@article{discovery1478233,
            note = {Copyright {\copyright} 2015 American Association for Cancer Research. The final, published version of the article is available on the AACR journal website at http://dx.doi.org/10.1158/1078-0432.CCR-15-0879},
          volume = {22},
           pages = {1734--1743},
          number = {7},
           month = {April},
         journal = {Clinical Cancer Research},
            year = {2016},
           title = {Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus},
          author = {Jenkinson, C and Elliott, VL and Evans, A and Oldfield, L and Jenkins, RE and O'Brien, DP and Apostolidou, S and Gentry-Maharaj, A and Fourkala, EO and Jacobs, IJ and Menon, U and Cox, T and Campbell, F and Pereira, SP and Tuveson, DA and Park, BK and Greenhalf, W and Sutton, R and Timms, JF and Neoptolemos, JP and Costello, E},
            issn = {1078-0432},
        abstract = {PURPOSE: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated. EXPERIMENTAL DESIGN: Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS,n= 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n= 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n= 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model. RESULTS: iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively;P{\ensuremath{<}} 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P{\ensuremath{<}} 0.05) and patients with benign biliary obstruction (P{\ensuremath{<}} 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P{\ensuremath{<}} 0.05) and at clinical diagnosis (P{\ensuremath{<}} 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P{\ensuremath{<}} 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P= 0.01). CONCLUSIONS: Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies.},
             url = {http://dx.doi.org/10.1158/1078-0432.CCR-15-0879}
}