414 chapter 8 and [18F]FDG uptake are also associated in various cancer types [628, 629]. Finally, as [18F]FDG uptake is related to tumour dedifferentiation in thyroid carcinoma, an inverse relationship is observed between [18F]FDG and iodine uptake. While the glucose metabolism enhances, dedifferentiating thyroid carcinomas gradually lose their functional iodine uptake, reflected by the loss of the basal membranous expression of the sodium-iodide symporter (NIS) [630-632]. The association between [18F]FDG uptake and the expression of various metabolic markers has been investigated in papillary thyroid carcinoma (PTC) in a limited number of studies with mixed results [487, 615, 623, 628, 633-635]. Studies in other benign and malignant thyroid nodules infrequently included [18F]FDG-PET/CT data [619-621, 624, 628, 635-638]. To the best of our knowledge, no studies were previously performed in cytologically indeterminate thyroid nodules. In the current study, we explored the association between [18F]FDG uptake and the expression of immunohistochemical markers related to glucose transport, glucose metabolism, hypoxia, and cell proliferation in (hemi)thyroidectomy specimens of thyroid nodules with indeterminate cytology. We aimed to find correlations to explain why many benign thyroid nodules show increased [18F]FDG uptake and why the specificity of [18F]FDG-PET/CT is limited in indeterminate nodules, ultimately aiming to better understand the pathophysiology of these nodules. Material and Methods Study design and case selection The study included patients with a Bethesda III or IV thyroid nodule who underwent an [18F]FDGPET/CT scan of the neck and had diagnostic thyroid surgery in the context of their participation in the Efficacy of FDG-PET in Evaluation of Cytological indeterminate Thyroid nodules prior to Surgery (EfFECTS) trial. This prospective, randomized controlled multicentre trial included 132 patients and was performed in 15 hospitals in the Netherlands between July 2015 and December 2019 (Clinicaltrials.gov: NCT02208544). Inclusion criteria and comprehensive study procedures of this trial were previously described [501]. For the current explorative study, including post hoc analyses of the trial data, an individually matched case-control design was chosen. We aimed to include 24 patients in three groups: eight true-positives (TP), defined as patients with a visually [18F] FDG-positive and histopathologically malignant index nodule (i.e., differentiated (non-medullary) thyroid carcinoma), eight false-positives (FP), defined as patients with a visually [18F]FDG-positive and histopathologically benign index nodule, and eight true-negatives (TN), defined as patients with a visually [18F]FDG-negative and histopathologically benign index nodule. [18F]FDG-negative,
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