RET mutation

The Bethesda system provides high diagnostic accuracy for definitive cytological categories in pediatric thyroid nodules. Even indeterminate categories carry elevated malignancy risk, supporting careful surgical consideration and the value of BRAF V600E testing for preoperative risk stratification.

Depending on the Bethesda category, the positive predictive value for malignancy of the seven-gene panel ranged between 18.18% (Bethesda III) and 91.07% (Bethesda V), while the negative predictive value ranged between 93.92% (Bethesda III) and 24.14% (Bethesda V). In conclusion, molecular testing with the seven-gene panel can improve ROM estimation in cytopathologically indeterminate thyroid nodules, but its clinical utility depends on the detected gene alteration.

Systematic genetic screening and counselling are essential for the early diagnosis and appropriate management of MEN2A, particularly in sporadic cases. Broader implementation of molecular testing and genetic counselling in Algeria is recommended to improve patient outcomes and prevent transmission to future generations.

Recent developments in personalized medicine, including the introduction of new molecular diagnostic tools and targeted agents, have made considerable progress in the risk stratification and treatment strategies for papillary thyroid carcinoma. The current article reviews molecular mechanisms of activation of MAPK and PI3K/AKT pathways, their interaction, clinicopathological importance, and targeted treatments in papillary thyroid carcinoma.

P2, N=152, Not yet recruiting, The Third Xiangya Hospital of Central South University

Resistance to RET inhibitors can be acquired through RET copy-number gain and secondary mutations as well as NF1 loss-mediated MAPK pathway activation. This mechanism of resistance can be overcome with dual inhibition of RET and downstream RAS/MAPK signaling, demonstrating clinical potential in RET-mutant MTC.

Among cases with follow-up data (n=35), all 17 tumors with disease progression were DLL3 positive (13 RET-mutated tumors, 1 RAS-mutated tumor, and 3 RET/RAS wild-type tumors), including 5 with moderate expression and 12 with high expression. Most MTCs express DLL3; moreover, DLL3 expression is associated with lymph node metastases at diagnosis and disease progression, indicating that DLL3 may be an effective therapeutic target in MTC.

The present investigation suggests that tumor progression in MTC before clinical detection is a function of the time passed since tumor onset, whereas tumor onset is defined by the transformatory strength of the RET mutation. This notion, debunking the myth of immanent tumor 'aggressiveness' or "risk" imparted by RET mutations in favor of the concept of genetically encoded tumor onset, emphasizes the need for early diagnosis and intervention, ideally while tumors are still confined to the thyroid.

This case underscores the value of liquid biopsy detected mutations in guiding targeted therapy. Clinical, biochemical, and radiological findings support the potential use of selective RET tyrosine kinase inhibitors for this rare mutation. Serum calcitonin serves as a reliable quantitative biomarker of therapeutic efficacy.

The observation is hypothesis-generating rather than proof of sensitivity. This case provides a reference for precision treatment strategies after resistance to RET inhibitors.

The patient was treated with selpercatinib, resulting in radiographic response and clearance of circulating RET-mutant DNA. She remains progression-free 10 months into therapy and the infant continues normal development. This is the first reported case of RET p.M918T-mutated neuroendocrine lung cancer with placental metastases diagnosed during pregnancy, highlighting the importance of molecular profiling and multidisciplinary care.

Pralsetinib and selpercatinib are novel, highly selective RET tyrosine kinase inhibitors (RET-TKIs). Given the low prevalence of RET gene alterations (＜5%), which are regarded as rare genetic mutations, clinical experience in the use pf RET-TKIs and and patient management remains limited. Base on the current status of adverse event management of RET-TKIs in China, and integrating the latest international evidence and clinical experience, the Chinese Medical Doctor Association Tumor Multidisciplinary Diagnosis and Treatment Professional Committee and the Shenzhen Medical Doctor Association Tumor Multidisciplinary Diagnosis and Treatment Professional Committee organized discussion among experts from medical oncology, respiratory medicine, radiation oncology, thoracic surgery, and other related disciplines to formulate this expert consensus on the management of adverse events of RET-TKIs.