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This study aims to investigate 1) the prognostic potential of circulating cell-free (CF) and extracellular vesicles (EVs)-derived microRNA (miRNAs), and 2) their added value with respect to known prognostic factors (PFs).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The RESTING study is a multicentre prospective observational cohort study on resected stage IA-IIIA patients with NSCLC. The primary end-point was disease-free survival (DFS), and the main analyses were carried out separately for CF- and EV-miRNAs. CF- and EV-miRNAs were isolated from plasma, and miRNA-specific libraries were prepared and sequenced. To reach the study aims, three statistical models were specified: one using the miRNA data only (Model 1); one using both miRNAs and known PFs (age, gender, and pathological stage) (Model 2), and one using the PFs alone (Model 3). Five-fold cross-validation (CV) was used to assess the predictive performance of each. Standard Cox regression and elastic net regularized Cox regression were used.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 222 patients were enrolled. The median follow-up time was 26.3 (95% CI 25.4\u201327.6) months. From Model 1, three CF-miRNAs and 21 EV-miRNAs were associated with DFS. In Model 2, two CF-miRNAs (miR-29c-3p and miR-877-3p) and five EV-miRNAs (miR-181a-2-3p, miR-182-5p, miR-192-5p, miR-532-3p and miR-589-5p) remained associated with DFS. From pathway enrichment analysis, TGF-beta and NOTCH were the most involved pathways.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>This study identified promising prognostic CF- and EV-miRNAs that could be used as a non-invasive, cost-effective tool to aid clinical decision-making. However, further evaluation of the obtained miRNAs in an external cohort of patients is warranted.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13046-024-03156-y","type":"journal-article","created":{"date-parts":[[2024,8,23]],"date-time":"2024-08-23T10:31:45Z","timestamp":1724409105000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Circulating cell-free and extracellular vesicles-derived microRNA as prognostic biomarkers in patients with early-stage NSCLC: results from RESTING study"],"prefix":"10.1186","volume":"43","author":[{"given":"Elisabetta","family":"Petracci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Pasini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Urbini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enriqueta","family":"Felip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Stella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Davoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Salvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Beau-Faller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Tebaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Azzali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Canale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piergiorgio","family":"Solli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Amat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Carbonell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Emmanuel","family":"Falcoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Martinez-Marti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Pencreach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelo","family":"Delmonte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucio","family":"Crin\u00f2","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Ulivi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"issue":"3","key":"3156_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, et al. 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