HCV-related Hepatocellular Carcinoma Research Articles

Identification of the possible therapeutic targets in the insulin-like growth factor 1 receptor pathway in a cohort of Egyptian hepatocellular carcinoma complicating chronic hepatitis C type 4.

Molecular targeted drugs are the first line of treatment of advanced hepatocellular carcinoma (HCC) due to its chemo- and radioresistant nature. HCC has several well-documented etiologic factors that drive hepatocarcinogenesis through different molecular pathways. Currently, hepatitis C virus (HCV) is a leading cause of HCC. Therefore, we included a unified cohort of HCV genotype 4-related HCCs to study the expression levels of genes involved in the insulin-like growth factor 1 receptor (IGF1R) pathway, which is known to be involved in all aspects of cancer growth and progression. Determine the gene expression patterns of IGF1R pathway genes in a cohort of Egyptian HCV-related HCCs. Correlate them with different patient/tumor characteristics. Determine the activity status of involved pathways. Total ribonucleic acid (RNA) was extracted from 32 formalin-fixed paraffin-embedded tissues of human HCV-related HCCs and 6 healthy liver donors as controls. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) using RT2 Profiler PCR Array for Human Insulin Signaling Pathway was done to determine significantly up- and downregulated genes with identification of most frequently coregulated genes, followed by correlation of gene expression with different patient/tumor characteristics. Finally, canonical pathway analysis was performed using the Ingenuity Pathway Analysis software. Six genes - AEBP1, AKT2, C-FOS, PIK3R1, PRKCI, SHC1 - were significantly overexpressed. Thirteen genes- ADRB3, CEBPA, DUSP14, ERCC1, FRS3, IGF2, INS, IRS1, JUN, MTOR, PIK3R2, PPP1CA, RPS6KA1- were significantly underexpressed. Several differentially expressed genes were related to different tumor/patient characteristics. Nitric oxide and reactive oxygen species production pathway was significantly activated in the present cohort, while the growth hormone signaling pathway was inactive. The gene expression patterns identified in this study may serve as possible therapeutic targets in HCV-related HCCs. The most frequently coregulated genes may serve to guide combined molecular targeted therapies. The IGF1R pathway showed evidence of inactivity in the present cohort of HCV-related HCCs, so targeting this pathway in therapy may not be effective.

Clinical relevance of increased serum preneoplastic antigen in hepatitis C-related hepatocellular carcinoma.

BACKGROUNDThe prognosis of hepatocellular carcinoma (HCC) patients remains poor despite advances in treatment modalities and diagnosis. It is important to identify useful markers for the early detection of HCC in patients. Preneoplastic antigen (PNA), originally reported in a rat carcinogenesis model, is increased in the tissues and serum of HCC patients.AIMTo determine the diagnostic value of PNA for discriminating HCC and to characterize PNA-positive HCC.METHODSPatients with hepatitis C virus (HCV)-related hepatic disorders were prospectively enrolled in this study, which included patients with hepatitis, with cirrhosis, and with HCC. A novel enzyme-linked immunosorbent assay was developed to measure serum PNA concentrations in patients.RESULTSSerum PNA concentrations were measured in 89 controls and 141 patients with HCV infections (50 hepatitis, 44 cirrhosis, and 47 HCC). Compared with control and non-HCC patients, PNA was increased in HCC. On receiver operating characteristic curve analysis, the sensitivity of PNA was similar to the HCC markers des-γ-carboxy-prothrombin (DCP) and α-fetoprotein (AFP), but the specificity of PNA was lower. There was no correlation between PNA and AFP and a significant but weak correlation between PNA and DCP in HCC patients. Importantly, the correlations with biochemical markers were completely different for PNA, AFP, and DCP; glutamyl transpeptidase was highly correlated with PNA, but not with AFP or DCP, and was significantly higher in PNA-high patients than in PNA-low patients with HCV-related HCC.CONCLUSIONPNA may have the potential to diagnose a novel type of HCC in which glutamyl transpeptidase is positively expressed but AFP or DCP is weakly or negatively expressed.

LncRNAs in HCV Infection and HCV-Related Liver Disease.

Long non-coding RNAs (lncRNAs) are transcripts with poor coding capacity that may interact with proteins, DNA, or other RNAs to perform structural and regulatory functions. The lncRNA transcriptome changes significantly in most diseases, including cancer and viral infections. In this review, we summarize the functional implications of lncRNA-deregulation after infection with hepatitis C virus (HCV). HCV leads to chronic infection in many patients that may progress to liver cirrhosis and hepatocellular carcinoma (HCC). Most lncRNAs deregulated in infected cells that have been described function to potentiate or block the antiviral response and, therefore, they have a great impact on HCV viral replication. In addition, several lncRNAs upregulated by the infection contribute to viral release. Finally, many lncRNAs have been described as deregulated in HCV-related HCC that function to enhance cell survival, proliferation, and tumor progression by different mechanisms. Interestingly, some HCV-related HCC lncRNAs can be detected in bodily fluids, and there is great hope that they could be used as biomarkers to predict cancer initiation, progression, tumor burden, response to treatment, resistance to therapy, or tumor recurrence. Finally, there is high confidence that lncRNAs could also be used to improve the suboptimal long-term outcomes of current HCC treatment options.

Differential expression of Tim-3, PD-1, and CCR5 on peripheral T and B lymphocytes in hepatitis C virus-related hepatocellular carcinoma and their impact on treatment outcomes.

Activation of the immune checkpoints and expression of chemokines and chemokine receptors have been reported to promote HCC progression. This study aimed to assess the differential expression of Tim-3, PD-1, and CCR5 on peripheral blood lymphocytes from patients with HCV-related HCC and correlate their expression with the treatment outcomes. The study incorporated 40 patients with chronic HCV-related HCC and 40 healthy controls. Patients were radiologically assessed for hepatic focal lesions and portal vein thrombosis. Response to HCC treatment and overall survival (OS) outcomes were determined. The expression of Tim-3, PD-1, and CCR5 among CD19+, CD4+, and CD8+ lymphocytes was assessed by flow cytometry. Higher frequencies of CD4+ and CD8+ cells expressing each of Tim-3 and PD-1 and PD-1+CD19+ cells were observed in the HCV-related HCC patients in comparison with controls. The highest expression of Tim-3 and PD-1 was by the CD8+ cells. Strong relations were detected among PD-1+CD19+, PD-1+CD4+ and PD-1+CD8+ cells. Elevated levels of PD-1+ lymphocytes were significantly associated with poor treatment response and shorter OS. Modulation of the expression of immune checkpoints as Tim-3 and PD-1, and of CCR5 on T cells is somehow related to HCC. CD8+ T cells expressing PD-1 were the most relevant to HCC prognosis (OS and treatment response) and could represent a promising target for immune therapy against HCC. Future studies need to focus on exploring PD-1+ B cells and Tim-3+CD4+ cells, which seem to play a significant role in the pathogenesis of HCC.

The Beginning of Ending Hepatitis C Virus: A Summary of the 26th International Symposium on Hepatitis C Virus and Related Viruses.

Hepatitis C virus (HCV) infects ~71 million people worldwide, and 399,000 people die annually due to HCV-related liver cirrhosis and hepatocellular carcinoma. The use of direct-acting antivirals results in a sustained virologic response in >95% of patients with chronic HCV infection. However, several issues remain to be solved to eradicate HCV. At the 26th International Symposium on Hepatitis C Virus and Related Viruses (HCV2019) held in Seoul, South Korea, October 5–8, 2019, virologists, immunologists, and clinical scientists discussed these remaining issues and how we can achieve the elimination of HCV.

The association between etiology of hepatocellular carcinoma and race-ethnicity in Florida.

The incidence of hepatocellular carcinoma (HCC) has risen considerably in the US since 1980. The main causes include metabolic disorders (NAFLD, diabetes, obesity, metabolic syndrome), alcohol-related disease (ALD) and hepatitis C and B virus infections (HCV, HBV). Etiology-specific HCC incidence rates by detailed race-ethnicity are needed to improve HCC control and prevention efforts. All HCC cases diagnosed in Florida during 2014-2015 were linked to statewide hospital discharge data to determine etiology. Age-specific and age-adjusted rates were used to assessthe intersection between etiology and detailed racial-ethnicities, including White, African American, Afro-Caribbean, Asian, Cuban, Puerto Rican and Continental Hispanic (Mexican, South and Central American). Of 3666 HCC cases, 2594 matched with discharge data. HCV was the leading cause of HCC among men and women (50% and 43% respectively), followed by metabolic disorders (25% and 37%) and ALD (16% and 9%). Puerto Rican and African American men had the highest HCV-HCC rates, 7.9 and 6.3 per 100000 respectively. Age-specific rates for HCV-HCC peaked among baby boomers (those born in 1945-1965). Metabolic-HCC rates were highest among populations above age 70 and among Continental Hispanics. Afro-Caribbean men had high rates of HBV-HCC, whereas Puerto Rican men had high ALD-HCC. HCC etiology is associated with specific race/ethnicity. While HCV-related HCC rates are projected to decrease soon, HCC will continue to affect Hispanics disproportionately, based on higher rates of metabolic-HCC (and ALD-HCC) among Continental Hispanics, who demographically represent 80% of all US Hispanics. Multifaceted approaches for HCC control and prevention are needed.

Neutrophil Lymphocyte Ratio and Platelet Lymphocyte Ratio as Diagnostic and Prognostic Markers for Hepatitis C Virus – Related Hepatocellular Carcinoma in Egyptian Patients

Abstract Background hepatocellular carcinoma (HCC), a highly prevalent and lethal cancer, it is the sixth most common cancer and the third leading cause of cancer-related death worldwide. Aim of the work to evaluate the role of inflammatory markers Neutrophil lymphocyte ratio and Platelet lymphocyte ratio (NLR & PLR) as biomarkers for diagnosis of HCV related HCC. Patients and Methods this study was conducted in tropical medicine department, HCC clinic Ain-shams university hospitals. Our study included 174 candidates who were divided into three groups. Group A included 60 Patients with HCV-related HCC diagnosed according to American Association for the Study of Liver Diseases (AASLD) guidelines; HCC patients were subdivided into three subgroups According to BCLC Results group A included 114 Patients with HCV-related HCC, which was subdivided into three subgroups according to BCLC. Group 1 included 30 patients underwent Radio-frequency ablation (RF), 76.67% of them were males while 23.33% were females with mean age 57.433. Group 2 included 41 patients underwent Trans-arterial chemo-embolization (TACE), 80.49% were males while 19.51% were females with mean age 60.268. Group 3 included 43 Patients with BCLC stage C and D For best supportive care, 76.74% were males while 23.26% were females with mean age 60.372. Male to female ratio in HCC patients was 3.56:1. Conclusion AFP remains the gold standard marker for diagnosis of HCC. NLR and PLR has no role as early prognostic markers for HCC.

Therapy with DAA increases post-OLT survival but not the risk of recurrence in patients undergoing liver transplantation for HCV-related HCC

Introduction: The role of direct acting antivirals (DAAs) for hepatitis C virus (HCV) in hepatocellular carcinoma (HCC) recurrence is a source of great debate. Current evidence is unable to determine whether DAAs increases or decreases risk of recurrence. However, it has not been investigated the role of DAAs in patients undergoing orthotopic liver transplantation (OLT) for HCC. As a post-OLT recurrence is a deadly event, we compared the risk of recurrence and the overall survival (OS) of patients treated with DAA and obtaining SVR before OLT with an historical cohort of patients transplanted for HCC before the arrival of DAAs.

Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma.

Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.

Serum soluble Toll-like receptor 4 and the risk of hepatocellular carcinoma in hepatitis C virus patients.

IntroductionSoluble Toll-like receptor 4 (sTLR4) is a negative regulator of TLR4 signalling that has been reported in different diseases. In this study, we aimed to assess the serum levels of sTLR4 in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) and to investigate the correlation of sTLR4 with clinicopathological and biochemical parameters among HCV-related HCC patients and hepatitis C without HCC patients.Material and methodsFifty patients with HCV-related HCC, 50 patients with hepatitis C without HCC and 50 healthy control volunteers were enrolled. Clinicopathological and biochemical parameters were examined in all patients. Serum levels of sTLR4 were measured using enzyme-linked immunosorbent assay.ResultsA significant increase in serum sTLR4 was detected in patients with HCV-related HCC (4436.1 ±7089.8) (pg/ml) ± compared to the level in patients with hepatitis C without HCC (1561.4 ±532.0) (pg/ml) (p = 0.002) and the level in the control group (1170.38 ±159.42) (pg/ml) (p < 0.001). Serum sTLR4 was positively correlated with serum AST activity, serum direct bilirubin levels, serum alpha fetoprotein levels, tumour stages of HCC according to the Barcelona Clinic Liver Cancer staging system (BCLC), and the severity of liver cirrhosis according to the Child-Pugh classification among the patients with HCV-related HCC. The combination of serum alpha fetoprotein and serum sTLR4 increased the sensitivity of HCC detection to 76% and the specificity to 94%.ConclusionsSerum sTLR4 may be a marker for HCC susceptibility among HCV-infected patients.

Clinical utility of serum chromogranin A as a marker of hepatocellular carcinoma in chronic hepatitis patients

<br><b>Background</b><br>Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third most common cause of cancer deaths accounting for about 745 000 deaths per year globally. HCC is often diagnosed at an advanced stage where effective therapies are lacking.<br><b>Aim</b><br>Is to investigate the role of serum chromogranin A (CgA) as a marker for detection of HCC in patients with HCC complicating chronic hepatitis and correlate its serum levels with alpha fetoprotein (AFP).<br>This study was conducted on 90 HCC patients (group I), 30 patients with hepatic cirrhosis (group II), and 30 age-matched and sex-matched healthy-controls (group III). Group I was further subdivided into group Ia (30 patients) with HCC complicating chronic hepatitis B, and group Ib (60 patients) with HCC complicating chronic hepatitis C. All participants included in the study were subjected to full history taking and clinical examination, laboratory investigations, including complete blood count, liver-function tests, renal-function tests, and viral markers. Serum AFP and serum CgA levels were also determined.<br><b>Results</b><br>Our results revealed that there was a highly significant elevation (<i>P</i> < 0.01) in the median serum CgA in hepatitis-B virus -related HCC (200 ng/ml) and hepatitis-C virus-related HCC (190 ng/ml) when compared with the control group (30 ng/ml) and when compared with cirrhotic group (60 ng/ml) with no significant difference between the median serum CgA in hepatitis-B virus -related HCC and hepatitis-C virus-related HCC (<i>P</i> > 0.05). A highly significant positive correlation between chromogranin and AFP (<i>P</i> < 0.01) was found in HCC patients. On the other hand, no significant correlations were found between chromogranin and complete blood count, kidney functions, and liver-function tests in patient groups. Diagnostic reliability testing revealed that for CgA, the best cutoff for discriminating HCC patients was 100 ng/ml at which the sensitivity was 77.78%, the specificity 93.3% with positive predictive value 94.59% and negative predictive value 73.68%. Regarding the combination between CgA and AFP, it showed a sensitivity of 97.78% and a specificity of 86.67%.<br><b>Conclusion</b><br>Serum CgA is a promising sensitive and specific tumor marker for identification of HCC. Addition of serum CgA to the current standard tests will improve the sensitivity and accuracy of diagnosis of HCC patients and thus could allow them to benefit from earlier treatment.<br>

Metavir Fibrosis Stage in Hepatitis C–Related Hepatocellular Carcinoma and Association with Noninvasive Liver Reserve Models

BackgroundHepatitis C virus (HCV) infection is the major etiology for cirrhosis and hepatocellular carcinoma (HCC). The severity of liver fibrosis is a crucial factor in prognostic prediction. We aimed to evaluate the prognostic role of Metavir fibrosis stage in HCV-related HCC and its association with noninvasive liver reserve models. MethodsBetween 2004 and 2016, 172 patients with HCV-related HCC undergoing surgical resection were enrolled. Multivariate Cox proportional hazards model was used to identify prognostic predictors. The area under receiver operating curve (AUROC) was used for comparison in predicting cirrhosis among different noninvasive liver reserve models. ResultsIn the multivariate Cox analysis, AST > 45 IU/mL, multiple tumors, tumor size greater than 3 cm, and serum AFP > 20 ng/mL were independent risk factors linked with tumor recurrence. There was no significant association between Metavir fibrosis stage/ inflammatory activity and tumor recurrence. In the Cox model, Child-Turcotte-Pugh class B, tumor size greater than 3 cm, and Metavir fibrosis stage F3-F4 were independent predictors associated with decreased survival (all p < 0.001). In subgroup analysis, survival differences were consistently observed between patients with fibrosis stage F0–F2 and F3–F4 (p < 0.05) in either small (≤ 3 cm) or large (> 3 cm) HCC group. Among the noninvasive models, FIB-4 had the highest predictive accuracy (AUROC = 0.768, p < 0.001) to indicate cirrhosis compared to other models. ConclusionsMetavir fibrosis stage can predict survival in HCV-related HCC patients independent of tumor size. FIB-4 is the best noninvasive model to predict cirrhosis in these patients.

The clinical significance of serum miRNA-224 expression in hepatocellular carcinoma.

Aim of the studyMicro-ribonucleic acids (miRNA) are small single stranded RNA molecules. They act as key regulators of several cellular processes such as proliferation, apoptosis, tumor differentiation, invasion and metastasis. Hepatocellular carcinoma (HCC) represents the most common primary liver cancer. miRNA-224 is an oncomiR that is highly upregulated in HCC tissues. The aim of the present study was to measure the relative expression of circulating miRNA-224 in the serum of patients with HCV-related liver cirrhosis and HCC and to assess its usefulness in the diagnosis of HCC.Material and methodsForty-eight patients were classified into two groups: 24 HCV-related HCC patients (HCC group), and 24 HCV-related liver cirrhosis patients (LC group). A third group included 24 healthy volunteers (control group). Clinical examination, imaging studies and routine laboratory investigations, including serum α-fetoprotein (AFP), were done. Quantification of serum miRNA-224 expression was performed using real time reverse transcription polymerase chain reaction (RT-PCR).ResultsThe relative expression of serum miRNA-224 was significantly higher in HCC patients compared to LC patients and healthy control subjects. Its level correlated positively with the serum concentration of AFP and with Barcelona Clinic Liver Cancer (BCLC) stage of HCC. By combining miRNA-224 relative expression with AFP, their diagnostic sensitivity, specificity and accuracy increased significantly (95.0%, 92.1% and 93.2%, respectively) compared with either of the two markers alone in discriminating HCC from liver cirrhosis.ConclusionsSerum miRNA-224 relative expression may aid in the diagnosis of HCC. Better diagnostic performance is obtained if miRNA-224 is combined with other tumor markers such as AFP.

From cirrhosis to hepatocellular carcinoma: An investigation into hepatitis C viral oncogenesis.

Background and AimHepatitis C is a leading cause of chronic liver disease and hepatocellular carcinoma (HCC). Understanding the evolution and biology of HCC among HCV patients may lead to novel therapeutic avenues and risk stratification.Material and MethodsUsing meta-analysis platform STARGEO, we performed two separate meta-analyses as follows: 357 HCV-related HCC tumor samples with 220 adjacent non-tumor samples and 92 HCV-related cirrhotic liver samples with 53 healthy liver samples as a control. Then, we analyzed the signature in Ingenuity Pathway Analysis.ResultsHCV cirrhosis analysis demonstrated LPS/IL-1 mediated inhibition of RXR function, LXR/RXR activation, sirtuin signaling, IL-10 signaling and hepatic fibrosis/stellate cell activation as top canonical pathways. IL1β, TNF, and TGF-β1 were top upstream regulators. Cellular morphologic and signaling changes were noted through the up-regulation of RGS1/2, WNT receptor FZD7, the TGF-β1-induced gap junction gene GJA1, and the zinc finger transcription factor repressor SNAI2. Apoptosis was inhibited through the down-regulation of OMA1. Metabolic dysfunction was noted through the down-regulation of SCLY and CBS. HCV-related HCC analysis showed FXR/RXR and LXR/RXR signaling, LPS/IL1-mediated inhibition of RXR activation, and melatonin degradation as top canonical pathways.ConclusionOur results suggest that the genetic changes in the setting of chronic HCV infection predispose patients to developing HCC.

Evaluation of Golgi Protein 73 (GP73) as a Potential Biomarkers for Hepatocellular Carcinoma.

Early detection of hepatocellular carcinoma is very important in the treatment which is feasible. Alpha-fetoprotein plus ultrasound in surveillance programs is controversial. GP73 is a protein. Golgi increase significantly in the sera of patients with hepatitis B virus and HCV-related HCC, providing a marker for its early detection. The aim is to detect serum Golgi protein 73 (GP73) in patients with cirrhosis and with hepatocellular carci-noma (HCC), and to determine its sensitivity and specificity as a screening tool for the detection of HCC. A case control study was conducted in four groups of 32 participants each: 1- healthy controls; 2 - chronic liver disease; 3 - decompensated liver disease; 4 - HCC group. The HCC group included 25 males and 7 females with a mean age of 58 ± 7 years, fulfilling diagnostic criteria for HCC. GP73 was estimated in the serum samples taken from the HCC group and control groups. GP73 was elevated in patients with HCC and liver cirrhosis. Serum level was very high in HCC patients (p < 0.01) when compared with the other studied groups. GP73 had a sensitivity of 96.9% and specificity of 96.9% at a cutoff value of 17.5 ng/mL when compared with α-fetoprotein (AFP) that showed a sensitivity of 75% and specificity of 92% at a cutoff value of 9.4 ng/mL. GP73 can be used as a screening tool for the detection of HCC with higher diagnostic performance than AFP.

Fibroscan and FIB-4 Assessment Versus Lymphocyte / Monocyte Ratio as Predictors of Post-Hepatectomy Liver Failure in HCV Egyptian Patients with Hepatocellular Carcinoma

Background: Post-hepatectomy liver failure (PHLF) is the most leading cause of mortality in patients diagnosed with hepatocellular carcinoma (HCC) and undergoing resection of the affected part of the liver. Objectives: This research aimed to determine the value of the lymphocyte to monocyte ratio (LMR), fibrosis score 4 (FIB-4) and liver stiffness measurements (LSM) using Fibroscan as pre-operative predictors of PHLF in Egyptian patients with post- hepatitis C virus (HCV) liver cirrhosis and HCC. Methods: In this prospective cohort study definition of PHLF was done according to the “50-50 criteria”. Multivariate analysis was done to identify PHLF independent predictors. The predictive accuracy of the pre-operative LMR, FIB-4 and LSM with Fibroscan were evaluated by receiver operating characteristic (ROC) curve. Results: Enrollment of fifty Egyptian patients was done. 14 patients (28%) experienced PHLF. The presence of oesophageal varices, serum AST, serum albumin, LMR, FIB-4 score, and LSM (P<0.05) were independent pre-operative predictors for PHLF. According to ROC curve analysis, LMR yielded the best accuracy for predicting PHLF at cutoff <3.33 [AUC = 0.940; sensitivity = 93.65%; specificity = 94.44%; positive predictive value = 86.67%; negative predictive value = 97.14%]. FIB-4 score and LSM had lower AUC (0.886 and 0.875) respectively. Conclusion: The pre-operative LMR has a higher predictive ability for PHLF in patients with HCV-related HCC undergoing hepatectomy compared with FIB-4 score and LSM using Fibroscan.

Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus (HCV) Liver Transplant Recipients Treated with Pretransplant Direct-Acting Antiviral (DAA) Therapy

Background: Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV). The impact of DAAs on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains uncertain. Objective: We aimed to evaluate the risk of HCC recurrence in LT recipients cleared of HCV with DAAs at the time of LT compared to a control group of LT recipients who were viremic at the time of LT. Methods: The study was a single-center, retrospective cohort study of patients undergoing LT for HCV-related HCC from 2002 to 2017. We compared time to post-LT HCC recurrence in patients with a sustained virological response (SVR) from DAAs prior to LT (DAA group) to patients who were viremic at LT (HCV+ group) using Kaplan-Meier analysis. We performed a secondary analysis comparing post-LT HCC recurrence in the DAA group to LT recipients with SVR from interferon-based treatment prior to LT (IFN group). Results: One hundred fifty-one patients underwent LT for HCC related to HCV: 34 patients in DAA group, 95 patients in HCV+ group, and 22 in IFN group. Kaplan-Meier estimates of being HCC free were 96.2, 96.2, and 78.8% at 6, 12, and 24 months in DAA group, respectively, and 100, 98.6, and 95.8% at 6, 12, and 24 months in the HCV+ group, respectively; p = 0.08. There was no difference observed for HCC recurrence between the DAA and IFN groups. In a multivariate Cox proportional hazards model, DAA use increased the risk of post-LT HCC recurrence (HR 5.2, 95% CI 0.9–29.81, p = 0.07). Conclusions: A strong trend was observed on both Kaplan-Meier and multivariate analyses toward increased post-LT HCC recurrence in patients who achieved SVR prior to LT with DAAs compared to patients who were viremic at LT. Caution is required when considering pre-LT treatment of HCV with DAAs in patients with HCC.

Alterations in microRNA-15a and “γ-synuclein” Expression Levels Among HCV-Related Hepatocellular Carcinoma Patients in Egypt.

Alterations in microRNA-15a and “γ-synuclein” Expression Levels Among HCV-Related Hepatocellular Carcinoma Patients in Egypt.

Impact of Direct Acting Antivirals on Survival in Patients with Chronic Hepatitis C and Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) represents a global public health burden, affecting an estimated 14 million persons worldwide, and is the third leading cause of cancer mortality. Within the United States, HCC is ranked 7th for cancer related mortality and has seen a doubling in incidence from 1975 to 2007. The primary predisposing factors for HCC carcinogenesis is liver cirrhosis. Cirrhosis risk factors include chronic alcohol use, viral hepatitis, including hepatitis c (HCV), and non-alcoholic fatty liver disease. Chronic HCV infection is the second most common risk factor for HCC and is responsible for 10–25% of all HCC cases. Over 20–30 years, 20–30% of patients with chronic HCV infections will develop cirrhosis and end stage liver disease and 1–4% of these patients will progress to HCC each year. Of all HCV related HCC cases, 80–90% occur in the setting of cirrhosis. With more than 3.5 million HCC patients in the United States and an estimated 130–170 million patients worldwide currently infected with HCV, the importance of HCV management in HCC therapeutic care and prevention is clear. The major current therapeutic goal for HCV and prevention of liver disease progression is sustained viral response (SVR), which is defined by negative HCV RNA at 12 weeks post-treatment (SVR12) and appears to be durable with a late virologic relapse rate of less than 1%. Therapeutic management of HCV has recently shifted from interferon-based therapies to all-oral interferon-free direct-acting antiviral (DAA) combination regimens. DAAs are a new class of drugs that target nonstructural proteins responsible for replication and infection of the hepatitis c virus. Genotype specific DAA therapies have been shown to reach SVR12 exceeding 90% of patients with fewer adverse effects compared with historic interferon-based regiments. SVR12 from DAA regimens have been associated with a decrease in liver outcomes including cirrhosis, hepatic decompensation, HCC and mortality. However, the impact of DAA regimens on clinical outcomes in patients with HCC remain limited. This study evaluates the impact of DAA on overall survival in HCV patients with HCC with the a priori hypothesis that SVR12 would be associated with improved outcome.

Serum microRNA expression profiling identifies serum biomarkers for HCV-related hepatocellular carcinoma.

The identification of high-sensitivity biomarkers for detection of hepatocellular carcinoma (HCC) from high-risk individuals is essential. The present study was undertaken to identify and validate serum microRNAs (miRNAs) as potential biomarkers for hepatitis C virus (HCV)-related HCC. Illumina sequencing was employed to screen the expression profiles of miRNAs in serum samples of HCV-related HCC patients and liver cirrhosis (LC) patients. RT-qPCR was used to confirm the altered miRNAs between the two groups. Moreover, candidate miRNAs were examined in serum samples of 40 HCC patients, 54 LC patients, 55 patients with chronic HCV hepatitis and 45 healthy controls. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic performance of the miRNAs for the detection of HCC. Four miRNAs (miR-122-5p, miR-331-3p, miR-494-3p, miR-224-5p) were significantly increased and two miRNAs (miR-185-5p, miR-23b-3p) were significantly decreased in HCC patients compared to LC patients. ROC curve analysis demonstrated that the six miRNAs could be used as potential biomarkers for HCC detection. Combination of the six miRNAs could efficiently detect HCC in LC patients with the area under the ROC curve (AUC) of 0.995 and combination of the six miRNAs also provided high diagnostic accuracy (AUC = 0.961) for detection of HCC in non-HCC subjects. The six serum miRNAs can be utilized as a surrogate and non-invasive biomarker for HCV-related HCC diagnosis.