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Oncotarget Apr 2017Alpha-fetoprotein-producing gastric cancer (AFPGC) accounts for 1.5%-7.1% of all gastric cancer cases. Compared with other types of gastric cancer, AFPGC is more...
Alpha-fetoprotein-producing gastric cancer (AFPGC) accounts for 1.5%-7.1% of all gastric cancer cases. Compared with other types of gastric cancer, AFPGC is more aggressive and prone to liver and lymph node (LN) metastasis, with extremely poor prognosis. To improve understanding of AFPGC we reviewed a consecutive series of 82 AFPGC patients and investigated the prognostic factors. The incidence of AFPGC among our gastric cancer patients was 1.95%, and 29.27% of AFPGCs were diagnosed with metastasis at the time of presentation, mainly liver metastasis. The serum AFP level of patients with AFPGC was significantly associated with tumor differentiation. Histologically, these AFPGC patients were composed of 34.55% hapatiod type, 58.18% fetal gastrointestinal type, 9.09% yolk sac tumor-like type, and 14.55% mixed type. Patient gender, tumor differentiation, Lauren classification, and number of metastatic lymph nodes showed significant differences among these four subtypes. The overall survival time was 42.02 months and the 3-year cumulative survival rate was 53.13%. Age, American Joint Committee on Cancer (AJCC) TNM staging classification (TNM stage), serum AFP level, and surgery were prognostic factors for overall survival; however, TNM stage was the only independent risk factor for prognosis of AFPGC. In short, AFPGC is a rare, unique, and heterogeneous entity, and its proper identification and treatment remain a challenge. More attention should be paid to AFPGC to improve patient care and the dismal prognosis.
Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Prognosis; Risk Factors; Stomach Neoplasms; Survival Analysis; Young Adult; alpha-Fetoproteins
PubMed: 28423604
DOI: 10.18632/oncotarget.15909 -
Frontiers in Bioscience (Landmark... Jan 2020Failure of immune tolerance leads to production of autoantibodies to self-antigens. The repertoire of autoantibodies detected in cancer patients can indicate the... (Review)
Review
Failure of immune tolerance leads to production of autoantibodies to self-antigens. The repertoire of autoantibodies detected in cancer patients can indicate the presence of autoimmune disease. Alpha-fetoprotein (AFP) autoantibodies have been found in patients with hepatocellular carcinoma (HCC) and in juvenile Batten disease (BD), a neurodegenerative condition involving autoimmunity. Variant conformational forms of AFP together with exposed occult antigenic determinant sites on the AFP polypeptide resemble the features of a disordered protein which can impair central immune tolerance. These aberrant structural protein forms can lead to the persistence of autoantibody production by immune sensitized B-lymphocytes. Thus, it is not surprising that AFP, a self-antigen, can induce autoimmune responses in humans. Herein, we discuss the molecular and antigenic properties of AFP which make it a disordered protein, and its ability to induce autoantibody production to AFP cryptic epitopes in both HHC and BD patients. Such insights might aid in the future design of AFP-based vaccines and to discovery of novel pathogenic mechanisms of autoimmune diseases which demonstrate the presence of denatured intermediate forms of AFP.
Topics: Autoantibodies; Autoantigens; Autoimmunity; B-Lymphocytes; Carcinoma, Hepatocellular; Humans; Immune Tolerance; Liver Neoplasms; Neuronal Ceroid-Lipofuscinoses; alpha-Fetoproteins
PubMed: 31585923
DOI: 10.2741/4840 -
Cancer Immunology, Immunotherapy : CII Jun 2024Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was...
BACKGROUND
Alpha-fetoprotein elevated gastric cancer (AFPGC) got growing interests for its aggressive nature and unfavorable prognosis. Here, a phase 1 dose escalation study was conducted to evaluate safety and efficacy of zimberelimab (GLS-010, anti-PD-1) plus lenvatinib and chemotherapy (XELOX) as the first-line treatment for AFPGC.
METHODS
Histologically confirmed HER2-negative, advanced GC patients with elevated serum AFP level (≥ 20 ng/ml) were screened. Using a 3 + 3 dose escalation design, patients were administered varying doses of lenvatinib (12, 16, 20 mg) with GLS-010 and XELOX. The primary endpoints were safety and determination of recommended phase II dose (RP2D). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and disease control rate.
RESULTS
Nine patients were enrolled with no dose-limiting toxicities observed. Most frequent treatment-related AEs were fatigue (55.6%), hand-foot syndrome (55.6%) and rash (55.6%), and no grade ≥ 4 AEs were reported. All patients exhibited disease control with ORR reaching 33.3%. The median PFS and OS reached 7.67 months (95% CI 4.07-11.27) and 13.17 months (95% CI 2.78-23.56), respectively. Serum AFP level was found correlated with therapeutic responses. Further 16s rRNA sequencing analysis demonstrated altered gut microbiota with elevated abundance of Lachnospiraceae bacterium-GAM79 and Roseburia hominis A2-183.
CONCLUSIONS
GLS-010 plus lenvatinib and XELOX demonstrated a manageable safety profile with promising efficacy for AFPGC. With RP2D of lenvatinib determined as 16 mg, further expansion cohort is now ongoing. Translational investigation suggested that serum AFP can be indictive for therapeutic responses and certain microbiota species indicating favorable responses to immunotherapy was elevated after the combinational treatment.
Topics: Humans; Quinolines; Male; Female; Middle Aged; Phenylurea Compounds; Antineoplastic Combined Chemotherapy Protocols; Stomach Neoplasms; Aged; alpha-Fetoproteins; Antibodies, Monoclonal, Humanized; Adult; Prognosis
PubMed: 38833154
DOI: 10.1007/s00262-024-03743-0 -
Clinical and Molecular Hepatology Jul 2020Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As... (Review)
Review
Hepatitis B virus (HBV) cannot be eliminated completely from infected hepatocytes because of the presence of intrahepatic covalently closed circular DNA (cccDNA). As chronic hepatitis B (CHB) can progress to cirrhosis and hepatocellular carcinoma (HCC), it is important to manage CHB to prevent HCC development in high-risk patients with high viral replicative activity or advanced fibrosis. Serum biomarkers are noninvasive and valuable for the management of CHB. Hepatitis B core-related antigen (HBcrAg) correlates with serum HBV DNA and intrahepatic cccDNA. In CHB patients with undetectable serum HBV DNA or loss of HBsAg, HBcrAg still can be detected and the decrease in HBcrAg levels is significantly associated with hopeful outcomes. Therefore, HBcrAg can predict HCC occurrence or recurrence. Measurement of the Mac-2 binding protein glycosylation isomer (M2BPGi) has been introduced for the evaluation of liver fibrosis. Because elevated M2BPGi in CHB is related to liver fibrosis and the prediction of HCC development, monitoring its progression is essential. Because alpha fetoprotein (AFP) has insufficient sensitivity and specificity for early-stage HCC, a combination of AFP plus protein induced by vitamin K absence factor II, or AFP plus Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein might improve the diagnosis of HCC development. Additionally, Dickkopf-1 and circulating immunoglobulin G antibodies are the novel markers to diagnose HCC or assess HCC prognosis. This review provides an overview of novel HBV biomarkers used for the management of intrahepatic viral replicative activity, liver fibrosis, and HCC development.
Topics: Antigens, Neoplasm; Antiviral Agents; Biomarkers; DNA, Viral; Hepatitis B Core Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Cirrhosis; Membrane Glycoproteins; alpha-Fetoproteins
PubMed: 32536045
DOI: 10.3350/cmh.2020.0032 -
Discovery Medicine Jun 2016Human hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. Alpha-fetoprotein (AFP) is perhaps the best-defined tumor marker for HCC,... (Review)
Review
Human hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. Alpha-fetoprotein (AFP) is perhaps the best-defined tumor marker for HCC, and as such, it is widely used in clinical settings as an adjuvant diagnostic and prognostic tool. Up to 70% of HCC cases exhibit elevated serum level of AFP, but its pathophysiological functions in HCC are poorly defined. It is now known that AFP is not just a fetal form of carrier protein and a tumor marker, it is also critically involved in the regulation of several important cellular functions, such as cell growth, differentiation, apoptosis, angiogenesis, and immune regulation. In this mini-review, we summarize the recent development of AFP in hepatocellular carcinoma.
Topics: Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Dendritic Cells; Early Detection of Cancer; Humans; Immune Tolerance; Immunity, Cellular; Immunotherapy, Adoptive; Liver; Liver Neoplasms; Molecular Targeted Therapy; Prognosis; Risk Factors; alpha-Fetoproteins
PubMed: 27448785
DOI: No ID Found -
Frontiers in Immunology 2023Alpha-fetoprotein(AFP) is a cancer biomarker for the diagnosis of hepatocellular carcinoma(HCC); however, its role in macrophage polarization and phagocytosis remains...
Alpha-fetoprotein(AFP) is a cancer biomarker for the diagnosis of hepatocellular carcinoma(HCC); however, its role in macrophage polarization and phagocytosis remains unclear. In the present study, we explored the correlation between AFP regulation of macrophage function and the possible regulatory mechanisms. Human mononuclear leukemia cells (THP-1) and monocytes from healthy donors were used to analyze the effect of AFP on the macrophages' phenotype and phagocytosis. THP-1 cells and healthy human donor-derived monocytes were polarized into M0 macrophages induced by phorbol ester (PMA), and M0 macrophages were polarized into M1 macrophages induced by lipopolysaccharide(LPS) and interferon-γ(IFN-γ). Interleukin-4(IL-4) and interleukin-13(IL-13) were used to induce M0 macrophage polarization into M2 macrophages. Tumor-derived AFP(tAFP) stimulated M0 macrophage polarization into M2 macrophages and inhibited M1 macrophages to phagocytize HCC cells. The role of AFP in promoting macrophage polarization into M2 macrophages and inhibiting the M1 macrophages to phagocytize HCC cells may be involved in activating the PI3K/Akt signaling pathway. AFP could also enhanced the migration ability of macrophages and inhibited the apoptosis of HCC cells when co-cultured with M1-like macrophages. AFP is a pivotal cytokine that inhibits macrophages to phagocytize HCC cells.
Topics: Humans; alpha-Fetoproteins; Carcinoma, Hepatocellular; Phosphatidylinositol 3-Kinases; Liver Neoplasms; Macrophages; Interferon-gamma; Phenotype
PubMed: 36911723
DOI: 10.3389/fimmu.2023.1081572 -
Annals of Hepatology 2021The purpose of this study was to investigate the expression levels and prognostic roles of α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and Ki67 in tumor...
INTRODUCTION AND OBJECTIVE
The purpose of this study was to investigate the expression levels and prognostic roles of α-fetoprotein (AFP), carcinoembryonic antigen (CEA), and Ki67 in tumor tissues of intrahepatic cholangiocarcinoma (ICC) patients.
PATIENTS OR MATERIALS AND METHODS
The study involved ninety-two ICC patients with complete clinicopathological data and follow-up information, who had previously undergone radical surgery. AFP, CEA, CD10, CD34, and Ki67 were detected in tumor tissues using immunohistochemistry. Statistical tests were used to identify independent risk factors and their associations with overall survival (OS) and disease-free survival (DFS).
RESULTS
AFP, CEA and Ki67 were strongly correlated with prognosis. Univariate analysis indicated that higher AFP (P = 0.002), CEA (P < 0.0001), Ki67 (P < 0.0001), CA19-9 (P = 0.039), and CA12-5 (P = 0.002), and larger tumor size (P = 0.001), as well as more advanced tumor node metastasis (TNM) staging (P < 0.0001) were all associated with worse OS. Meanwhile, higher AFP (P = 0.002), CEA (P = 0.001), and Ki67 (P < 0.0001), as well as more advanced TNM staging (P = 0.005) were associated with worse DFS. Multivariate analysis showed that higher AFP (HR = 2.004, 95%CI: 1.146-3.504 P = 0.015), CEA (HR = 2.226, 95%CI: 1.283-3.861 P = 0.004), and Ki67 (HR = 3.785, 95%CI: 2.073-6.909 P < 0.0001), as well as more advanced TNM staging (HR = 2.900, 95%CI: 1.498-5.757 P = 0.002) had associations with worse OS. Furthermore, higher AFP (HR = 2.172, 95%Cl: 1.291-3.654 P = 0.003), CEA (HR = 1.934, 95%Cl: 1.180-3.169 P = 0.009), and Ki67 (HR = 2.203, 95%Cl: 1.291-3.761 P = 0.004) had associations with worse DFS.
CONCLUSION
High AFP, CEA, and Ki67 are significant prognostic indicators in ICC patients, and can be used to evaluate ICC biological behavior and prognosis.
Topics: Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers; Carcinoembryonic Antigen; Cholangiocarcinoma; Disease-Free Survival; Female; Humans; Ki-67 Antigen; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; alpha-Fetoproteins
PubMed: 32841741
DOI: 10.1016/j.aohep.2020.07.010 -
American Journal of Physiology.... Feb 2020Hepatocellular carcinoma (HCC) is the sixth common malignant tumor worldwide, but current efficient and convenient screening methods remain lacking. This study aimed to...
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 ( = 40). The selected proteins were confirmed using ELISA in a validation cohort ( = 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 = 0.944, < 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. 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.
Topics: Adult; Aged; Biomarkers; Carcinoma, Hepatocellular; Cohort Studies; Female; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Male; Mass Screening; Middle Aged; Orosomucoid; Proteome; Reproducibility of Results; alpha-Fetoproteins
PubMed: 31736338
DOI: 10.1152/ajpgi.00267.2019 -
Clinical and Experimental Medicine Dec 2023We previously identified the AKT-phosphorylation sites in nuclear receptors and showed that phosphorylation of S379 in mouse retinoic acid γ and S518 in human estrogen...
We previously identified the AKT-phosphorylation sites in nuclear receptors and showed that phosphorylation of S379 in mouse retinoic acid γ and S518 in human estrogen receptor α regulate their activity independently of the ligands. Since this site is conserved at S510 in human liver receptor homolog 1 (hLRH1), we developed a monoclonal antibody (mAb) that recognized the phosphorylation form of hLRH1S510 (hLRH1) and verified its clinicopathological significance in hepatocellular carcinoma (HCC). We generated the anti-hLRH1 mAb and assessed its selectivity. We then evaluated the hLRH1 signals in 157 cases of HCC tissues by immunohistochemistry because LRH1 contributes to the pathogenesis of diverse cancers. The developed mAb specifically recognized hLRH1 and worked for immunohistochemistry of formalin-fixed paraffin-embedded tissues. hLRH1 was exclusively localized in the nucleus of HCC cells, but the signal intensity and positive rates varied among the subjects. According to the semi-quantification, 45 cases (34.9%) showed hLRH1-high, and the remaining 112 cases (65.1%) exhibited hLRH1-low. There were significant differences in the recurrence-free survival (RFS) between the two groups, and the 5-year RFS rates in the hLRH1-high and hLRH1-low groups were 26.5% and 46.1%, respectively. In addition, high hLRH1 was significantly correlated with portal vein invasion, hepatic vein invasion, and high levels of serum alpha-fetoprotein (AFP). Furthermore, multivariable analysis revealed that hLRH1-high was an independent biomarker for HCC recurrence. We conclude that aberrant phosphorylation of hLRH1S510 is a predictor of poor prognosis for HCC. The anti-hLRH1 mAb could provide a powerful tool to validate the relevance of hLRH1 in pathological processes such as tumor development and progression.
Topics: alpha-Fetoproteins; Biomarkers, Tumor; Carcinoma, Hepatocellular; Liver Neoplasms; Phosphorylation; Prognosis; Serine; Humans
PubMed: 37285077
DOI: 10.1007/s10238-023-01098-x -
BMC Gastroenterology Jun 2024Type C hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), which is based on decompensated cirrhosis, has different laboratory tests, precipitating events,...
BACKGROUND
Type C hepatitis B-related acute-on-chronic liver failure (HBV-ACLF), which is based on decompensated cirrhosis, has different laboratory tests, precipitating events, organ failure and clinical outcomes. The predictors of prognosis for type C HBV-ACLF patients are different from those for other subgroups. This study aimed to construct a novel, short-term prognostic score that applied serological indicators of hepatic regeneration and noninvasive assessment of liver fibrosis to predict outcomes in patients with type C HBV-ACLF.
METHOD
Patients with type C HBV-ACLF were observed for 90 days. Demographic information, clinical examination, and laboratory test results of the enrolled patients were collected. Univariate and multivariate logistic regression were performed to identify independent prognostic factors and develop a novel prognostic scoring system. A receiver operating characteristic (ROC) curve was used to analyse the performance of the model.
RESULTS
A total of 224 patients with type C HBV-ACLF were finally included. The overall survival rate within 90 days was 47.77%. Age, total bilirubin (TBil), international normalized ratio (INR), alpha-fetoprotein (AFP), white blood cell (WBC), serum sodium (Na), and aspartate aminotransferase/platelet ratio index (APRI) were found to be independent prognostic factors. According to the results of the logistic regression analysis, a new prognostic model (named the A3Twin score) was established. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.851 [95% CI (0.801-0.901)], the sensitivity was 78.8%, and the specificity was 71.8%, which were significantly higher than those of the MELD, IMELD, MELD-Na, TACIA and COSSH-ACLF II scores (all P < 0.001). Patients with lower A3Twin scores (<-9.07) survived longer.
CONCLUSIONS
A new prognostic scoring system for patients with type C HBV-ACLF based on seven routine indices was established in our study and can accurately predict short-term mortality and might be used to guide clinical management.
Topics: Humans; Male; Female; alpha-Fetoproteins; Acute-On-Chronic Liver Failure; Retrospective Studies; Middle Aged; Prognosis; Adult; Biomarkers; Aspartate Aminotransferases; ROC Curve; Platelet Count; Hepatitis B, Chronic; Liver Cirrhosis; Survival Rate; Predictive Value of Tests; Logistic Models
PubMed: 38834942
DOI: 10.1186/s12876-024-03276-x