BACKGROUNDMultiple endocrine neoplasia (MEN) is relatively rare. But more patients could be found by detailed examination. We discuss the diagnosis and surgical treatment of MEN.

METHODSThe clinical data of 95 MEN cases were retrospectively analyzed. There were 30 cases of MEN1 including 19 cases from 6 families. The MEN1 gene mutation was detected in 81.48% of cases admitted after 1997. There were 22 cases of primary hyperparathyroidism (PHPT), 10 cases of enteropanceatic tumor including 9 cases of insulinoma, 15 cases of pituitary adenoma, 9 cases of adrenal adenoma, 2 cases of thymic carcinoid. Two patients had 4 glands involved, 3 patients had 3 glands involved, 16 patients had 2 glands involved, and 6 patients had only one gland involved. Three patients had neither clinical symptoms nor biochemical changes, and was diagnosed by MEN1 gene mutation. Six patients presented with nephrolithasis and 6 patients had impaired pancreatic endocrine function. There were 60 cases of MEN2a and 5 cases of MEN2b. 58 cases of MEN2a belongs to 19 kindreds. All MEN2a patients but one presented RET gene mutation in codon 634, and all MEN2b cases had mutation in codon 918. 48 cases of MEN2a had thyroid masses with elevated calcitonin levels. 27 patients had pheochromocytoma including 12 cases of multiple foci and 5 malignancy. 13 patients presented with hyperparathyroidism. 5 MEN2b patients had medullary thyroid carcinoma and mucosal ganglioneuromatosis with Marfanoid. Among them, 3 patients had bilateral pheochromocytoma.

RESULTSIn MEN1, subtotal parathyroidectomy was performed in 12 patients with PHPT and one patient received parathyroid adenoma enucleation. Insulinomas were enucleated in 4 patients. Two patients underwent thymus tumor extirpation. Total thyroidectomy with bilateral dissection of regional lymph nodes was performed in 16 patients with MEN2a and nodule enucleation was performed in 9 patients. Twenty two MEN2a patients underwent pheochromocytoma enucleation including bilateral adrenal resection in 10 cases. 5 MEN2b patients underwent total thyroidectomy with bilateral lymph node dissection. Among them, 3 cases underwent bilateral adrenal operations.

CONCLUSIONSMEN varies in symptoms. Germline mutation test is helpful in establishing a diagnosis. Surgical management should be aimed at the improvement of life quality in MEN1 and prevention of the fetal tumors in MEN2.

Adolescent ; Adult ; Aged ; Child ; Codon ; Female ; Humans ; Male ; Middle Aged ; Multiple Endocrine Neoplasia ; complications ; diagnosis ; genetics ; surgery ; Mutation ; Proto-Oncogene Proteins ; genetics ; Proto-Oncogene Proteins c-ret ; genetics

Child ; Female ; Head and Neck Neoplasms ; Humans ; Multiple Endocrine Neoplasia Type 2b ; Proto-Oncogene Proteins c-ret ; genetics

Carcinoma, Non-Small-Cell Lung/genetics* ; China ; Consensus ; Humans ; Lung Neoplasms/genetics* ; Oncogene Proteins, Fusion/genetics* ; Proto-Oncogene Proteins c-ret/genetics*

Adolescent ; Humans ; Male ; Multiple Endocrine Neoplasia Type 2b ; genetics ; Oncogene Proteins ; genetics ; Point Mutation ; Proto-Oncogene Proteins c-ret ; Receptor Protein-Tyrosine Kinases ; genetics

Base Sequence ; Carcinoma, Medullary ; genetics ; surgery ; Codon ; genetics ; Exons ; genetics ; Female ; Humans ; Middle Aged ; Mutation ; Proto-Oncogene Proteins c-ret ; genetics ; Thyroid Neoplasms ; genetics ; surgery ; Thyroidectomy

Rearranged during transfection (RET) fusions are found in 0.7% to 2% of non-small cell lung cancer (NSCLC). Fusions between RET gene and other domains represent the distinct biological and clinicopathological subtypes of NSCLC. Recent years have witnessed the remarkable advancement of RET fusion-positive advanced NSCLC therapy. Conventional chemotherapy produced moderate clinical benefits. Prior to the introduction of targeted therapy or in the context of unavailability, platinum-based systemic regimens are initial therapy options. Immunotherapy predicted minimal response in the presence of RET fusions while currently available data have been scarce, and the single-agent immunotherapy or in combination with chemotherapy regimens are not recommended as initial systemic therapy in this population. The repurpose of multi-target kinase inhibitors in patients with RET fusion-positive NSCLC showed encouraging therapeutic activity, with only cabozantinib and vandetanib being recommended as initial or subsequent options under certain circumstances. However, there are still unmet clinical needs. Pralsetinib and selpercatinib have been developed as tyrosine kinase inhibitors (TKI) selectively targeting RET variation of fusions or mutations, and both agents significantly improved the prognosis of patients with RET fusion-positive NSCLC. Pralsetinib and selpercatinib have been established as preferred first-line therapy or subsequent therapy options. As observed with other TKIs treatment, resistance has also been associated with RET targeted inhibition, and the acquired resistance eventually affect the long-term therapeutic effectiveness, leading to limited subsequent treatment options. Therefore, it is essential to identify resistance mechanisms to TKI in RET fusion-positive advanced NSCLC to help reveal and establish new strategies to overcome resistance. Here, we review the advances in the treatment of RET fusion-positive advanced NSCLC.
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Carcinoma, Non-Small-Cell Lung/genetics* ; Humans ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-ret/genetics*

Adult ; Carcinoma, Neuroendocrine ; Female ; Genetic Testing ; Humans ; Multiple Endocrine Neoplasia Type 2a ; genetics ; Proto-Oncogene Proteins c-ret ; genetics ; Thyroid Neoplasms ; genetics

OBJECTIVETo identify the genotype of RET gene in one multiple endocrine neoplasia type 2A (MEN2A) kindred.

METHODSGenome DNA was extracted from peripheral blood leucocytes. The DNA sequence of gel-purified polymerase chain reaction (PCR) products was determined with the previously reported 6 pairs of primers of PCR amplification of 10, 11, 13, 14, 15, and 16 exons of RETgene.

RESULTSNo abnormalities were found in exon 10, 13, 14, 15, and 16. C to G replacement in nucleotide 14 996 of exon 11 was identified in DNA samples obtained from both peripheral blood of 2 affected brothers. This missense point mutation arisen in heterozygosity and caused a substitution of Cys to Trp residue at codon 634 ( Cys 634 Trp) in RET protein.

CONCLUSIONThe genotype of the family is identified as Cys 634 Trp substitution of RET gene.

Adult ; Exons ; genetics ; Female ; Humans ; Male ; Multiple Endocrine Neoplasia Type 2a ; genetics ; Pedigree ; Point Mutation ; Polymerase Chain Reaction ; Proto-Oncogene Proteins c-ret ; genetics

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.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Neoplasm, Residual ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-ret/genetics*

Lung cancer is the most common cancer and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer. Mutations of driver genes have major impacts on incidence and progression of lung cancer. Advances in molecular biology research and clinical research have promoted the discovery of rare tumor driver genes, as well as the development and application of new targeted drugs. Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy. After the new highly selective RET inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) entered clinical application, the diagnosis and treatment of RET fusion positive NSCLC has made breakthrough progress. At present, there is a lack of guiding consensus on the standardized diagnosis and treatment of RET fusion-positive NSCLC in China. The Society of Cancer Precision of Chinese Anti-Cancer Association and Lung Cancer Expert Group of Chinese Medical Journal, invited 38 experts form respiratory medicine, medical oncology, oncology radiotherapy and pathology to form a consensus development group. Based on the existing research evidence, combined with China's clinical practice experience, a standardized process for the diagnosis and treatment of advanced RET fusion-positive NSCLC is proposed, including suitable populations and methods for RET gene fusion, treatment drug selection, treatment of resistance to highly selective RET inhibitors, and management of adverse reactions to treatment, with a view to providing guidance for clinicians.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; China ; Consensus ; Lung Neoplasms/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-ret/genetics*