Thyroid Gland Medullary Carcinoma

Understanding these mechanisms is crucial for identifying therapeutic opportunities to overcome resistance. Successful treatment targeting bypass oncogenes has been reported in several instances, at least for short-term outcomes; in contrast, although several compounds have been reported to overcome on-target RET alterations, none have yet been translated into routine clinical practice and this remains an area of urgent clinical need.

P1, N=24, Recruiting, University Hospital, Basel, Switzerland | Trial completion date: Jun 2025 --> Jun 2027 | Trial primary completion date: Jun 2024 --> Jun 2026

Laboratory investigations confirmed hypercortisolism with elevated cortisol and Adrenocorticotropic Hormone(ACTH), with non-suppression on dexamethasone suppression tests...The patient was diagnosed with ectopic Cushing's syndrome secondary to MTC and underwent bilateral adrenalectomy followed by total thyroidectomy. Postoperatively, ACTH levels normalised; however, residual tumour was detected, necessitating external beam radiotherapy.

Patients were treated with selpercatinib (n = 13) or pralsetinib (n = 10), 57% (13/23) within a clinical trial. In patients with advanced hMTC, selective RETis appear safe and effective with outcomes similar to clinical trial cohorts, which mostly comprised patients with sMTC. Duration of response and AE profile was similar to sMTC, although longer follow-up and larger patient numbers are needed to confirm this.

P3, N=205, Active, not recruiting, Sanofi | Trial completion date: Jun 2024 --> Nov 2024

Survival outcomes observed in our cohort mirror those reported in the literature and highlight the need for improved therapy options, especially in those presenting with metastatic disease. Our data reaffirmed a lack of survival benefit with adjuvant radiotherapy for MTC with a high rate of systemic relapse and future research should focus on evolving mechanisms of resistance to novel tyrosine kinase inhibitors.

In this context, peptide receptor radionuclide therapy (PRRT) may be a treatment option, but its clinical utility remains under investigation. The aim of this review is to evaluate the evidence of PRRT in MTC and discuss its limitations in the RET inhibitor era.

While an increasing cfDNA was associated with worse progression free survival (p < 0.01). cfDNA is a novel biomarker with potential to monitor disease progression in patients with advanced thyroid cancers.

Finally, we observed that DLK1+ cells (those expressing DLK1) in both cell lines exhibited significantly higher levels of stemness markers compared to DLK1- cells (those lacking DLK1 expression). These findings underscore DLK1's role in enhancing the stemness phenotype, providing valuable insights into MTC progression and resistance and suggesting potential therapeutic implications.

The higher expression of PD-1 and PD-L1 may contribute to tumor progression. Therefore, combinational immunotherapy by these immune checkpoint inhibitors might be a promising strategy for clinical improvement in patients with thyroid cancer, especially those with ATC.

This case series highlights the following key message: awareness of the dermatologic findings in MTC/MEN2 patients is essential since lesions such as cutaneous lichen amyloidosis might represent the skin signature of the endocrine condition even before the actual endocrine manifestations. These data add to the limited published reports with respect to this particular presentation, noting the fact that RET-C634 is the most frequent pathogenic variant in MEN2-associated lichen amyloidosis; females are more often affected; the interscapular region is the preferred site; the age of diagnosis might be within the third decade of life, while we reported one of the youngest patients with the lesion. The same RET pathogenic variant is not associated with the same dermatologic features as shown in the vignette. The same RET mutation does not mean that all family members will present the same skin anomaly.

However, the rates of thyroid malignancy and parathyroid adenomas were substantial. Prospective studies are needed to determine the optimal diagnostic and therapeutic strategies for these incidental findings.

This case highlights the importance of comprehensive genetic testing in patients with pheochromocytoma and paraganglioma, particularly when hereditary syndromes are suspected. Genetic insights ensure precise management, allowing for tailored treatment and improved outcomes in patients with hereditary pheochromocytoma and paraganglioma.

Our data demonstrate that British Thyroid Association U-score has limited value for medullary thyroid cancer detection in this high-risk group and cannot be used for risk stratification or surveillance. As a rarer thyroid cancer subtype, medullary thyroid cancer and the high-risk multiple endocrine neoplasia 2 population are under-represented in British Thyroid Association 2014 guidance and deserve consideration in future editions.

The clinical characteristics and biological behavior of these cancer types can vary. The prognosis is directly related to the stage at presentation and the condition at the time of diagnosis.

Total thyroidectomy with central neck dissection remains as the primary treatment. A multimarker approach may improve the sensitivity and specificity of CNMTC diagnosis and surveillance, particularly when calcitonin and CEA levels are inconclusive.

Although further research is needed to firmly establish a possible association, this case also highlights the necessity of exploring genetic backgrounds when patients present with clinical manifestations not readily explained by a single endocrine disorder. Investigating potential genetic associations is crucial since a positive genetic test allows for the testing of relatives, genetic counseling, and proper surveillance of individuals at risk.

The detection of BRAF fusions and their many partners was enabled by the Afirma XA exome-enriched RNASeq panel. Although BRAF fusions occurred in only 0.2% of thyroid nodules, they were GSC-Suspicious and lacked typical BRAF/RAS mutations. Interestingly, expression signatures associated with malignancy varied by fusion partner.

P2, N=8, Active, not recruiting, Dana-Farber Cancer Institute

P1/2, N=856, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting

P2, N=79, Terminated, Grupo Espanol de Tumores Neuroendocrinos | Trial completion date: Dec 2025 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2025 --> Nov 2024; In compliance with current legislation applicable to Clinical Trials, following the instructions of the Spanish Agency for Medicines and Health Products.

P=N/A, N=0, Not yet recruiting, West China Hospital of Sichuan University; West China Hospital of Sichuan University

P=N/A, N=0, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P=N/A, N=0, Recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

The earlier diagnosis of MTC significantly improves survival and prompts better management of MEN2A. In this editorial, we will discuss the significance of molecular diagnostic approaches in detecting RET oncogene mutations in MEN2A.

Other radiopharmaceuticals offering new theranostic avenues in thyroid cancers are also discussed, such as prostate-specific membrane antigen (PSMA) and fibroblast activation protein (FAP). After decades of a "one-size fits all" approach in thyroid cancer management, molecular imaging is paving the way towards personalized medicine.

The development of multi-kinase inhibitors cabonzantinib and vandetanib, and RET-targeted inhibitors selpercatinib, has completely changed the therapeutic arsenal for advanced disease, but their prescription is reserved to progressive disease with high tumor volume or to symptomatic disease inaccessible to local treatment in expert centers from the ENDOCAN-TUTHYREF network. Active surveillance is the alternative of choice for slowly progressing disease.

Extrathyroidal extension was identified as the strongest prognostic factor for RFS and DSS. Older age and larger tumor size were associated with decreased DSS, while RET mutation and lymph node metastasis significantly impacted RFS.

P2, N=30, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

In addition, despite improved genotype/phenotype correlation in MEN2, we highlight that not all cases are 'typical' which emphasises the need for all MEN2 patients to be cared for in a centre of expertise and experience. Some of our case study patients or parents also took this opportunity to personally tell us more about their lives with MEN2, illustrating the need for more research into the psychosocial impact of these hereditary diseases.

Long-term treatment with selpercatinib is feasible. AEs are manageable with dose modifications, allowing most patients to continue safely on therapy.

The loss of claudin-1 and claudin-4 characterized more aggressive cancers. Several studies have shown the benefits of targeting claudins in cancers, but their implementation into clinical practice requires further trials.

Preoperative calcitonin can be helpful in the diagnostic workup of thyroid nodules. Due to different treatment strategies, precise histological differentiation of potential lymph node metastasis is essential.

Our findings highlight it is crucial to understand and interpret the various combinations of CEA and Ctn fluctuations within a clinical context. Furthermore, to reduce diagnostic errors and improve patient outcomes, we recommend follow-up diagnostic and treatment protocols designed to address the potential pitfalls associated with the use of these biomarkers.

To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma. However, the signal observed in ATC may merit further evaluation. ClinicalTrials.gov Identifier: NCT03246958.

Together, changes in specific combinations of RET-mediated effects associated with different mutations give rise to the distinct MEN2 disease phenotypes. Here, we discuss the current understanding of the intrinsic and extrinsic characteristics of RET MEN2A cysteine and MEN2B mutants and how these contribute to transforming cellular processes and to differences in tumour progression and disease aggressiveness.

This comprehensive review synthesizes the latest advancements in the molecular genetics of MTC, the evolution of precision therapies, and the identification of novel biomarkers. We also discuss the implications of these findings for clinical practice and the future direction of MTC research.

At univariate analysis, factors associated with persistent and recurrent disease during follow-up in patients with sMTC were tumor size, extrathyroidal extension, presence of lymph node metastases at diagnosis, pre- and post-operative calcitonin, post-operative CEA; in patients with hMTC, features associated with persistent and recurrent disease were lymph node metastases, post-operative calcitonin and pre- and post-operative CEA values. Patients with hMTC and sMTC had similar histopathological characteristics and clinical outcome.

Most MTC cases present with thyroid nodules in the initial steps and are confined to the thyroid gland or the adjacent LNs. These cases are mostly cured by thyroidectomy and LN dissection. This neuroendocrine cancer infrequently becomes aggressive and involves other parts of the body. However, involving BM or adrenal gland has been scarcely reported. Due to ineffective red and white blood cell production, BM metastasis can cause pancytopenia and, consequently, pallor, fatigue, dyspnea, and susceptibility to infections. High calcitonin levels can also cause diarrhea. The initial diagnosis is mostly with neck ultrasound (US) and fine needle aspiration (FNA). Total thyroidectomy is the main therapeutic option for these patients. Calcitonin and carcinoembryonic antigen (CEA) are sensitive indicators of recurrence or remaining tumors, which might be helpful for the initial diagnosis and postoperation follow-up. Although extremely rare, invasive metastasis of MTC might involve unusual body organs such as the BM or adrenal glands. In cases of unjustifiable pancytopenia or adrenal dysfunction in MTC-positive patients, these possibilities should be considered and ruled out by some specific evaluations, such as bone marrow biopsy and contrast-enhanced imaging.

Our data demonstrate high feasibility of [18F]SiTATE PET/CT in a small cohort of patients with MTC and DTC. The use of [18F]SiTATE may overcome logistical disadvantages of 68Ga-based tracers and facilitate SSTR-targeted PET/CT imaging of thyroid carcinoma.

Improving our understanding of the genotype-phenotype correlations would allow individualizing the management and follow-up of patients with MEN 2. The aim of this brief review is to discuss the main genotype-phenotype correlations in MEN 2 and the potential factors that might influence these correlations.

P2, N=120, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting