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Thyroid Cancer Diagnosis and Treatment / Thyroid Disorders and Treatments / Renal Cell Carcinoma Treatment · Journal article
Frontiers in Endocrinology · August 10, 2026
Encouraging direction, but not yet definitive.
This retrospective cohort integrates longitudinal thyroglobulin kinetics, dual-modal imaging (¹³¹I and ¹⁸F-FDG PET/CT), and next-generation sequencing to characterize RAIR-DTC phenotypes and their genomic drivers. The study identifies TERT promoter mutations, particularly when co-occurring with BRAFV600E, as enriched in RAIR-DTC and associated with metabolically aggressive disease and early TKI resistance, but these associations require prospective validation and are reported from a single institution.
Retrospective cohort study with integrated multi-modal biomarker, imaging, and genomic analysis. 424 patients with intermediate- to high-risk differentiated thyroid cancer; setting not explicitly stated but appears to be a single institution.. Intervention: Serial stimulated thyroglobulin measurement, dual-modal imaging (¹³¹I whole-body scan and ¹⁸F-FDG PET/CT), next-generation sequencing of tumor tissue, and first-line tyrosine kinase inhibitor therapy in those with RAIR-DTC. Compared with: RAIR-DTC cases (n=64) compared with non-RAIR-DTC cases (n=360); genotype subgroups (TERTp mutation, BRAFV600E, and co-mutation status) compared within and across phenotypes. n = 424.
64 of 424 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 AUC 0.911 (95% CI 0.856–0.967; optimal threshold 10.77 ng/mL)
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The findings suggest that pre-treatment and serial thyroglobulin levels, dual-modal imaging phenotyping, and genotyping for TERT promoter and BRAFV600E mutations could help identify patients at high risk of RAIR-DTC progression and early TKI resistance. However, these associations are from a retrospective, single-centre study and require prospective validation before informing routine treatment selection or surveillance algorithms.
Retrospective integration of longitudinal biomarkers, dual-modal imaging, and genomics in a single-centre cohort identifies genotype-phenotype associations in RAIR-DTC, but lacks prospective validation or a randomized comparator to establish clinical utility.
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Quoted from the source exactly as published.
The findings suggest that pre-treatment and serial thyroglobulin levels, dual-modal imaging phenotyping, and genotyping for TERT promoter and BRAFV600E mutations could help identify patients at high risk of RAIR-DTC progression and early TKI resistance. However, these associations are from a retrospective, single-centre study and require prospective validation before informing routine treatment selection or surveillance algorithms.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Background 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 with their consequences for targeted therapy response, remain insufficiently characterized. Methods We retrospectively analyzed 424 patients with intermediate- to high-risk differentiated thyroid cancer. Longitudinal serial stimulated thyroglobulin (sTg) measurements, paired ¹³¹I whole-body scan and ¹ 8 F-FDG PET/CT, and next-generation sequencing of postoperative tumor tissue were integrated. Imaging-defined phenotypes (¹³¹I-avid, ¹ 8 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). Results 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 0.856–0.967; optimal threshold 10.77 ng/mL). With increasing sTg, imaging phenotypes evolved non-binarily, shifting from mixed ¹³¹I/¹ 8 F-FDG-avid lesions toward predominantly ¹ 8 F-FDG-avid disease; metastatic co-occurrence network analysis identified cervical lymph nodes and bilateral lungs as central dissemination hubs. TERT promoter ( TERTp ) mutations were significantly enriched in RAIR-DTC (43.8% vs 5.3% in non-RAIR-DTC; p 0.001) and clustered with BRAFV600E within a tightly connected oncogenic network; patients harboring TERTp mutations had markedly shorter progression-free survival (median 18.2 vs 47.6 months; p 0.0001). Lesions in patients with BRAFV600E / TERTp co-mutation exhibited significantly higher metabolic activity (maximum standardized uptake value; p 0.0001) and earlier radiographic progression on first-line TKIs (68.4% vs 23.5% within six months; p = 0.001). Conclusion Coupling longitudinal sTg kinetics with evolving dual-modal imaging phenotypes delineates genotype-associated disease courses in RAIR-DTC, in which TERTp mutation, particularly when co-occurring with BRAFV600E, 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.
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