Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.
Humans ; Female ; Blood Platelets/pathology* ; Biomarkers, Tumor/genetics* ; Ovarian Neoplasms/pathology* ; China

Immune checkpoint inhibitors are a promising strategy in the treatment of cancer, especially advanced types. However, not all patients are responsive to immune checkpoint inhibitors. The response rate depends on the immune microenvironment, tumor mutational burden (TMB), expression level of immune checkpoint proteins, and molecular subtypes of cancers. Along with the Cancer Genome Project, various open access databases, including The Cancer Genome Atlas and Gene Expression Omnibus, provide large volumes of data, which allow researchers to explore responsive or resistant biomarkers of immune checkpoint inhibitors. In this review, we introduced some methodologies on database selection, biomarker screening, current progress of immune checkpoint blockade in solid tumor treatment, possible mechanisms of drug resistance, strategies of overcoming resistance, and indications for immune checkpoint inhibitor therapy.
Biomarkers, Tumor ; blood ; immunology ; Data Mining ; Drug Resistance, Neoplasm ; Humans ; Immunotherapy ; Mutation ; Neoplasms ; genetics ; therapy ; Tumor Microenvironment

Non-small-cell lung cancer (NSCLC), the most common type of lung cancer accounting for 85% of the cases, is often diagnosed at advanced stages owing to the lack of efficient early diagnostic tools. 5-Hydroxymethylcytosine (5hmC) signatures in circulating cell-free DNA (cfDNA) that carries the cancer-specific epigenetic patterns may represent the valuable biomarkers for discriminating tumor and healthy individuals, and thus could be potentially useful for NSCLC diagnosis. Here, we employed a sensitive and reliable method to map genome-wide 5hmC in the cfDNA of Chinese NSCLC patients and detected a significant 5hmC gain in both the gene bodies and promoter regions in the blood samples from tumor patients compared with healthy controls. Specifically, we identified six potential biomarkers from 66 patients and 67 healthy controls (mean decrease accuracy >3.2, P < 3.68E-19) using machine-learning-based tumor classifiers with high accuracy. Thus, the unique signature of 5hmC in tumor patient's cfDNA identified in our study may provide valuable information in facilitating the development of new diagnostic and therapeutic modalities for NSCLC.
5-Methylcytosine ; analogs & derivatives ; blood ; Biomarkers, Tumor ; blood ; genetics ; Carcinoma, Non-Small-Cell Lung ; blood ; diagnosis ; genetics ; Case-Control Studies ; Circulating Tumor DNA ; blood ; DNA Methylation ; Epigenomics ; Female ; Humans ; Lung Neoplasms ; blood ; diagnosis ; genetics ; Male ; Middle Aged

Gastroenteropancreatic neuroendocrine neoplam (GEP-NEN) is a rare group of tumors with its incidence rising significantly in recent decades. Because of the late presentation of the disease and limitations in conventional biomarkers, about 50% of GEP-NEN patients manifests advanced disease when diagnosed. Therefore, it is vital to identify circulating biomarkers which can not only be used for early diagnosis but also accurately evaluating the biological behavior of GEP-NEN. This review summarizes the advances of circulating biomarkers in diagnosing and evaluating efficacy of treatment in GEP-NEN. Well-known circulating biomarkers include chromogranin A (CgA), pancreastatin (PST), chromogranin B (CgB), neuron-specific enolase (NSE) and pancreatic peptide(PP). Novel biomarkers including circulating tumor cell(CTC), microRNA and NETest are promising biomarkers with potential clinical benefit, but further researches are needed before their clinical applications.
Biomarkers, Tumor ; blood ; Chromogranin A ; blood ; Chromogranin B ; blood ; chemistry ; Gastrointestinal Neoplasms ; blood ; chemistry ; diagnosis ; genetics ; Humans ; MicroRNAs ; blood ; Neoplastic Cells, Circulating ; Neuroendocrine Tumors ; blood ; chemistry ; diagnosis ; genetics ; Pancreatic Neoplasms ; blood ; chemistry ; diagnosis ; genetics ; Pancreatic Polypeptide ; blood ; Phosphopyruvate Hydratase ; blood

OBJECTIVETo investigate the value of serum miR-17-92 cluster in the diagnosis of retinoblastoma (RB).

METHODSSerum samples were collected from 20 children with RB and 20 healthy controls. Quantitative real-time PCR was used to measure the expression of miR-17-92 cluster. The expression of miR-17-92 cluster was compared between children with different stages of RB and the changes in the expression of miR-17-92 cluster after multimodality therapy were analyzed. The receiver operating characteristic (ROC) curve was used to investigate the value of serum miR-17-92 cluster in the diagnosis of RB.

RESULTSCompared with the healthy controls, the children with RB had significantly higher relative expression of miR-17-3P, miR-17-5P, miR-18a, and miR-20a in serum (P<0.05), and miR-18a showed the greatest increase. There were no significant differences in the relative expression of miR-19a, miR-19b-1, and miR-92a-1 between children with RB and healthy controls (P>0.05). There were no significant differences in the expression of miR-17-5P, miR-17-3P, miR-18a, and miR-20a between the children with early-to-moderate stage of RB and those with advanced stage of RB (P>0.05), but there were significant reductions after multimodality therapy (P<0.05). In the diagnosis of RB, the areas under the ROC curve (AUCs) for serum miR-17-3P, miR-17-5P, miR-18a, and miR-20a were 0.770, 0.755, 0.828, and 0.665 respectively, and miR-18a had the largest AUC, with a sensitivity of 90% and a specificity of 65%.

CONCLUSIONSmiR-17-3P, miR-17-5P, miR-18a, and miR-20a are highly expressed in the serum of children with RB, and miR-18a may be used as a new marker for the diagnosis of RB.

Biomarkers, Tumor ; blood ; Child, Preschool ; Female ; Humans ; Infant ; Male ; MicroRNAs ; blood ; ROC Curve ; Retinoblastoma ; blood ; diagnosis ; genetics

PURPOSE: The roles of circulating tumor cells (CTCs) as predictive and prognostic factors, as well as key mediators in the metastatic cascade, have been investigated. This study aimed to validate a method to quantify CTCs in peripheral blood using a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay for cytokeratin (CK)-19 and to evaluate the utility of this assay in detecting CTCs in breast cancer patients. MATERIALS AND METHODS: Real-time monitoring PCR of fluorescently labeled specific hybridization probes for CK-19 mRNA was established. Peripheral blood samples from 30 healthy donors, 69 patients with early breast cancer, 47 patients with locally advanced breast cancer, and 126 patients with metastatic breast cancer were prospectively obtained and analyzed for CTC detection. RESULTS: CK-19 mRNA was not detectable in healthy subjects using the real-time RT-PCR method. The detection rates of CK-19 mRNA in breast cancer patients were 47.8% for early breast cancer (33/69), 46.8% for locally advanced breast cancer (22/47), and 61.1% for metastatic breast cancer (77/129). The detection rate of CK-19-positive CTCs in metastatic disease was slightly higher than early or locally advanced breast cancer; however, the detection rate according to disease burden was not statistically different (p=0.097). The detection rate was higher in patients with pleural metastasis (p=0.045). CTC detection was associated with poor survival (p=0.014). CONCLUSION: A highly specific and sensitive CK-19 mRNA-based method to detect CTCs in peripheral blood in breast cancer patients can be used in further prospective studies to evaluate the predictive and prognostic importance of CTCs.
Biomarkers, Tumor/*blood ; Breast Neoplasms/blood/*pathology ; Female ; Humans ; Keratin-19/*blood/genetics ; *Neoplastic Cells, Circulating ; Prognosis ; Prospective Studies ; RNA, Messenger/*blood ; Real-Time Polymerase Chain Reaction ; *Reverse Transcriptase Polymerase Chain Reaction/methods

PURPOSE: Tumor-associated microRNAs have been detected in cancer, though whether plasma microRNA-155 (miR-155) could be a potential biomarker for laryngeal squamous cell carcinoma (LSCC) prognosis is unclear. We aimed to determine how miR-155 can be used to predict the clinical characteristics of patients with LSCC and correctly diagnose them. MATERIALS AND METHODS: We collected tissue samples and peripheral blood samples before and after treatment from 280 LSCC cases and 560 controls. Real-time quantitative reverse transcription PCR was employed in this study to compare the relative expression of miR-155. RESULTS: A total of 280 LSCC patients and 560 age- and sex-matched controls were included in the study. The miR-155 level was more up-regulated in LSCC tissue than in the non-tumor tissues (13.6+/-2.4 vs. 3.1+/-0.80, p<0.001). Additionally, a significantly higher miR-155 level in plasma samples from LSCC patients than in those of the controls (8.9+/-1.25 vs. 1.8+/-0.8, p<0.001) was reported. Tissue miR-155 showed an area under the curve (AUC) of 0.933, with a sensitivity of 82.6% and a specificity of 89.2%. The AUC for plasma miR-155 was 0.757, with a sensitivity of 58.4% and a specificity of 69.5%. When early LSCC in TNM I stage was considered, tissue miR-155 showed an area under the curve of 0.804, with a sensitivity of 85.2% and a specificity of 87.3%. CONCLUSION: The expression of tissue and plasma miR-155 were significantly up-regulated in patients with LSCC. Our work will serve as a basis for further investigation, preferably large-scale validation in clinical trials.
Aged ; Biomarkers, Tumor/blood/*genetics ; Carcinoma, Squamous Cell/blood/diagnosis/*genetics ; Case-Control Studies ; Early Diagnosis ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Head and Neck Neoplasms ; Humans ; Laryngeal Neoplasms/blood/diagnosis/*genetics ; Male ; MicroRNAs/*blood ; Middle Aged ; Prognosis ; Real-Time Polymerase Chain Reaction ; Up-Regulation

BACKGROUNDAs the clinical value of cytokeratin-19 (CK19) and thymidine kinase-1 (TK1) in advanced gastrointestinal cancer remains controversial, we investigated their expression and clinical significance in this disease.

METHODSA total of 171 advanced gastrointestinal cancer patients were prospectively enrolled in this study. The mRNA level of CK19 was detected using quantitative real-time reverse transcription-polymerase chain reaction (PCR) in all patients, along with a control group of fifty healthy individuals. Furthermore, detection of TK1 protein was carried out in 96 patients using a chemiluminescence dot blot assay. The primary endpoint was overall survival (OS) time.

RESULTSPositive CK19 mRNA expression was detected in 74 (43.3%) of the 171 patients and positive TK1 expression was detected in 66 (68.8%) of the 96 patients. Furthermore, of the 96 patients, 36 (37.5%) were positive for both TK1 protein and CK19 mRNA, 30 (31.3%) were negative for TK1 protein, and 15 (15.6%) were negative for TK1 protein and positive for CK19 mRNA. The results indicated that patients who were positive for CK19 mRNA expression had significantly shorter OS times than those who were negative for it (median OS 7.7 vs. 9.7 months, respectively; P = 0.02). Moreover, patients who were positive for CK19 mRNA and TK1 protein expression had shorter OS times (median OS 6.1 months) than those who were positive for CK19 mRNA and negative for TK1 protein expression (median OS 9.1 months; P = 0.028). Positive CK19 mRNA expression was significantly associated with shorter OS in the univariate analysis (P = 0.027). Based on a multivariate Cox regression analysis, CK19 mRNA together with TK1 protein expression (P = 0.024) was an independent predictor for OS in gastrointestinal cancer patients.

CONCLUSIONSOur results suggest that positive expression of CK19 mRNA and TK1 protein is closely correlated with poor prognosis in advanced gastrointestinal cancer. Furthermore, both CK19 and TK1 are possible gastrointestinal cancer biomarkers.

Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; blood ; genetics ; Female ; Gastrointestinal Neoplasms ; blood ; genetics ; mortality ; Humans ; Keratin-19 ; blood ; genetics ; Male ; Middle Aged ; Prospective Studies ; Thymidine Kinase ; blood ; genetics

The death of patients with gastric cancer is mainly due to its recurrence and metastasis, and circulating tumor cell (CTC) is the necessary condition of metastasis. As liquid biopsy, CTC detection has its certain clinical significance. The detection is required after enrichment because circulating tumor cells are rare. Many enrichment methods have been developed: methods based on physical characteristics of TCT, like density, size and dielectric properties and so on; immunogenicity, like Cell Search System; and microfluidic chip technology. The immunofluorescence is commonly used to identify CTC in gastric cancer and the isolated CTC can also be used for the following analysis on the level of nucleic acid, protein and gene regulation. Detection of CTC in gastric cancer is helpful to judge the prognosis, assess staging, monitor the curative effect and guide the development of drug. There are many challenges for clinical transformation of CTC: the lower enrichment efficiency, the less specific surface markers, the uncertain diagnostic efficiency and so on, but it also has the good research prospect because it is non-invasive, repeatable and can real-time monitor the condition and guide the clinical treatment compared with pathological biopsy. In this paper, the detection and identification methods, and clinical value of CTC in gastric cancer patients are reviewed.
Biomarkers, Tumor ; Biopsy ; Cell Separation ; methods ; Cytodiagnosis ; methods ; Flow Cytometry ; methods ; Fluorescent Antibody Technique ; methods ; Humans ; Microchip Analytical Procedures ; methods ; Neoplasm Recurrence, Local ; prevention & control ; Neoplasm Staging ; methods ; Neoplastic Cells, Circulating ; metabolism ; pathology ; Prognosis ; Secondary Prevention ; Stomach Neoplasms ; blood ; diagnosis ; genetics ; therapy ; Treatment Outcome

BACKGROUND: Macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-9 (MMP-9), and its specific tissue inhibitor - tissue inhibitor of metalloproteinases-1 (TIMP-1) may play an important role in the pathogenesis and spread of cancer. We investigated the plasma levels of M-CSF, MMP-9, and TIMP-1 in comparison with a commonly accepted tumor marker CA 15-3 in breast cancer patients and in control groups. METHODS: The cohort included 110 breast cancer patients in groups at stages I-IV. The control group consisted of 50 healthy volunteers and 50 benign tumor patients. Plasma levels of M-CSF, MMP-9, and TIMP-1 were determined by using ELISA, while CA 15-3 concentrations were determined by using chemiluminescent microparticle immunoassay (CMIA). RESULTS: The results showed significant differences in concentrations of the analyzed parameters and in levels of CA 15-3 between the groups of breast cancer patients and the two control groups. Diagnosis using these markers was equal to that using CA 15-3 in terms of sensitivity, predictive values of positive and negativetest results (PPV, NPV) and area under the ROC curve (AUC) in the studied groups. The diagnostic specificities of MMP-9, TIMP-1, M-CSF, and CA 15-3 showed equally high values (95%). The combined use of all tested parameters with CA 15-3 resulted in increased sensitivity, NPV, and AUC, especially in the combination of M-CSF with tumor markers (76%, 64%, and 0.8653). CONCLUSIONS: These findings suggest the tested parameters are useful in the diagnosis of breast cancer patients (except stage I), when combined with CA 15-3.
Adult ; Aged ; Area Under Curve ; Biomarkers, Tumor/*blood ; Breast Neoplasms/*diagnosis/genetics/pathology ; Case-Control Studies ; Female ; Humans ; Macrophage Colony-Stimulating Factor/*blood ; Matrix Metalloproteinase 9/*blood ; Middle Aged ; Mucin-1/blood ; Neoplasm Staging ; Poland ; ROC Curve ; Sensitivity and Specificity ; Tissue Inhibitor of Metalloproteinase-1/*blood