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    • vorapaxar Serum biomarkers could be used as

    2018-11-14

    Serum biomarkers could be used as an invasive, cost-effective way to differentiate lung cancer patients. Several serum tumor markers have been studied extensively, such as carcinoembryonic antigen (CEA), serum cytokeratin 19 fragments, and pro-gastrin-releasing peptide; however, none has been demonstrated to provide clinical utility, mainly because of the poor reproducibility and lack of sufficient sensitivity and specificity (Buccheri et al., 2003; Pastor et al., 1997). Recently, we described a non-invasive diagnostic system on Luminex xMAP platform to detect serum autoantibodies for diagnosis of lung cancer (Jia et al., 2014). Given the biological properties of cancer as a systemic disease, we predict that a combination of cancer associated serum vorapaxar and autoantibody can be used to achieve superior levels of sensitivity and specificity. Here, we identified a diverse set of circulating proteins in the sera of patients with lung cancer and designed a large-scale, multicenter validation study to evaluate their utility in distinguishing lung cancer patients from matched healthy controls, with the goal of using these biomarkers to aid clinicians in making case management decisions.
    Methods
    Results A total of 844 patients with lung cancer were included in this study, 40 in the discovery cohort, 543 in the training cohort and 261 in the validation cohort (Fig. 1). The healthy controls included 620 healthy participants. There is no significant difference in term of age and sex in both case and control groups, however, more current smokers in cases than controls. Clinicopathological characteristics of the study participants are summarized in Table 1. We also recruited 70 patients with various benign lung diseases, and 80 blinded patients with suspicious pulmonary nodule detected by LDCT. All these high-risk patients were either continuously followed for 2years or underwent surgical resection if the CT image progressed. Our objective for the discovery phase was to identify a robust subset of biomarkers to discriminate the patients with lung cancer from the matched controls. Of the 20 circulating proteins evaluated in our study (Supplementary Fig. 1), three proteins, namely C-reactive protein (CRP), prolactin and hepatocyte growth factor (HGF), were found to differ significantly between the lung cancer and control group (p<0.01) (Fig. 2A). Previously, we had demonstrated that circulating autoantibody against cancer-testis antigen NY-ESO-1 had the potential to separate patients with lung cancer from healthy participants in a multivariate statistical model (Jia et al., 2014). In this study, we further validated its performance and found that NY-ESO-1 autoantibody was significantly higher in patients with lung cancer than healthy controls (p<0.05) (Fig. 2A), indicating its discriminatory utility for lung cancer detection. The panel of 4 biomarkers consisted of three serum proteins and one autoantibody was further analyzed in the training and validation cohorts to determine their clinical utilities for non-invasive detection of lung cancer in a larger set of cases and controls. Importantly, the biomarkers were elevated in the cases with lung cancer in the training set than in the controls with a p value<0.05. The scatter dot plots of these biomarkers appear in Fig. 2. The mean concentrations for CRP, Prolactin, HGF and NY-ESO-1 antibody in cancer group vs control group of the population are 18.20μg/mL (95% CI 16.59–19.80) vs 5.03μg/mL (95% CI 4.11–5.90), 1.27ng/mL (95% CI 1.19–1.34) vs 1.03ng/mL (95% CI 0.96–1.11), 0.36ng/mL (95% CI 0.33–0.38) vs 0.22ng/mL (95% CI 0.21–0.23) and 2.19 RU (95% CI 1.75–2.61) vs 1.06 RU (95% CI 1.02–1.10), respectively. As expected, the mean concentration of CEA in serum was higher in the cancer group compared with that in healthy controls (p<0.001). There is no correlation between the 4 biomarkers and the clinical factors, such as gender, age and smoking status (Supplementary Table 1).