RET fusion

In conclusion, CLCVPTC is a rare variant of PTC characterized by distinctive clear-cell change with canonical PTC nuclear features. The detection of an NCOA4-RET fusion in half of our cases suggests a recurrent genetic alteration that may contribute to its pathogenesis, though this finding requires validation in larger cohorts.

Several multikinase blockers targeting RET have been approved by the FDA for the treatment of cancer: (i) vandetanib for medullary thyroid carcinoma and (ii) cabozantinib, lenvatinib, and sorafenib for differentiated thyroid cancer. Pralsetinib is a specific RET blocker that is FDA-approved for the treatment of medullary thyroid cancer, RET-fusion positive thyroid cancer and NSCLC. Selpercatinib is FDA-approved for the management of RET-mutant medullary thyroid cancer, RET-fusion-positive thyroid cancer, and other RET-fusion-positive solid tumors...Currently, the number of new cases of thyroid cancer bearing RET mutations or RET-fusion proteins is about 13,000 per year and the number of cases of RET-driven NSCLC range from about 2000-4000 per year in the United States. Inactivating RET mutations result in Hirschsprung disease, a congenital disorder leading to aganglionosis of the gastrointestinal tract.

This case highlights the importance of an integrated morphologic, immunophenotypic, and molecular diagnostic approach in atypical spitzoid lesions. Identification of an isolated RET fusion supports classification within the Spitz tumor spectrum and provides valuable information for risk stratification and clinical management in pediatric patients.

The new discoveries of RET fusion partners were founded in NSCLC. In addition, the broad-panel NGS is essential for NSCLC patients to catch these rare/novel fusions that PCR or small panels might miss.

A high proportion of inconclusive results was observed, likely reflecting technical limitations related to the use of formalin-fixed, paraffin-embedded tissue. In conclusion, RET fusions were relatively uncommon in this Brazilian cohort but were enriched in younger patients, underscoring age-related differences in the molecular landscape of pediatric thyroid carcinoma and highlighting the need for larger, standardized multicenter studies.

These findings indicate that the targeted NGS 4-gene panel provides high diagnostic precision in distinguishing benign from malignant nodules. Its implementation offers a cost-effective, efficient molecular diagnostic strategy that may reduce unnecessary diagnostic procedures and facilitate optimized clinical management.

P2, N=50, Completed, University College, London | Active, not recruiting --> Completed | Trial completion date: May 2026 --> Nov 2025 | Trial primary completion date: May 2026 --> Nov 2025

Kinase profiling revealed moderate selectivity, with off-target activity mainly restricted to a limited group of receptor tyrosine kinases. These results support CN-3 as a promising lead for next-generation RET-targeted therapies.

P2, N=28, Not yet recruiting, Shanghai Juncell Therapeutics

RET fusions represent a rare mechanism of acquired resistance in EGFR-mutant NSCLC. Combined RET and EGFR inhibition may offer clinical benefit, particularly in patients with co-occurring alterations. Personalized ddPCR-based liquid biopsy is a promising tool for real-time, non-invasive monitoring of treatment response and resistance evolution.

The validation of the NMA results could be assessed for progression-free survival of selpercatinib versus pembrolizumab + pemetrexed + platinum-based chemotherapy. Enabling the earlier assessment of single-arm trials, via pseudo comparator arms, will provide payers with greater confidence in anticipated treatment effects. In light of the joint clinical assessment, incorporation of single-arm trials within NMA facilitates the reporting of predicted treatment effects relative to multiple relevant comparators, which is important when considering the use of interventions for the global market.

Molecular testing of effusion samples is feasible even at low fluid volumes, provided tumor cellularity is adequate. Prioritizing tumor fraction over volume ensures a higher likelihood of successful molecular analysis. Effusion-based NGS reliably identifies actionable alterations with diagnostic and prognostic relevance. Male patients, smokers, concurrent or primary presentation with MPE, and those with TP53 mutations had poorer outcomes.