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We prospectively evaluated whether the combination of ultrasound (US) risk stratification and molecular testing improves the assessment of malignancy risk in Bethesda Category IV thyroid nodules.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Ninety-one consecutively diagnosed Bethesda Category IV thyroid nodules were prospectively evaluated before surgery by both ACR- and EU-TIRADS US risk-stratification systems and by a further US-guided fine-needle aspiration cytology (FNAC) for the following molecular testing: BRAFV600E, N-RAS codons 12\/13, N-RAS codon 61, H-RAS codons 12\/13, H-RAS codon 61, K-RAS codons 12\/13, and K-RAS codon 61 point-mutations, as well as PAX8\/PPAR\u03b3, RET\/PC1, and RET\/PTC 3 rearrangements.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>At histology, 37% of nodules were malignant. No significant association was found between malignancy and either EU- or ACR-TIRADS. In total, 58 somatic mutations were identified, including 3 BRAFV600E (5%), 5 N-RAS 12\/13 (9%), 13 N-RAS 61 (22%), 7 H-RAS 12\/13 (12%), 11 H-RAS 61 (19%), 6 K-RAS 12\/13 (10%), 8 K-RAS 61 (14%) mutations and 2 RET\/PTC1 (4%), 0 RET\/PTC 3 (0%), 3 PAX8\/PPAR\u03b3 (5%) rearrangements. At least one somatic mutation was found in 28% and 44% of benign and malignant nodules, respectively, although malignancy was not statistically associated with the outcome of the mutational test. However, the combination of ACR-, but not EU-, TIRADS with the presence of at least one somatic mutation, was significantly associated with malignant histology (<jats:italic>P<\/jats:italic>\u2009=\u20090.03).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>US risk stratification and FNAC molecular testing may synergistically contribute to improve malignancy risk estimate of Bethesda category IV thyroid nodules.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s40618-021-01571-y","type":"journal-article","created":{"date-parts":[[2021,4,16]],"date-time":"2021-04-16T05:43:43Z","timestamp":1618551823000},"page":"2635-2643","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Combination of ultrasound and molecular testing in malignancy risk estimate of Bethesda category IV thyroid nodules: results from a single-institution prospective study"],"prefix":"10.1007","volume":"44","author":[{"given":"M.","family":"Marina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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