415 [18F]FDG uptake and expression of immunohistochemical markers 8 histopathologically malignant index nodules (i.e., false-negative [18F]FDG-PET/CT) are rare and were not selected for the current study [501]. Prior to any immunohistochemical study procedures, patients were selected for the current study from the original trial cohort by two of the researchers (EK and DV) based on the best possible match of individual patients between the three study groups whilst securing a balanced selection of histopathological diagnoses within groups, representative for the diagnoses found in the original trial and with a representative range in the degree of [18F]FDG uptake (expressed as the maximum standardized uptake value, or SUVmax, in g/mL) per diagnosis [501]. Between groups, patients were matched based on sex, age at the time of the [18F]FDG-PET/CT scan, histopathological size of the index nodule, and the presence of Hürthle cells in the histopathology sample. TP and FP cases were additionally matched based on the SUVmax of the index nodule. Patients were not eligible for inclusion in the current study if the thyroid nodule was smaller than 10 mm (due to possible limitations regarding the spatial resolution of the PET/CT scanner), if there was either an [18F]FDG-positive hotspot within an [18F]FDG-positive nodule or central photopenia (to limit the possibility of sampling error), if the [18F]FDG-PET/CT images showed signs of thyroiditis throughout the thyroid including the index nodule, if the last fine needle aspiration cytology procedure (FNAC) and [18F]FDG-PET/CT scan were less than four weeks apart (i.e., to limit the possibility of [18F]FDGpositivity due to reactive tissue damage repair changes following FNAC), if no histopathology was available (i.e., following patient treatment allocation in the EfFECTS trial), and/or if review of the histopathology showed signs of lymphocytic thyroiditis or necrosis in the index nodule (i.e., to limit the possibility of false-positive or false-negative [18F]FDG-PET/CT readings, respectively). The trial, including the current secondary analysis, was approved by the Medical Research Ethics Committee on Research Involving Human Subjects region Arnhem-Nijmegen, Nijmegen, the Netherlands. Written informed consent was obtained from each of the participants prior to any study activities. FDG-PET/CT acquisition, reconstruction and analysis During the EfFECTS trial, all participants underwent a single [18F]FDG-PET/CT of the neck. Scans were acquired by 20 different scanners at 12 EARL-accredited study sites using a standard acquisition and reconstruction protocol in accordance with European Association of Nuclear Medicine (EANM) guidelines [468]. Patients fasted for at least 6 hours and serum glucose levels were between 4 and 11 mmol/L. PET-acquisition was scheduled 60 (55-75) minutes after intravenous bolus administration of [18F]FDG. The administered activity was dependent on body weight, scan speed, bed overlap and scanner sensitivity, equivalent to 3.45 MBq/kg (4 min/bed, <25% bed overlap). Low-dose, noncontrast-enhanced CT (ldCT) scans were acquired for attenuation correction of PET images. All scans were centrally assessed by two independent, experienced nuclear medicine physicians (DV, LF). They were blinded to patient allocation and all clinical and cytological data except for
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