Background: Most neuroendocrine tumors express chromogranin A (CgA). The posttranslational processing of neuroendocrine proteins such as CgA is often specific for the individual tumor. To cope with this variability and improve tumor diagnosis, we developed a processing-independent analysis (PIA) method to measure the total CgA product. Methods: For PIA, samples underwent trypsin treatment followed by measurement of CgA by the "CgA(3403)" assay, in which the antiserum binds an epitope starting at amino acid 340 of CgA and including amino acid residues located in the C-terminal direction. The diagnostic accuracy of the CgA PIA and 3 sequencespecific assays for CgA were evaluated on plasma samples from patients with neuroendocrine tumors and small-cell lung carcinomas. Furthermore, we investigated whether the CgA plasma concentrations correlated with the tumor burden. Results: Size-exclusion chromatography of plasma showed that CgA immunoreactivity mainly consisted of high-molecular-weight forms, indicating that neuroendocrine tumors may secrete large amounts of poorly processed CgA. Accordingly, trypsination of plasma from 54 patients with neuroendocrine tumors or smallcell lung carcinomas increased the CgA(3403) immunoreactivity up to 500-fold. Both the CgA(3403) assay and the PIA measured significantly higher plasma concentrations in patients with very extensive disease than in patients with less widespread disease. The diagnostic

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