A nuclear medicine physician assessed all scans for routine care at the time they were performed. All 18F-FDG avid tumor lesions were reassessed by three investigators (AMH, AHB, PG). A region of interest (ROI) was drawn around each visible 18F-FDG avid tumor lesion. In case of doubt whether an 18F-FDG avid tumor lesion was malignant, the images were reviewed together with the corresponding CT images. Based on the threshold method, the tumor lesion's 18F-FDG uptake was determined based on all voxels with an uptake higher than 40% of the maximum measured standardized uptake value (SUVmax) in the ROI 26. The mean of all SUVs measured in these voxels (SUVmean) was used as the parameter for tumor lesion glucose uptake per ROI. SUVmean was chosen since it represents the overall uptake value in the measured area, instead of SUVmax which represents just one voxel 27. SUVmean values were corrected for patients' serum glucose levels according to the EARL guidelines (SUVcorrected = SUVmeasured × (fasting serum glucose level (mmol/L) / 5)) 24,25. These corrected SUVmean values were used for all analyses unless indicated otherwise. The volume of the area on the PET image in which the SUVmean was determined was defined as the MTV 28.

The analysis of glucose uptake was only performed for tumor lesions with a MTV ≥1 mL to avoid underestimation of SUVs in smaller tumor lesions due to partial volume effects (PVE). PVE refers to factors influencing the measured amount of radioactivity within a volume of interest (e.g. tumor), such as the spatial resolution of the imaging system, the size and shape of the tumor lesions, and reconstruction procedures followed after acquisition of the images 29. The cut-off value of 1 mL was chosen based on the resolution of the camera used. For determining the sum of the MTV measured in all tumor lesions per patient (MTVpatient), tumor lesions with a MTV <1 mL were taken into account to minimize underestimation of the total volume. The range of all measured SUVmean values in a patient was used as a measure for intra-patient heterogeneity and was defined as the highest minus the lowest SUVmean value measured in all tumor lesions per patient. Since no studies have been performed to determine cut-off values for high 18F-FDG uptake using SUVmean, cut-off values were chosen based on published SUVmax data. High tumor glucose uptake was defined as a SUVmean >5 and very high glucose uptake as a SUVmean >8 30-34.

18F-FDG uptake in the ROIs and the associated volumes were calculated using AMIDE software, which provides raw non-smoothed data, as described in the supplemental methods.

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