The effect of chronic viral hepatitis on prognostic value of inflammatory biomarkers in hepatocellular carcinoma.
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ABSTRACT: Background
Inflammation and the immune system significantly impact the development, progression, and treatment response of hepatocellular carcinoma (HCC). This retrospective study investigated the neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in Western patients with HCC in the setting of chronic viral hepatitis.Methods
Patients diagnosed with HCC from 2005 to 2016 were selected from a tertiary care institution. NLR was calculated within 30 days prior to treatment and dichotomized at the median. Kaplan-Meier overall survival (OS) curves and Cox hazard proportional models were utilized. Tumor and liver reserve parameters were included in multivariable analyses (MVA).Results
A total of 581 patients met inclusion criteria (median age 61.0 yr; 78.3% male; 66.3% Caucasian) with median OS = 34.9 mo. 371 patients (63.9%) had viral hepatitis, of which 350 had hepatitis C (94.3%). The low-NLR group (
SUBMITTER: Sellers CM
PROVIDER: S-EPMC8366096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe immunological inflammatory biomarkers for advanced hepatocellular carcinoma are unclear. We aimed to investigate the association of immunity and inflammatory status with treatment outcomes in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment.Patients and methodsWe enrolled 728 consecutive patients with advanced hepatocellular carcinoma who received sorafenib (n = 554) or lenvatinib (n = 174) as primary treatment in Japan between May 2009 and June 2020. Changes in the neutrophil-to-lymphocyte ratio before and 1 month after treatment and their impact on survival were evaluated. The cut-off values of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for predicting overall and progression-free survival were calculated using receiver operating characteristic curves.ResultsThe neutrophil-to-lymphocyte ratio, but not the platelet-to-lymphocyte ratio, was an independent prognostic factor. Patients with decreased neutrophil-to-lymphocyte ratio survived significantly longer than patients with increased neutrophil-to-lymphocyte ratio (median overall survival: 14.7 versus 10.4 months, P = 0.0110). Among patients with a low pre-treatment neutrophil-to-lymphocyte ratio, the overall survival did not differ significantly between those with decreased and those with increased neutrophil-to-lymphocyte ratio after 1 month (median: 19.0 versus 14.8 months, P = 0.1498). However, among patients with high pre-treatment neutrophil-to-lymphocyte ratio, those whose neutrophil-to-lymphocyte ratio decreased after 1 month showed significantly longer survival than those whose neutrophil-to-lymphocyte ratio increased (median: 12.7 versus 5.5 months, P < 0.0001). The therapeutic effect was not correlated with pre-treatment neutrophil-to-lymphocyte ratio or platelet-to-lymphocyte ratio.ConclusionsThe neutrophil-to-lymphocyte ratio is a prognostic factor, along with liver function and tumor markers, in patients with advanced hepatocellular carcinoma who received molecular-targeted agents as primary treatment. Thus, the neutrophil-to-lymphocyte ratio could be a prognostic biomarker for advanced hepatocellular carcinoma primarily treated with immunotherapy.
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Project description:BackgroundCancer-related inflammation has been correlated with cancer prognosis. This study evaluated inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR), programmed death ligand (PD-L) 1 expression, and tumour microenvironment in relation to prognosis and clinicopathological features of patients with hepatocellular carcinoma (HCC) undergoing curative hepatic resection.MethodsPatients who had liver resection for HCC in 2000-2011 were analysed. Univariable and multivariable analyses were conducted for overall (OS) and recurrence-free (RFS) survival. Immunohistochemical analyses of PD-L1, CD8 and CD68 expression were performed. HCC cell lines were evaluated for PD-L1 expression. A subgroup analysis was conducted to determine patient features, survival and the tumour microenvironment. Results were validated in a cohort of patients with HCC treated surgically in 2012-2016.ResultsSome 281 patients who underwent hepatic resection for HCC were included. Multivariable analysis showed that low LMR was an independent prognostic factor of OS (hazard ratio (HR) 1·59, 95 per cent c.i. 1·00 to 2·41; P = 0·045) and RFS (HR 1·47, 1·05 to 2·04; P = 0·022) after resection. Low preoperative LMR values were correlated with higher α-fetoprotein values (P < 0·001), larger tumour size (P < 0·001), and high rates of poor differentiation (P = 0·035) and liver cirrhosis (P = 0·008). LMR was significantly lower in PD-L1-positive patients than in those with PD-L1 negativity (P < 0·001). Results were confirmed in the validation cohort. PD-L1 expression was upregulated in HCC cell lines treated with interferon-γ and co-cultured with THP-1 monocyte cells.ConclusionLMR is an independent predictor of survival after hepatic resection in patients with HCC. Modulation of the immune checkpoint pathway in the tumour microenvironment is associated with a low LMR.
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Project description:Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies and a major cause of cancer involved death worldwide. Prognosis remains poor because of high recurrence rates and lack of effective relapse prevention strategies. Notch pathway plays an important role in tumor progression and metastasis, and it is associated with the prognosis of cancer. A total of 465 hepatitis B virus (HBV)-related HCC patients who underwent surgery were enrolled. Single nucleotide polymorphisms (SNP) of Notch pathway receptors were genotyped using Sanger DNA sequencing. Kaplan-Meier curves and the Cox proportional hazards regression model were adopted to analyze the association of polymorphisms and mRNA expression with clinical and pathological features, respectively. Four SNPs (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) were significantly associated with overall survival (OS) (P = 0.023, P = 0.042, P = 0.028, and P = 0.001 respectively). Patients carrying the AA genotype in rs1043996 and TT/TC genotypes in rs422951 and rs520692 significantly decreased risks of death, compared to those carrying the AG/GG genotype in rs1043996 and CC genotype in rs422951 and rs520692, respectively. Patients carrying the TT genotype in rs3830041 showed poorer OS, compared with those carrying the TC/CC genotype. A haplotype block (rs422951 was in strong LD with rs520692, r2 = 0.843) was identified in Notch4. Notch3 mRNA expression significantly increased in tumor tissue, compared with nontumor normal tissue (P < 0.0001). Moreover, higher expression of Notch3 was associated with poorer OS (HR = 2.11, 95% CI = 1.32-3.37, P = 0.002) and shorter recurrence time of HBV-related HCC (HR = 1.96, 95% CI = 1.31-2.93, P = 0.001). Our findings collectively indicate that Notch receptors variants (rs1043996 in Notch3 and rs422951, rs520692, rs3830041 in Notch4) are independent predictive targets for OS in HBV-related HCC patients. Notch3 expression is a potential prognostic biomarker of OS and recurrence-free survival (RFS) prediction in HBV-related HCC patients following surgical treatment.
| S-EPMC5504312 | biostudies-literature
Project description:BackgroundThe prognosis of hepatocellular carcinoma (HCC) is not optimistic. Our study focused on present inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aspartate aminotransferase-to-lymphocyte ratio (ALR) and fibrinogen-to-albumin ratio (FAR), and explored their optimal combination for the prognosis of HCC after resection.MethodsA total of 347 HCC patients who underwent curative resection were enrolled. The optimal cutoff values of the inflammatory markers were calculated using receiver operating characteristic (ROC) curve analysis, and used to divide patients into two groups whose differences were compared by Kaplan-Meier analysis. Cox univariate and multivariate analyses were used to analyze the independent prognostic inflammatory markers. The χ2 test was chosen to determine the relationship between independent prognostic inflammatory markers and clinicopathological features. We created combined scoring models and evaluated them by Cox univariate and multivariate methods. The concordance index (C-index), Akaike information criterion (AIC) and likelihood ratio were calculated to compare the models. The selected optimal inflammatory markers and their combinations were tested in different stages of HCC by Kaplan-Meier analysis.ResultsThe ALR and GPR were independent prognostic factors for disease-free survival (DFS); the ALR, PLR, and GPR were independent prognostic factors for overall survival (OS). The proposed GPR and ALR-GPR-PLR score models were independent predictors for DFS and OS, respectively.ConclusionThe preoperative GPR and ALR-GPR-PLR score models were independent predictors for DFS and OS, respectively, and performed well in stratifying patients with HCC. The higher the score in the model was, the worse the prognosis.
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Project description:The aim of the present study was to investigate the diagnostic and prognostic value of Wingless‑type MMTV integration site (WNT) gene family expression in patients with hepatitis B virus (HBV)‑related hepatocellular carcinoma (HCC). The clinical data of the patients and gene expression levels were downloaded from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Receiver operating characteristic curve analysis was used to investigate the diagnostic value of WNT genes. Cox proportional hazard regression analysis and Kaplan‑Meier survival analysis were performed to evaluate the association of WNT gene expression level with overall survival (OS) and recurrence‑free survival (RFS). A nomogram was constructed for the prediction of prognosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Diagnostic receiver operating characteristic curve analysis suggested that WNT2 had a high diagnostic value, with an area under the curve (AUC) of >0.800 (P<0.0001, AUC=0.810, 95% CI: 0.767‑0.852). Survival analysis indicated that the expression level of WNT1 was significantly associated with OS and RFS (adjusted P=0.033, adjusted HR=0.607, 95% CI: 0.384‑0.960; and adjusted P=0.007, adjusted HR=0.592, 95% CI: 0.404‑0.868, respectively). In the TCGA validation cohort, we also observed that WNT2 was significantly differentially expressed between HCC tissues and adjacent non‑tumor tissues, and WNT1 was associated with both the OS and RFS of HCC. Therefore, through the GSE14520 HBV‑related HCC cohort we concluded that WNT2 may serve as a diagnostic biomarker and WNT1 may serve as a prognostic biomarker. These results may also be extended to TCGA HCC verification cohort.
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Project description:RNA was extracted from 48 pairs of intratumoral and peritumoral formalin-fixed, paraffin-embedded (FFPE) tissue from hepatocellular carcinoma (HCC) patients with and without bone metastases (BM). The Human Cancer Panel DASL Assay containing 502 cancer-related genes was used to identify novel BM-associated genes. A cDNA-mediated annealing, selection, extension, and ligation assay was performed with an array of 502 known cancer-related genes to identify differentially expressed genes in 96 RNA samples. Total RNA was purified from the tissue specimens using the High Pure RNA Paraffin Kit according to the manufacturer’s protocol. DASL experiments were performed to identify genes that were differentially expressed between the BM and NBM groups of matched intratumoral and peritumoral tissues by using A cDNA-mediated annealing, selection, extension, and ligation assay.
2011-10-27 | E-GEOD-27635 | biostudies-arrayexpress
Project description:RNA was extracted from 48 pairs of intratumoral and peritumoral formalin-fixed, paraffin-embedded (FFPE) tissue from hepatocellular carcinoma (HCC) patients with and without bone metastases (BM). The Human Cancer Panel DASL Assay containing 502 cancer-related genes was used to identify novel BM-associated genes. A cDNA-mediated annealing, selection, extension, and ligation assay was performed with an array of 502 known cancer-related genes to identify differentially expressed genes in 96 RNA samples.
2011-10-28 | GSE27635 | GEO
Project description:Numerous articles reported that dysregulated expression levels of miRNAs correlated with survival time of HCC patients. However, there has not been a comprehensive meta-analysis to evaluate the accurate prognostic value of miRNAs in HCC.Meta-analysis.Studies, published in English, estimating expression levels of miRNAs with any survival curves in HCC were identified up until 15 April, 2017 by performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two independent authors. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS).54 relevant articles about 16 miRNAs, with 6464 patients, were ultimately included. HCC patients with high expression of tissue miR-9 (HR = 2.35, 95% CI = 1.46-3.76), miR-21 (HR = 1.76, 95% CI = 1.29-2.41), miR-34c (HR = 1.64, 95% CI = 1.05-2.57), miR-155 (HR = 2.84, 95% CI = 1.46-5.51), miR-221 (HR = 1.76, 95% CI = 1.02-3.04) or low expression of tissue miR-22 (HR = 2.29, 95% CI = 1.63-3.21), miR-29c (HR = 1.35, 95% CI = 1.10-1.65), miR-34a (HR = 1.84, 95% CI = 1.30-2.59), miR-199a (HR = 2.78, 95% CI = 1.89-4.08), miR-200a (HR = 2.64, 95% CI = 1.86-3.77), miR-203 (HR = 2.20, 95% CI = 1.61-3.00) have significantly poor OS (P < 0.05). Likewise, HCC patients with high expression of blood miR-21 (HR = 1.73, 95% CI = 1.07-2.80), miR-192 (HR = 2.42, 95% CI = 1.15-5.10), miR-224 (HR = 1.56, 95% CI = 1.14-2.12) or low expression of blood miR-148a (HR = 2.26, 95% CI = 1.11-4.59) have significantly short OS (P < 0.05).In conclusion, tissue miR-9, miR-21, miR-22, miR-29c, miR-34a, miR-34c, miR-155, miR-199a, miR-200a, miR-203, miR-221 and blood miR-21, miR-148a, miR-192, miR-224 demonstrate significantly prognostic value. Among them, tissue miR-9, miR-22, miR-155, miR-199a, miR-200a, miR-203 and blood miR-148a, miR-192 are potential prognostic candidates for predicting OS in HCC.
| S-EPMC5739810 | biostudies-other
Project description:Background: Hepatitis B virus infection had been identified its relationship with liver diseases, including liver tumors. We aimed to explore diagnostic and prognostic values between the Human Leukocyte Antigen (HLA) complex and hepatocellular carcinoma (HCC). Methods: We used the GSE14520 dataset to explore diagnostic and prognostic significance between HLA complex and HCC. A nomogram was constructed to predict survival probability of HCC prognosis. Gene set enrichment analysis was explored using gene ontologies and metabolic pathways. Validation of prognostic values of the HLA complex was performed in the Kaplan-Meier Plotter website. Results: We found that HLA-C showed the diagnostic value (P <0.0001, area under curve: 0.784, sensitivity: 93.14%, specificity: 62.26%). In addition, HLA-DQA1 and HLA-F showed prognostic values for overall survival, and HLA-A, HLA-C, HLA-DPA1 and HLA-DQA1 showed prognostic values for recurrence-free survival (all P ? 0.05, elevated 0.927, 0.992, 1.023, 0.918, 0.937 multiples compared to non-tumor tissues, respectively). Gene set enrichment analysis found that they were involved in antigen processing and toll like receptor signalling pathway, etc. The nomogram was evaluated for survival probability of HCC prognosis. Validation analysis indicated that HLA-C, HLA-DPA1, HLA-E, HLA-F and HLA-G were associated with HCC prognosis of overall survival (all P ? 0.05, elevated 0.988 and 0.997 multiples compared to non-tumor tissues, respectively). Conclusion: HLA-C might be a diagnostic and prognostic biomarker for HCC. HLA-DPA1 and HLA-F might be prognostic biomarkers for HCC.
| S-EPMC6775598 | biostudies-literature
Project description:BackgroundDespite advances in multiple disciplinary diagnoses and treatments, the prognosis of hepatocellular carcinoma (HCC) remains poor. Some evidence has identified that the aberrant expression of tropomyosins (TPMs) is involved with some cancers development. However, prognostic values of TPMs in HCC have not been thoroughly investigated.MethodsOriginal TPM1-4 mRNA expression of TCGA HCC data and GTEx was downloaded from UCSC XENA. Oncomine database and GSE46408 were used for verification. Clinical stages and survival analysis of TPM1-4 in HCC were performed by GEPIA2. cBioPortal was utilized to assess TPM1-4 gene alteration in HCC. TIMER2.0 was used for investigating the relevance of TPM1-4 to tumor-infiltrating immune cells in HCC. Additionally, we constructed a TPM1-4 prognostic model to explore the value of TPM1-4 for prognostic evaluation in HCC. LinkedOmics was applied to elucidate TPM3 co-expression networks in HCC.ResultsThis present study showed that TPM1-4 was upregulated in all HCC tissues, and TPM3 overexpression was correlated with poor survival outcomes in patients with HCC. Besides, TPM3 amplification was the main altered type in TPM1-4 genetic alteration, which affected the prognosis of HCC patients. The risk model revealed that TPM1, TPM2, and TPM3 were applied to risk assessment of HCC prognosis, among which TPM3 expression was significantly higher in the high-risk group than that in the low-risk group. Univariate and multivariate cox regression analyses indicated that TPM3 may be an independent prognostic factor of HCC prognosis. In addition, TPM3 co-expression genes mainly participated in the cell cycle by maintaining microtubule cytoskeleton in HCC progression. TPM1-4 was associated with some tumor-infiltrating immune cells in HCC.ConclusionOur study detected that the expression level of TPM1-4 was all remarkably elevated in HCC, suggesting that TPM1-4 may serve an important role in HCC development. High TPM3 expression was found to be correlated with poor overall survival, and TPM3 may be an independent prognostic factor for HCC.
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