Summary 535 & Concluding this part of the thesis, in two letters to the editor in Chapter 9 and Chapter 10, our team advocated the added value of the results of the EfFECTS trial for the current diagnostic dilemmas in clinical decision making for indeterminate thyroid nodules and replied to the main concerns that were raised against the trials’ results: the limited follow-up of patients undergoing active surveillance for an [18F]FDG negative nodule, and the absence of the TI-RADS classification in trials’ main analysis. In Chapter 9, we furthermore described how [18F]FDG-PET(/CT) progressed as an additional diagnostic for indeterminate thyroid nodules over the past decades. The highly promising results from the first PET studies and the more modest and varying findings from more recent literature can be explained by the varying inclusion of smaller nodules, between-study heterogeneity due to global variations in case-mix, progressive insights in thyroid cyto- and histopathology (e.g., the implementation of the Bethesda system and the determination of FT-UMP and NIFTP as separate entities), and technical advances in PET imaging including the transition from PET to PET/CT and improved scanner resolution. In Chapter 10, we replied to the latest version of the French thyroid guidelines. These practice guidelines appeared after the main results of the EfFECTS trial were published but made no reference to its results and - above all - did not recommend the use of [18F]FDG-PET/CT in indeterminate thyroid nodules. In both Chapter 9 and Chapter 10, we concluded that the high level of evidence that was generated by the EfFECTS trial has confirmed the results from previous studies and has provided unique, valuable and practice-changing data, and that [18F]FDG-PET/CT should be offered to patients with indeterminate thyroid nodules in clinical practice. Part III. Efficacy of molecular diagnostics in indeterminate thyroid nodules Part III explored the efficacy of MD in the diagnostic work-up of thyroid nodules. In Chapter 11, we described the copy number alteration (CNA) and loss of heterozygosity (LOH) patterns that can be distinguished in benign and malignant oncocytic thyroid nodules. Whole-chromosome instability with near-whole genome haploidization (GH) and subsequent endoreduplication is considered a main genomic driver in the tumorigenesis of oncocytic thyroid neoplasms. As these CNA occur less frequently in oncocytic thyroid adenoma than in oncocytic carcinoma, a continuous process is suggested. The distinguished patterns included GH-type CNA without or with suspected genome doubling, which is associated with malignant disease, and the reciprocal chromosomal imbalance type CNA, which is associated with benign disease. We subsequently assessed the described patterns in a retrospective cohort of 30 benign and malignant oncocytic thyroid neoplasms using a custom, locally developed 1,500 single-nucleotide polymorphism next-generation sequencing panel. In contrast to other complex and time-consuming molecular methods, this panel is feasible for clinical practice. In this cohort, we demonstrated that the distinguished CNA patterns were different between the histopathological subgroups (p<0.001) and that CNA-LOH analysis using our custom panel could have great additional diagnostic value to
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