18 chapter 1 and therapeutic consequences of incidental PET/CT findings, and to assess the implementability of [18F]FDG-PET/CT. Whereas a visual analysis of the [18F]FDG-PET/CT images is applied in Chapter 4, Chapter 5 discusses whether quantitative [18F]FDG-PET/CT assessment improves the preoperative differentiation of indeterminate thyroid nodules. These assessments include receiver operating characteristic curve analysis and threshold analysis using the standardized uptake value (SUV) and SUV ratios, as well as radiomic analysis of [18F]FDG positive nodules, with a specific focus on separate evaluation of nodules with non-oncocytic and oncocytic cytology. Chapter 6 describes an extensive cost-utility analysis of an [18F]FDG-PET/CT-driven workup as compared to diagnostic surgery for indeterminate thyroid nodules. The observed 1-year data from the EfFECTS trial are first used to calculate the 1-year societal costs and QALYs. Subsequently, these data are extrapolated using a 12-health state Markov Model to estimate lifelong cost-effectiveness. Univariate sensitivity analyses are performed to evaluate the impact of individual model probabilities, costs, and utilities. In Chapter 7, the HRQoL of an [18F]FDG-PET/CT-driven diagnostic workup is studied in greater detail, using the EQ-5D-5L, the RAND 36-item Health Survey v2.0, and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire. In order to most genuinely distinguish the impact of the [18F] FDG-PET/CT scan, its consequent surgical or non-surgical management, and a benign or malignant histopathological diagnosis, patients were categorised into three groups for this study: patients who underwent diagnostic surgery and had (1) benign or (2) malignant histopathology, and (3) patients who had an [18F]FDG-negative nodule and underwent active surveillance. As the last original chapter of this part of the thesis, Chapter 8 explores the association between [18F]FDG uptake and the quantitative expression of several immunohistochemical markers related to glucose metabolism, hypoxia, and cell proliferation. This study aims to expand the understanding of the metabolic changes in benign and malignant thyroid nodules of indeterminate cytology, and better understand why part of the benign nodules are [18F]FDG-positive while others are not. Chapter 9 discusses how the results of the EfFECTS trial should be interpreted in light of previous literature, and considers the trials’ limitations. It also attempts to explain how the varying results from these and other trials using [18F]FDG-PET/CT in indeterminate nodules may be explained by varying inclusion criteria and definitions, progressive insights in thyroid cyto- and histopathology, improved cytological differentiation, and technical advances in PET imaging including the transition from PET to PET/CT. In Chapter 10, we respond to the latest version of the French thyroid guidelines, the SFA-AFCE-SFMN 2022 consensus on the management of thyroid nodules, which appeared not long after the main results of the EfFECTS trial were published. In these guidelines, [18F]FDG-PET/CT is not recommended in indeterminate thyroid nodules. Part III explores the efficacy of molecular diagnostics in thyroid nodules. Chapter 11 describes the copy number alteration patterns and loss of heterozygosity (CNA-LOH) that can be distinguished in benign and malignant oncocytic thyroid nodules using a custom 1,500 single-nucleotide polymorphism next-generation sequencing panel that is feasible for clinical practice, and provides considerations for their structured interpretation. In Chapter 12, the diagnostic accuracy of molecular
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