17 General introduction and outline of this thesis 1 PET/CT in indeterminate thyroid nodules, international guidelines acknowledged its potential but stopped short of recommending its routine use, because randomized controlled trials to validate the impact of [18F]FDG-PET/CT on improved patient outcomes were lacking [17, 39, 40]. And thus, the EfFECTS trial was designed. Aim Confirming the position of [18F]FDG-PET/CT in the diagnostic workup of cytologically indeterminate thyroid nodules is central to this thesis. To achieve this, all efficacy levels that are involved in the implementation of a new imaging strategy are investigated. The ultimate aim of this thesis is to improve the diagnostic workup of indeterminate thyroid nodules and reduce unbeneficial patient management, including unbeneficial diagnostic tests as well as futile diagnostic surgical procedures, to benefit the individual patient as well as our health care system on a societal level. Outline This thesis consists of three parts. Part I provides an introduction to additional diagnostics for cytologically indeterminate thyroid nodules. Chapter 2 provides a comprehensive, systematic overview of the literature on additional diagnostic tests for indeterminate thyroid nodules. This review discusses the complete range of available molecular and imaging biomarkers, from conventional tests such as ultrasound and immunocytochemistry, to state-of-the-art techniques including [18F]FDG-PET/CT and molecular diagnostics. Besides discussing the ability of each test to distinguish between malignant and benign indeterminate nodules in a pre-operative setting, we also zoom in on clinical validation and utility, cost-effectiveness and availability of these techniques, where appropriate. Chapter 3 zooms in further on imaging biomarkers and reviews non-invasive diagnostic imaging techniques for indeterminate thyroid nodules, from conventional to artificialintelligence-based imaging. Part II investigates the efficacy of [18F]FDG-PET/CT in indeterminate thyroid nodules. In Chapter 4, the main results of the EfFECTS trial are presented. In a Dutch multicentre setting, the safety and impact of an [18F]FDG-PET/CT-driven diagnostic workup for Bethesda III/IV thyroid nodules is assessed in a randomized comparison to diagnostic surgery without additional preoperative diagnostics. The primary objective of this study is to accurately reduce the rate of unbeneficial patient management, i.e., avoid futile diagnostic surgery for benign nodules and wrongful avoid active surveillance for malignant and borderline nodules that do require surgical resection. Secondary objectives include the influence of [18F]FDG-PET/CT-driven management on the surgical complication rate, general HRQoL using the EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaire, societal costs, diagnostic
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