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The Standardized Uptake Value (SUV) in single lesions on 18F-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUV mean/max , metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up. In 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed. S-100B was elevated (>0.15 μg/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R2 = 0.19). S-100B was correlated to both MATV (R2 = 0.375) and TLG (R2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p < 0.001) and also in patients with elevated LDH (>250 U/l) (p < 0.001). There was no association between the biomarkers and SUV mean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival. In newly diagnosed stage IV melanoma patients S-100B correlates with 18F-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis. [ABSTRACT FROM AUTHOR]