289 Non-invasive imaging biomarkers 3 showed that [18F]FDG PET/CT decreased the number of futile surgeries by 47%, thereby reducing the expected 5-year direct medical costs per patient by €822 (from €8,804 to €7,983) as compared to surgical treatment while maintaining health-related quality of life (HRQoL). This study also concluded that, from a European perspective, [18F]FDG PET/CT would be cost-effective over molecular testing [53]. Another cost-effectiveness study performed by the same group was recently conducted using the observed health care consumption and HRQoL data of the EfFECTS trial, which had found a similar reduction in futile surgeries [460]. This study assessed all societal costs over a lifelong horizon, and found that an [18F]FDG PET/CT-driven management reduced the lifelong societal costs by almost €10,000 as compared to diagnostic surgery, with similar HRQoL for both strategies. While diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, the reassurance of a negative [18F]FDG PET/ CT resulted in sustained HRQoL throughout the first year of active surveillance [461]. Combined approaches Every currently known engagement point from the genotype to the phenotype of the tumour is being explored. Combined, the various research fields encompass an extensive range of investigative methods. Individually they usually focus on one or two methods only, making one-to-one comparison of these diagnostics difficult. The 2015 American Thyroid Association (ATA) guidelines suggested several additional tests, but a definitive answer or complete overview of all available tests is still lacking [17]. Alongside higher-level expert discussions and lobbying of MedTech companies, clinical endocrinologists and thyroid surgeons ponder about the best solution for their individual patients. Their choices depend on the characteristics of their patient populations, availability and costs of a certain test, and personal preference. In any case, a useful additional test should be accurate, accessible, affordable, and affect patient management. A multimodal stepwise approach using a sensitive rule-out test and a specific rule-in test might provide the most conclusive diagnosis, e.g., in a specific test a relatively higher threshold value may be recommended to minimise missing malignancy in screening, while when appended to another diagnostic test, a relatively lower threshold value may be recommended to reduce false-positive results. Nevertheless, research into combined approaches is limited. Piccardo et al. compared [18F]FDG PET/CT, multiparametric US (including elastosonography), and [99mTc]Tc-MIBI scintigraphy in 87 nodules with indeterminate cytology (according the Società Italiana di Anatomia e Citologia Patologica-International Academy of Pathology classification published in 2010), wherefrom 18 nodules were found to be malignant in histopathology. Separately, [18F] FDG PET/CT outperformed qualitative multiparametric US and [99mTc]Tc-MIBI scintigraphy for the detection of thyroid malignancy. Also, combined approaches were evaluated, demonstrating that (1) a negative [18F]FDG PET/CT correctly predicted benign findings on histopathology, (2) a positive
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