HCV-associated Hepatocellular Carcinoma Research Articles

Implementation of Universal Hepatitis C Virus Screening in a Tertiary Cancer Center.

The prevalence of chronic hepatitis C virus (HCV) infection in the United States is ≤1%. Universal HCV screening is recommended nationwide. Here we describe our experience implementing universal HCV screening at a cancer center. In October 2016, universal HCV screening with HCV antibody (anti-HCV) was initiated for all new outpatients. Universal screening was promoted through widespread provider education, orders in the Epic electronic health records (EHRs), SmartSets, and automated EHR reminders. The effort focused on patients with solid tumors, because universal screening in patients with hematologic malignancies was already standard practice. Primary outcomes were the proportion of patients screened and the proportion of patients with reactive anti-HCV test results linked to HCV care. The secondary outcome was the incidence of HCV-associated hepatocellular carcinoma as a second primary malignancy (HCC-SPM) in patients with a history of other cancers before HCC diagnosis. Epic's Reporting Workbench Business Intelligence tools were used. Statistical significance was defined as P<.05 on chi-square analysis. From April 2016 through April 2023, 56,075 patients with solid tumors were screened for HCV, of whom 1,300 (2.3%) had reactive anti-HCV test results. The proportion of patients screened was 10.1% in the 6 months before study implementation and 34.4% in the last 6 months of the study (P<.001). HCV screening was ordered using SmartSets in 39,332 (45.8%) patients and in response to automated EHR reminders in 10,972 (12.8%) patients. Most patients with reactive anti-HCV test results were linked to care (765/1,300; 59%), most with proven HCV infection were treated (425/562; 76%), and most treated patients achieved sustained virologic response (414/425; 97%). The incidence of HCC-SPMs was 15% in historical controls treated from 2011 to 2017 and 5.7% following implementation of universal screening (P=.0002). Universal HCV screening can be successfully implemented in cancer hospitals using an EHR-based multipronged approach to eliminate HCV and prevent HCV-associated HCC-SPMs.

Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity.

Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

Efficacy of combined antiretroviral therapy (cART) in Hepatitis B and C associated hepatocellular carcinoma (HCC): a narrative review

Introduction: HCC is the 3rd leading cancers in the world. Majority of HCC are due to chronic viral hepatitis including HBV, HCV, and HDV. Progression to cirrhosis and HCC in HBV and HCV infection is linked to level of replication and high serum viral DNA load. The use of antiviral agents is an effective strategy of treating HBV- and HCV- associated HCC. Aim: To assess the effectiveness of combined antiretroviral therapy on HBV and HCV-associated HCC Method: A narrative review of literature involving RCT and observational studies was performed. Blinding scores was used to evaluate the quality of the studies. This review was informed by one of the author’s experience with hepatitis virus in Africa. Discussion: The five studies were found to be useful in reducing viral load and improving the pathology of HBV- and HCV- associated cirrhosis, HCC, and decompensated liver disease. The combinations are sofosbuvir plus ledipasvir, declatasvir plus asunaprevir, grazoprevir plus elbasvir with or without ribavirin, ombitasvir, paritaprevir, ritonavir plus ribavirin, sofosbuvir plus ribavirin. However, resistance to either drug or both is a problem that needs to be addressed.

Anti-hepatitis C antibody carriage and risk of liver impairment in rural-Cameroon: adapting the control of hepatocellular carcinoma for resource-limited settings

BackgroundThe Viral hepatitis elimination by 2030 is uncertain in resource-limited settings (RLS), due to high burdens and poor diagnostic coverage. This sounds more challenging for hepatitis C virus (HCV) given that antibody (HCVAb) sero-positivity still lacks wide access to HCV RNA molecular testing. This warrants context-specific strategies for appropriate management of liver impairment in RLS. We herein determine the association between anti-HCV positivity and liver impairment in an African RLS.MethodsA facility-based observational study was conducted from July-August 2021 among individuals attending the “St Monique” Health Center at Ottou, a rural community of Yaounde,Cameroon. Following a consecutive sampling, consenting individuals were tested for anti-HCV antibodies, hepatitis B surface antigen (HBsAg) and HIV antibodies (HIVAb) as per the national guidelines. After excluding positive cases for HBsAg and/or HIVAb, liver function tests (ALT/AST) were performed on eligible participants (HBsAg and HIVAb negative) and outcomes were compared according to HCVAb status; with p < 0.05 considered statistically significant.ResultsOut of 306 eligible participants (negative for HBsAg and HIVAb) enrolled, the mean age was 34.35 ± 3.67 years. 252(82.35%) were female and 129 (42.17%) were single. The overall HCVAb sero-positivity was 15.68%(48/306), with 17.86% (45/252) among women vs. 5.55%(3/54) among men [OR (95%CI) = 3.69(2.11-9.29),p = 0.04]. HCVAb Carriage was greater among participants aged > 50 years compared to younger ones [38.46%(15/39) versus 12.36% (33/267) respectively, OR(95%CI) = 4.43(2.11-9.29), p < 0.000] and in multipartnership [26.67%(12/45)vs.13.79%(36/261) monopartnership, OR (95%CI) = 2.27(1.07-4.80),p = 0.03]. The liver impairment rate (abnormal ALT+AST levels) was 30.39%(93/306), with 40.19%(123/306) of abnormal ALT alone. Moreover, the burden of Liver impairment was significantly with aged> 50 versus younger ones [69.23% (27/39) versus 24.72%(66/267) respectively, p < 0.000). Interestingly, the burden of liver impairment (abnormal AST + ALAT) was significantly higher in HCVAb positive (62.5%, 30/48) versus HCVAb negative (24.42%, 63/258) participants, OR: 3.90 [1.96; 7.79], p = 0.0001.ConclusionsIn this rural health facility, HCVAb is highly endemic and the burden of liver impairment is concerning. Interestingly, HCVAb carriage is associated with abnormal liver levels of enzyme (ALT/AST), especially among the elderly populations. Hence, in the absence of nuclei acid testing, ALT/AST are relevant sentinel markers to screen HCVAb carriers who require monitoring/care for HCV-associated hepatocellular carcinoma in RLS.

Incidence of Hepatocellular Carcinoma in Hepatitis C Patients Treated with Direct-Acting Antivirals and Its Relation to Hepatic Fibrosis Stage

Abstract Introduction Significant advances in understanding of the molecular virology, life cycle, and pathogenesis of Hepatitis C Virus (HCV) led to the Direct-Acting Anti-viral (DAA) era of HCV therapy in 2011 (Hezode et al.,2015). It can be expected that rates of HCV-associated hepatocellular carcinoma (HCC) will decrease significantly after the widespread adoption of DAAs, However Hepatitis C patients with cirrhosis who were treated with direct-acting antivirals had increased likelihood of developing HCC (Tayyab et al., 2020) (Kozbial et al., 2016). HCC was also associated with greater liver stiffness according to transient elastography and lower platelet counts (Conti et al., 2016). The aim of this study is to investigate incidence of HCC in Egyptian HCV patients in whom other predominant HCV genotypes are prevalent and different treatment protocols followed. Methods This was a retrospective study including 400 chronic HCV patients who were following up their medical condition at Kobri El-Koba Military Hospital hepatology outpatient clinic from January 2018 to September 2019. Patients were divided into two main equal groups regarding either received HCV direct acting antivirals or not. Incidence of HCC after 18 months of follow up were compared between two groups. Its relation to hepatic fibrosis stage was calculated in both groups. Results DAA receiving group had significantly lower incidence of HCC than non DAA receiving group (control group). Eleven patients in DAA receiving group developed HCC (5.5%) compared to twenty-two patients in control group (11%) with P- value 0.04. Although there was no significant difference between two groups regarding pre-treatment prevalence of ascites, splenomegaly, or esophageal varices, DAA receiving group had statistically significant advanced hepatic fibrosis when compared to control group. Before starting treatment, DAA Receiving group shows (4.5% F0, 14% F1, 7% F2, 11.5% F3 and 63% F4) versus (20.5% F0, 14% F1, 18.5% F2, 6.5% F3 and 40.5% F4) in control group with highly significant P value 0.00. Conclusion Incidence of HCC decreased significantly after DAA in chronic HCV patients. Decreased incidence occurred despite advanced hepatic fibrosis in this group of patients.

Trends in long-term outcomes of patients with HCV-associated hepatocellular carcinoma after hepatectomy: A comparison before and after introduction of direct-acting antivirus therapy.

The success of direct-acting antiviral (DAA) therapy provides a cure for patients chronically infected with hepatitis C virus (HCV); however, outcomes after hepatectomy for HCV-associated hepatocellular carcinoma (HCC) before and after DAA introduction remain poorly studied. Patients who underwent R0/R1 hepatectomy for HCV-associated HCC were retrospectively analyzed. Two time periods were defined: Pre-DAA (2007-2011, December 2013 was defined as the end of follow-up) and Post-DAA groups (2014-2018, December 2020 was defined as the end of follow-up). Propensity score matching (PSM) analyses were performed to highlight the effect of DAA therapy. A total of 155 patients with HCV-associated HCC were included in this study (Pre-DAA group, n = 103 and post-DAA group, n = 52). In the Post-DAA group, DAA therapy was performed in 26 patients (50.0%), and all of these patients achieved sustained virologic response (SVR) (preoperative SVR, n = 7; postoperative SVR, n = 19). There was no significant difference between the two groups regarding surgical settings and tumor pathology. There was no significant difference in the 5-year overall survival (OS) rate (61.1% and 64.8%, pre- and post-DAA group, respectively, p = 0.441); meanwhile, the 5-year recurrence-free survival (RFS) rate in the post-DAA group was better than the pre-DAA group (21.1% and 40.2%, p = 0.073) with a trend toward significance. After PSM except for the postoperative SVR status, there were no significant differences in OS (p = 0.586) and RFS (p = 0.888). This study showed that survival outcomes were not changed in hepatectomized cases of HCV-associated HCC before and after the introduction of DAA therapy.

Innovative model of surface-enhanced Raman spectroscopy for exosomes identification: An approach for the diagnosis of hepatocellular carcinoma

BackgroundThe current hepatocellular carcinoma (HCC) diagnostic approaches lack adequate sensitivity and specificity. So, this study was performed to develop an innovative model of surface-enhanced Raman spectroscopy (SERS) that can detect HCC patients by identifying the circulating tumor-derived exosomes. MethodologySixty participants, including normal controls, hepatitis C virus (HCV)-infected patients, and HCV-associated HCC patients, had their whole blood samples and exosomes separated from these samples analyzed using Raman spectroscopy (RS). A revolutionary model of SERS, based on an innovative glass and nano-gold, was designed to directly identify exosomes. Its measurements were simulated by Comsol Multiphysics (5.6). ResultsThe RS examination of the whole blood samples revealed no Raman peaks. Yet, the isolated exosomes from these samples generated Raman peaks at 400 and 1000 cm−1 wavenumbers in the HCV group. A Raman shift was detected in HCC patients at 812, 852, and 878 cm−1 wavenumbers with intensity ratios of 120, 130, and 60, respectively. The RS had a sensitivity and specificity of 95 % and 100 %, respectively, for detecting HCC. However, the newly-designed SERS was able to identify the HCC-derived exosomes, at 812 and 878 cm−1 wavenumbers, with boosted intensity ratios of 9*106 and 4*106, respectively, in the whole blood samples. ConclusionThe newly-developed SERS model has the potential to detect HCC patients through recognizing the tumor-derived exosomes non-invasively, with high accuracy, and without the need for laborious exosomal separation. Nonetheless, bringing this technology into the clinic demands the establishment of spectral databases and their validation using the current gold standards.

High-Resolution Genomic Profiling of Liver Cancer Links Etiology With Mutation and Epigenetic Signatures

Hepatocellular carcinoma (HCC) is a model of a diverse spectrum of cancers because it is induced by well-known etiologies, mainly hepatitis C virus (HCV) and hepatitis B virus. Here, we aimed to identify HCV-specific mutational signatures and explored the link between the HCV-related regional variation in mutations rates and HCV-induced alterations in genome-wide chromatin organization. To identify an HCV-specific mutational signature in HCC, we performed high-resolution targeted sequencing to detect passenger mutations on 64 HCC samples from 3 etiology groups: hepatitis B virus, HCV, or other. To explore the link between the genomic signature and genome-wide chromatin organization we performed chromatin immunoprecipitation sequencing for the transcriptionally permissive H3K4Me3, H3K9Ac, and suppressive H3K9Me3 modifications after HCV infection. Regional variation in mutation rate analysis showed significant etiology-dependent regional mutation rates in 12 genes: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4, and ARSD. We found an enrichment of C->T transversion mutations in the HCV-associated HCC cases. Furthermore, these cases showed regional variation in mutation rates associated with genomic intervals in which HCV infection dictated epigenetic alterations. This signature may be related to the HCV-induced decreased expression of genes encoding key enzymes in the base excision repair pathway. We identified novel distinct HCV etiology-dependent mutation signatures in HCC associated with HCV-induced alterations in histone modification. This study presents a link between cancer-causing mutagenesis and the increased predisposition to liver cancer in chronic HCV-infected individuals, and unveils novel etiology-specific mechanisms leading to HCC and cancer in general.

Down-regulation of hepatic expression of GHR/STAT5/IGF-1 signaling pathway fosters development and aggressiveness of HCV-related hepatocellular carcinoma: Crosstalk with Snail-1 and type 2 transforming growth factor-beta receptor.

So far, few clinical trials are available concerning the role of growth hormone receptor (GHR)/signal transducer and activator of transcription 5 (STAT5)/insulin like growth factor-1 (IGF-1) axis in hepatocarcinogenesis. The aim of this study was to evaluate the hepatic expression of GHR/STAT5/IGF-1 signaling pathway in hepatocellular carcinoma (HCC) patients and to correlate the results with the clinico-pathological features and disease outcome. The interaction between this signaling pathway and some inducers of epithelial-mesenchymal transition (EMT), namely Snail-1 and type 2 transforming growth factor-beta receptor (TGFBR2) was studied too. A total of 40 patients with HCV-associated HCC were included in this study. They were compared to 40 patients with HCV-related cirrhosis without HCC, and 20 healthy controls. The hepatic expression of GHR, STAT5, IGF-1, Snail-1 and TGFBR2 proteins were assessed by immunohistochemistry. Compared with cirrhotic patients without HCC and healthy controls, cirrhotic patients with HCC had significantly lower hepatic expression of GHR, STAT5, and IGF-1proteins. They also displayed significantly lower hepatic expression of TGFBR2, but higher expression of Snail-1 versus the non-HCC cirrhotic patients and controls. Serum levels of alpha-fetoprotein (AFP) showed significant negative correlations with hepatic expression of GHR (r = -0.31; p = 0.029) and STAT5 (r = -0.29; p = 0.04). Hepatic expression of Snail-1 also showed negative correlations with GHR, STAT5, and IGF-1 expression (r = -0.55, p = 0.02; r = -0.472, p = 0.035, and r = -0.51, p = 0.009, respectively), whereas, hepatic expression of TGFBR2 was correlated positively with the expression of all these proteins (r = 0.47, p = 0.034; 0.49, p = 0.023, and r = 0.57, p&lt;0.001, respectively). Moreover, we reported that decreased expression of GHR was significantly associated with serum AFP level&gt;100 ng/ml (p = 0.048), increased tumor size (p = 0.02), vascular invasion (p = 0.002), and advanced pathological stage (p = 0.01). Similar significant associations were found between down-regulation of STAT5 expression and AFP level &gt; 100 ng/ml (p = 0.006), vascular invasion (p = 0.009), and advanced tumor stage (p = 0.007). Also, attenuated expression of IGF-1 showed a significant association with vascular invasion (p &lt; 0.001). Intriguingly, we detected that lower expression of GHR, STAT5 and IGF-1 were considered independent predictors for worse outcome in HCC. Decreased expression of GHR/STAT5/IGF-1 signaling pathway may have a role in development, aggressiveness, and worse outcome of HCV-associated HCC irrespective of the liver functional status. Snail-1 and TGFBR2 as inducers of EMT may be key players. However, large prospective multicenter studies are needed to validate these results.

Contribution of DNA methylation to the risk of hepatitis C virus-associated hepatocellular carcinoma: A meta-analysis.

DNA methylation is a crucial epigenetic modification in hepatocellular carcinoma (HCC), and hepatitis C virus (HCV) can induce hepatocarcinogenesis. Nevertheless, the interaction mechanism between DNA methylation and HCV infection in HCC is still ambiguous. In this study, we performed a comprehensive meta-analysis to assess the contribution of DNA methylation in HCV-associated HCC. After four steps of literature screening, we finally obtained 33 qualified case-control studies for this meta-analysis. These studies consisted of 587 HCV-positive cancer tissues and 326 HCV-negative cancer tissues. Our results revealed that four genes (p16, GSTP1, APC, and RUNX3) were more hypermethylated in the HCV-positive liver cancer tissues than in the HCV-negative liver cancer tissues. In addition, the p16 gene was more hypermethylated in the HCV-positive paracancerous tissues than in the HCV-negative paracancerous tissues. Subgroup meta-analysis by geographical populations showed that p16 methylation was significantly higher in HCV-positive cancerous tissues from Japanese and Chinese. Besides, p16 methylation was significantly higher among patients (>60 years) but not among the others (≤60 years). However, there was no obvious association between DNA methylation and other clinicopathological characteristics, including gender, tumor size, differentiation, and clinical stage. Our study suggested that DNA methylation could become potential biomarkers for HCV-associated HCC. DNA methylation contributed to the risk of HCV-associated HCC.

Identification of prognostic miRNA-mRNA regulatory network in the progression of HCV-associated cirrhosis to hepatocellular carcinoma.

Long-term hepatitis C virus (HCV) infection is strongly associated with hepatocellular carcinoma (HCC), yet the mechanisms of the progression process remain unclear. The research is aiming to establish a crucial prognostic model that indicates the risk of HCV-associated cirrhosis evolving into HCC. Differentially expressed microRNAs (DE-miRNAs) and differentially expressed genes (DEGs) between HCV-associated cirrhosis and HCC were screened from the GSE40744 and GSE6764 datasets, respectively. Downstream target genes of DE-miRNAs were predicted by the miRNet tool and then overlapped with the DEGs to select intersection genes. The GSE15654 was downloaded to establish a prognostic model. Expression levels of risk genes and their corresponding miRNAs were measured in liver tissues of clinical patients. HCC cell lines with UHRF1 knockdown or overexpression were assayed for cell proliferation and migration. Thirty-nine DE-miRNAs and 796 DEGs are identified between HCV-associated cirrhosis and HCC. Main intersection genes and their corresponding miRNAs constitute a miRNA-mRNA regulatory network. PABPC1 (Polyadenylate-binding protein 1), SLC2A9 (solute carrier gene family 2, member 9), and UHRF1 (ubiquitin-like with PHD and ring finger domains 1) form a prognostic model indicating the risk of HCC development among HCV-associated cirrhosis. The genetic mutations of PABPC1, SLC2A9, and UHRF1 in HCC patients are 9%, 0.8%, and 0.6%, respectively. Compared to that in HCV-associated cirrhosis, the expression levels of PABPC1 and UHRF1 are higher while the expression level of SLC2A9 is lower in clinical HCV-associated HCC samples. UHRF1 enhances the proliferation and migration ability of HCC cells. PABPC1, SLC2A9, and UHRF1 and their corresponding miRNAs are involved in the evolution process of HCV-associated cirrhosis into malignant HCC. UHRF1 serves as an oncogene that promotes the proliferation and migration of HCC cells.

S1195 Assessment of TLL1 Variant and Risk of Hepatocellular Carcinoma in Latin Americans

Introduction: Hepatocellular carcinoma (HCC) is an important global health problem accounting for 800,000 deaths per year. Recently, assessment of host genetics by identification of single nucleotide polymorphisms (SNPs) has shown to play a crucial role in identifying those at risk for HCC. Tolloid like protein 1 (TLL1) is one such SNP found on chromosome 4 which has been mainly shown to increase risk in hepatitis C virus (HCV)-associated HCC. However, most studies addressing its risk-association have been performed in Asian populations. Methods: This was a cross-sectional analysis performed in Latin American individuals through the ESCALON network (www.escalon.eu). We analyzed DNA from 120 HCC patients and 293 cirrhotic controls from Argentina, Chile, Brazil, Colombia, Ecuador, and Peru for the variant rs1704200 in TLL1. The pathogenic variant of TLL1 was genotyped using TaqMan-genotyping assay. Multiple logistic regression was used to evaluate the association between TLL1 and HCC. Results: The median age for HCC in Latin Americans was 68 years (IQR 62-72) with 59% being males. The most common cause of HCC was non-alcoholic fatty liver disease (59%) followed by alcohol-use related liver disease (27%). The proportions of individuals who developed HCC with a TLL1 pathogenic variant (AT/TT) was 18% and 26% for cirrhotics without HCC. The calculated Odds-Ratio (OR) for HCC among Latin Americans with the TLL1 variant was 0.699 (CI 0.379-1.291), suggesting non-significant decreased odds for HCC. When examining HCV-associated HCC (11%) we found that the OR for HCV-associated HCC in Latin Americans was 2.07 (CI 0.934-4.586), suggesting a non-significant increased odds of being diagnosed with HCC in Latin Americans with the variant. Conclusion: TLL1 mutations do not seem to associate with HCC development in Latin Americans considering all cause of HCC. Preliminary results suggest that there could be an increased risk for HCC in Latin Americans with HCV infection. Our results do not express a significant value as the cohort is limited in size. Currently, a larger study is ongoing.

HCV and tumor-initiating stem-like cells.

Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.

Diagnostic Performance of AFP, AFP-L3, or PIVKA-II for Hepatitis C Virus-Associated Hepatocellular Carcinoma: A Multicenter Analysis.

Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.

Improving Liver Transplant Outcomes for Hepatitis C Virus Hepatocellular Carcinoma in the Direct-Acting Antiviral Therapy Era

Direct-acting antiviral (DAA) therapy has transformed the outcomes of liver transplant (LT) with hepatitis C virus (HCV). This study aimed to analyze the effects of DAA treatment for HCV-associated hepatocellular carcinoma (HCC) in LT. We included patients confirmed with HCC on explant, analyzed data from United Network for Organ Sharing, and defined the pre-DAA era (2012-2013) and DAA era (2014-2016). HCV-associated HCC cases totaled 4778 (62%) during the study period. In the DAA era, the median recipient age was older and the median days on the waiting list were longer. For the donor, median age, body mass index, and the rate of HCV significantly increased in the DAA era. In pathology, the median largest tumor size was significantly higher; however, the rate of completed tumor necrosis was significant higher in the DAA era. The 3-year graft/patient survival had significantly improved in the DAA era. In multivariable analysis, the DAA era (hazard ratio, 0.79; 95% confidence interval, 0.68-0.91) had significantly affected the 3-year graft survival. DAA has a significant beneficial effect on LT. In the DAA era, graft survival for HCV-associated HCC has been significantly improving.

Significance of MicroRNA-200a and Long Noncoding RNA-HULC Expression in HCV-Associated Hepatocellular Carcinoma

Significance of MicroRNA-200a and Long Noncoding RNA-HULC Expression in HCV-Associated Hepatocellular Carcinoma

Prognostic MicroRNA Panel for HCV-Associated HCC: Integrating Computational Biology and Clinical Validation.

Simple SummaryHepatocellular carcinoma (HCC) is a disease of poor prognosis. The early diagnosis of HCC will restrain the disease progression and thus improve patients’ quality of life. We aimed in this study to define a panel of microRNAs (miRNAs) that could facilitate the early prognosis of HCC focal lesions in the cirrhotic livers of patients previously infected with hepatitis C virus (HCV). A minimally invasive technique was used to measure the differential expression of isolated miRNAs from the serum of 201 HCV infected and HCV-HCC patients. We suggest that a panel of five serum miRNAs (miR-150, miR-199a, miR-224, miR-424, and miR-3607) might provide a potentially promising tool in the prognosis of HCC disease in cirrhotic HCV patients.Early detection of hepatocellular carcinoma (HCC) will reduce morbidity and mortality rates of this widely spread disease. Dysregulation in microRNA (miRNA) expression is associated with HCC progression. The objective is to identify a panel of differentially expressed miRNAs (DE-miRNAs) to enhance HCC early prediction in hepatitis C virus (HCV) infected patients. Candidate miRNAs were selected using a bioinformatic analysis of microarray and RNA-sequencing datasets, resulting in nine DE-miRNAs (miR-142, miR-150, miR-183, miR-199a, miR-215, miR-217, miR-224, miR-424, and miR-3607). Their expressions were validated in the serum of 44 healthy individuals, 62 non-cirrhotic HCV patients, 67 cirrhotic-HCV, and 72 HCV-associated-HCC patients using real-time PCR (qPCR). There was a significant increase in serum concentrations of the nine-candidate miRNAs in HCC and HCV patients relative to healthy individuals. MiR-424, miR-199a, miR-142, and miR-224 expressions were significantly altered in HCC compared to non-cirrhotic patients. A panel of five miRNAs improved sensitivity and specificity of HCC detection to 100% and 95.12% relative to healthy controls. Distinguishing HCC from HCV-treated patients was achieved by 70.8% sensitivity and 61.9% specificity using the combined panel, compared to alpha-fetoprotein (51.4% sensitivity and 60.67% specificity). These preliminary data show that the novel miRNAs panel (miR-150, miR-199a, miR-224, miR-424, and miR-3607) could serve as a potential non-invasive biomarker for HCC early prediction in chronic HCV patients. Further prospective studies on a larger cohort of patients should be conducted to assess the potential prognostic ability of the miRNAs panel.

DETECT: Development of Technologies for Early HCC Detection

DETECT: Development of Technologies for Early HCC Detection

Epithelial-Mesenchymal Transition Markers in HCVAssociated Hepatocellular Carcinoma: A Multivariate Follow Up Study.

Objective:Validated markers to predict recurrence after surgical resection of hepatocellular carcinoma (HCC) are needed. Little data is available regarding epithelial-mesenchymal transition (EMT) markers in HCC. The objective of this study was to investigate the expression of EMT markers and their correlation with clinicopathological variables and survival in hepatitis C virus (HCV)-associated HCC. Methods:This longitudinal study included 109 cases of HCV-associated HCC treated with surgical resection. Nine different EMT markers (vimentin, E-cadherin, N-cadherin, Stat3, Snail1, Slug, Twist1, Zeb1 and integrin α5) were evaluated on liver tissue from HCC cases. Twenty fresh HCC samples from the studied cases were used for gene expression of EMT markers by quantitative real time polymerase chain reaction (PCR). Results:EMT markers expression was 71%, 25%, 26%, 27%, 9%, 4%, 72%, 47%, 87% for vimentin, E-cadherin, N-cadherin, Stat3 snail1, slug, twist1, Zeb1 and integrin α5 respectively. EMT mRNA in HCC tissues correlated with protein expression by 50-70%. Vimentin was independent predictor of large tumor size (P=0.001), high risk of recurrence (HRR) (P=0.006) and shorter disease free survival (P=0.03) in multivariate analysis. Reduced E-cadherin was a predictor of HRR (P=0.002). Conclusion:Vimentin and E-cadherin were the most powerful prognostic EMT markers in HCV-associated HCC in prediction of recurrence.

Treatment Disparities among Mental Health Patients with Hepatitis C-Associated Hepatocellular Carcinoma: An US Safety Net Collaborative (USSNC) Analysis

Introduction: Hepatocellular carcinoma (HCC) is most commonly caused by hepatitis C(HCV)-induced cirrhosis in the United States. Among patients with HCV-associated HCC, HCV treatment is associated with improved survival. Patients with mental health disorders face disparate access to HCV treatment. We sought to evaluate whether mental health impacted HCV treatment at academic and safety net hospitals (SNH) using the US Safety Net Collaborative (USSNC) database.