{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:32:51Z","timestamp":1793287971004,"version":"4.5.0"},"reference-count":29,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T00:00:00Z","timestamp":1769212800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"European Union through the Italian Ministry of University and Research","award":["Project PE_00000019 \u00e2\u20ac\u0153HEAL ITALIA\u00e2\u20ac? to R.E., CUP"],"award-info":[{"award-number":["Project PE_00000019 \u00e2\u20ac\u0153HEAL ITALIA\u00e2\u20ac? to R.E., CUP"]}]},{"name":"Associazione Italiana per la Ricerca sul Cancro","award":["30526"],"award-info":[{"award-number":["30526"]}],"id":[{"id":"https:\/\/ror.org\/02g2x7380","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      One of the challenges in tumor molecular profiling for therapeutic decisions is the unavailability of tumor tissue or its inadequacy to provide high-quality nucleic acids. Although tissue biopsy remains the \u201cgold-standard,\u201d analysis of circulating tumor DNA (ctDNA) may offer an alternative to characterize mutations necessary to initiate systemic therapy with selective inhibitors in eligible patients. This study aimed to identify cases of sporadic medullary thyroid carcinoma (sMTC) in which plasma ctDNA analysis may be useful for\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      gene testing when tumor tissue is unavailable.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We conducted a retrospective cohort study analyzing plasma from 36 patients affected by\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      -mutated sMTC. Patients were divided into three cohorts (1) 18 patients with progressive sMTC; (2) nine patients with stable disease under treatment with a multikinase inhibitor; and (3) nine patients with metastatic but stable disease without treatment. For patients in cohort 1, we studied plasma collected at the time of progression just before the initiation of systemic therapy, while in cohorts 2 and 3, we studied last plasma available at follow-up. The\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      driver mutation was analyzed in ctDNA using specific digital droplet PCR assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      driver mutation was detected in 16\/36 (44.4%, CI 27.9\u201361.9) ctDNA samples, with a statistically significant difference among the three cohorts 16\/18 (88.9%, CI 65.3\u201398.6) in cohort 1 and 0\/9 (0%, CI 0\u201333.6) in cohorts 2 and 3 (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      &lt; 0.001) with a mean variant allele frequency of 5.4%. The presence of detectable\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      -mutated ctDNA was associated with disease progression (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      &lt; 0.001), higher percentage of metastatic sites with &gt; five lesions (i.e., tumor burden;\n                      <jats:italic toggle=\"yes\">p = 0.001<\/jats:italic>\n                      ), and higher levels of serum calcitonin (Ct) (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      = 0.009), and carcinoembryonic antigen (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      = 0.038).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Our study demonstrates that ctDNA analysis may be a valid approach to genotype sMTC patients. Thus, liquid biopsy-based\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      mutation profiling may be beneficial in advanced and progressive sMTC cases when primary tumor tissue is unavailable or inadequate for high-quality nucleic acid extraction, enabling\n                      <jats:italic toggle=\"yes\">RET<\/jats:italic>\n                      -inhibitor therapy, if needed, according to specific indications. However, to obtain reliable results, ctDNA molecular profiling should be performed when tumor burden is high and the disease is progressing.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256261416836","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T08:52:22Z","timestamp":1769244742000},"page":"188-194","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":3,"title":["Liquid Biopsy-Based\n                    <i>RET<\/i>\n                    Mutation Profiling to Guide\n                    <i>RET<\/i>\n                    Inhibitor Treatment in Sporadic Medullary Thyroid Carcinoma May Be Useful in Cases with High Tumor Burden and Progressive Disease"],"prefix":"10.1177","volume":"36","author":[{"given":"Raffaele","family":"Ciampi","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Casalini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Ramone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Romei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Matrone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Prete","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Gambale","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Piaggi","sequence":"additional","affiliation":[{"name":"Department of Information Engineering, University of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liborio","family":"Torregrossa","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Area, Pathology Unit, University Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Ugolini","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical, Molecular Pathology and Critical Area, Pathology Unit, University Hospital of Pisa, Pisa, Italy."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossella","family":"Elisei","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Unit of Endocrinology, University-Hospital of Pisa, Pisa, 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