• Alpha-fetoprotein
• Diagnostic biomarkers
• Early diagnosis
• Exosome
• Gender
• HBV infection
• Hepatic cirrhosis
• Hepatocellular carcinoma
• Liquid biopsy
• microRNAs

• Humans
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/virology
• Carcinoma, Hepatocellular/genetics
• Liver Neoplasms/blood
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Liver Neoplasms/virology
• MicroRNAs/blood
• MicroRNAs/genetics
• Male
• Female
• Exosomes/metabolism
• Middle Aged
• Hepatitis B virus/genetics
• Cross-Sectional Studies
• Hepatitis B/complications
• Hepatitis B/blood
• Hepatitis B/diagnosis
• ROC Curve
• Reproducibility of Results
• Adult

• 201704020153 Guangzhou Municipal Science and Technology Project
• 202002030387 Guangzhou Municipal Science and Technology Project
• 2021-2023 Key Laboratory in Science and Technology Development Project of Suzhou
• 2023 Guangzhou digestive disease high-quality integrated treatment system construction project

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Serum biomarkers play an important role in the early diagnosis and prognosis of HCC. Because a certain percentage of HCC patients are negative for alpha-fetoprotein (AFP), the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC.

To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers.

A total of 180 HCC patients were enrolled in this study. The expression levels of GP73, des-γ-carboxyprothrombin (DCP), CK18-M65, and CK18-M30 were detected by a fully automated chemiluminescence analyser. The variables were selected by logistic regression analysis. Several models were constructed using stepwise backward logistic regression. The performance of the models was compared using the C statistic, integrated discrimination improvement, net reclassification improvement, and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA).

The results showed that the expression levels of GP73, DCP, CK18-M65, and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls (P < 0.001). Multivariate logistic regression analysis revealed that GP73, DCP, and CK18-M65 were independent factors for diagnosing AFP-negative HCC. By comparing the diagnostic performance of multiple models, we included GP73 and CK18-M65 as the model variables, and the model had good discrimination ability (area under the curve = 0.946) and good goodness of fit. The DCA curves indicated the good clinical utility of the nomogram.

Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC. The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC.

• Hepatocellular carcinoma
• Alpha-fetoprotein-negative
• Diagnostic
• Nomogram
• Biomarker

• Alpha-fetoprotein-negative
• Biomarker
• Diagnostic
• Hepatocellular carcinoma
• Nomogram

• DNA methylation
• FBXO43
• MethyLight
• diagnosis
• hepatitis B virus-associated hepatocellular carcinoma

• Diagnosis
• Hepatocellular carcinoma
• Post-translational modification
• Prognosis

• HCC
• early detection
• frizzled-7
• glypican-3

• HBV DNA
• IL-6
• Immune-clearance phase
• TNF-α
• alpha-fetoprotein

• Cirrhosis
• Diagnostic
• Golgi protein 73 (GP73)
• Hepatocellular carcinoma (HCC)
• Meta-analysis

• 2022AAC02065 the Natural Science Foundation of Ningxia
• 81760363 the Fund for Less Developed Regions of the Natural Science Foundation of China

• SP70
• diagnostic performance
• early recurrence
• hepatocellular carcinoma
• recurrence-free survival

• National Natural Science Foundation of China

• AFP-NHCC
• alpha-fetoprotein
• early diagnosis
• marker
• nomogram model

• butylated hydroxytoluene
• diethylnitrosamine
• hepatocellular carcinoma
• initiation stage
• protective

Hepatitis B virus (HBV) causes acute and chronic infection in the clinic. Hepatocellular carcinoma (HCC) is closely linked to HBV infection. Serum Golgi protein 73 (GP73) increases during HBV infection. However, the role of GP73 during HBV infection and the occurrence of HBV-related HCC is still poorly understood.

The underlying role of HBV-induced GP73 in regulating HCC development was investigated in this study. GP73 expression in HBV-related clinical HCC tissues and in HBV-infected hepatoma cells and primary human hepatocytes was evaluated by immunohistochemistry, ELISAs, Western blotting and quantitative real-time PCR (qRT-PCR) analysis. Tumorigenicity of GP73 overexpressed cells was detected by flow cytometry, qRT-PCR, xenograft nude mouse analyses and sphere formation assays. The effects of GP73 and HBV infection on host innate immune responses in hepatocytes were further investigated by Western blotting and qRT-PCR analysis.

Initially, we confirmed that HBV-positive HCC tissues had significantly higher expression of GP73. Ectopic expression of the HBV gene could induce GP73 expression in primary human hepatocytes and hepatoma cells in vitro. In addition, we discovered that GP73 promotes HCC in both normal liver cells and hepatoma cells. We also found that ectopic expression of HBV genes increases GP73 expression, suppressing the host's innate immune responses in hepatocytes.

Our results demonstrate that HBV facilitates HCC development by activating GP73 to repress the host's innate immune response. This study adds to our understanding of the pathogenesis of HBV infection-induced HCC. The findings also provide preclinical support for GP73 as a potential HCC prevention or treatment target.

The online version contains supplementary material available at 10.1186/s13027-022-00462-y.

• Golgi Protein 73
• Hepatitis B virus
• Hepatocellular carcinoma

• diethylnitrosamine
• hepatocellular carcinoma
• initiation stage
• protective
• thymoquinone

• alpha-fetoprotein
• biomarkers
• hepatocellular carcinoma
• meta-analysis
• molecular diagnosis

• Biomarkers, Tumor
• Carcinoma, Hepatocellular/diagnosis
• Humans
• Liver Neoplasms/diagnosis
• Prothrombin
• ROC Curve
• Sample Size
• Sensitivity and Specificity
• alpha-Fetoproteins/analysis

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has been acknowledged as a leading cause of death among cirrhosis patients. Difficulties in early diagnosis and heterogeneity are obstacles to effective treatment, especially for advanced HCC. Liver transplantation (LT) is considered the best therapy for HCC. Although many biomarkers are being proposed, alpha-fetoprotein (AFP), which was identified over 60 years ago, remains the most utilized. Recently, much hope has been placed in the immunogenicity of AFP to develop novel therapies, such as AFP vaccines and AFP-specific adoptive T-cell transfer (ACT). This review summarizes the performance of AFP as a biomarker for HCC diagnosis and prognosis, as well as its correlation with molecular classes. In addition, the role of AFP in LT is also described. Finally, we highlight the mechanism and application prospects of two immune therapies (AFP vaccine and ACT) for HCC. In general, our review points out the prevalence of AFP in HCC, accompanied by some controversies and novel directions for future research.

• Alpha-fetoprotein
• Chimeric antigen receptor (CAR) T-cell therapy
• Hepatocellular carcinoma
• Liver transplantation
• T-cell receptor-engineered T-cell therapy

• alpha-fetoprotein isoform l3
• biomarker
• diagnostic performance
• early diagnosis
• hepatocellular carcinoma
• meta-analysis

• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/diagnosis
• Humans
• Liver Neoplasms/blood
• Liver Neoplasms/diagnosis
• Neoplasm Staging
• ROC Curve
• Sensitivity and Specificity
• alpha-Fetoproteins/analysis
• alpha-Fetoproteins/chemistry

Epidermal growth factor-like domain 7 (Egfl7), a recently identified secreted protein, was significantly increased in patients with HCC by our previous studies. However, its efficacy in the diagnosis of early HCC remains unknown. In this study, we therefore evaluate the efficacy of serum Egfl7 for early HCC diagnosis and compare it with alpha-fetoprotein (AFP).

Serum Egfl7 levels in testing cohort (1081 participants) and validation cohort (476 participants) were measured by a sandwich enzyme-linked immunoassay (ELISA). The cut-off value of Egfl7 was determined by Youden’s index and the efficacies of Egfl7 and AFP in diagnosing early HCC were estimated by receiver operating characteristic (ROC).

Serum Egfl7 was significantly elevated in patients with early HCC than all non-HCC controls in whatever Testing Cohort or Validation Cohort. In the Testing Cohort, ROC curves showed the optimum cut-off value of Egfl7 was 2610 ng/mL and Egfl7 showed a significantly higher sensitivity than AFP in discriminating early HCC from healthy individuals (77.4% vs. 65.3%, P = 0.0013) but the area under ROC (AUROC) and accuracy of Egfl7 and AFP were similar (0.860 vs. 0.868, P = 0.704; 80.2% vs. 83.8%, P = 0.184). In distinguishing patients with early HCC from patients with chronic liver disease (CLD), the AUROC, sensitivity, specificity and accuracy of Egfl7 were 0.800, 75.2, 71.7 and 73.5%, which were all significantly higher than AFP (0.675, 61.8, 62.0 and 61.9% in order). Egfl7 also showed a significant higher sensitivity and accuracy than AFP (76.6% vs. 64.0%, P = 0.0031; 79.9% vs. 66.1%, P < 0.0001) in differentiating early HCC patients from non-HCC individuals. Additionally, 70.8% of early HCC patients with negative AFP could be diagnosed by Egfl7 and the combined use of Egfl7 and AFP increased the sensitivity to 91.0%. These results were confirmed by a validation cohort.

Egfl7 is a valuable serum marker in the diagnosis of early HCC and could complement the efficacy of AFP, especially in distinguishing early HCC from CLD and identifying patients with AFP-negative early HCC.

• Alpha-fetoprotein
• Early diagnosis
• Eepidermal growth factor-like domain 7
• Hepatocellular carcinoma
• Serum marker

• alanine aminotransferase to aspartate aminotransferase ratio
• alpha-fetoprotein-negative hepatocellular carcinoma
• diagnostic markers
• gamma-glutamyl transpeptidase to alkaline phosphatase ratio
• gamma-glutamyl transpeptidase to aspartate aminotransferase ratio

• Adult
• Aged
• Aged, 80 and over
• Alanine Transaminase/blood
• Alkaline Phosphatase/blood
• Aspartate Aminotransferases/blood
• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/diagnosis
• Case-Control Studies
• Clinical Enzyme Tests
• Female
• Hepatitis, Chronic/blood
• Hepatitis, Chronic/diagnosis
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/diagnosis
• Liver Neoplasms/blood
• Liver Neoplasms/diagnosis
• Logistic Models
• Male
• Middle Aged
• Predictive Value of Tests
• ROC Curve
• Statistics, Nonparametric
• Young Adult
• alpha-Fetoproteins
• gamma-Glutamyltransferase/blood

• 81902839 National Natural Science Foundation of China
• National Natural Science Foundation of China

• Circulating tumor cells
• Hepatocellular carcinoma
• Microwave ablation
• α-fetoprotein
• α-fetoprotein alloplasm 3

• Alpha-fetoprotein
• Golgi protein 73
• Hepatitis C virus
• Hepatocellular carcinoma
• Liver cirrhosis

Des-gamma-carboxyprothrombin (DCP) is an important serum biomarker for the clinical screening of hepatocellular carcinoma (HCC). This study aimed to evaluate the value of DCP for the early diagnosis of alpha-fetoprotein (AFP)-negative hepatitis B virus (HBV)-related HCC.

We retrospectively enrolled patients with AFP-negative HBV-related HCC and benign liver disease. Serum DCP levels in all participants were measured by chemiluminescent enzyme immunoassay. The value of DCP for the early diagnosis of AFP-negative HBV-related HCC was evaluated by receiver operating characteristic curve (ROC) and area under the curve (AUC) analyses.

A total of 210 patients, including 87 cases with AFP-negative HBV-related HCC and 123 control cases with chronic HBV infection (CHB) or liver cirrhosis (LC), were included. Serum DCP levels were significantly increased in patients with AFP-negative HBV-related HCC compared with those with CHB or LC. The AUC for DCP for distinguishing between the two groups was 0.731 (95% confidence interval (CI), 0.657 to 0.805) and that for early diagnosis was 0.685 (95%CI, 0.596 to 0.774).

DCP may be a favorable biomarker to improve the early diagnosis rate of AFP-negative HBV-related HCC.

• Des-gamma-carboxyprothrombin
• alpha-fetoprotein
• early diagnosis
• hepatitis B virus
• hepatocellular carcinoma
• serum level

• Alpha-fetoprotein (AFP)
• Diagnostic markers
• Gamma-glutamyl transferase (GGT)
• Golgi protein 73 (GP73)
• Hepatitis B virus (HBV)
• Hepatitis C virus (HCV)
• Hepatocellular carcinoma (HCC)
• Liver cancer

• R01 CA222490 NCI NIH HHS
• U01 CA179582 NCI NIH HHS

• EGFR
• GOLM1
• PD-L1
• STAT3
• hepatocellular carcinoma

The role of α-fetoprotein (AFP) in the surveillance and diagnosis of hepatocellular carcinoma (HCC) has been questioned in recent years due to its low sensitivity and specificity. In addition to AFP, several new serum biomarkers, such as lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-gamma-carboxy prothrombin (DCP), have also been identified as useful HCC serological markers. However, the exact diagnostic value of the combinations of these biomarkers for detecting HCC in patients with liver disease remains unclear. Thus, we performed the current meta-analysis to assess performance of AFP+AFP-L3%+DCP for diagnosing HCC. Studies were systematically searched in PubMed, Embase, the Cochrane Library, CNKI, and WanFang Data databases. After full-text evaluation, 13 studies from 11 articles focusing on the combination of the three serum biomarkers for HCC detection were enrolled. Random-effects models were used due to the presence of heterogeneity. The pooled sensitivity and specificity for AFP+AFP-L3%+DCP were 88% and 79%, respectively. The area under the summary receiver operating characteristic (sROC) curve was 0.91, and the diagnostic odds ratio (DOR) was 28.33 (95% CI 16.78-47.83). Subgroup analysis showed that the pooled sensitivity and specificity of AFP+AFP-L3%+DCP in the diagnosis of HCC versus cirrhosis patients were 0.81 and 0.82, respectively. In conclusion, the combination of AFP, AFP-L3%, and DCP may prove to be useful in the diagnosis and screening of HCC.

The expression levels of α-enolase, also known as enolase 1 (ENO1), in liver cancer tissues and the autoantibody levels of ENO1 in the sera of patients with liver cancer were detected to investigate the function of ENO1 in the invasion and metastasis of liver cancer, as well as its clinical diagnostic value. Small interfering RNA (siRNA) was used to disrupt ENO1 gene expression in HepG2 and Huh7 liver cancer cells. The proliferation ability of liver cancer cells was assessed using Cell Counting Kit-8 (CCK-8); the migration ability of liver cancer cells was assessed using scratch tests; and the migration and invasion abilities of liver cancer cells were assessed using Transwell assays. ENO1 expression in liver cancer tissues (43.8%) was significantly higher than that in benign liver lesions (15.2%) (P=0.005). The serum anti-ENO1 antibody levels in the liver cancer group were significantly higher than those in the control and benign liver lesion groups (P<0.001). After ENO1 gene interference, the proliferation, migration and invasion abilities of HepG2 and Huh7 liver cancer cells exhibited different degrees of suppression. The results revealed that ENO1 promotes liver cancer invasion and metastasis; ENO1 plays an important role in liver cancer and can be used as a potential liver cancer-associated marker.

• diagnostic value
• invasion
• liver cancer
• metastasis
• α-enolase

An early diagnosis of hepatocellular carcinoma (HCC) followed by effective treatment is currently critical for improving the prognosis and reducing the associated economic burden. Alpha-fetoprotein (AFP) is the most widely used biomarker for HCC diagnosis. Based on elevated serum AFP levels as well as typical imaging features, AFP-positive HCC (APHC) can be easily diagnosed, but AFP-negative HCC (ANHC) is not easily detected due to lack of ideal biomarkers and thus mainly reliance on imaging. Imaging for the diagnosis of ANHC is probably insufficient in sensitivity and/or specificity because most ANHC tumors are small and early-stage HCC, and it is involved in sophisticated techniques and high costs. Moreover, ANHC accounts for nearly half of HCC and exhibits a better prognosis compared with APHC. Therefore, the diagnosis of ANHC in clinical practice has been a critical issue for the early treatment and prognosis improvement of HCC. In recent years, tremendous efforts have been made to discover new biomarkers complementary to AFP for HCC diagnosis. In this review, we systematically review and discuss the recent advances of blood biomarkers for HCC diagnosis, including DNA biomarkers, RNA biomarkers, protein biomarkers, and conventional laboratory metrics, focusing on their diagnostic evaluation alone and in combination, in particular on their diagnostic performance for ANHC.

• AFP-negative
• DNA
• RNA
• blood biomarkers
• diagnosis
• hepatocellular carcinoma
• protein

In this retrospective study, we investigated clinicopathological features and prognosis of hepatocellular carcinoma (HCC) patients applying an immunosubtyping method based on the serum α-fetoprotein (AFP) levels and glypican-3 (GPC3) immunohistochemical expression.

Two hundred and twenty-nine HCC patients, who had been subjected to hepatectomy and accepted serum AFP and GPC immunohistochemical expression tests, were divided into four groups: AFP⁺GPC3⁺, AFP⁺GPC3^–, AFP^–GPC3⁺, and AFP^–GPC3^– groups. During the study, HCC patients’ sex ratios, ages, incidence of cirrhosis, clinicopathological features—such as tumor lesion, tumor size, histological grade, vascular invasion, regional lymph node involvement, distant metastasis—and their follow-up time were observed and continuously recorded.

Regarding their clinicopathological features, the four groups only differed in the histological grade with statistical significance. Furthermore, the four subtypes showed statistically significant differences in sex ratios and incidence of cirrhosis. Among the four subtypes, the prognosis was just statistically different between the AFP⁺GPC3⁺ and AFP^–GPC3⁺ groups, and AFP^–GPC3⁺ was associated with a better prognosis.

A new HCC subtype could guide the personalized therapy of HCC patients to a certain extent. The four different subtypes resulting from the AFP- and GPC3-based subclassification of HCC, especially for AFP⁺GPC3⁺ and AFP⁻GPC3⁻ groups, were meaningful prognostic markers for HCC.

• Hepatocellular carcinoma (HCC)
• glypican-3 (GPC3)
• prognosis
• subtype
• α-fetoprotein (AFP)

• AFP-negative hepatocellular carcinoma
• Diagnostic
• Fibrinogen to prealbumin ratio
• Gamma-glutamyl transpeptidase to platelet ratio

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers globally. In contrast to the declining death rates observed for all other common cancers such as breast, lung, and prostate cancers, the death rates for HCC continue to increase by ~2–3% per year because HCC is frequently diagnosed late and there is no curative therapy for an advanced HCC. The early diagnosis of HCC is truly a big challenge. Over the past years, the early diagnosis of HCC has relied on surveillance with ultrasonography (US) and serological assessments of alpha-fetoprotein (AFP). However, the specificity and sensitivity of US/AFP is not satisfactory enough to detect early onset HCC. Recent technological advancements offer hope for early HCC diagnosis. Herein, we review the progress made in HCC diagnostics, with a focus on emerging imaging techniques and biomarkers for early disease diagnosis.

• Biomarker
• Early diagnosis
• Hepatocellular carcinoma
• Imaging
• Liquid biopsy

Background: Hepatocellular carcinoma (HCC) frequently occurs in cirrhosis and closely relates to poor prognosis of cirrhotic patients. Alpha-fetoprotein (AFP) is the most widely used biomarker in HCC diagnosis but not sensitive and specific to detect HCC at low AFP levels. In order to enhance the ability of AFP to detect HCC developed on cirrhosis, we attempted to combine AFP with conventional clinical metrics to develop a simple and effective method for identifying cirrhotic patients with complicating HCC at various AFP levels.

Methods: Cirrhotic patients with or without HCC hospitalized to receive therapy for the first time were recruited and their clinical data were retrospectively collected. A model for diagnosing HCC was developed with routine clinical metrics and AFP by binary logistic regression analysis and internally validated. The goodness of fit, diagnostic accuracy and clinical usefulness of the model were evaluated using a calibration curve, the area under the receiver operating characteristic curve (AUROC) and a decision curve analysis, respectively.

Results: A total of 574 patients with cirrhosis mainly caused by hepatitis B were recruited in this study, including 286 cases of simple cirrhosis (LC) and 288 cases of cirrhosis with HCC (LCC) (124 AFP-negative), with an average age of 53.2 ± 12.1 years and 81.4% males. Twelve of the 19 clinical metrics (age, gender, AFP, liver function tests, serum electrolytes, and coagulation tests) significantly differed between the LC and LCC groups. A model was successfully developed with age, AFP, Na⁺, Cl⁻, alkaline phosphatase, and activated partial thromboplastin time, which exhibited good performance in diagnosing LCC, with an AUROC of 0.918 (95%CI 0.895–0.940), 82.3% sensitivity, 89.5% specificity, and 85.9% accuracy for all patients, which were much higher values than those for AFP [0.846 (95%CI 0.815–0.878), 72.9, 81.5, and 77.2%, respectively]. For cirrhotic patients complicated with AFP-negative HCC, the model showed an AUROC of 0.854 (95%CI 0.812–0.896), 68.5% sensitivity, 86.6% specificity, and 80.0% accuracy. A high net benefit could be obtained in clinical decision making according to the model.

Conclusion: A diagnostic model combining simple clinical metrics with AFP is valuable for the identification of cirrhotic patients complicating HCC with various AFP levels.

• alpha-fetoprotein
• calibration curve analysis
• clinical metrics
• decision curve analysis
• diagnostic model
• hepatocellular carcinoma
• liver cirrhosis

• ESI-MS
• MALDI-MS
• biomarkers
• cancer
• early detection
• fucosylation
• glycans
• glycopeptides
• hepatocellular carcinoma
• lectins

• Animals
• Biomarkers, Tumor/analysis
• Carcinoma, Hepatocellular/diagnosis
• Early Detection of Cancer/methods
• Electrophoresis, Capillary/methods
• Electrophoresis, Gel, Two-Dimensional/methods
• Glycopeptides/analysis
• Glycoproteins/analysis
• Glycosylation
• Humans
• Immunoassay/methods
• Liver Neoplasms/diagnosis
• Polysaccharides/analysis
• Proteomics/methods
• Spectrometry, Mass, Electrospray Ionization/methods
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods

• R01 CA106402 NCI NIH HHS
• U01 CA225753 NCI NIH HHS
• R01 CA160254 NCI NIH HHS
• R01 CA154455 NCI NIH HHS
• R01 GM049500 NIGMS NIH HHS
• R50 CA221808 NCI NIH HHS

Glycocholic acid (GCA) is a novel identified biomarker for hepatocellular carcinoma (HCC). However, clinical pathological study of GCA has not been extensive due to the limited availability of anti-GCA monoclonal antibodies (mAbs) and restricted detection methods. In the present study, using human GCA conjugated with bovine serum albumin as the immunogen to immunize BALB/c mice, a novel anti-GCA mAb was generated and characterized. The isotypes of heavy chain and light chain of anti-GCA mAb were examined to be IgG2a and κ, respectively, with a high affinity constant (2.6×10⁸ mol/l). The anti-GCA mAb binds GCA with high specificity and sensitivity, and the 50% inhibitory rate was 77.09 ng/ml. The present study also established a rapid, sensitive and efficient indirect competitive ELISA analysis using this anti-GCA mAb to detect the level of GCA produced by different HCC cell lines. Therefore, the present study may successfully develop a novel method for early HCC diagnosis, and also provide insights for further research and treatment of HCC.

• glycocholic acid
• hepatocellular carcinoma
• indirect competitive enzyme-linked immunoassay
• monoclonal antibody

• Golgi glypican73
• Sandwich ELISA
• RT-PCR
• early surveillance
• HCC
• Saudi Arabia

• Adult
• Aged
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/metabolism
• Early Detection of Cancer/methods
• Female
• Glypicans/metabolism
• Humans
• Leukocytes, Mononuclear/metabolism
• Liver Cirrhosis/metabolism
• Liver Neoplasms/diagnosis
• Liver Neoplasms/metabolism
• Male
• Middle Aged
• RNA, Messenger/metabolism
• Saudi Arabia
• Sensitivity and Specificity
• Young Adult
• alpha-Fetoproteins/metabolism

• Animals
• Cancer Vaccines
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/therapy
• Humans
• Immunotherapy
• Liver Neoplasms/immunology
• Liver Neoplasms/therapy
• Tumor Escape
• alpha-Fetoproteins/immunology

More than 70% of hepatocellular carcinoma (HCC) cases develop as a consequence of liver cirrhosis (LC). Here we have evaluated the diagnostic potential of four serum biomarkers, and developed models for HCC diagnosis and differentiation from LC patients. Serum levels of α-fetoprotein (AFP), AFP-L3, des-γ-carboxy prothrombin (DCP), and Golgi protein 73 (GP73) were analyzed in 114 advanced HCC patients, 81 early stage HCC patients, and 152 LC patients. Multilayer perceptron (MLP) and radial basis function (RBF) neural networks were used to construct the diagnostic models. Using all stages, HCC diagnostic models had a higher sensitivity (>70%) than the individual serum biomarkers, whereas only early stage HCC diagnostic models had a higher specificity (>80%). The early stage HCC diagnostic models could not be used as HCC screening tools due to their low sensitivity (about 40%). These results suggest that a combination of the two models might be used as a screening tool to distinguish early stage HCC patients from LC patients, thus improving prevention and treatment of HCC.

• artificial neural network
• hepatocellular carcinoma
• serum tumor biomarker

To determine the prevalence and diagnostic value of autoantibodies in α-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC).

Fifty-six serum samples from AFP-negative HCC cases, 86 from AFP-positive HCC cases, 168 from chronic liver disease cases, and 59 from normal human controls were included in this study. Autoantibodies to nucleophosmin (NPM)1, 14-3-3zeta and mouse double minute 2 homolog (MDM2) proteins in AFP-negative HCC serum were evaluated by enzyme-linked immunosorbent assay. Partially positive sera were further evaluated by western blotting. Immunohistochemistry was used to detect the expression of three tumor-associated antigens (TAAs) in AFP-negative HCC and normal control tissues.

The frequency of autoantibodies to the three TAAs in AFP-negative HCC sera was 21.4%, 19.6% and 19.6%, which was significantly higher than in the chronic liver disease cases and normal human controls (P < 0.01) as well as AFP-positive HCC cases. The sensitivity of the three autoantibodies for diagnosis of AFP-negative HCC ranged from 19.6% to 21.4%, and the specificity was approximately 95%. When the three autoantibodies were combined, the sensitivity reached 30.4% and the specificity reached 91.6%.

Autoantibodies to NPM1, 14-3-3zeta and MDM2 may be useful biomarkers for immunodiagnosis of AFP-negative HCC.

• α-fetoprotein
• Nucleophosmin 1
• 14-3-3zeta
• Mouse double minute 2 homolog
• Immunodiagnosis
• Autoantibody
• Hepatocellular carcinoma

• 14-3-3 Proteins/immunology
• 14-3-3 Proteins/metabolism
• Aged
• Autoantibodies/blood
• Autoantibodies/immunology
• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/metabolism
• Enzyme-Linked Immunosorbent Assay
• Female
• Humans
• Immunohistochemistry
• Immunologic Tests
• Liver Diseases/metabolism
• Liver Neoplasms/diagnosis
• Liver Neoplasms/metabolism
• Male
• Middle Aged
• Nuclear Proteins/immunology
• Nuclear Proteins/metabolism
• Nucleophosmin
• Proto-Oncogene Proteins c-mdm2/immunology
• Proto-Oncogene Proteins c-mdm2/metabolism
• Recombinant Proteins/metabolism
• Retrospective Studies
• alpha-Fetoproteins/immunology
• alpha-Fetoproteins/metabolism

• Adult
• Aged
• Aged, 80 and over
• Alanine Transaminase/blood
• Biomarkers, Tumor/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/pathology
• Early Detection of Cancer
• Female
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/pathology
• Liver Neoplasms/blood
• Liver Neoplasms/pathology
• Male
• Membrane Proteins/blood
• Middle Aged
• Prognosis
• Risk Factors
• alpha-Fetoproteins/metabolism

• afp
• afp-l3
• diagnostic value
• hepatocellular carcinoma
• pivka-ii

• Aged
• Biomarkers/blood
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/diagnosis
• Female
• Humans
• Liver Neoplasms/blood
• Liver Neoplasms/diagnosis
• Male
• Middle Aged
• Plant Lectins
• Protein Precursors/blood
• Prothrombin
• Retrospective Studies
• Sensitivity and Specificity
• alpha-Fetoproteins/metabolism