Salivary duct carcinoma. D'heygere Emmanuel,Meulemans Jeroen,Vander Poorten Vincent Current opinion in otolaryngology & head and neck surgery PURPOSE OF REVIEW:The review puts new information on geno- and phenotype of salivary duct carcinoma (SDC) in the perspective of the updated 2017 WHO classification. RECENT FINDINGS:The proportion of SDC is increasing. This may be because of a true rise in incidence, but certainly to better diagnostic tests and changed WHO definitions. In this light, a substantial proportion of carcinoma expleomorphic adenoma is now attributed to the category of SDC. 'Low-grade SDC' and 'SDC in-situ' of the former WHO classification, are now named low-grade and high-grade intraductal carcinoma (IDC), respectively. Recent series quantify biologic aggressiveness: perineural growth, vascular invasion, and extracapsular extension in lymph node metastasis are each observed in two out of three patients with SDC. Most patients die within 3 years, but once 5-year disease-free survival is reached, further disease activity is exceptional. The typical molecular biological profile with high human epidermal growth factor receptor 2 and androgen receptor expression is increasingly successfully exploited in clinical trials for advanced SDC. SUMMARY:The aggressive SDC is increasingly diagnosed. Despite intensive combined surgery and radiation therapy, many patients recur, for whom new bullets, targeting the molecular biological mechanisms, are the subject of ongoing clinical trials. 10.1097/MOO.0000000000000436

Progress and challenges in RET-targeted cancer therapy. Frontiers of medicine The rearranged during transfection (RET) is a receptor protein tyrosine kinase. Oncogenic RET fusions or mutations are found most often in non-small cell lung cancer (NSCLC) and in thyroid cancer, but also increasingly in various types of cancers at low rates. In the last few years, two potent and selective RET protein tyrosine kinase inhibitors (TKIs), pralsetinib (BLU-667) and selpercatinib (LOXO-292, LY3527723) were developed and received regulatory approval. Although pralsetinib and selpercatinib gave high overall response rates (ORRs), < 10% of patients achieved a complete response (CR). The RET TKI-tolerated residual tumors inevitably develop resistance by secondary target mutations, acquired alternative oncogenes, or MET amplification. RET G810 mutations located at the kinase solvent front site were identified as the major on-target mechanism of acquired resistance to both selpercatinib and pralsetinib. Several next-generation of RET TKIs capable of inhibiting the selpercatinib/pralsetinib-resistant RET mutants have progressed to clinical trials. However, it is likely that new TKI-adapted RET mutations will emerge to cause resistance to these next-generation of RET TKIs. Solving the problem requires a better understanding of the multiple mechanisms that support the RET TKI-tolerated persisters to identify a converging point of vulnerability to devise an effective co-treatment to eliminate the residual tumors. 10.1007/s11684-023-0985-y