536 Appendices the malignancy risk stratification of oncocytic thyroid nodules. To aid the transparency in future MD research and to aid physicians to implement these molecular methods in their own daily practice, we finally provided considerations for the structured interpretation of the described CNA patterns. Chapter 11 also formed the methodological basis for part of the MD presented in Chapter 12, in which these CNA-LOH analysis methods were validated in the prospective EfFECTS trial cohort. In Chapter 12, the final original chapter of this thesis, the diagnostic accuracy of MD was compared to [18F]FDG-PET/CT in indeterminate thyroid nodules for the first time. Using the EfFECTS trial cohort and its [18F]FDG-PET/CT data as described in Chapter 4, MD was additionally performed on cytology smears and - if unavailable or nondiagnostic on cytology - additionally on histopathological specimens using custom next generation sequencing panels for somatic mutations, gene fusions, and the CNA-LOH panel as described in Chapter 11. We compared the diagnostic accuracy of MD and [18F]FDG-PET/CT, and showed that with 80% (95% CI, 61%-92%) and 93% (78%-99%) sensitivity and 57% (47%-66%) and 32% (24%-42%) benign call rates, respectively, MD and [18F]FDG-PET/CT are both accurate and useful rule-out tests in Bethesda III/IV nodules. In line with the results from Chapter 4 and Chapter 11, Chapter 12 showed that MD was the superior techniques in oncocytic indeterminate thyroid nodules, with 88% (95% CI, 47%-100%) sensitivity and a 38% (21%-58%) benign call rate. Next, we assessed the therapeutic efficacy of the combined use of both techniques - putting our hypothesis from Chapter 2 on multimodality stepwise diagnostics to the test. MD and [18F]FDG-PET/CT were concordant in 63% of patients and although both techniques were complementary, benefits of their combined use were likely confined when therapeutic consequences were considered. Their combined application should therefore not routinely be recommended. Only in non-oncocytic indeterminate thyroid nodules, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic indeterminate thyroid nodules, after further validation studies, MD might be considered. Finally, supporting the hypothesis in Chapter 8 that molecular alterations may drive the differences in [18F]FDG uptake that is observed in benign nodules, we demonstrated that there were more MD positive nodules among the [18F]FDG positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [18F]FDG negative benign nodules (7/30, 19%, p=0.02). Part IV: epilogue In the epilogue, this thesis concluded with a general discussion on the studies presented in this thesis and future prospects. Some of the remaining challenges in the optimization of the diagnosis and management of indeterminate thyroid nodules were extensively vetted, including the current thyroid guidelines and the progressive insights from their most recent versions. Also, based on our experiences from the EfFECTS trial, we discussed the current and future challenges for clinical practice and diagnostic (randomized-controlled) research.
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