Primary resistance to selpercatinib in a patient with advanced medullary thyroid cancer.

Selpercatinib, a selective RET kinase inhibitor, has demonstrated remarkable efficacy in treating patients with advanced medullary (MTC) and differentiated thyroid cancer with RET alterations. Primary resistance to selpercatinib is a very uncommon situation, and its underlying mechanisms are poorly understood. We report the case of a 42-year-old female with advanced MTC harboring a somatic M918T RET mutation who exhibited a primary resistance to selpercatinib. Despite prompt treatment initiation after the diagnosis of progressive disease, the patient continued experiencing rapid spread of disease, characterized by the appearance of new metastatic lesions and increased tumor burden. Genomic analysis revealed no additional mutations associated with on-target or off-target resistance. This case highlights a rare clinical scenario of primary resistance to selpercatinib in advanced MTC. While secondary resistance mechanisms have been well-documented, primary resistance remains poorly understood. Possible explanations include tumor heterogeneity and activation of alternative signaling pathways that stills need to be elucidated. Emerging therapies targeting resistance mechanisms and next-generation RET inhibitors offer promising avenues for further investigation.

New insights in thyroid diagnosis and treatment.

The prevalence of thyroid disease continues to rise. As a consequence, the research in the thyroid field has significantly increased over time. Thus, clinicians, and endocrinologists first, have to be aware of the important continuous progress achieved, in particular of thyroid cancer, to better manage their patients. This themed issue, titled "New Insights in Thyroid Diagnosis and Treatment," delves deep into contemporary hot topics in thyroid field. These papers included in the present issue are focused on several aspects in this area, such as imaging, molecular analysis, machine learning and radiomics, nuclear medicine, clinical, and laboratory. Seven papers centers around thyroid cancer. Three papers review imaging modalities for thyroid nodule/cancer assessment. Two papers report a comprehensive review of metabolic issues involving thyroid gland. Finally, a large overview about genetics of Graves' disease is reported in another study. Clinicians will find this issue very interesting.

New approaches for patients with advanced radioiodine-refractory thyroid cancer.

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient's features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.