Related Hepatocellular Carcinoma Patients Research Articles

Monitoring hepatocellular carcinoma using tumor content in circulating cell-free DNA.

To evaluate the utility of tumor content in circulating cell-free DNA (ccfDNA) for monitoring hepatocellular carcinoma (HCC) throughout its natural history. We included 67 hepatitis B virus (HBV)-related HCC patients, of whom 17 had paired pre- and post-treatment samples, and 90 controls. Additionally, in a prospective cohort with HBV surface antigen-positive participants recruited in 2012 and followed up biannually with blood sample collections until 2019, we included 270 repeated samples before diagnosis from 63 participants who later developed HCC (pre-HCC samples). Shallow whole-genome sequencing and the ichorCNA method were used to analyze genome-wide copy number and tumor content in ccfDNA. High tumor content was associated with advanced tumor stage (P < 0.001) and a poor survival after HCC diagnosis (HR=12.35; 95% confidence interval [CI]=1.413-107.9; P = 0.023). Tumor content turned negative after surgery (P = 0.027), while remained positive after transarterial chemoembolization treatment (P = 0.578). In non-HCC samples, the mean tumor content (±SD) was 0.011 (±0.007) and had a specificity of 97.8% (95%CI=92.2%-99.7%). In pre-HCC samples, tumor content increased from 0.014 in 4 years before diagnosis to 0.026 in 1 year before diagnosis. The sensitivity of tumor content in detecting HCC increased from 22.7% (95%CI=11.5%-37.8%) within one year before diagnosis to 30.4% (95%CI=13.2%-52.9%) at BCLC stage 0/A, 81.8% (95%CI=59.7%-94.8%) at stage B, and 95.5% (95%CI=77.2%-99.9%) at stage C. The tumor content in ccfDNA is correlated with tumor burden and may help in monitoring HCC one year earlier than clinical diagnosis and in predicting patient prognosis.

Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up

BackgroundGenetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported.MethodsWe enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case–control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi.ResultsThrough a case–control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032–2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival.ConclusionThe ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.

Diagnosis and monitoring of hepatocellular carcinoma in Hepatitis C virus patients using attenuated total reflection Fourier transform infrared spectroscopy

BackgroundCurrent diagnostic methods for assessment of hepatitis C virus related hepatocellular carcinoma and subsequent categorization of hepatocellular carcinoma into non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma, to establish appropriate treatment strategies, are costly, invasive and requires multiple screening steps. This demands alternative diagnostic approaches that are cost-effective, time-efficient, and minimally invasive, while maintaining their efficacy for screening of hepatitis c virus related hepatocellular carcinoma. In this study, we propose that attenuated total reflection Fourier transform infrared in conjunction with principal component analysis – linear discriminant analysis and support vector machine multivariate algorithms holds a potential as a sensitive tool for the detection of hepatitis C virus-related hepatocellular carcinoma and the subsequent categorization of hepatocellular carcinoma into non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma. MethodsFreeze-dried sera samples collected from 31 hepatitis c virus related hepatocellular carcinoma patients and 30 healthy individuals, were used to acquire mid-infrared absorbance spectra (3500–900 cm-1) using attenuated total reflection Fourier transform infrared. Chemometric machine learning techniques were utilized to build principal component analysis – linear discriminant analysis and support vector machine discriminant models for the spectral data of hepatocellular carcinoma patients and healthy individuals. Sensitivity, specificity, and external validation on blind samples were calculated. ResultsMajor variations were observed in the two spectral regions i.e., 3500–2800 and 1800–900 cm-1. IR spectral signatures of hepatocellular carcinoma were reliably different from healthy individuals. Principal component analysis – linear discriminant analysis and support vector machine models computed 100% accuracy for diagnosing hepatocellular carcinoma. To classify the non-angio-invasive hepatocellular carcinoma/ angio-invasive hepatocellular carcinoma status, diagnostic accuracy of 86.21% was achieved for principal component analysis – linear discriminant analysis. While the support vector machine showed a training accuracy of 98.28% and a cross-validation accuracy of 82.75%. External validation for support vector machine based classification observed 100% sensitivity and specificity for accurately classifying the freeze-dried sera samples for all categories. ConclusionsWe present the specific spectral signatures for non-angio-invasive hepatocellular carcinoma and angio-invasive hepatocellular carcinoma, which were prominently differentiated from healthy individuals. This study provides an initial insight into the potential of attenuated total reflection Fourier transform infrared to diagnose hepatitis C virus related hepatocellular carcinoma but also to further categorize into non-angio-invasive and angio-invasive hepatocellular carcinoma.

Screening for Lipid-Metabolism-Related Genes and Identifying the Diagnostic Potential of ANGPTL6 for HBV-Related Early-Stage Hepatocellular Carcinoma.

Lipid metabolic reprogramming is one of the hallmarks of hepatocarcinogenesis and development. Therefore, lipid-metabolism-related genes may be used as potential biomarkers for hepatocellular carcinoma (HCC). This study aimed to screen for genes with dysregulated expression related to lipid metabolism in HCC and explored the clinical value of these genes. We screened differentially expressed proteins between tumorous and adjacent nontumorous tissues of hepatitis B virus (HBV)-related HCC patients using a Nanoscale Liquid Chromatography-Tandem Mass Spectrometry platform and combined it with transcriptomic data of lipid-metabolism-related genes from the GEO and HPA databases to identify dysregulated genes that may be involved in lipid metabolic processes. The potential clinical values of these genes were explored by bioinformatics online analysis tools (GEPIA, cBioPortal, SurvivalMeth, and TIMER). The expression levels of the secreted protein (angiopoietin-like protein 6, ANGPTL6) in serum were analyzed by ELISA. The ability of serum ANGPTL6 to diagnose early HCC was assessed by ROC curves. The results showed that serum ANGPTL6 could effectively differentiate between HBV-related early HCC patients with normal serum alpha-fetoprotein (AFP) levels and the noncancer group (healthy participants and chronic hepatitis B patients) (AUC = 0.717, 95% CI: from 0.614 to 0.805). Serum ANGPTL6 can be used as a potential second-line biomarker to supplement serum AFP in the early diagnosis of HBV-related HCC.

Development and Validation of a nomogram for forecasting survival of alcohol related hepatocellular carcinoma patients.

With the increasing incidence and prevalence of alcoholic liver disease, alcohol-related hepatocellular carcinoma has become a serious public health problem worthy of attention in China. However, there is currently no prognostic prediction model for alcohol-related hepatocellular carcinoma. The retrospective analysis research of alcohol related hepatocellular carcinoma patients was conducted from January 2010 to December 2014. Independent prognostic factors of alcohol related hepatocellular carcinoma were identified by Lasso regression and multivariate COX proportional model analysis, and the nomogram model was constructed. The reliability and accuracy of the model were assessed using the concordance index(C-Index), receiver operating characteristic (ROC) curve and calibration curve. Evaluate the clinical benefit and application value of the model through clinical decision curve analysis (DCA). The prognosis was assessed by the Kaplan-Meier (KM) survival curve. In sum, 383 patients were included in our study. Patients were stochastically assigned to training cohort (n=271) and validation cohort (n=112) according to 7:3 ratio. The predictors included in the nomogram were splenectomy, platelet count (PLT), creatinine (CRE), Prealbumin (PA), mean erythrocyte hemoglobin concentration (MCHC), red blood cell distribution width (RDW) and TNM. Our nomogram demonstrated excellent discriminatory power (C-index) and good calibration at 1-year, 3-year and 5- year overall survival (OS). Compared to TNM and Child-Pugh model, the nomogram had better discriminative ability and higher accuracy. DCA showed high clinical benefit and application value of the model. The nomogram model we established can precisely forcasting the prognosis of alcohol related hepatocellular carcinoma patients, which would be helpful for the early warning of alcohol related hepatocellular carcinoma and predict prognosis in patients with alcoholic hepatocellular carcinoma.

Identification and Verification of a Novel MAGI2-AS3/miRNA-374-5p/FOXO1 Network Associated with HBV-Related HCC.

Hepatocellular carcinoma (HCC) is a very common neoplasm worldwide, and competitive endogenous RNA (ceRNA) plays an important role in the development of HCC. The purpose of this study is to investigate the molecular mechanisms of ceRNAs in HCC. This study detects potential ceRNAs from HCC through whole genome analysis of lncRNA, miRNA and mRNA expression. We then performed high-throughput sequencing of tissues from five hepatitis B related HCC patients to screen ceRNAs and those screened ceRNAs expressions were verified on tissues from an independent group of six patients. Finally, the function of ceRNAs of interest was illustrated in vitro. Functional and pathway analysis of The Cancer Genome Atlas revealed ceRNA networks. The high-throughput sequencing identified 985 upregulated and 1612 downregulated lncRNAs and 887 upregulated and 1116 downregulated mRNAs in HCC patients. Differentially expressed genes were parallel to cancer-associated processes, comprising 18 upregulated and 35 downregulated significantly enriched pathways including alcoholism and viral carcinogenesis. Among them, a potential ceRNA network was detected and verified in six HCC patients. CeRNAs of the lncRNA MAGI2-AS3/miR-374-5p/FOXO1 pathway were significantly dysregulated in HCC, and validation in vitro showed that FOXO1 is positively regulated by MAGI2-AS3 through the induction of miR-374a/b-5p in HCC cells. In addition, the overexpression of FOXO1 is associated with proliferation, migration, and invasion of HCC cells and increases apoptosis of HCC cells. MiR-374a/b-5p caused an opposite effect by directly suppressing FOXO1 in HCC cells. CeRNA networks were found in HCC and aberrantly expressed ceRNAs of lncRNA MAGI2-AS3/miR-374-5p/FOXO1 plays a crucial role in HCC, assisting in diagnosis and providing a method for treatment.

Prognostic Nomograms Combined Adjuvant Lenvatinib for Hepatitis B Virus-related Hepatocellular Carcinoma With Microvascular Invasion After Radical Resection.

Background and AimMicrovascular invasion (MVI) has been established as one of the most important contributors to the prognosis of primary hepatocellular carcinoma (HCC). The objective of this study was to investigate the potential effect of postoperative adjuvant therapy with lenvatinib on the long-term prognosis after radical resection in hepatitis B virus (HBV)-related HCC patients with MVI, as well as to predict the long-term survival based on nomograms.MethodsData from 293 HBV-related hepatocellular carcinoma patients with histologically confirmed MVI who underwent R0 resection at Eastern Hepatobiliary Surgery Hospital (EHBH) was retrospectively analyzed. 57 patients received postoperative adjuvant therapy with lenvatinib, while 236 patients did not. The survival outcome of patients who received postoperative adjuvant lenvatinib versus those who did not was analyzed.ResultsThe 1-year, 2-year recurrence rates and survival rates of the lenvatinib group were improved compared to the non-lenvatinib group (15.9%, 43.2% vs 40.1%, 57.2%, P=0.002; 85.8%, 71.2% vs 69.6%, 53.3%, P=0.009, respectively). Similar findings were also observed after Propensity Score Matching (PSM) compared to non-PSM analyses The 1-year, 2-year recurrence rates and survival rates were more favorable for the lenvatinib group compared to the non-lenvatinib group (15.9%, 43.2% vs 42.1%, 57.4%, P=0.028; 85.8%, 71.2% vs 70.0%, 53.4%, P=0.024, respectively). As shown by univariate and multivariate analyses, absence of adjuvant lenvatinib treatment was identified as an independent risk factor for recurrence and survival. The established nomograms displayed good performance for the prediction of recurrence and survival, with a C-index of 0.658 and 0.682 respectively.ConclusionsPostoperative adjuvant therapy with lenvatinib was associated with improved long-term prognosis after R0 Resection in HBV-related HCC patients with MVI, which could be accurately predicted from nomograms.

Prognostic Value of Aspartate Transaminase/Alanine Transaminase Ratio in Patients With Hepatitis B Virus-Related Hepatocellular Carcinoma Undergoing Hepatectomy

BackgroundAspartate transaminase/alanine transaminase (De Ritis) ratio is a good predictor of liver function damage, but its prognostic value in patients with hepatocellular carcinoma (HCC) undergoing hepatectomy remains unclear. This study aimed to assess the association of the De Ritis ratio with overall survival (OS) among hepatitis B virus (HBV)-related HCC patients undergoing hepatectomy.MethodsA total of 1,147 HCC patients were recruited. Cox regression analysis was used to identify the independent risk factors. Restricted cubic spline (RCS) was used to evaluate the association between the De Ritis ratio and mortality risk. Nomogram was constructed to determine the predictive power of the De Ritis ratio.ResultsMultivariate Cox regression analysis revealed that the tertile of the De Ritis ratio was an independent risk factor for mortality. After adjustment for confounding factors, the adjusted hazard ratios (HRs) with corresponding 95% CIs of mortality for the 2nd tertile and 3rd tertile were 1.175 (0.889–1.554) and 1.567 (1.199–2.046), respectively. RCS confirmed a non-linear association between the natural logarithm of the De Ritis ratio and the risk of mortality (p for non-linearity = 0.0375). The nomogram showed that the natural logarithm of the De Ritis ratio contributed the most to the prediction of prognosis in HBV-related HCC patients, and Harrell’s C-index was 0.680 with a 95% CI of 0.645–0.715.ConclusionThe De Ritis ratio is an independent predictor for OS in HBV-related HCC patients undergoing hepatectomy, which allows for prognostic stratification of patients, hence, individualized treatment and follow-up.

Evaluation of Transient Elastography in Prediction Of De novo Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation

Abstract Background Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and it is also a common cause of death in patients with chronic liver disease. The curative treatment options for HCC that are currently available are surgical resection, liver transplantation and radiofrequency ablation .Despite progressive improvements in the efficacy of RFA, the survival of patients with HCC who undergo RFA remains disappointing, mainly due to frequent intrahepatic recurrence of HCC after RFA. Aim of the work To evaluate the role of transient elastography (as an indirect indicator to degree of liver fibrosis) in prediction of denovo recurrence of hepatocellular carcinoma after radiofrequency ablation in hepatitis C related hepatocellular carcinoma .And to compare between transient elastography and other non invasive fibrosis indices in prediction of denovo recurrence of hepatocellular carcinoma after radiofrequency ablation hepatitis C related hepatocellular carcinoma Patients and methods This prospective cohrt study was conducted on hepatocellular carcinoma patient, who underwent radiofrequency ablation in Tropical Medicine Department in Eldemerdash and Ain Shams Specialized Hospital, HCC clinic Ain Shams University Hospitals, Cairo, Egypt between march, 2017 and May, 2019. Data of the patient, who underwent radiofrequency ablation during the study period, were reviewed and the patients who fulfilled the inclusion criteria were enrolled into this study. The patients who fulfilled the inclusion criteria and underwent radiofrequency ablation were followed up for 12 months. Results TE revealed 28 patients with F4 and only 2 patients with F3, the mean measurement of liver stiffness was (22.45 ± 10.36) KPa. There was a significant negative correlation between LS and denovo recurrence of HCC (mean of LS in patients with complete response was 17.19 ± 3.32 and the mean of LS in patient with denovo recurrence was 36,94 ± 5.93,with the The best cut off value ≥24.65 (p value &amp;lt; 0.001)). There was no significant correlation between CDC, FIB4, API scores and denovo recurrence of HCC. Also it was found that the LS was significantly associated with prediction of manifestation of hepatic decompensation after RFA (means of LS in patient without manifestation decompensation after RFA (p value &amp;lt;0.001) .Regarding prediction of mortality, LS at cut off value &amp;gt; 42 .75 (p value = 0,031) was significantly associated with prediction of mortality after one year of RFA. As regard serum non invasive fibrosis indices our results showed correlation between FIB4 score and hepatic decompensation after one year of intervention (the mean of FIB4 score in patients ascites and jaundice was 6.05 ± 4.71 (p value = 0.05) ).Therewas no statistically significant correlation between CDS and API with hepatic decompensation after RFA .As regard role of serum non invasive fibrosis indices in prediction of mortality after RFA, FIB4 score, CDS and API were statistically non significant. Conclusion Our data suggest that LS measurement is a useful predictor of HCC de novorecurrence overall survival and possibility of hepatic decompensation after RFA

A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

BackgroundHepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.MethodsThe expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.ResultALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo.ConclusionsHBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

A novel index for staging hepatitis B related liver cirrhosis in patients with hepatocellular carcinoma.

Information on the stage of liver cirrhosis is essential for prognostication and decisions on surgical planning for hepatocellular carcinoma (HCC) patients. But a non-invasive liver cirrhosis staging model is still lacking. The aim of our study was to develop a non-invasive model based on routine clinical parameters to evaluate the severity of cirrhosis in hepatitis B related HCC patients. A total of 226 HCC patients with chronic hepatitis B virus (HBV) infection who had liver resection were analyzed in this retrospective study. We found that platelets, prothrombin activity, maximum oblique diameter of right hepatic lobe and spleen length were the independent predictors of liver cirrhosis in HCC patients. By cumulating the weight of risk scores of independent variables, we constructed the PPMS (PLT/PTA/maximum oblique diameter of right hepatic lob/spleen length) index. The areas under the receiver operating characteristic curves (AUROC) of PPMS index were 0.820, 0.667, and 0.650 in predicting ≥cirrhosis 1 (C1), ≥cirrhosis 2 (C2), and ≥cirrhosis 3 (C3), respectively. The optimal cut-off value of the PPMS index for predicting ≥C1, ≥C2, and ≥C3 was 4.392, 4.471, and 4.784, respectively. And the corresponding sensitivity was 63.1%, 63.2%, and 64.7%, the corresponding specificity was 89.4%, 64.3%, and 62.5%, respectively. Our study constructed a non-invasive liver cirrhosis index (PPMS) could distinguish patients from different stages of liver cirrhosis, which might add more preoperative information for HCC patients.

Prognostic Nomogram for Sorafenib Benefit in Hepatitis B Virus-Related Hepatocellular Carcinoma After Partial Hepatectomy.

BackgroundPredicting the long-term prognosis of individuals who experienced sorafenib treatment following partial hepatectomy due to hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is difficult. This work aims to create an effective prognostic nomogram for HBV related HCC patients who are receiving sorafenib treatment as adjuvant therapy after surgery.MethodsA total of 233 HBV-related HCC patients treated with or without sorafenib following partial hepatectomy at the Eastern Hepatobiliary Surgery Hospital from 2008 to 2013 were matched with propensity score matching analysis. The optimal cut-off point of the overall survival (OS) factor level was determined by x-tile. The selection of indicators was based on clinical findings. The Cox regression model with an interaction term was employed for evaluating the predictive value. Using a multivariate Cox proportional hazards model, a nomogram was subsequently formulated to analyze 111 patients treated with sorafenib. The nomogram’s discriminative ability and predictive accuracy were determined using the concordance index (C-index), calibration, and ROC curve.ResultsThe matched sorafenib cohort of 111 patients and control cohort of 118 patients were analyzed. Subgroup analysis revealed that low GPC3, pERK, pAKT, serum AFP levels, without MVI, under 50 years old, male, TNM stage I/II and BCLC stage 0/A were significantly associated with a better OS in patients subjected to sorafenib treatment compared to those without sorafenib treatment after surgery. Multivariate analysis of the sorafenib cohort revealed GPC3, pERK, pAKT, serum AST, and BCLC stage as independent factors for OS, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.73(95% CI, 0.67–0.78). The area under the ROC curve (AUC) for the nomogram to predict the survival for 1, 3, and 5-year was 0.726, 0.816, and 0.823, respectively.ConclusionThis proposed nomogram shows the potential to make a precise prediction regarding the prognosis of HBV-related HCC patients and may help to stratify patients for personalized therapy following partial hepatectomy.

PROGNOSTIC IMPACT OF PRETREATMENT FIB-4 INDEX AFTER RADIOFREQUENCY ABLATION FOR HEPATOCELLULAR CARCINOMA

Intrahepatic distant recurrence, after successful radiofrequency ablation for hepatocellularcarcinoma, is related to many factors. Underlying liver fibrosis/cirrhosis severity thought to beone of these contributors. FIB-4 index is a non-invasive marker which reflects the severity ofliver fibrosis. The aim of this study was to evaluate the prognostic value of FIB-4 index afterradiofrequency ablation for hepatocellular carcinoma with curative intent. This retrospectivestudy included 121 HCV related hepatocellular carcinoma patients with Child class A who underwentradiofrequency ablation between 1/2010 & 12/2014. The study assessed the overallsurvival and denovo intrahepatic distant recurrence using pretreatment FIB-4 index.The result showed that pretreatment FIB-4 index of ≤3.25 patients had significant better freeintrahepatic distant recurrence and overall survival rates after radiofrequency ablation when comparedto those with pretreatment FIB-4 index of > 3.25, even in subsets of patients with Childscore 5, single lesion or lesions< 3cm. Also, FIB-4 index was useful prognostic predictor of intrahepaticdistant recurrence and overall survival after radiofrequency ablation in Child class Apatients in uni and multivraite analysis.

Tumor aggression among hepatitis-C related hepatocellular carcinoma patients: an observational study regarding the impact of anti-HCV therapy

BackgroundHepatitis C virus (HCV) represents a major risk factor for hepatocellular carcinoma (HCC) development and anti-HCV therapy is a significant measure to reduce the incidence of HCC, however development of HCC in HCV treated patients is an emerging clinical problem which needs to be investigated. In this study we aim to analyze association between anti-HCV therapy and tumor pattern of HCV related HCC patients.MethodsHepatocellular Carcinoma (HCC) patients with seropositivity for hepatitis C virus (HCV) antibodies, registered at three tertiary care hospitals of Rawalpindi and Islamabad, Pakistan during August 2017 to July 2018 were enrolled. Selected patients were then segregated in two groups on the basis of their HCV treatment history i.e., “TN” (HCV Treatment Naïve i.e. having no history/medical record for treatment prior to HCC diagnosis) and “TH” (Treated for HCV infection). Aggressiveness index (AgI) scoring system was applied to determine the tumor pattern. Univariate and multivariate analysis was carried out to analyze the independent effect of anti-HCV therapy on tumor pattern.ResultsOut of 234 consecutive HCC patients, 171 HCV-related HCC patients were enrolled in final analysis and labeled as “TN” (n = 120) and “TH” (n = 51). Tumor pattern was found to be significantly aggressive (P = 0.02) in the treated cohort with an adjusted odds of 2.47 for aggressive and 6.92 for highly aggressive tumor. Neutrophil to lymphocyte ratio (NLR) was strongly associated with highly aggressive tumor pattern (P = 0.012). Patients in TN group were found to be marginally older than those in the TH group (59.5 vs. 55 years) where mean age of the patients treated with direct acting anti-viral agents was found to be visibly lower than mean age of patients who received interferon based treatment (53.5 vs. 57 years) with significant masculine predominance (62.1 vs. 37.9%, P = 0.049).ConclusionWe observed raised neutrophil to lymphocyte ratio and prominence of younger age with aggressive tumor biology in HCV treated HCC patients. These observations highlight the need for a longitudinal prospective study on HCV positive subjects treated with antivirals, irrespective of treatment response.

Survival advantage associated with metformin usage in hepatocellular carcinoma patients with diabetes mellitus receiving radical resection: a propensity score matching analysis.

BackgroundMetformin is associated with improved survival among hepatocellular carcinoma (HCC) patients with diabetes mellitus. However, the role of metformin in the survival of hepatitis B virus (HBV)-related HCC patients with diabetes mellitus after radical resection is unclear, so this study aimed to assess the effects of metformin on the clinical outcomes of patients who received radical resection for HCC.Patients and methodsA total of 250 HCC patients (30–78 years old) diagnosed with diabetes mellitus were selected between 2000 and 2013 from the First Affiliated Hospital of Nanchang University and the Eastern Hepatobiliary Surgery Hospital in China. Patients were divided into the metformin group (n = 66) and the nonmetformin group (n = 184). A propensity score matching analysis was performed to evaluate the effect of metformin in patients receiving radical resection for HCC.ResultsIn the propensity score-matched cohort (n = 176), the overall survival (OS) in the metformin group at 1, 3, and 5 years was significantly higher than in the nonmetformin group (P = 0.002), and a similar treatment effect was observed for disease-free survival (DFS) (P = 0.030). The adjusted Cox proportional hazards model showed that metformin usage significantly improved OS [hazard ratio: 0.558, 95% confidence interval (CI): 0.385–0.810].ConclusionsMetformin is associated with satisfactory clinical outcomes among HBV-related HCC patients with diabetes mellitus after radical resection. The use of metformin could significantly improve the OS and reduce the risk of HCC recurrence in patients after radical resection. A prospective controlled study is recommended to verify the metformin effect and explore its possible mechanisms.

Urine α-fetoprotein and orosomucoid 1 as biomarkers of hepatitis B virus-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the sixth common malignant tumor worldwide, but current efficient and convenient screening methods remain lacking. This study aimed to discover a diagnostic or a screening biomarker from the urine of hepatitis B virus (HBV)-related HCC patients. We used iTRAQ coupled with mass spectrometry to identify candidate urinary proteins in a discovery cohort (n = 40). The selected proteins were confirmed using ELISA in a validation cohort (n = 140). Diagnostic performance of the selected proteins was assessed using receiver operating characteristic (ROC) and qualitative diagnostic analysis. A total of 96 differentially expressed proteins were identified. Urinary α-fetoprotein (u-AFP) and orosomucoid 1 (u-ORM1) were selected as target proteins by bioinformatics analysis and were significantly higher in HCC than in non-HCC patients, as validated by Western blot analysis and ELISA. u-AFP had a strong correlation with serum AFP-L3 (Pearson's r = 0.944, P < 0.0001), indicating that u-AFP may be derived from circulating blood. The area under the curve (AUC) of u-AFP was 0.795 with a sensitivity of 62.5% and a specificity of 95.4%, which showed no significantly difference with serum AFP (se-AFP). The AUC was 0.864 as u-AFP and u-ORM1 were combined, and they performed much better than u-AFP or u-ORM1 alone. Qualitative diagnostic analysis showed that the positive predictive value of u-AFP was 90.1% and the diagnostic sensitivity of parallel combination of u-AFP and u-ORM1 was 85.1%. Taken together, AFP and ORM1 in the urine may be used as a diagnostic or screening biomarker of HCC, and studies on large samples are needed to validate the result.NEW & NOTEWORTHY This study provides a novel way to find biomarkers of hepatocellular carcinoma (HCC) and a new perspective of α-fetoprotein clinical application. The urine reagent strips may be helpful in high epidemic areas of HCC and in low-resource settings.

PRDM1 levels are associated with clinical diseases in chronic HBV infection and survival of patients with HBV-related hepatocellular carcinoma

PR domain zinc finger protein 1 (PRDM1)/B lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor involved in B and T cell responses which are implicated in chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study investigated the association of PRDM1 with clinical diseases of chronic HBV infection and prognosis of HBV -related HCC patients. Serum PRDM1 levels were determined in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 cirrhosis and 113 HCC), 70 HBV infection resolvers and 96 healthy control individuals. The PRDM1 levels were analyzed with regard to clinical diseases and overall survival of HCC patients. Serum PRDM1 concentrations in patients with chronic HBV infection were significantly elevated compared with infection resolvers and healthy controls. HBV-related HCC patients had the most significantly elevated PRDM1 levels. PRDM1 levels could considerably differentiate HCC from chronic hepatitis [area under receiver operating characteristic curve (AUC) 0.889, p < 0.001] or cirrhosis (AUC 0.910, p < 0.001). HCC patients with high PRDM1 levels had a poor prognosis (>300 pg/mL vs. ≤300 pg/mL, p = 0.001). High PRDM1 levels were independently associated with increased mortality in HCC patients (hazard ratio 2.997, 95% confidence interval 1.103–4.722, p = 0.003). Overall, this study demonstrated that PRDM1 levels are associated with the clinical diseases of chronic HBV infection. Highly elevated PRDM1 levels are discriminative of HCC from other clinical diseases and indicative of a poor prognosis of HCC patients. The potential association of PRDM1 levels with disease progression and treatment response warrants further investigation.

Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.

BackgroundMicrovascular invasion (MVI) is the most important risk factor associated with early postoperative recurrence in patients with hepatocellular carcinoma (HCC). However, the efficacy of postoperative adjuvant treatment for preventing recurrence in HCC patients with MVI has not been assessed. This study investigated the efficacy of postoperative adjuvant radiotherapy (RT) and transcatheter arterial chemoembolization (TACE) in HCC patients with MVI.Materials and methodsFrom July 2008 to December 2016, 117 hepatitis B virus (HBV)-related HCC patients with MVI were retrospectively divided into two groups based on postoperative adjuvant treatments. Propensity score matching (PSM) was performed to adjust for significant differences in baseline characteristics. Relapse-free survival (RFS) and overall survival (OS) of the two groups were analyzed before and after PSM.ResultsOf all patients, the RT group had significantly smaller tumor size and milder MVI classification. PSM analysis created 46 pairs of patients. After matching, the two groups of patients were similar in baseline characteristics. Multivariate analysis indicated that tumor size, MVI classification, and postoperative treatment strategies were independently associated with RFS; tumor size and MVI classification were independently associated with OS. Similar multivariate analysis results were demonstrated after matching propensity score. Survival analysis revealed that the estimated median RFS and OS of patients with RT and TACE were 25.74±8.12 vs 9.18±1.67 months (P=0.003) and 60.69±7.36 vs 36.53±5.34 months (P=0.262), respectively. The RT group had significantly longer RFS than the TACE group.ConclusionPostoperative adjuvant RT offers better RFS for HCC patients with MVI than TACE.

NAFLD-Associated Comorbidities in Advanced Stage HCC Do Not Alter the Safety and Efficacy of Yttrium-90 Radioembolization

Background: Patients with advanced hepatocellular carcinoma (HCC) arising in nonalcoholic fatty liver disease (NAFLD) may not be suitable for systemic therapy due to metabolic syndrome-related diseases. Recent trials did not show a survival benefit of radioembolization (RE) compared to sorafenib in advanced stage HCC but RE may represent an adequate alternative in patients with contraindications to systemic therapy due to its favorable safety profile. Aim: To investigate the impact of NAFLD-related comorbidities on safety and efficacy of RE for HCC treatment in a retrospective monocentric cohort study. Patients and Methods: Safety and efficacy of RE were evaluated in patients with NAFLD-associated HCC. Hepatitis B virus (HBV)-related HCC patients served as controls, exhibiting matching Barcelona Liver Cancer Clinic (BCLC) stages while showing significantly fewer metabolic comorbidities. Results: Overall, 87 HCC patients with NAFLD (mean age 71.3 ± 6.9 years) and 62 HCC patients with HBV (mean age 58.8 ± 10.9 years) not amenable to surgical or conventional locoregional treatments were included. Patients with HBV-related HCC had a comparable liver function to HCC patients with NAFLD. RE treatment-related toxicity did not differ between the two groups (increase in bilirubin Common Terminology Criteria for Adverse Events grade in 29 [38.7%] NAFLD and 20 [39.2%] HBV patients, p = 0.91). Overall survival was similar in HCC patients with NAFLD and HBV (11.1 [interquartile range, IQR, 18.27] vs. 9.3 months [IQR 14.73], p = 0.38), also in the subgroup analyses of BCLC B and C stages. Conclusion: RE showed similar survival outcomes at a comparable toxicity profile in HCC patients with NAFLD and HBV. NAFLD-associated metabolic comorbidities did not exhibit limitations for RE while offering comparable therapeutic efficacy as compared to HBV patients.

MicroRNA-224 Expression and Polymorphism Predict the Prognosis of Hepatitis B Virus-Related Hepatocellular Carcinoma Patients After Liver Resection.

Hepatocellular carcinoma (HCC) is one of the common lethal types of tumors all over the world. Overexpression of mircoRNA-224 (miR-224) has been reported to act as a potential biomarker for HCC patients. The goal of our study was to assess the prognostic impact of the expression and polymorphism of miR-224 in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after liver resection. A total of 62 cases of HBV-positive HCC patients, 17 HCC patients without HBV, and 13 healthy cases were enrolled in this study. Blood leukocyte miR-224 level were determined by qRT-PCR. Genotyping analysis of miR-224 rs188519172 was performed using an allele-specific PCR assay. All patients were undergoing partial liver resection and the prognostic values of miR-224 rs188519172 polymorphism for tumor development, survival rate, and liver injury after liver resection were examined. When we compared the blood leukocyte miR-224 level between HCC patients and healthy cases, we found that it was significantly increased in HCC patients. By subgroup analysis, it demonstrated that miR-224 expression was significantly increased in the HBV positive group compared with the HBV negative group. miR-224 rs188519172 AG + GG phenotype was significantly associated with severe liver injury after liver resection and patients carrying miR-224 rs188519172 AG + GG phenotype have a higher risk of cirrhosis and lower overall and disease-free survival rate. Meanwhile, the combination of miR-224 rs188519172 AG + GG phenotype and AFP value could improve the prognosis assessment of HBV related HCC. miR-224 rs188519172 polymorphism is an indicator of liver injury and a novel prognostic biomarker for tumor development and survival of HBV related HCC patients after liver resection.