490 chapter 12 In the current study, a wide range of molecular alterations was observed in small numbers and it was not possible to correlate the type of molecular alteration to the [18F]FDG uptake (i.e., SUV max). In the discordant cases (Table 7), we found two DICER1, two PTEN, one NRAS, one TERT, one EGFR, and one CDKN2A mutation, and one ETV6/NTRK3 fusion. To the best of our knowledge, none of these mutations has previously been investigated in relation to [18F]FDG uptake in thyroid disease. Somatic DICER1 and isolated PTEN mutations are primarily associated with benign thyroid nodules, although somatic DICER1 mutations are also seen in different forms of paediatric thyroid carcinoma and in 5%-10% of adult follicular thyroid carcinoma [709, 710]. NRAS is the most frequently observed RAS variant and has a 38%-65% rate of malignancy in ITN [711]. The rate of malignancy in ITN with an NTRK fusion is >95% [712]. In presence of concurrent mutations, TERT promotor and loss-offunction CDKN2A mutations are associated with aggressive tumour behaviour and PTC or anaplastic thyroid carcinoma, respectively. Isolated TERT promotor mutations are occasionally described in benign disease [698, 713-715]. Mostly known for their presence in non-small cell lung cancer, EGFR mutations are observed in PTC, too [716]. To the best of our knowledge, the correlation between isolated CDKN2A or EGFR mutations and benign thyroid disease has infrequently been studied [717]. The costs of MD and [18F]FDG-PET/CT should also be taken into consideration. In the Netherlands, costs of a partial-body [18F]FDG-PET/CT are approximately €754 ($793; $1 = €0.95 on 28-09-2023) [28]. The costs of MD are estimated at approximately €800 ($841) per patient (on average, range €450-€1350 [$473-$1,420]) based on the careful sequential application of the custom NGS panels in non-oncocytic cytology as performed in the current study (Supplementary data). A careful costutility analysis is required to determine cost-effectiveness of the combined use of MD and [18F] FDG-PET/CT, also considering the cost savings of the reduction of unbeneficial thyroid surgeries for benign nodules, costs for active surveillance or delayed treatment for initially missed malignancies, and other lifelong societal costs. [18F]FDG-PET/CT was previously estimated cost-effective in a Dutch setting, saving nearly €10,000 ($10,517) in lifelong societal costs while sustaining health-related quality of life [28, 718]. The MD panels that were applied in the current study were previously estimated cost-effective for Bethesda III and V nodules [525]. Previous cost-effectiveness studies of commercial MD panels demonstrated varying results from an American perspective [495, 496, 579, 719]. The preoperative differentiation of ITN may improve if an ultrasound classification system such as EU-TIRADS or ATA is applied in addition to [18F]FDG-PET/CT, but may not in addition to MD [17, 39, 40, 720]. Although ultrasound classification systems are part of routine clinical practice today, their use was very limited when the EfFECTS trial was initiated in 2015. For the current study, per protocol, data was unavailable to compare all three diagnostics with each other [501]. The main limitation of the current study is the rate of nondiagnostic MD results on cytology and consequent exclusion of patients for the primary analysis. Fortunately, the excluded patients were
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