scholarly journals Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives

2019 ◽  
Vol 26 (9) ◽  
pp. R499-R518 ◽  
Author(s):  
Lucieli Ceolin ◽  
Marta Amaro da Silveira Duval ◽  
Antônio Felippe Benini ◽  
Carla Vaz Ferreira ◽  
Ana Luiza Maia
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Intracellular Signaling ◽  
Progression Free Survival ◽  
Thyroid Neoplasms ◽  
Rare Type ◽  
Medullary Thyroid ◽  
Men 2 ◽  
Thyroid C Cells ◽  
Molecular Therapies

Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.

scholarly journals Role of genetic diagnosis in thyroid neoplasms

2019 ◽  
pp. 40-42
Author(s):  
Vaktangova N ◽  
Garcia Castañon S ◽  
Martinez Gago ◽  
Corrales B ◽  
Rodríguez Aguilar R
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Genetic Diagnosis ◽  
Malignant Neoplasm ◽  
Thyroid Neoplasms ◽  
Prophylactic Surgery ◽  
Early Age ◽  
Medullary Thyroid ◽  
Men 2

Carcinoma medullary thyroid is a rare, malignant neoplasm. Affected patients can be hereditary carriers, but in most cases they are spontaneously affected. In hereditary cases, prophylactic surgery is recommended at an early age. We present a case of the patient carrier of mutation of the proto-oncogene type RET with medullary thyroid carcinoma prophylactic surgery already in adulthood. Keywords: Medullary thyroid carcinoma; MEN 2; Prophylactic surgery

scholarly journals Comprehensive Assessment of Copy Number Alterations Uncovers Recurrent AIFM3 and DLK1 Copy Gain in Medullary Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 218
Author(s):  
Aline Neves Araujo ◽  
Cléber Pinto Camacho ◽  
Thais Biude Mendes ◽  
Susan Chow Lindsey ◽  
Lais Moraes ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Copy Number ◽  
Snp Array ◽  
In Silico Analysis ◽  
Pcr Analysis ◽  
Copy Number Alterations ◽  
Medullary Thyroid ◽  
Thyroid C Cells ◽  
Ajcc Staging

Medullary thyroid carcinoma (MTC) is a malignant tumor originating from thyroid C-cells that can occur either in sporadic (70–80%) or hereditary (20–30%) form. In this study we aimed to identify recurrent copy number alterations (CNA) that might be related to the pathogenesis or progression of MTC. We used Affymetrix SNP array 6.0 on MTC and paired-blood samples to identify CNA using PennCNV and Genotyping Console software. The algorithms identified recurrent copy number gains in chromosomes 15q, 10q, 14q and 22q in MTC, whereas 4q cumulated losses. Coding genes were identified within CNA regions. The quantitative PCR analysis performed in an independent series of MTCs (n = 51) confirmed focal recurrent copy number gains encompassing the DLK1 (14q32.2) and AIFM3 (22q11.21) genes. Immunohistochemistry confirmed AIFM3 and DLK1 expression in MTC cases, while no expression was found in normal thyroid tissues and few MTC samples were found with normal copy numbers. The functional relevance of CNA was also assessed by in silico analysis. CNA status correlated with protein expression (DLK1, p = 0.01), tumor size (DLK1, p = 0.04) and AJCC staging (AIFM3p = 0.01 and DLK1p = 0.05). These data provide a novel insight into MTC biology, and suggest a common CNA landscape, regardless of if it is sporadic or hereditary MTC.

Anlotinib treatment in locally advanced or metastatic medullary thyroid carcinoma: A multicenter, randomized, double-blind, placebo-controlled phase IIB trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6019-6019 ◽  
Author(s):  
Dapeng Li ◽  
Ping Zhang Tang ◽  
Xiaohong Chen ◽  
Minghua Ge ◽  
Yuan Zhang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Primary Endpoint ◽  
Target Therapy ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Double Blind ◽  
Medullary Thyroid ◽  
Therapy Strategy

6019 Background: Anlotinib (AL3818) is a novel multi-target TKI, inhibiting tumor angiogenesis and proliferative signaling. Our previous single-arm phase 2 ALTN/MTC trial (NCT01874873) has demonstrated that anlotinib has a durable antitumor activity with a manageable adverse event profile in locally advanced or metastatic medullary thyroid carcinoma (MTC). Here we report results of the phase IIB trial (ALTER01031, NCT02586350) of anlotinib for locally advanced or metastatic MTC with a larger samples. Methods: Between September 2015 and September 2018, 91 patients were enrolled in China. Eligible patients have diagnosed as phase IV MTC with relapsed and measurable disease and without antiangiogenetic target therapy. The patients were randomly assigned in a 2:1 ratio to receive anlotinib or a matched placebo (12 mg QD from day 1 to 14 of a 21-day cycle). Patients who have been diagnosed with disease progression by the Independent Imaging Committee could be unblinded and crossed to the treatment group if the patient previous treated by placebo. The primary endpoint was progression-free survival (PFS). Results: 91 patients were randomized 62 to anlotinib arm and 29 to placebo arm. Until the data cutoff date (1 Feb 2019), median PFS was 20.67 months (95%CI, 14.03-34.63) in anlotinib arm vs 11.07 (95%CI, 5.82-14.32) months in placebo arm (HR 0.53, p = 0.0289). The OS data were not sufficiently mature for analysis. Considerable improvement in ORR was observed over the two arms (48.39% vs 3.45%, p < 0.0001). The adverse events (AEs) were 100% in anlotinib arm and 89.66% in placebo arm. The most common AEs in anlotinib arm were hand-foot syndrome, hypertension, hypertriglyceridemia and diarrhea. Conclusion: ALTER01031 met its primary endpoint of PFS shows that anlotinib treatment is effective and well tolerated. The safety profile was consistent and no new adverse events were identified. These data potentially extend the role of anlotinib monotherapy as a new therapy strategy for MTC patients. Clinical trial information: NCT02586350.

scholarly journals RAS proto-oncogene in medullary thyroid carcinoma

2015 ◽  
Vol 22 (5) ◽  
pp. R235-R252 ◽  
Author(s):  
Margarida M Moura ◽  
Branca M Cavaco ◽  
Valeriano Leite
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Malignant Tumors ◽  
Point Mutations ◽  
Follicular Epithelium ◽  
Driver Mutations ◽  
Medullary Thyroid ◽  
Human Cancers ◽  
Thyroid C Cells ◽  
Rare Malignancy

Medullary thyroid carcinoma (MTC) is a rare malignancy originating from the calcitonin-secreting parafollicular thyroid C cells. Approximately 75% of cases are sporadic. Rearranged during transfection (RET) proto-oncogene plays a crucial role in MTC development. BesidesRET, other oncogenes commonly involved in the pathogenesis of human cancers have also been investigated in MTC. The family of humanRASgenes includes the highly homologousHRAS,KRAS, andNRASgenes that encode three distinct proteins. Activating mutations in specific hotspots of theRASgenes are found in about 30% of all human cancers. In thyroid neoplasias,RASgene point mutations, mainly inNRAS, are detected in benign and malignant tumors arising from the follicular epithelium. However, recent reports have also describedRASmutations in MTC, namely inHRASandKRAS. Overall, the prevalence ofRASmutations in sporadic MTC varies between 0–43.3%, occurring usually in tumors with WTRETand rarely in those harboring aRETmutation, suggesting that activation of these proto-oncogenes represents alternative genetic events in sporadic MTC tumorigenesis. Thus, the assessment ofRASmutation status can be useful to define therapeutic strategies inRETWT MTC. MTC patients withRASmutations have an intermediate risk for aggressive cancer, between those withRETmutations in exons 15 and 16, which are associated with the worst prognosis, and cases with otherRETmutations, which have the most indolent course of the disease. Recent results from exome sequencing indicate that, besides mutations inRET,HRAS, andKRAS, no other recurrent driver mutations are present in MTC.

scholarly journals Animal models of medullary thyroid cancer: state of the art and view to the future

2017 ◽  
Vol 24 (1) ◽  
pp. R1-R12 ◽  
Author(s):  
Giovanni Vitale ◽  
Germano Gaudenzi ◽  
Luisa Circelli ◽  
Marco F Manzoni ◽  
Andrea Bassi ◽  
...  
Keyword(s):  
Animal Models ◽  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
State Of The Art ◽  
Neuroendocrine Tumour ◽  
Progression Free Survival ◽  
Therapeutic Approaches ◽  
Medullary Thyroid ◽  
New Therapeutic Approaches ◽  
Treatment Responses

Medullary thyroid carcinoma is a neuroendocrine tumour originating from parafollicular C cells accounting for 5–10% of thyroid cancers. Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid carcinoma. These drugs increase progression-free survival; however, they are often poorly tolerated and most treatment responses are transient. Animal models are indispensable tools for investigating the pathogenesis, mechanisms for tumour invasion and metastasis and new therapeutic approaches for cancer. Unfortunately, only few models are available for medullary thyroid carcinoma. This review provides an overview of the state of the art of animal models in medullary thyroid carcinoma and highlights future developments in this field, with the aim of addressing salient features and clinical relevance.

Multiple endocrine neoplasia type 2

2011 ◽  
pp. 951-953
Author(s):  
Niamh M. Martin ◽  
Karim Meeran ◽  
Stephen R. Bloom
Keyword(s):  
Thyroid Carcinoma ◽  
Medullary Thyroid Carcinoma ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Medullary Thyroid ◽  
Men 2 ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Men 2A

Multiple endocrine neoplasia type 2 (MEN 2) is a rare cancer susceptibility syndrome which has at least three distinct variants: MEN 2A, MEN 2B, and familial medullary thyroid carcinoma (FMTC). The syndrome was first described by John Sipple in 1961 (1). The features of MEN 2A and its clinical variants are outlined in Box 6.12.1. Medullary thyroid carcinoma (MTC) is seen in all variants of MEN 2A and is frequently the earliest neoplastic manifestation, reflecting its earlier and overall higher penetrance. MEN 2 is due to the autosomal dominant inheritance of a germline missense mutation in the ‘hot-spot’ regions of the rearranged during transfection (RET) (OMIM 164761) proto-oncogene (2, 3). MEN 2 has an estimated prevalence of 1:30 000, with MEN 2A accounting for more than 75% of cases. The introduction of RET screening in family members of affected individuals has significantly altered the clinical outcome of MEN 2, by allowing prophylactic surgery for MTC, and screening enabling early intervention for phaeochromocytoma (4, 5). Prior to the availability of genetic screening, more that half of MEN 2 affected individuals died before or during the fifth decade from metastatic MTC or cardiovascular complications from an underlying phaeochromocytoma.

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