{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T16:44:50Z","timestamp":1790959490129,"version":"4.1.0"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) is a clinically aggressive disease state with limited treatment options. While individual biomarkers, imaging modalities, and genomic drivers have each been studied in isolation, the dynamic relationships among longitudinal thyroglobulin kinetics, evolving dual-modal imaging phenotypes, and underlying genotypes, together\u00a0with their consequences for targeted therapy response, remain insufficiently characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We retrospectively analyzed 424 patients with intermediate- to high-risk differentiated thyroid cancer. Longitudinal serial stimulated thyroglobulin (sTg) measurements, paired \u00b9\u00b3\u00b9I whole-body scan and \u00b9\n                      <jats:sup>8<\/jats:sup>\n                      F-FDG PET\/CT, and next-generation sequencing of postoperative tumor tissue were integrated. Imaging-defined phenotypes (\u00b9\u00b3\u00b9I-avid, \u00b9\n                      <jats:sup>8<\/jats:sup>\n                      F-FDG-avid, or dual-avid) were stratified across sTg levels and correlated with metastatic distribution, genotype, and response to first-line tyrosine kinase inhibitors (TKIs).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sixty-four patients (15.1%) progressed to RAIR-DTC. Median sTg rose from 18.7 ng\/mL at initial radioiodine therapy to 302.7 ng\/mL at RAIR-DTC diagnosis; pre-radioiodine sTg discriminated RAIR-DTC progression with an area under the curve of 0.911 (95% CI 0.856\u20130.967; optimal threshold 10.77 ng\/mL). With increasing sTg, imaging phenotypes evolved non-binarily, shifting from mixed \u00b9\u00b3\u00b9I\/\u00b9\n                      <jats:sup>8<\/jats:sup>\n                      F-FDG-avid lesions toward predominantly \u00b9\n                      <jats:sup>8<\/jats:sup>\n                      F-FDG-avid disease; metastatic co-occurrence network analysis identified cervical lymph nodes and bilateral lungs as central dissemination hubs.\n                      <jats:italic>TERT<\/jats:italic>\n                      promoter (\n                      <jats:italic>TERTp<\/jats:italic>\n                      ) mutations were significantly enriched in RAIR-DTC (43.8% vs 5.3% in non-RAIR-DTC;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.001) and clustered with\n                      <jats:italic>BRAFV600E<\/jats:italic>\n                      within a tightly connected oncogenic network; patients harboring\n                      <jats:italic>TERTp<\/jats:italic>\n                      mutations had markedly shorter progression-free survival (median 18.2 vs 47.6 months;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.0001). Lesions in patients with\n                      <jats:italic>BRAFV600E<\/jats:italic>\n                      \/\n                      <jats:italic>TERTp<\/jats:italic>\n                      co-mutation exhibited significantly higher metabolic activity (maximum standardized uptake value;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&amp;lt;\u00a00.0001) and earlier radiographic progression on first-line TKIs (68.4% vs 23.5% within six months;\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0=\u00a00.001).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Coupling longitudinal sTg kinetics with evolving dual-modal imaging phenotypes delineates genotype-associated disease courses in RAIR-DTC, in which\n                      <jats:italic>TERTp<\/jats:italic>\n                      mutation, particularly when co-occurring with\n                      <jats:italic>BRAFV600E<\/jats:italic>\n                      , characterizes a metabolically aggressive, TKI-resistant subset. These findings support a dynamic phenotyping approach for refining surveillance and informing genotype-guided treatment decisions in RAIR-DTC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1891291","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:21:35Z","timestamp":1786335695000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dynamic phenotyping of radioiodine-refractory differentiated thyroid cancer: thyroglobulin trajectories, dual-modal imaging, and genotype-defined treatment resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Gongxun","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Geriatrics, Affiliated People\u2019s Hospital of Jiangsu University","place":["Zhenjiang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Shuyang Hospital of Chinese Traditional Medicine","place":["Shuyang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenwei","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Laboratory, Affiliated Fourth People\u2019s Hospital of Jiangsu University","place":["Zhenjiang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canhong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, Affiliated People\u2019s Hospital of Jiangsu University","place":["Zhenjiang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Shuyang Hospital of Chinese Traditional Medicine","place":["Shuyang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingquan","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Shuyang Hospital of Chinese Traditional Medicine","place":["Shuyang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xu","sequence":"additional","affiliation":[{"name":"Nanjing D.A. 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