Summary 537 & Our society is facing enormous challenges to maintain the current accessibility and quality of our general health care system due to the (globally) aging population, rising societal health care costs, and increasing staffing shortages, among others. In light of the latter, it is highly relevant that we focus on effective de-escalation strategies to support the selective use of valuable resources and prevent overdiagnosis and overtreatment of asymptomatic benign thyroid nodules as well as other low-risk thyroid neoplasms to manage the increasing number of thyroid nodules. Before implementing costly techniques to optimize the diagnostic workup, local implementability and costutility should be deliberated, preferably based on carefully performed cost-utility studies. Moreover, patient and societal outcomes (i.e., clinical utility, higher levels of evidence) rather than mere diagnostic accuracy should likely become the standard for progressive research on the development of diagnostic strategies. One should critically consider the most appropriate study design to achieve this goal, as diagnostic randomized controlled trials are especially complex to design and manage well with regard to bias, blinding, and diagnostic misconception, as we experienced during the execution of the EfFECTS trial. In addition, patient-bound implementabilityrelated factors, such as diagnostic confidence, should be considered, too. In clinical trials, active surveillance will likely remain challenging as the reference standard, as its validity is determined by the duration and quality of the follow-up. This especially applies to index conditions with limited morbidity and mortality, such as differentiated thyroid carcinoma, for which long follow-up will be required. In global PET/CT research, the main challenges are in harmonizing PET protocols to enable highquality multicentric collaborations and in smart solutions to limit the use of valuable resources (e.g., scanner time) and/or exposure to ionizing irradiation, such as partial-body scanning for the right indications. The future of thyroid nodule diagnostics, including cytological and histopathological assessments, may be based on tumour biology rather than morphology. This is endorsed by various conclusions from this thesis, including the recurring, clear conclusion that oncocytic indeterminate thyroid nodules should be treated as a separate entity with different tumour genotype and phenotype than non-oncocytic nodules. Finally, from the studies presented in this thesis we concluded that [18F]FDG-PET/CT would be a valuable addition to the routine diagnostic workup of indeterminate thyroid nodules. In an oncologically safe manner, it cost-effectively reduces the number of unbeneficial diagnostic surgeries for benign nodules while sustaining HRQoL. The local decision favouring or opposing any additional diagnostic likely varies globally, depending on local multidisciplinary expertise, accessibility to different tests, case-mix, and cost-effectiveness considerations. To keep general health care accessible, more general challenges regarding health care expenditure and capacity should always be considered, too.
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