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BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.ResultsMinimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.Trial registration numberNCT00704730.

Graph: Figure 1: Thyroid ultrasound: medullary thyroid carcinoma presenting as an hypoechoic and heterogeneous nodule with irregular margins and intense vascularization. Keywords: calcitonin; carcinoembryonic antigen; medullary thyroid cancer; smoke EN calcitonin carcinoembryonic antigen medullary thyroid cancer smoke e203 e205 3 08/22/23 20230901 NES 230901 To the Editor, Carcinoembryonic antigen (CEA) is glycoprotein associated with various functions of endothelial cells, including adhesion, proliferation, and migration. [Extracted from the article]

BackgroundCalcitonin (Ctn) is widely used as a marker in the diagnosis, prognosis, and postoperative follow-up of patients with medullary thyroid carcinoma (MTC). The prognostic value of postoperative calcitonin-to-preoperative calcitonin ratio (CR), reflecting the change in Ctn level of response to initial treatment, remains uncertain in long-term disease outcomes. This study aims to determine the cut-off value of CR for predicting structural recurrence and assess the prognostic role of CR in patients with MTC.MethodsWe retrospectively reviewed patients with MTC in Sun Yat-sen University Cancer Center (SYSUCC) between 2000 and 2022. CR is defined as the ratio of postoperative Ctn level on the day of discharge divided by preoperative Ctn level. In order to determine the optimal cut-off value of CR, the receiver operating characteristic (ROC) analysis was performed. We evaluate the effect of CR on recurrence-free survival (RFS) by using the Kaplan-Meier method and Cox regression analysis. Then, a nomogram based on CR was constructed.ResultsIn total, 112 sporadic MTC patients were included in this study. The optimal cut-off value of CR that predicted disease recurrence was 0.125. Patients with CR≥0.125 showed significantly worse RFS than patients with CR

To evaluate the impact of social vulnerability and social determinants of health on outcomes in pediatric medullary thyroid cancer. A SEER database review looking at cases of pediatric medullary thyroid cancer from 1975 to 2016 was conducted and analyzed including data from the American Community Survey. A total of 174 patients were included in analysis. Five-year overall survival was 97.7 % and the disease specific survival (DSS) was 98.3 %. On univariate analysis, male sex was associated with worsened overall survival (HR = 4.2, CI 1.1–15.5, p < 0.05) but did not reach statistical significance on multivariate analysis. Asian or Pacific Islander race was associated with worsened overall survival on both univariate and multivariate analysis (HR = 5.5, CI 1.4–22.2, p < 0.05). Presenting with localized disease without nodal or distant metastasis was found to be a protective factor (HR = 0.2, CI 0.05–0.53, p < 0.01). Asian American/Pacific Islander patients and male patients may have poorer survival in pediatric medullary thyroid cancer. More research should be completed to better understand underlying factors. [ABSTRACT FROM AUTHOR]

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib. Selpercatinib (also known by the brand name Retevmo®/Retsevmo®) is a new treatment available in multiple countries for people with advanced or metastatic RET-mutant medullary thyroid cancer (MTC). Thyroid cancer starts in your thyroid gland and may spread or metastasize to other parts of the body, including lungs, bones, and occasionally the brain, which means the cancer is likely to be advanced. Advanced thyroid cancer can be driven by a gene in your body, one of which is RET. This is a summary of the LIBRETTO-531 study which compares selpercatinib, which is a strong and selective inhibitor of RET, with two approved drugs, cabozantinib and vandetanib. Patients with advanced or metastatic RET-mutant MTC who have not already received treatment with kinase inhibitors are being enrolled. This trial will evaluate how long people during and after treatment live with the disease without it getting worse. Selpercatinib may affect both healthy cells and tumor cells, which can result in side effects, which will also be evaluated in this study. This study is active and currently recruiting new patients. Clinical Trial Registration: NCT04211337 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Context: Medullary thyroid cancer (MTC) is usually caused by gain-of-function mutations in the proto-oncogene RET. Objective: This study aimed to determine the underlying mechanism in a male patient diagnosed with MTC at age 51 years. Methods: Genomic DNA extracted from leukocytes or tumor tissues of patients was used for next-generation sequencing (NGS)-panel sequencing and Sanger sequencing. Wild-type (WT) and p.C630 deletion RET were expressed in HEK 293T cells. Activation of phosphorylation of the crucial tyrosine-905 of RET and MAPK/ERK was analyzed by Western blotting. The effect of RET mutants on cell viability and colony formation ability was determined by CCK8 assay and a colony forming assay. Results: NGS-Panel sequencing revealed a 3-nucleotide/1-amino acid C630 in-frame deletion in exon 11 of RET (c.1887_1889delGTG p.C630del). In vitro expression showed that phosphorylation of the crucial tyrosine 905 was much stronger in the p.C630del RET mutant than in WT RET, indicating ligand-independent activation of the Ret protein tyrosine kinase. Furthermore, p.C630del RET mutant induced strong activation of the MAPK/ERK pathway. In addition, p.C630del RET mutant cells exhibited increased HEK 293T cell viability and colony formation compared with WT RET cells. Pralsetinib (BLU-667), a highly selective RET inhibitor, inhibited the viability of WT RET and p.C630del RET mutant-transfected HEK 293T cells (IC50s: 18.54 and 16.49 μM after treatment for 24 hours), followed by inhibition of the RET-induced MAPK/ERK pathway. Conclusion: The finding in our patient with MTC was a 3-base-pair deletion in exon 11 of RET, a p.C630 deletion not previously reported. The p.C630del RET stimulates cell proliferation by increasing ligand-independent phosphorylation and activation of MAPK/ERK pathway, demonstrating the pathogenic nature of the mutation. We therefore recommend screening panel sequence of RET in MTC patients with indications of a genetic cause. [ABSTRACT FROM AUTHOR]

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib. [ABSTRACT FROM AUTHOR]

Background: To investigate sonographic features of cervical lymph node metastases from medullary thyroid cancer (LNM-MTC), as compared with lymph node metastases from papillary thyroid cancer (LNM-PTC). Methods: A total of 42 MTC patients with 52 metastatic LNs and 222 PTC patients with 234 metastatic LNs who were confirmed by fine needle aspiration and post-operative pathology, were enrolled in this study. The clinical characteristics and sonographic features of LNs were compared between the two groups. Univariate analysis and multivariate logistic regression analysis were performed on the sonographic features of LNs, including short and long-axis diameter, long-axis diameter/short-axis, shape, border, hilum, echogenicity, calcifications, cystic change and vascularity pattern. The discriminating performance was assessed with the area under the receiver operating characteristic curve (AUC). Results: The mean age of patients with LNM-MTC was older than that of patients with LNM-PTC (46.81 ± 13.05 vs 39.09 ± 12.05, P < 0.001). No differences were observed in gender, location, long-axis diameter/short-axis, shape, border, echogenicity, cystic change and vascularity pattern between LNM-MTC and LNM-PTC groups (P > 0.05, for all). However, long-axis and short-axis diameter, hilum and calcifications were statistically different between these two groups (P < 0.05, for all). The AUC of discriminate value between LNM-MTC and LNM-PTC was 0.808 (95% confidence interval 0.739–0.877). Conclusion: Compared with LNM-PTC, LNM-MTC tended to have the sonographic characteristics of larger size, absence of hilum, and less calcifications, and awareness of these features might be helpful to in the diagnosis of LNM-MTC. [ABSTRACT FROM AUTHOR]

Background: Medullary thyroid cancer (MTC) can only be cured by surgery, but the management of lateral lymph nodes is controversial, especially for patients with cN0+cN1a. To address this challenge, we developed a multivariate logistic regression model to predict lateral lymph node metastases (LNM). Methods: We retrospectively collected clinical data from 124 consecutive MTC patients who underwent initial surgery at our institution. The data of 82 patients (from 2010 to 2018) and 42 patients (from January 2019 to November 2019) were used as the training set for building the model and as the test set for validating the model, respectively. Results: In the training group, the multivariate analyses indicated that male and MTC patients with higher preoperative basal calcitonin levels were more likely to have lateral LNM (P = 0.007 and 0.005, respectively). Multifocal lesions and suspected lateral LNM in preoperative ultrasound (US) were independent risk factors (P = 0.032 and 0.002, respectively). The identified risk factors were incorporated into a multivariate logistic regression model to generate the nomogram, which showed good discrimination (C-index = 0.963, 95% confidence interval [CI]: 0.9286--0.9972). Our model was validated with an excellent result in the test set and even superior to the training set (C-index = 0.964, 95% CI: 0.9121--1.000). Conclusion: Higher preoperative basal calcitonin level, male sex, multifocal lesions, and lateral lymph node involvement suspicion on US are risk factors for lateral LNM. Our model and nomogram will objectively and accurately predict lateral LNM in patients with MTC. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is a rare neoplasm that is responsible for a fair proportion of thyroid carcinoma related deaths. The current diagnostic and therapeutic standards are not always effective and need to be upgraded. The role of biomarkers and immunohistochemistry in the diagnosis of MTC is highlighted. Opportunities for improved diagnostics have been seen with the development of nuclear medicine. Some studies have highlighted the possibility of reducing the number of complications during surgical treatment, which is the basic therapeutic method in patients with MTC. Current pharmacotherapy is imperfect, but there is ongoing research into the use of new, more selective drugs. The following paper discusses recent advances in the diagnosis and treatment of MTC. Medullary thyroid carcinoma (MTC) is a neoplasm originating from parafollicular C cells. MTC is a rare disease, but its prognosis is less favorable than that of well-differentiated thyroid cancers. To improve the prognosis of patients with MTC, early diagnosis and prompt therapeutic management are crucial. In the following paper, recent advances in laboratory and imaging diagnostics and also pharmacological and surgical therapies of MTC are discussed. Currently, a thriving direction of development for laboratory diagnostics is immunohistochemistry. The primary imaging modality in the diagnosis of MTC is the ultrasound, but opportunities for development are seen primarily in nuclear medicine techniques. Surgical management is the primary method of treating MTCs. There are numerous publications concerning the stratification of particular lymph node compartments for removal. With the introduction of more effective methods of intraoperative parathyroid identification, the complication rate of surgical treatment may be reduced. The currently used pharmacotherapy is characterized by high toxicity. Moreover, the main limitation of current pharmacotherapy is the development of drug resistance. Currently, there is ongoing research on the use of tyrosine kinase inhibitors (TKIs), highly specific RET inhibitors, radiotherapy and immunotherapy. These new therapies may improve the prognosis of patients with MTCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Lately, a more personalized approach in the management of advanced thyroid cancer patients has improved the outcomes, and several novel molecularly guided therapies, including selective RET inhibitors (sRETis), have demonstrated promising efficacy in clinical trials. RET (rearranged during transfection) variants are the most prevalent oncogenic event in medullary thyroid cancer (MTC). We here found RET oncogene variants in 44/48 prospectively collected MTC tumor samples from patients treated with more unselective kinase inhibitors vandetanib and/or cabozantinib. Our study shows that RET variants were highly prevalent in patients with advanced MTC, and the treatment results in RET-positive cases were similar to those reported in unselected cohorts. Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare malignancy comprising 1-2% of all thyroid cancers in the United States. Approximately 20% of cases are familial, secondary to a germline RET mutation, while the remaining 80% are sporadic and also harbour a somatic RET mutation in more than half of all cases. Up to 15-20% of patients will present with distant metastatic disease, and retrospective series report a 10-year survival of 10-40% from time of first metastasis. Historically, systemic therapies for metastatic MTC have been limited, and cytotoxic chemotherapy has demonstrated poor objective response rates. However, in the last decade, targeted therapies, particularly multitargeted tyrosine kinase inhibitors (TKIs), have demonstrated prolonged progression-free survival in advanced and progressive MTC. Both cabozantinib and vandetanib have been approved as first-line treatment options in many countries; nevertheless, their use is limited by high toxicity rates and dose reductions are often necessary. New generation TKIs, such as selpercatinib or pralsetinib, that exhibit selective activity against RET, have recently been approved as a second-line treatment option, and they exhibit a more favourable side-effect profile. Peptide receptor radionuclide therapy or immune checkpoint inhibitors may also constitute potential therapeutic options in specific clinical settings. In this review, we aim to present all current therapeutic options available for patients with progressive MTC, as well as new or as yet experimental treatments. [ABSTRACT FROM AUTHOR]

• This special article provides updated treatment recommendations on thyroid cancer. • New targeted systemic therapies have now been approved for treating patients with advanced/metastatic thyroid cancers. • This article summarises these new options and the order in which they should be used. • Recommendations are based on available scientific data and the authors' collective expert opinion. • ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies. • Authorship includes a multidisciplinary group of thyroid cancer experts. [ABSTRACT FROM AUTHOR]

Background: Medullary thyroid cancer (MTC) is a rare malignancy originating from the calcitonin-producing C cells of the thyroid. Despite recent therapeutic advances, metastatic MTC remains incurable. Adoptive cell therapy (ACT) using genetically engineered T cells targeting either tissue-restricted tumor-associated antigens or mutated neoantigens has led to durable remissions in other metastatic solid tumors. The majority of MTC express the tumor-associated antigens calcitonin and carcinoembryonic antigen (CEA), and ∼40% of MTC harbor the RET M918T oncogenic driver mutation. Methods: We developed and characterized three immunoreceptors that recognize extracellular CEA, a calcitonin epitope presented by HLA-A*24:02, or an RET M918T neoepitope restricted by HLA-DPB1*04:01/02. The chimeric antigen receptor (CAR) targeting CEA was synthetically designed, while the T cell receptors (TCRs) targeting calcitonin and RET M918T were isolated from a transgenic mouse and patient with MTC, respectively. These immunoreceptors were genetically engineered into peripheral blood T cells and tested for antigen specificity and antitumor activity. Results: T cells expressing the anti-CEA CAR or the calcitonin-reactive TCR produced effector cytokines and displayed cytotoxicity against cell lines expressing their cognate antigen in vitro. In immunodeficient mice harboring a human MTC cell line, the adoptive transfer of T cells engineered to express the anti-CEA CAR or calcitonin-reactive TCR led to complete tumor regression. T cells expressing the HLA-DPB1*04:01/02-restricted TCR targeting RET M918T, which was cloned from peripheral blood CD4+ T cells of a patient with MTC, demonstrated specific reactivity against cells pulsed with the mutated peptide and MTC tumor cells that expressed HLA-DPB1*04:01 and RET M918T. Conclusion: The preclinical data presented herein demonstrate the potential of using genetically engineered T cells targeting CEA, calcitonin, and/or RET M918T to treat metastatic MTC. [ABSTRACT FROM AUTHOR]

Abstract Background Medullary thyroid cancer (MTC) represents 13.4 % of all thyroid cancers-related deaths. The treatments for MTC are very limited especially for patients with distal metastasis. Therefore, it is critical to understand the mechanisms of MTC to pursue novel therapeutic avenues. Here, we studied the function of circPVT1/miR-455-5p in MTC. Methods Human MTC tissues and cell lines were used. qRT-PCR and Western blotting were employed to measure expression levels of miR-455-5p, circPVT1, CXCL12, and epithelial mesenchymal transformation (EMT)-related proteins. Colony formation assay, flow cytometry, transwell assay, and scratch wound healing assay were used to assess the abilities of cell proliferation, apoptosis, migration and invasion, respectively. Dual luciferase assay and RNA immunoprecipitation were employed to validate interactions of circPVT1/miR-455-5p and miR-455-5p/CXCL12. Nude mouse xenograft model was used to evaluate the effects of shcircPVT1 and miR-455-5p mimics on tumor growth and metastasis in vivo. Results miR-455-5p was reduced in MTC tissues and cells while circPVT1 was elevated. Their levels were correlated with prognosis of MTC. Overexpression of miR-455-5p or sh-circPVT1 suppressed EMT and MTC cell proliferation, migration and invasion. miR-455-5p targeted CXCL12 while circPVT1 sponged miR-455-5p. Knockdown of CXCL12 or CXCL12/CXCR4 signaling inhibitor reversed the effects of circPVT1 overexpression or miR-455-5p inhibitor on EMT and MTC cell proliferation, migration and invasion. Knockdown of circPVT1 or miR-455-5p overexpression repressed MTC tumor growth and lung metastasis in vivo. Conclusions miR-455-5p suppresses MTC growth and metastasis by targeting CXCL12/CXCR4 signaling pathway while circPVT1 promotes MTC by sponging miR-455-5p. Our study sheds light on the mechanisms of MTC growth and metastasis.

Abstract Background Medullary thyroid cancer (MTC) has more aggressive behavior and poor prognosis. Ultrasound (US) has facilitated the qualitative diagnosis of thyroid nodules, however, some MTC may be diagnosed as a benign nodule on ultrasound because ultrasound features of malignancy are lacking. The aim of the study was to investigate the association between ultrasound features and biological behavior of MTC. Methods Ultrasound findings and medical records of patients with MTC between Jan 2015 to Jun 2017 were retrospectively reviewed at Tianjin Medical University Cancer Institute and Hospital. MTC were categorized using modified TI-RADS classification, then were classified as “malignant” (m-MTC) or “US-low-suspicious” (l-MTC). We compared the biological behavior between the two groups, and further analyzed the risk factors for the recurrence. Results A total of 78 patients were enrolled, of which 55 m-MTC (70.5%) and 23 l-MTC (29.5%) were identified. The N staging of the m-MTC was significantly higher than that of l-MTC(P = 0.000). The preoperative serum Ct level in m-MTC were significantly higher than that of l-MTC(P = 0.035). Biochemical cure were more frequent in l-MTC than that of m-MTC (P = 0.002). Disease recurrence rates were 19.7% (14 of 71). Disease recurrence was more frequent in m-MTC than that of l-MTC (P = 0.013). Disease recurrence was positively associated with extrathyroid extension (P = 0.047), N staging (P = 0.003), preoperative serum Ct level (P = 0.009) and negatively associated with biochemical cure(P = 0.000). In multivariable Cox regression analysis, extrathyroid extension and biochemical cure were independent risk factors for recurrence of MTC. Conclusions L-MTC has a more indolent character than m-MTC. The extrathyroid extension and biochemical cure were independent risk factors for recurrence of MTC.

Objective. Medullary (MTC) and papillary (PTC) thyroid carcinoma are two different types of thyroid carcinoma with significant differences in origin. Their co-occurrence in a patient is a rare phenomenon. We report a patient with simultaneous presentation of both MTC and PTC.

Abstract Background Germline RET mutations and variants are involved in development of multiple endocrine neoplasia type 2 (MEN2). The present study investigated a spectrum of RET variants, analyzed genotype-phenotype relationships, and evaluated their effect on the MEN2 phenotype in Han Chinese patients. Methods Targeted sequencing detected germline RET variants in 697 individuals, including 245 MEN2, 120 sporadic medullary thyroid cancer (MTC), and 15 pheochromocytoma (PHEO) patients and their 493 relatives. In silico analyses and classifications following ACMG-2015 were performed. Demographic, clinical variant types, and endocrine neoplasia molecular diagnosis records were also analyzed. Results Nineteen different RET mutations (18 point and 1 del/ins mutations) in 214 patients with MEN2A (97.7%) or MEN2B (2.3%) were found, of which exon 11/10 mutations accounted for 79% (169/214). Nineteen compound mutations were found in 31 patients with MEN2A. Twenty-three variants (18 single and 5 double base substitution/compound variants) non-classification were also found. Of these, 17 (3 of pathogenic, 10 of uncertain significance, 2 of likely benign and 2 as benign) were found in 31 patients with MTC/PHEO. The remaining 6 variants (4 of uncertain significance and 2 of likely benign) found in 8 carriers had no evidence of MEN2. The entire cohort showed MEN2A-related PHEO, all occurring in exons 11/10, particularly at C634. Kaplan-Meier curves showed age-dependent penetration rates of MTC and PHEO, and occurrence rates of PHEO in patients with exon 11 mutations were all higher than those within exon 10; these bilateral PHEO were always associated with exon 11 mutations (all P

BackgroundMultiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.MethodsThe clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed.ResultsFour probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.ConclusionsFrom this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

BackgroundRace, gender and socioeconomic disparities have been suggested to adversely influence stage at presentation, treatment options and outcomes in patients with cancer. Underserved minorities and those with a low socioeconomic status (SES) present with more advanced disease and have worse outcomes for differentiated thyroid cancer, but this relationship has never been evaluated for medullary thyroid cancer (MTC).MethodsWe used the California Cancer Registry (CCR) to evaluate disparities in the presentation, treatment and outcomes of patients diagnosed with MTC.ResultsWe identified 634 patients with MTC diagnosed between 1988 and 2011. Almost everyone (85%) underwent thyroidectomy with 50% having a central lymph node dissection (CLND). There were no statistically significant differences by age, race or SES in mean tumor size or the proportion of patients diagnosed with localized disease, but men were diagnosed with larger tumors than women and were less likely to be diagnosed at a localized stage. Younger patients and women were more likely to be treated with a thyroidectomy. There were no statistically significant differences in surgical treatment by race or SES. Patients in the highest SES category had a better overall survival, but not disease specific survival, than those in the lowest SES (HR =0.3, CI =0.1-0.7). Patients treated with thyroidectomy had a better overall and cause specific survival, but the effect of CLND was not statistically significant after adjustment for other factors.ConclusionsIn MTC, we did not find that race, gender or SES influenced the presentation, treatment or outcomes of patients with MTC. Men with MTC present with larger tumors and are less likely to have localized disease. Half of the MTC patients in California do not undergo a CLND at the time of thyroidectomy, which may suggest a lack appropriate care across a range of healthcare systems.

A statistically significant higher prevalence of the RET p.Met918Thr somatic mutation, identified by direct sequencing, was previously reported in MTC > 2 cm than in smaller tumors. Aim of this study was to correlate the full RET and RAS mutation profile, identified by a Next Generation Sequencing approach, with the growth rate, proliferation and tumor size of MTC. Data of 149 sporadic MTC patients were correlated with RET mutations and Ki67 positivity. Eighty-one cases had a somatic RET mutation, 40 had a RAS mutation and 28 were negative. A statistically significant higher prevalence of RET mutations was found in MTC > 2 cm. A higher prevalence of RET more aggressive mutations, higher allelic frequencies and, higher percentage of Ki67 positive cells were found in larger tumors which had also a worse outcome. Our study highlights the predom inant role of RET somatic mutations in MTC tumorigenesis. We demonstrate that RET mutation prevalence and allelic frequency (AF) are significantly higher in larger tumors. Based on these results, we can conclude that RET mutated C-cells’s growth and proliferation are more rapid than those of non-mutated cells and give origin to bigger and more aggressive MTC.

ABSTRACT Objective: To verify the cytopathological Bethesda System classification of thyroid nodule fine-needle aspiration biopsy (FNAB) in MTC patients and to assess the role of preoperative serum calcitonin (CT) levels in the investigation of this neoplasm in medullary thyroid cancer (MTC) patients under observation at the Uopeccan (União Oeste Paranaense de Estudos e Combate ao Câncer). Materials and methods: This is a cross-sectional review of medical records of patients monitored at the thyroid cancer outpatient clinic of Uopeccan. Clinical and demographic data, laboratory tests, ultrasound images, and cytopathological findings of MTC patients were evaluated. Results and discussion: Among the 360 patients with thyroid cancer monitored in the outpatient clinic, 5.2% (n: 19/360) had MTC. The hereditary form was more prevalent (63.2%), and there was no sex preference. The most common ultrasound findings were hypoechogenicity, solid appearance and microcalcifications. The FNAB diagnoses showed a sensitivity of 47.1%, and the most common cytopathological report was Bethesda category III. Serum CT levels showed good sensitivity (84.6%) for the diagnosis of MTC, and sensitivity levels were directly associated with the size of the nodule and distant metastases. Conclusion: Bethesda category III was more prevalent in this group of MTC patients. Serum CT levels were more sensitive than cytopathology for diagnosis of this neoplasm and were able to identify all patients who could not be diagnosed by FNAB.

Purpose: 18F-DOPA Positron Emission Tomography/Computed Tomography (18F-DOPA PET/CT) is a sensitive functional imaging method (65–75%) for detecting disease localization in medullary thyroid cancer (MTC). We aimed: (i) to assess the clinical usefulness of 18F-DOPA PET/CT in patients with MTC and elevated calcitonin (Ctn) and CEA levels and, (ii) to evaluate changes in disease management secondary to the findings encountered with this methodology. Methods: Thirty-six patients with MTC and Ctn levels ≥150 pg/ml were prospectively included. Neck ultrasound, chest contrast-enhanced CT, liver magnetic resonance imaging/abdominal three-phase contrast-enhanced CT and bone scintigraphy were carried out up to 6 months before the 18F DOPA PET/CT. Results: Seventy eight percent of patients were female and 27% had hereditary MTC. Median Ctn level was 1450 pg/ml [150–56620], median CEA level 413 ng/ml [2.9–7436]. Median Ctn DT was 37.5 months [5.7–240]; median CEA DT was 31.8 [4.9–180]. 18F-DOPA PET/CT was positive in 33 patients (91.6%); in 18 (56%) uptake was observed in lymph nodes in the neck or mediastinum, in seven cases (22%) distant metastases were diagnosed, and in eight additional patients (24%) both locoregional and distant sites of disease were found. Ctn and CEA levels were higher in patients with ≥3 foci of distant metastases. In 14 patients (38.8%), findings on 18F-DOPA PET/CT led to changes in management; surgery for locoregional lymph nodes was the most frequent procedure in 8 patients (22%). Conclusion: 18F-DOPA PET/CT was useful for the detection of recurrent disease in MTC, providing incremental value over conventional imaging procedures that led to modification in treatment strategies in nearly 40% of patients. [ABSTRACT FROM AUTHOR]

Background: In current care, patients' personal and self-reported family histories are primarily used to determine whether genetic testing for hereditary endocrine tumor syndromes (ETS) is indicated. Population genomic screening for other conditions has increased ascertainment of individuals with pathogenic/likely pathogenic (P/LP) variants, leading to improved management and earlier diagnoses. It is unknown whether such benefits occur when screening broader populations for P/LP ETS variants. This manuscript assesses clinical utility outcomes of a large, unselected, healthcare-based genomic screening program by describing personal and family history of syndrome-related features, risk management behaviors after result disclosure, and rates of relevant post-disclosure diagnoses in patient-participants with P/LP ETS variants.Methods: Observational study of individuals informed of a P/LP variant in MEN1, RET, SDHAF2, SDHB, SDHC, SDHD, or VHL through Geisinger's MyCode Community Health Initiative between June 2016 and October 2019. Electronic health records (EHRs) of participants were evaluated for a report of pre-disclosure personal and self-reported family histories and post-disclosure risk management and diagnoses.Results: P/LP variants in genes of interest were identified in 199 of 130,490 (1 in 656) adult Geisinger MyCode patient-participants, 80 of which were disclosed during the study period. Eighty-one percent (n = 65) did not have prior evidence of the result in their EHR and, because they were identified via MyCode, were included in further analyses. Five participants identified via MyCode (8%) had a personal history of syndrome-related features; 16 (25%) had a positive self-reported family history. Time from result disclosure to EHR review was a median of 0.7 years. Post-disclosure, 36 (55.4%) completed a recommended risk management behavior; 11 (17%) were diagnosed with a syndrome-related neoplasm after completing a risk management intervention.Conclusions: Broader screening for pathogenic/likely pathogenic variants associated with endocrine tumor syndromes enables detection of at-risk individuals, leads to the uptake of risk management, and facilitates relevant diagnoses. Further research will be necessary to continue to determine the clinical utility of screening diverse, unselected populations for such variants. [ABSTRACT FROM AUTHOR]

The association of Hashimoto thyroiditis and Graves' disease with papillary, follicular, and medullary thyroid cancer has not been comprehensively investigated until now. This comparative clinicopathological study of consecutive patients thyroidectomized at a surgical referral center aimed to explore interdependencies between chronic autoimmune thyroiditis and thyroid cancer. Altogether, there were 852 (58.4%) patients with papillary thyroid cancer, 181 (12.4%) patients with follicular thyroid cancer, and 426 (29.2%) patients with sporadic medullary thyroid cancer, of whom 75 (5.1%) patients also had Hashimoto thyroiditis and 40 (2.7%) patients also had Graves' disease. Patients with papillary (medians of 42 vs. 48 years; P =0.008) and follicular (medians of 33 vs. 63 years; P =0.022) thyroid cancer, unlike patients with medullary thyroid cancer (medians of 57.5 vs. 57 years; P =0.989), were younger at thyroidectomy when they had Hashimoto thyroiditis concomitantly. No such associations were seen with Graves' disease. Primary thyroid cancers tended to be more localized in conjunction with Hashimoto thyroiditis, and less so with Graves' disease, although patterns were not consistent across tumor types. In conclusion, Hashimoto thyroiditis, but not Graves' disease, may be associated with differentiated (papillary and follicular) thyroid cancer but not with medullary thyroid cancer. [ABSTRACT FROM AUTHOR]

Objective: Ectopic Cushing′s syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. Design: Retrospective cohort study in three German and one Swiss referral centres. Patients: Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. Measurements: The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. Results: The median age at diagnosis of ECS was 59 years (range: 35–81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0–193). Median serum morning cortisol was 49 µg/dl (range: 17–141, normal range: 6.2–18). Eight (73%) patients received treatment for ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval [95% CI]: 64–111) than matched controls (190 months, 95% CI: 95–285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. Conclusion: This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case. [ABSTRACT FROM AUTHOR]

The improper expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) and the GIP/GIPR axis activation has been increasingly recognized in endocrine tumors, with a potential diagnostic and prognostic value. A high tumor-to-normal tissue ratio (T/N ratio) of GIPR was reported both in humans' and in rats' m edullary thyroid cancer (MTC), suggesting a direct link between the neoplastic transformation and the mechanism of receptor overexpression. In this study, we evaluated the potential diagnostic and prognostic significance of GIPR expression in a large cohort of MTC patients by correlating GIPR mRNA steady-state levels to clinical phenotypes. The molecular effect of GIP/GIPR axis stimulation in MTC-derived cells was also determined. We detected GIPR expression in ~80% of tumor specimens, especially in sporadic, larger, advanced-stage cancers with higher Ki-67 values. GIPR stimulation induced cAMP elevation in MTC-derived cells and a small but significant fluctuation in Ca2+, both likely associated with increased calcitonin secretion. On the contrary, the effects on PI3K-Akt and MAPK-ERK1/2 signaling pathways were marginal. To conclude, our data confirm the high T/N GIPR r atio in MTC tumors and suggest that it may represent an index for the degree of advanc ement of the malignant process. We have also observed a functional coupling between GIP/GIPR axis and calcitonin secretion in MTC models. However, the molecular mechanisms underlying this process and the possible implication of GIP/GIPR axis activation in MTC diagnosis and prognosis need further evaluation. [ABSTRACT FROM AUTHOR]

Selpercatinib, a RET kinase inhibitor, is an effective treatment for patients with medullary thyroid cancer with RET mutations. In this paper, we present the case of a 62-year-old man with ectopic Cushing's syndrome due to medullary thyroid cancer who received treatment with selpercatinib. Six months later, all the cushingoid features had resolved, and s-calcitonin had decreased from 580 pmol/L to 3.5 pmol/L (normal < 3). After further 6 months, s-calcitonin had normalized (1.5 pmol/L), and radiological evaluation showed a profound tumour volume reduction. We are aware of two other cases where treatment with selpercatinib has also been successful. Thus, selpercatinib may be a promising treatment alternative in patients with ectopic Cushing's syndrome due to medullary thyroid cancer, especially when other treatment options are ineffective or not tolerated. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is a rare but clinically relevant tumor based on its aggressiveness and the limited therapeutic opportunities currently available for advanced cases. A better understanding of the mechanisms of MTC development is crucial to identify more effective means of intervention and therapies. Several studies have shown that RET and RAS genes play a central role in MTC. However, little is known about the signaling processes operating downstream of these genes. Here, we report mutation and gene expression profiles in proprietary sporadic MTCs, including both primary and metastatic tumors. We show that tumors derived from the same patient display similar expression profiles and that the latter can be used to obtain information about specific downstream signaling, identifying distinct molecular subtypes. Furthermore, by reviewing the relevant literature, we highlight that, along with RET and RAS, other less frequent genes are emerging as possible new players in MTC. Medullary thyroid carcinoma (MTC) is a rare but aggressive tumor. Although RET and RAS genes are recognized drivers in MTC, associated downstream signaling pathways are largely unknown. In this study, we report 17 sporadic MTCs, collected at our institution, comprising patient-matched primary and lymph node metastatic tumors investigated for mutational and transcriptional profiles. As we identified two uncommon RET deletions (D898_E901del and E632_L633del), we also performed a literature review and meta-analysis to assess the occurrence of unconventional alterations in MTC, focusing on next-generation sequencing studies. We found that new gene alterations are emerging, along with the known RET/RAS drivers, involving not only RET by multiple concurrent mutations or deletions but also other previously underestimated cancer-related genes, especially in sporadic MTCs. In our MTC gene profiles, we found transcriptome similarity between patient-matched tissues and expression of immune genes only by a few samples. Furthermore, we defined a gene signature able to stratify samples into two distinct signaling types, termed MEN2B-like and MEN2A-like. We provide an updated overview of the MTC mutational spectrum and describe how transcriptional profiles can be used to define distinct MTC signaling subtypes that appear to be shared by various gene drivers, including the unconventional ones. [ABSTRACT FROM AUTHOR]

Tumoral secretion of various molecular factors, such as calcitonin (Ct), can cause diarrhea in patients with medullary thyroid cancer (MTC). We report 3 patients (age 26–38 years, serum Ct levels ranging from 2,890 to 52,894 ng/L) with chronic diarrhea, and the diagnosis of MTC was delayed. Diarrheal symptoms improved after thyroid surgery. Two patients with elevated Ct had no diarrhea. The link between tumor humoral secretion and diarrhea is not well established in patients with MTC. Diarrhea is more common in patients with metastatic disease and improves after resection of the tumor. Diarrhea may result from elevated circulating levels of Ct or other substances, such as prostaglandins or serotonin. Other proposed mechanisms include decreased absorption in the colon secondary to gastrointestinal motor disturbances. In conclusion, MTC should be considered when evaluating chronic diarrhea.

The study objective is to perform retrospective analysis of the efficacy and safety of vandetanib for metastatic and non-resectable medullary thyroid cancer in routine clinical practice. Materials and methods. We analyzed treatment outcomes in 46 patients treated with vandetanib. We also evaluated progression-free survival, overall survival, time to progression, and frequency of adverse events. Results. At a median follow-up time of 27.4 months (range: 2.5–106.5 months) and median duration of vandetanib therapy of 21 months, disease progression was registered in 32.6 % of cases, whereas stable disease was observed in 28.3 % of cases and 8.7 % of study participants demonstrated partial response. One patient had complete response to treatment. Almost one-third of patients (28.2 %) died, including 2 individuals whose death was not associated with cancer. The one-year and three-year progression-free survival rates were 67.3 % and 33.3 %, respectively; the two-year and five-year overall survival rates were 82.4 % and 29.4 %, respectively. The efficacy of therapy was confirmed by a 79.4 % decrease in the serum level of calcitonin after treatment initiation. Side effects were observed in 33.9 % of patients (primarily skin and gastrointestinal toxic reactions) and were easily managed in most of the cases. Eight individuals (17.4 %) required cessation of vandetanib due to adverse events. Conclusion. Our findings suggest high efficacy and acceptable safety profile of vandetanib in the treatment of progressive locally advanced non-resectable and disseminated medullary thyroid cancer

Background: Medullary Thyroid Cancer (MTC) is a very aggressive type of thyroid carcinoma. Mutation in RET proto-oncogene is demonstrated in MTC development. We aimed to knock-out of RET-oncogene using CRISPR/Cas9 genome editing method in MTC cell-lines. Methods: This research was conducted in Shahid Beheshti University of Medical Sciences, Tehran, Iran during 2019-2020. Four different sgRNAs were designed to target exons one, two, and four of RET-oncogene in TT and MZ-CRC-1 cell-lines using bioinformatics tools, then the CRISPR/Cas9 constructs was made. About 72-hours after cell transfection, T7EI method and DNA sequencing were used to confirm the knock-out of RET-oncogene. Expression of RET, Calcitonin genes and RET protein were evaluated by Real-time PCR and ELISA, respectively. Results: The results of T7E1, and DNA sequencing of transfected cells confirmed RET gene knock-out by CRISPR/Cas9. There was a significant decrease in RET gene expression and RET protein in transfected TT and MZ cells compared to controls. The rate of cell apoptosis in transfected cells was significantly increased. Calcitonin gene expression was also significantly reduced in transfected cells. p-RET, p-PI3K, p-AKT, p-MEK, p-ERK protein levels were significantly reduced in TT and MZ transfected cells. Conclusion: For the first time, knock-out of RET gene was performed and confirmed using CRISPR/Cas9. Inhibition of this gene leads to inhibition of the tyrosine kinase RET signal transduction pathway. Therefore, it can be one of the most effective and specific therapeutic goals in the field of Personalized Medicine in the treatment of diseases caused by over activity of RET molecular pathway.

Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.

Abstract: Multiple endocrine neoplasia type 2 (MEN 2) is a rare hereditary endocrine tumor syndrome caused by mutations in the rearranged during transfection (RET) gene. MEN 2 is divided into two main entities, MEN 2A and MEN 2B, both of which present with medullary thyroid cancer (MTC) in approximately 100% of cases and pheochromocytoma in 50% of cases. Specific RET mutations are associated with a risk of early onset of MTC, from 1 year of age (highest risk) to 5 years of age (high risk). This risk defines the optimal timing for thyroidectomy, ideally at an age when the disease has not spread. This is the most important genotype-phenotype correlation observed in MEN 2. Specific RET mutations also define the penetrance of pheochromocytoma. However, despite the presence of these highest/high-risk variants, some patients unexpectedly present with non-aggressive MTC or never present with pheochromocytoma, suggesting that factors other than the major RET variant may modify the natural history and genotype-phenotype correlations. 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.

Context: Medullary thyroid cancer (MTC) has a historic recurrence rate up to 50%, and surgery remains the only cure., Objective: This study aims to assess factors related to recurrence and metastatic spread in MTC., Methods: Retrospective chart review was performed from 1990 to 2023 at a single specialized tertiary care referral center. Descriptive analysis and regression models were used for analysis. Sixty-eight patients with MTC, who underwent surgery, were included and the main outcome measure was recurrence., Results: Mean age at diagnosis was 54.9 years (42.2-64.1), 65% (n = 44) females. Lymph node and distant metastases were found in 24% (n = 16) and 4% (n = 3), respectively. RET mutations were present in 52% (n = 35): MTC risk levels were highest 6%, high 7%, and moderate 39%. Mean tumor size was 1.9 cm (1.2-3.2) and mean preoperative calcitonin was 504.4 pg/mL (133.2-1833.8). Total thyroidectomy (TT) was performed in 10 patients, TT + central neck dissection (CND) in 28, and TT + CND + lateral neck dissection (LND) in 25. On final pathology, 40% had positive central nodes and 25% had positive lateral nodes. Recurrence was 22%, median follow-up 4.7 years (1.2-28.0). Male gender (hazard ratio [HR] 5.81, P = .021), positive lateral neck nodes (HR 8.10, P = .011), and high/highest MTC risk level RET mutations (HR 8.66, P = .004) were significantly associated with recurrence. Preoperative calcitonin >2175 pg/mL was a strong predictor for distant metastasis (area under the curve [AUC] 0.893) and a good predictor for lateral neck disease (AUC 0.706). Extent of surgery was not significantly associated with recurrence (P = .634)., Conclusion: One of 4 patients undergoing surgery for MTC will recur. Risk factors associated with recurrence are male gender, lateral lymph node metastasis, and high/highest MTC risk level mutations, but not necessarily surgery type. Preoperative calcitonin >2175 pg/mL is suggestive of advanced disease and should prompt further evaluation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Glucagon-like peptide 1 receptor agonists (GLP1RA) have rapidly changed the landscape of diabetes and obesity treatment. Enthusiasm for their use is tempered with concerns regarding their risk for inducing C-cell tumors based on preclinical studies in rodents. A black-box warning from the United States Food and Drug Administration (USFDA) recommends against using GLP1RA in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2A or 2B (MEN2), providing clear guidance regarding this cohort of patients. However, emerging data also suggest an increased incidence of differentiated thyroid cancer (DTC) in patients treated with these agents. Other studies, though, have not confirmed an association between GLP1RA and DTC. With conflicting results concerning thyroid cancer risk, there is no clear consensus regarding the optimal approach to screening patients prior to initiating the medications and/or evaluating for thyroid cancer during GLP1RA treatment. Within the context of patient cases, this review will summarize the existing data, describe ongoing controversies, and outline future areas for research regarding thyroid cancer risk with GLP1RA use., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Pheochromocytoma can occur in patients with multiple endocrine neoplasia type 2, placing them at increased risk of tumour recurrence after surgical resection. Therefore, management of pheochromocytoma in these patients is a clinical challenge., Aims: We aim to present and discuss the nursing management of patient with recurrent pheochromocytoma., Study Design: Case studies. We reviewed and retrieved the necessary information from the medical records., Results: A 34-year-old female with a history of medullary thyroid carcinoma and pheochromocytoma complicated by cardiomyopathy, who had undergone surgical resections 6 years ago, presented with abdominal pain for 1 day and was diagnosed with recurrent bilateral pheochromocytoma, hypertensive crisis, acute heart failure, and acute renal failure. Eight hours after hospital admission, she experienced sudden cardiac arrest and received cardiopulmonary resuscitations. She was then supported under extracorporeal membrane oxygenation and continuous renal replacement therapy (CRRT). The adrenal tumour was successfully treated with absolute ethanol ablation followed by gelatin sponge particle embolization, a management approach which has not been reported previously. She had a satisfactory recovery., Conclusions: A comprehensive nursing management approach, including prone ventilation; safe transportation; close cardiopulmonary monitoring; pre-, intra- and post-procedure care; individualized early rehabilitation; and psychological supports, should be applied to improve the prognoses in patients with similar medical conditions., Relevance to Clinical Practice: Bilateral adrenal pheochromocytoma can be managed by absolute ethanol ablation followed by gelatin sponge particle embolization. Comprehensive nursing management, including a team effort regarding patient positioning, transportation, close monitoring, early rehabilitation and psychological support, should be provided during the peri-procedure period., (© 2024 British Association of Critical Care Nurses. Published by John Wiley & Sons Ltd.)

Background: Medullary thyroid cancer (MTC) is one of the rare neuroendocrine malignancies. This cancer is hereditary in approximately 20% of cases. Although lymph node (LN) metastasis is prevalent in MTC, distant metastasis is not commonly seen in these patients. The most common locations for metastasis are the lungs, liver, and bones. This study presents an extremely rare MTC metastasis to bone marrow (BM) and adrenal gland, which has not been reported before., Case: The patient was a 50-year-old man with a diagnosis of MTC and total thyroidectomy 2 months before his presentation. He came to the emergency department (ED) complaining of dyspnea, diffuse bone pain, nonbloody diarrhea, and abdominal cramps starting in the last month before. Initial treatment with intravenous fluid infusion and loperamide, due to the provisional diagnosis of infectious diarrhea, was ineffective. Further assessments revealed severe pancytopenia and a massive tumor above the left kidney. Bone marrow aspiration (BMA) and biopsy (BMB) led to the diagnosis of invasive metastasis of the MTC to the BM and the left adrenal gland. In the initial evaluations, his COVID-19 test became positive, and despite all efforts, his condition deteriorated, and he died 5 days after admission due to respiratory distress., Conclusion: 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., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)