C virus (HCV) infected patients (group I: without cirrhosis, group II with cirrhosis and group III with HCV associated HCC) and a control group of 20 healthy volunteers. All patients were submitted to history taking, clinical examination in addition to categorization and staging of HCC patients. Following extraction of RNA from serum samples, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed. Calculation of serum miR-23a was done using the comparative cycle threshold (Ct) method (2–ΔΔCT). Results: Serum miR-23a levels (2-ΔΔCT) were significantly higher in cirrhotic and HCC patients compared to chronic hepatitis C patients (CHC). However, no significant difference was noted between cirrhotic and HCC patients. The sensitivity and specificity of miR-23a levels for discriminating HCC patients from cirrhotic patients were 55% and 65%, respectively. MiR-23a levels had sensitivity of 90% and specificity of 70% for discriminating metastatic from non-metastatic HCC patients. Conclusion: Higher miR-23a levels were detected among metastatic HCC patients than among those without metastasis. The sensitivity and specificity of miR-23a levels for discriminating HCC patients from cirrhotic patients were lower than those of alpha fetoprotein (AFP).

WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3β by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of β-catenin by promoting the function of APC, AXIN1, CK1, and GSK3β complex. Nuclear translocation of p-Stat3 Y705 and β-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/β-catenin signaling, accompanied by the inhibition of MMPs and C-MYC.

LncRNA MORT Overexpression Inhibits Cancer Cell Migration and Invasion in Hepatocellular Carcinoma by Downregulating NOTCH1.

Background: Long noncoding RNA (lncRNA) MORT is silenced in many malignancies, but its role in cancer remains hardly known. Methods: The expression of MORT and NOTCH1 was determined by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Correlation between MORT and NOTCH1 was analyzed by Pearson's correlation analysis. To further investigate the interaction between MORT and NOTCH1, overexpression experiments were performed. Results: In our study, MORT expression was downregulated in hepatocellular carcinoma (HCC), while NOTCH1 expression was upregulated in HCC patients. Hepatitis B virus and hepatitis C virus infection and tumor size did not significantly affect MORT expression, but MORT expression was lower in metastatic HCC patients compared with nonmetastatic HCC patients. MORT and NOTCH1 were inversely correlated across HCC tissues. MORT overexpression decreased NOTCH1 expression, while NOTCH1 overexpression did not significantly affect MORT. MORT overexpression inhibited the migration and invasion of HCC cells, while NOTCH1 overexpression promoted the migration and invasion of HCC cells. In addition, NOTCH1 overexpression attenuated the effects of MORT overexpression on cell migration and invasion. Conclusion: Therefore, MORT overexpression may inhibit HCC by downregulating NOTCH1.

RISK FACTORS ASSOCIATED WITH DELISTING OF HEPATOCELLULAR CARCINOMA PATIENT'S CANDIDATES FOR LIVER TRANSPLANTATION

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with morethan 1 million new cases diagnosed every year. Liver transplantation has been used as a curativetreatment for patients with HCC.Liver transplantation offers the best cure chance for unrespectable hepatocellular carcinoma(HCC), but the scarcity of cadaver liver grafts has seriously limited its role. With the recent advancesin adult living donor liver transplantation (LDLT), there is potentially a drastic change inthe role of liver transplantation. Recent Studies have demonstrated the theoretical survival benefitof LDLT over deceased donor liver transplantation (DDLT) which depends largely on thewaiting time and drop‐out rate. This study was conducted to analyze the different risk factorsleading to delisting in liver transplant patients with hepatocellular carcinoma. Fifty patients presentedto Ain Shams Specialized Hospitals from January 2017 to June 2018, with expected averagehepatocellular carcinoma eligible for Adult Living Donor Liver transplantation (ALDLT) werestudied. They were evaluated according to protocol of Ain Shams Center of Organ Transplantation(ASCOT). Inclusion criteria: 1-hepatocellular carcinoma with any underlying cause ofcirrhosis. HCC is first diagnosed using spiral computed tomography of liver and sometimesMagnetic Resonance Imaging (MRI). 2- Patients within University of California San Francisco(UCSF) criteria (one tumor ≤6·5 cm, three nodules with largest ≤4·5cm, & total tumor diameter≤8 cm). 3- Patients within these criteria underwent loco-regional therapy as bridging therapy includingradiofrequency ablation, radio-embolization, trans-arterial chemoembolization, microwaveablation or liver resection to avoid delisting. 4- Patients beyond these criteria underwentloco-regional treatment as means of down staging to be within Milan or UCSF and candidatesfor ALDLT. Exclusion criteria: 1- metastatic HCC patients, 2- macrovascular invasion, & 3-poor general condition for surgery.

RISK FACTORS ASSOCIATED WITH DELISTING OF HEPATOCELLULAR CARCINOMA PATIENT'S CANDIDATES FOR LIVER TRANSPLANTATION

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide, with morethan 1 million new cases diagnosed every year. Liver transplantation has been used as a curativetreatment for patients with HCC.Liver transplantation offers the best cure chance for unrespectable hepatocellular carcinoma(HCC), but the scarcity of cadaver liver grafts has seriously limited its role. With the recent advancesin adult living donor liver transplantation (LDLT), there is potentially a drastic change inthe role of liver transplantation. Recent Studies have demonstrated the theoretical survival benefitof LDLT over deceased donor liver transplantation (DDLT) which depends largely on thewaiting time and drop‐out rate. This study was conducted to analyze the different risk factorsleading to delisting in liver transplant patients with hepatocellular carcinoma. Fifty patients presentedto Ain Shams Specialized Hospitals from January 2017 to June 2018, with expected averagehepatocellular carcinoma eligible for Adult Living Donor Liver transplantation (ALDLT) werestudied. They were evaluated according to protocol of Ain Shams Center of Organ Transplantation(ASCOT). Inclusion criteria: 1-hepatocellular carcinoma with any underlying cause ofcirrhosis. HCC is first diagnosed using spiral computed tomography of liver and sometimesMagnetic Resonance Imaging (MRI). 2- Patients within University of California San Francisco(UCSF) criteria (one tumor ≤6·5 cm, three nodules with largest ≤4·5cm, & total tumor diameter≤8 cm). 3- Patients within these criteria underwent loco-regional therapy as bridging therapy includingradiofrequency ablation, radio-embolization, trans-arterial chemoembolization, microwaveablation or liver resection to avoid delisting. 4- Patients beyond these criteria underwentloco-regional treatment as means of down staging to be within Milan or UCSF and candidatesfor ALDLT. Exclusion criteria: 1- metastatic HCC patients, 2- macrovascular invasion, & 3-poor general condition for surgery.