{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:51:30Z","timestamp":1785905490036,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background: Ultrasound-guided radiofrequency ablation (RFA) has become an established minimally invasive treatment for selected benign and autonomously functioning thyroid nodules. Although clinical outcomes are well documented, the biological mechanisms underlying tissue remodeling after ablation remain incompletely characterized. The integration of imaging, molecular, and histopathological data may provide a more comprehensive understanding of treatment response. Methods: We conducted a prospective monocentric observational translational cohort study including 60 patients undergoing ultrasound-guided RFA for benign or autonomously functioning thyroid nodules between November 2024 and December 2025. Patients underwent standardized pre-procedural assessment including high-resolution ultrasound with volumetric evaluation, three-dimensional reconstruction, and collection of peripheral blood samples for exploratory extracellular vesicle (EV)-derived microRNA (miRNA) profiling. Clinical outcomes, volumetric changes, vascular remodeling, and procedural complications were assessed during scheduled follow-up visits (mean follow-up duration: 11 months; range: 5\u201317 months). A subgroup of patients who subsequently required surgery because of insufficient volumetric response underwent thyroidectomy, allowing histopathological evaluation of post-ablation tissue changes. Clinical, imaging, molecular, and pathological data were integrated within a multimodal translational framework. Results: RFA resulted in a mean nodule volume reduction of 56% at early follow-up, with progressive volumetric reduction observed during longitudinal ultrasound evaluation. A clinically relevant improvement in compressive symptoms was observed, with a 44% reduction in symptom burden. Doppler ultrasound demonstrated progressive changes in vascular patterns consistent with post-ablation devascularization and tissue remodeling. Ten patients underwent thyroidectomy after RFA because of insufficient volumetric response, providing histological validation of treatment-induced tissue alterations, including coagulative necrosis, fibrosis, inflammatory changes, and architectural remodeling. Exploratory EV-derived miRNA profiling was incorporated into the translational workflow to investigate potential molecular correlates of treatment response; however, molecular findings require further validation in larger cohorts. Conclusions: This study provides a multimodal translational characterization of tissue response after thyroid RFA by integrating clinical outcomes, ultrasound imaging, histopathology, and exploratory EV-derived miRNA analysis. The proposed framework may contribute to a deeper understanding of biological changes following thermal ablation and support future investigations aimed at identifying reliable biomarkers of treatment response.<\/jats:p>","DOI":"10.3390\/jcm15156031","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T12:57:56Z","timestamp":1785761876000},"page":"6031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multimodal Assessment of Tissue Response After Thyroid Radiofrequency Ablation: Clinical, Imaging, Histopathological and Molecular Insights"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1926-5562","authenticated-orcid":false,"given":"Domenico","family":"Parmeggiani","sequence":"first","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerardo","family":"Amabile","sequence":"additional","affiliation":[{"name":"Casa Di Cura Ospedale Internazionale\u2014NefroCenter, 80121 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0151-8230","authenticated-orcid":false,"given":"Alessio","family":"Cece","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Surfaro","sequence":"additional","affiliation":[{"name":"Medibit SRL, 80123 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Moccia","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7368-258X","authenticated-orcid":false,"given":"Francesco","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"Luongo","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Miccio","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Sperlongano","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3122-5531","authenticated-orcid":false,"given":"Agostino","family":"Fernicola","sequence":"additional","affiliation":[{"name":"Operative Unit of General and Emergency Surgery, Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2314-4548","authenticated-orcid":false,"given":"Paola","family":"Della Monica","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5630-3956","authenticated-orcid":false,"given":"Federica","family":"Colapietra","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Di Domenico","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Clery","sequence":"additional","affiliation":[{"name":"Pathology Unit, Departement of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Agresti","sequence":"additional","affiliation":[{"name":"Department of Integrated Activities in Surgery, Orthopedy and Hepato-Gastroenterology, Universitary Policlinico \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato","family":"Franco","sequence":"additional","affiliation":[{"name":"Pathology Unit, Departement of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.21037\/gs-22-539","article-title":"Radiofrequency ablation of thyroid nodules: A clinical review of treatment complications","volume":"13","author":"Issa","year":"2024","journal-title":"Gland. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s12020-020-02598-6","article-title":"Radiofrequency ablation and thyroid nodules: Updated systematic review","volume":"72","author":"Muhammad","year":"2021","journal-title":"Endocrine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s12020-019-02019-3","article-title":"Efficacy of thermal ablation in benign non-functioning solid thyroid nodule: A systematic review and meta-analysis","volume":"67","author":"Trimboli","year":"2020","journal-title":"Endocrine"},{"key":"ref_4","unstructured":"Feingold, K.R., Adler, R.A., Ahmed, S.F., Anawalt, B., Blackman, M.R., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., and Dungan, K. (2000). Thermal Ablation for Thyroid Nodules. Endotext [Internet], MDText.com, Inc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.3348\/kjr.2024.0963","article-title":"Radiofrequency Ablation for Recurrent Thyroid Cancers: 2025 Korean Society of Thyroid Radiology Guideline","volume":"26","author":"Ha","year":"2025","journal-title":"Korean J. Radiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1159\/000508484","article-title":"2020 European Thyroid Association Clinical Practice Guideline for the Use of Image-Guided Ablation in Benign Thyroid Nodules","volume":"9","author":"Papini","year":"2020","journal-title":"Eur. Thyroid. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"632","DOI":"10.3348\/kjr.2018.19.4.632","article-title":"2017 Thyroid Radiofrequency Ablation Guideline: Korean Society of Thyroid Radiology","volume":"19","author":"Kim","year":"2018","journal-title":"Korean J. Radiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/cncr.30360","article-title":"2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: What is new and what has changed?","volume":"123","author":"Haugen","year":"2017","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/lio2.517","article-title":"RFA and benign thyroid nodules: Review of the current literature","volume":"6","author":"Muhammad","year":"2021","journal-title":"Laryngoscope Investig. Otolaryngol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"75","DOI":"10.14366\/usg.20112","article-title":"Radiofrequency ablation of benign thyroid nodules: Recommendations from the Asian Conference on Tumor Ablation Task Force","volume":"40","author":"Ha","year":"2021","journal-title":"Ultrasonography"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"89","DOI":"10.7863\/ultra.16.03043","article-title":"Most Thyroid Cancers Detected by Sonography Lack Intranodular Vascularity on Color Doppler Imaging: Review of the Literature and Sonographic-Pathologic Correlations for 698 Thyroid Neoplasms","volume":"36","author":"Yang","year":"2017","journal-title":"J. Ultrasound Med."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Cece, A., Agresti, M., De Falco, N., Sperlongano, P., Moccia, G., Luongo, P., Miele, F., Allaria, A., Torelli, F., and Bassi, P. (2025). Role of Artificial Intelligence in Thyroid Cancer Diagnosis. J. Clin. Med., 14.","DOI":"10.3390\/jcm14072422"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"De Falco, N., Agresti, M., De Falco, M., Sperlongano, P., Moccia, G., Luongo, P., Cece, A., Bove, F., Miele, F., and Allaria, A. (2025). Simultaneous Medullary and Papillary Thyroid Carcinomas: Personal Experience Report and Literature Review. J. Clin. Med., 14.","DOI":"10.3390\/jcm14041382"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Parmeggiani, D., Cece, A., Agresti, M., Miele, F., Luongo, P., Moccia, G., Torelli, F., Sperlongano, R., Bassi, P., and Savabi Far, M. (2026). Improved Multisource Image-Based Diagnostic for Thyroid Cancer Detection: ANTHEM National Complementary Plan Research Project. Appl. Sci., 16.","DOI":"10.3390\/app16020830"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1909","DOI":"10.1007\/s13304-021-01140-1","article-title":"Hemithyroidectomy versus total thyroidectomy in the intermediate-risk differentiated thyroid cancer: The Italian Societies of Endocrine Surgeons and Surgical Oncology Multicentric Study","volume":"73","author":"Dobrinja","year":"2021","journal-title":"Updates Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1159\/000478927","article-title":"European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: The EU-TIRADS","volume":"6","author":"Russ","year":"2017","journal-title":"Eur. Thyroid. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1148\/radiol.2373050220","article-title":"Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement","volume":"237","author":"Frates","year":"2005","journal-title":"Radiology"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Li, S., Yu, M.A., Zhao, Z.L., Wei, Y., Peng, L.L., and Li, Y. (2025). Changes in thyroid function after thermal ablation of thyroid nodules. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1557725"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"661","DOI":"10.14366\/usg.21231","article-title":"Long-term follow-up of the radiofrequency ablation of benign thyroid nodules: The value of additional treatment","volume":"41","author":"Kim","year":"2022","journal-title":"Ultrasonography"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Mauri, G., Orsi, F., Carriero, S., Della Vigna, P., De Fiori, E., Monzani, D., Pravettoni, G., Grosso, E., Manzoni, M.F., and Ansarin, M. (2021). Image-Guided Thermal Ablation as an Alternative to Surgery for Papillary Thyroid Microcarcinoma: Preliminary Results of an Italian Experience. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.575152"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1055\/s-0041-1731377","article-title":"Radiofrequency Ablation of Benign Thyroid Nodules","volume":"38","author":"Huber","year":"2021","journal-title":"Semin. Interv. Radiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"eaau6977","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/ncb1596","article-title":"Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells","volume":"9","author":"Valadi","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10513","DOI":"10.1073\/pnas.0804549105","article-title":"Circulating microRNAs as stable blood-based markers for cancer detection","volume":"105","author":"Mitchell","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1056\/NEJMp1500523","article-title":"A new initiative on precision medicine","volume":"372","author":"Collins","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nature06917","article-title":"Imaging in the era of molecular oncology","volume":"452","author":"Weissleder","year":"2008","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41591-018-0316-z","article-title":"A guide to deep learning in healthcare","volume":"25","author":"Esteva","year":"2019","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.csbj.2014.11.005","article-title":"Machine learning applications in cancer prognosis and prediction","volume":"13","author":"Kourou","year":"2014","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"576576","DOI":"10.1155\/2015\/576576","article-title":"Surgical and Pathological Changes after Radiofrequency Ablation of Thyroid Nodules","volume":"2015","author":"Dobrinja","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3803\/EnM.2019.34.2.117","article-title":"Long-Term Outcomes Following Thermal Ablation of Benign Thyroid Nodules as an Alternative to Surgery: The Importance of Controlling Regrowth","volume":"34","author":"Sim","year":"2019","journal-title":"Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s41591-024-02850-w","article-title":"Heterogeneity and predictors of the effects of AI assistance on radiologists","volume":"30","author":"Yu","year":"2024","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nrclinonc.2017.141","article-title":"Radiomics: The bridge between medical imaging and personalized medicine","volume":"14","author":"Lambin","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/hed.26960","article-title":"Radiofrequency ablation and related ultrasound-guided ablation technologies for treatment of benign and malignant thyroid disease: An international multidisciplinary consensus statement of the American Head and Neck Society Endocrine Surgery Section with the Asia Pacific Society of Thyroid Surgery, Associazione Medici Endocrinologi, British Association of Endocrine and Thyroid Surgeons, European Thyroid Association, Italian Society of Endocrine Surgery Units, Korean Society of Thyroid Radiology, Latin American Thyroid Society, and Thyroid Nodules Therapies Association","volume":"44","author":"Orloff","year":"2022","journal-title":"Head Neck"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/15\/6031\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T04:39:09Z","timestamp":1785904749000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/15\/6031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":34,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jcm15156031"],"URL":"https:\/\/doi.org\/10.3390\/jcm15156031","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]}}}