66 chapter 2 et al. also performed the Afirma® GEC. The GEC yielded less false negatives and a much higher sensitivity. Even though technical limitations of the applied sequencing techniques could leave RNA transcriptions with low expression levels undetected and thus negatively influence sensitivity of the TCGA set, the scopes of the TCGA and GEC most likely explain their difference in performance. The TCGA was developed using PTC only. It did not include follicular lesions and their distinctive genetic alterations. Moreover, in contrast to the GEC, the TCGA set was not optimized for preoperative diagnostic application in indeterminate thyroid nodules [336]. Consequently, the comparison performed by this Veracyte-sponsored study seems unjust: it is obvious that the Afirma® GEC yielded better diagnostic performance in this specific clinical setting. Yet, the results of this study did prove that a large panel of genetic alterations such as the TCGA was not useful in clinical practice without further expansion of the scope of the panel towards follicular thyroid neoplasms. Still, the genetic alterations and their relations detected by TCGA are ground-breaking for the progression of research. From these comprehensive sets of biomarkers, we may select new combinations of genetic alterations for future clinical research to develop an accurate rule-in or rule-out molecular test for indeterminate thyroid nodules. Proteomics Other molecular advances include protein expression diagnostics, or proteomic profiling. These techniques allow for more detailed insight in the molecular biology and protein expression of thyroid neoplasms. For example, matrix-assisted laser desorption ionization / mass spectrometry imaging (MALDI-MSI) is able to simultaneously visualize the spatial distribution of proteins and profile up- and downregulated protein expression in relation to the morphological features of the thyroid specimen. These and related proteomic techniques could identify new biomarkers for preoperative cytological diagnosis, but require high levels of expertise. Application to thyroid cytology has so far been investigated by few studies [337, 338]. Ex-vivo cytology studies show accurate and reproducible differentiation between various lesions, including the currently difficult to diagnose Hürthle cell neoplasms [338]. No studies investigated the diagnostic value of proteomics in in-vivo indeterminate thyroid cytology yet.
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