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Purpose: Rare diseases occur in <50 per 100000 people and require lifelong management. However, essential epidemiological data on such diseases are lacking, and a consecutive monitoring system across time and regions remains to be established. Standardized digital phenotypes are required to leverage an international data network for research on rare endocrine diseases. We developed digital phenotypes for rare endocrine diseases using the observational medical outcome partnership common data model. Materials and Methods: Digital phenotypes of three rare endocrine diseases (medullary thyroid cancer, hypoparathyroidism, pheochromocytoma/paraganglioma) were validated across three databases that use different vocabularies: Severance Hospital;s electronic health record from South Korea; IQVIA's United Kingdom (UK) database for general practitioners; and IQVIA's United States (US) hospital database for general hospitals. We estimated the performance of different digital phenotyping methods based on International Classification of Diseases (ICD)-10 in the UK and the US or systematized nomenclature of medicine clinical terms (SNOMED CT) in Korea. Results: The positive predictive value of digital phenotyping was higher using SNOMED CT-based phenotyping than ICD-10- based phenotyping for all three diseases in Korea (e.g., pheochromocytoma/paraganglioma: ICD-10, 58%--62%; SNOMED CT, 89%). Estimated incidence rates by digital phenotyping were as follows: medullary thyroid cancer, 0.34--2.07 (Korea), 0.13--0.30 (US); hypoparathyroidism, 0.40--1.20 (Korea), 0.59--1.01 (US), 0.00--1.78 (UK); and pheochromocytoma/paraganglioma, 0.95--1.67 (Korea), 0.35--0.77 (US), 0.00--0.49 (UK). Conclusion: Our findings demonstrate the feasibility of developing digital phenotyping of rare endocrine diseases and highlight the importance of implementing SNOMED CT in routine clinical practice to provide granularity for research. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasias (MENs) are rare inherited endocrine tumor syndromes that occur due to an underlying constitutional RET mutation. After the phenotypic description in 1903 by Erdheim, Wermer described cases of endocrine gland tumors from the same family and proposed a genetic basis for the syndrome. The term MEN was coined by Steiner in 1968. Later, in 1990s MEN type 1 (MEN 1) and MEN type 2 (MEN 2) were described. Currently, MEN syndromes are defined as MEN 1, MEN 2A, MEN 2B, MEN 4, and MEN 5. Recent years have witnessed several advancements in genetic characteristics and associated clinical features of MEN 2 syndromes. The aim of this review is to summarize current information, novel genotype-phenotype associations, and future recommendations about MEN 2. [ABSTRACT FROM AUTHOR]

Introduction. Multikinase inhibitors are used to treat nonresectable locally advanced and/or metastatic medullary thyroid cancer (MTC). However they are characterized by high toxicity associated with kinase inhibition. Selective RET inhibitor selpercatinib demonstrates high selectivity and tolerance which makes it a promising agent for MTC treatment.Aim. To evaluate selpercatinib effectiveness and tolerance in patients with metastatic MTC associated with a mutation in the RET gene.Materials and methods. The study included 9 patients with metastatic MTC and mutation in the RET gene who received treatment with selpercatinib 160 mg 2 times a day. The drug effectiveness was evaluated every 2–3 months based on the results of multispiral computed tomography of the whole body and tumor marker (calcitonin and carcinoembryonic antigen) levels.Results. Median duration of therapy was 29 months overall response rate was 78 %; complete response was observed in 56 % of patients. After 12 months of therapy progression-free survival was 100 %; after 24 months it was 89 %. Persistent decrease in calcitonin level (by more than 90 %) was achieved in all patients. The most common adverse events were arterial hypertension and insignificant creatinine increase.Conclusion. The results of therapy show significant improvement in the rate of objective response and progression[1]free survival which makes selpercatinib a preferential treatment choice in this category of patients.

Abstract Background This psychometric analysis generated evidence to support the use of the Functional Assessment of Cancer Therapy item GP5 (GP5) as a measure of tolerability and confirms the appropriateness of categorizing “high side-effect burden” using a rating of 3 or 4 (score ranges 0–4) in patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC). Methodology Blinded, pooled interim data from the safety population (n=290) enrolled in the phase 3 LIBRETTO-531 trial (NCT04211337) were used. Intraclass correlation coefficients (ICC) were calculated for test-retest reliability using data from cycles 1-2 post-baseline. Construct validity was evaluated by examining the correlations of GP5 ratings with (a) symptomatic adverse events (AEs; measured by the PRO-CTCAE), and (b) functioning scores of EORTC QLQ-C30. The ability to detect change over time was examined by Cochrane-Mantel-Haenszel tests for GP5 ratings and PRO-CTCAE. The relationship of “high side-effect burden” categories with QLQ-C30 functioning scores was examined. Results ICCs for the GP5 ratings after cycle 1 ranged between 0.80 and 0.85, indicating good reliability. Correlations between GP5 and PRO-CTCAE items ranged from 0.18 to 0.62 and ranged from -0.37 to -0.50 for QLQ-C30 functioning scores, consistent with study assumptions. Post-baseline GP5 ratings showed significant associations with PRO-CTCAE scores (p

This article discusses the etiology of sporadic and hereditary forms of medullary thyroid cancer (MTC), diagnostic criteria that allow the most accurate and accurate diagnosis and differentiate it from similar symptoms, morphological changes in MTC, which is one of the least studied due to the peculiarities of its histogenetic genesis and low frequency of treatment of the population with this a problem. MTC is often diagnosed at the time of planned hospitalization of patients for problems in a related area, but not directly related to thyroid cancer. In this article, clinical manifestations presented in a specific clinical case are investigated, markers of immunohistochemical studies are determined. This case is interesting and unusual for the duration of the patient's treatment, as well as successful surgical interventions that were aimed at removing multiple metastases. To date, the number of referrals from patients with minimal structural and functional changes in the thyroid gland is small, which indicates that the disease is often diagnosed at a later date. In the minds of a certain percentage of the population, the idea of a possible self-healing of the body is firmly fixed, which is often decisive with the progression of the disease (especially with a sharp jump in progress, for example, after a general somatic decrease in the immune response after infectious diseases, hypothermia, radiation exposure). This article is indicative in this matter – it clearly demonstrates the need for timely vigilance and care for the body, timely medical examination of the population and attentive attitude in particular to the thyroid gland.

Background: This psychometric analysis generated evidence to support the use of the Functional Assessment of Cancer Therapy item GP5 (GP5) as a measure of tolerability and confirms the appropriateness of categorizing "high side-effect burden" using a rating of 3 or 4 (score ranges 0–4) in patients with advanced/metastatic RET-mutant medullary thyroid cancer (MTC). Methodology: Blinded, pooled interim data from the safety population (n=290) enrolled in the phase 3 LIBRETTO-531 trial (NCT04211337) were used. Intraclass correlation coefficients (ICC) were calculated for test-retest reliability using data from cycles 1-2 post-baseline. Construct validity was evaluated by examining the correlations of GP5 ratings with (a) symptomatic adverse events (AEs; measured by the PRO-CTCAE), and (b) functioning scores of EORTC QLQ-C30. The ability to detect change over time was examined by Cochrane-Mantel-Haenszel tests for GP5 ratings and PRO-CTCAE. The relationship of "high side-effect burden" categories with QLQ-C30 functioning scores was examined. Results: ICCs for the GP5 ratings after cycle 1 ranged between 0.80 and 0.85, indicating good reliability. Correlations between GP5 and PRO-CTCAE items ranged from 0.18 to 0.62 and ranged from -0.37 to -0.50 for QLQ-C30 functioning scores, consistent with study assumptions. Post-baseline GP5 ratings showed significant associations with PRO-CTCAE scores (p<0.001). Participants with GP5 ratings of 3 or 4 had worse physical function than those with GP5 ratings of 0 to 2 (p<0.0001). Conclusions: This analysis generated evidence supportive of the psychometric properties of the GP5 as a fit-for-purpose measure to assess treatment tolerability in patients with advanced/metastatic MTC. The definition of "high side-effect burden" was associated with the clinical feature of tolerability. Key summary points: This psychometric analysis provides evidence to support the usefulness of the categorization of "high side-effect burden" using GP5 scores of 3 and 4. The GP5 has good reliability and construct validity for assessing patient-reported tolerability. This analysis supports the use of the GP5 to assess patient-reported tolerability in patients with advanced or metastatic medullary thyroid cancer. [ABSTRACT FROM AUTHOR]

Given the limited availability of PET/CT scans, 99mTc‐(V) DMSA scintigraphy can be used to investigate possible metastases, especially in bone, in individuals with medullary thyroid cancer, even if there are no noticeable signs or symptoms of pain. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid cancer is a rare but severe variant of thyroid cancer. The mainstay treatment for this condition is surgery to remove the entire thyroid gland, or total thyroidectomy. However, recent studies have found that a less extensive thyroidectomy may optimize survival outcomes for early localized tumors. We compared the survival and mortality outcomes between patients with such tumors who underwent total thyroidectomy and lobectomy/subtotal thyroidectomy to understand which surgical approach can improve survival rates in early-stage medullary thyroid cancer. Background: The optimal surgical approach for localized T1 medullary thyroid cancer remains unclear. Total thyroidectomy is standard, but lobectomy and subtotal thyroidectomy may minimize mortality while maintaining oncologic control. Methods: This retrospective analysis utilized the National Cancer Institute's Surveillance, Epidemiology, and End Results registry to identify 2702 MTC patients including 398 patients with T1N0/1M0 MTC treated with total thyroidectomy or lobectomy/subtotal thyroidectomy from 2000 to 2019. Cox regression analyses assessed thyroid cancer-specific and overall mortality. Results: The majority (89.7%) underwent total thyroidectomy, while 10.3% had lobectomy/subtotal thyroidectomy. Nodal metastases were present in 29.6%. Over a median follow-up of 8.75 years, no significant difference was observed in cancer-specific mortality (5.7% vs. 8.1%, p = 0.47) or overall mortality (13.2% vs. 12.8%, p = 0.95). On multivariate analysis, undergoing cancer-directed surgery was associated with significantly improved overall survival (HR 0.18, p < 0.001) and cancer-specific survival (HR 0.17, p < 0.001) compared to no surgery. However, no significant survival difference was seen between total thyroidectomy and lobectomy/subtotal thyroidectomy for overall mortality (HR 0.77, p = 0.60) or cancer-specific mortality (HR 0.44, p = 0.23). The extent of surgery also did not impact outcomes within subgroups stratified by age, gender, T stage, or nodal status. Delayed surgery >1 month after diagnosis was associated with worse overall survival (p = 0.012). Conclusions: For localized T1 MTC, lobectomy/subtotal thyroidectomy appears to achieve comparable long-term survival to total thyroidectomy in this population-based analysis. The selective use of limited thyroidectomy may be reasonable for low-risk T1N0/1M0 MTC patients. Delayed surgery is associated with worse survival and additional neck dissection showed no benefit for this select group of patients. [ABSTRACT FROM AUTHOR]

Background: The current possible treatments of advanced medullary carcinoma (MTC) include different drugs belonging to the class of tyrosine kinase inhibitors (TKIs): vandetanib, cabozantinb, and selpercatinib. Although the effects of these TKIs have been well described in clinical trials, the real-practice evidence of the effectiveness and safety of these treatment is scant. This real-world case series aims to describe a niche of patients with advanced MTC treated with more than one TKI by focusing on treatment responses and any reported adverse events (AEs) and to provide additional insight on the individualized approach to the management of metastatic MTC. Methods: Five patients with a diagnosis of metastastic MTC, treated with at least two different molecules of TKIs, were retrospectively selected. Results: Three patients obtained a partial response (one with cabozantinb, one with selpercatinib, and one with vandetanib), and two patients obtained disease stability (both of them treated with all three TKIs, the first two lines discontinued for AEs). The AE profile agreed with the known clinical trials AEs except for non-neoplastic ascites related to selpercatinib and lung cavitations of non-neoplastic tissue related to cabozantinb. The latter was an AE never described so far in patients receiving TKIs. Conclusions: The best management of MTC relies on an individualized approach, keeping in mind and dealing with the potential toxicity in order to minimize the treatment withdrawal. [ABSTRACT FROM AUTHOR]

Background Selpercatinib is a selective RET inhibitor approved for treatment of RET -activated cancers. Adverse events (AEs) are manageable with dose modifications. This post hoc analysis characterized selpercatinib's clinical safety profile after long-term follow-up in the safety population of LIBRETTO-001. Patients and Methods LIBRETTO-001 is an ongoing phase I/II, single-arm, open-label trial (NCT03157128). Eligible patients were ≥18 years old with diagnosis of advanced/metastatic RET fusion-positive solid tumor, RET -mutant medullary thyroid cancer, or other RET -activated tumors. In phase I, patients received selpercatinib 20 mg QD or 20-240 mg BID; patients in phase II received 160 mg BID. The analyzed population comprised all patients who received ≥1 selpercatinib dose and were followed up until data cutoff (January 13, 2023). Results For the 837 patients, median follow-up was 45.4 months (95% CI, 44.5-46.6); median time on treatment was 30.1 months (range 0.1-66.8). Grade ≥3 treatment-emergent AEs (TEAEs) were reported in 76.2% of patients; most common events were hypertension (19.7%), ALT increased (11.8%), and hyponatremia (9.2%). Serious TEAEs were reported in 51.4% of patients. Most frequently reported any-grade AEs at <6 months of treatment were fatigue (36.6%), dry mouth (32.8%), and ALT increased (30.5%); at ≥24 months of treatment, these were edema (63.2%), diarrhea (60.7%), and fatigue (53.0%). Selpercatinib-related TEAEs leading to reduced dosage were reported in 39.3%, those leading to treatment interruption were reported in 47.1%, and those leading to discontinuation were reported in 4.3% of patients. Conclusion Long-term treatment with selpercatinib is feasible. AEs are manageable with dose modifications, allowing most patients to continue safely on therapy. [ABSTRACT FROM AUTHOR]

Objectives: To describe medullary thyroid cancer (MTC) onset in a boy affected previously by Langerhans cell histiocytosis (LCH) and review the literature for other reports of this association. Case presentation: A 6-year-old boy was treated for LCH diagnosis when he was 4 years old. After treatment, a rise in procalcitonin levels was observed (2.36–2.78 ng/ml) initially interpreted as inflammatory response. Further procalcitonin increase (4.61 ng/ml) with cervical lymphadenopathy and no infective focus was suspicious of thyroid involvement, confirmed by ultrasound, serum calcitonin, and cytological diagnosis. Total thyroidectomy with bilateral lymph node exeresis was performed. RET gene analysis revealed p.Met918Thr mutation. No association between the previous LCH and MTC had been identified to date. Conclusions: MTC is a rare condition in childhood presenting with an aggressive behaviour. It becomes crucial to increase the awareness of its features and anticipate diagnosis. Therefore, persistent high levels of pro-calcitonin without infective/inflammatory focus should lead to suspicion of thyroid involvement. [ABSTRACT FROM AUTHOR]

Medullary thyroid cancer (MTC) is a rare subtype of thyroid cancer originating from parafollicular C-cells of the thyroid. Tyrosine kinase inhibitors are used to treat patients with advanced MTC. Selpercatinib is a highly selective RET inhibitor used in the treatment of advanced RET-mutated MTC, having shown higher potency and fewer side effects compared to multikinase inhibitors in clinical trials. As a relatively new drug, its toxicity profile continues to be characterised. This report describes a case of severe acute hypocalcaemia in a 64-year-old male with advanced MTC treated with selpercatinib. The patient, who had stable hypoparathyroidism, experienced acute hypocalcaemia (corrected calcium 1.4 mmol/L) 2 weeks after initiating selpercatinib, requiring hospitalisation for calcium supplementation and monitoring. Selpercatinib was temporarily withheld and later reintroduced at a lower dose, successfully preventing recurrence of hypocalcaemia. Investigations excluded other common or important causes of hypocalcaemia, which led us to conclude that this could be a drug-related adverse event. This case highlights the need for careful monitoring of electrolyte disturbances in patients on selpercatinib, particularly those with pre-existing hypoparathyroidism. Although rare, the development of hypocalcaemia with RET inhibitors may necessitate dose interruptions and adjustments. Our experience has also illustrated that re-challenge with selpercatinib is feasible with appropriate management strategies.

Simple Summary: Total thyroidectomy and dissection of cervical lymph node compartments, depending on serum calcitonin levels and ultrasound findings, is standard treatment for patients with medullary thyroid cancer. The aim of this study was to evaluate whether pre-operative calcitonin and CEA levels can be useful as biomarkers of the extent of lymph node metastases at diagnosis. Results indicate that pre-operative serum calcitonin and CEA levels can predict presence, number, and site of lymph node metastases and, more specifically, values of 90 pg/mL for calcitonin and 17 ng/mL for CEA accurately indicate the N1b status. Since surgery is the only curative treatment for medullary thyroid cancer and there is not a strong indication regarding the extent of lymphadenectomy, these findings may help in the choice of the extent of neck dissection. Background: In medullary thyroid cancer (MTC), lymph node metastases are often present at diagnosis and the extent of surgery is usually based upon pre-operative calcitonin and CEA levels as well as ultrasound findings. The aim of this study was to evaluate the role of pre-operative calcitonin and CEA levels as predictive markers of the burden of lymph node metastases at diagnosis. Methods: we conducted a retrospective study analyzing 87 MTC patients. Results: The median levels of calcitonin and CEA were 88.4 pg/mL and 7.0 ng/mL, respectively, in patients with no lymph nodes metastases; 108.0 pg/mL and 9.6 ng/mL, respectively, in patients with metastases to 1–5 lymph nodes; 520.5 pg/mL and 43.2 ng/mL, respectively, in patients with metastases to >5 lymph nodes. There were no significant differences in pre-operative calcitonin and CEA values between N0 and N1a patients, whereas they were significantly higher in N1b patients. Pre-operative cut-off levels distinguishing N0/N1a from N1b patients were 90 pg/mL for calcitonin (sensitivity 100%, specificity 59.3%, AUC = 0.82) and 17 ng/mL for CEA (sensitivity 100%, specificity 75%, AUC = 0.89). Conclusions: in patients with MTC, pre-operative serum calcitonin and CEA levels may drive the decision-making process to better define the extent of surgery. [ABSTRACT FROM AUTHOR]

Medullary thyroid cancer (MTC) shows a relatively poor prognosis among thyroid cancers. Though calcitonin has been used as a diagnostic marker for MTC, it has disadvantages including poor sample stability and discrepancies among results by assay. This study aimed to compare the usefulness of preoperative calcitonin and procalcitonin (PCT) in the diagnosis of MTC. Serum calcitonin and PCT levels were measured before thyroidectomy from MTC (n = 23) and other types of thyroid cancers in patients (n = 1308). Diagnostic performances of calcitonin and PCT for discerning MTC were estimated. In a multivariate analysis, preoperative calcitonin level was independently associated with the diagnosis of MTC, whereas PCT was not. Calcitonin and PCT, respectively, exhibited area under the curve values of 0.997 and 0.979 for the diagnosis of MTC, without significant differences. For calcitonin, the sensitivity, specificity, and positive and negative predictive values were 0.957, 0.992, 0.688, and 0.999, respectively, at a cut-off of 7.2 pg/mL. The corresponding values for PCT were 0.913, 0.995, 0.778, and 0.998 at a cut-off of 0.19 ng/mL. Preoperative calcitonin and PCT showed similar diagnostic utility for MTC. Depending on the patient's clinical status and laboratory environment, these tests can be used as complementary methods for detecting MTC. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid carcinoma (MTC) is driven by a small number of pathogenic genetic variants and tumours usually exhibit a correspondingly low tumour mutational burden. This reduces tumour visibility to the immune system and impacts the immune cell profile of the tumour microenvironment. In the last decade targeted pathway inhibitors have revolutionized the therapeutic landscape for patients with advanced disease, with increasing options for systemic therapy tailored to the molecular signature of the tumour. Therefore, understanding the molecular basis of disease, pathogenesis of immune evasion and mechanisms of escape of pathway inhibition is of paramount importance. Here, we summarize genetic and molecular drivers of MTC and their relevance to tumour immunogenicity, the cellular milieu of the tumour microenvironment, and response to targeted therapy. In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specific RET (REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME). [ABSTRACT FROM AUTHOR]

Introduction: Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer and the main treatment is surgery. The extent of surgery depends on the spread of tumour and often involves thyroidectomy and neck dissection. Recurrent or metastasis tumour can be detected with raising calcitoninand there are various options of treatment. Methods: This was a retrospective study of MTC over seven years in a tertiary cancer centre which evaluated the treatment outcome and the non-surgical options available in recurrent and metastatic tumours. Results: Among the 601 thyroid cancers, 34 patients (5.3%) were MTC, of which 29 were studied. Majority were women, below 60 years, were diagnosed with fine needle aspiration cytology of thyroid nodule or nodes and had raised calcitonin value (Ctn). The value of Ctn was correlated with tumour burden rather than extent (p=0.7). Recurrence was seen in 35% and all patients with locoregional recurrence had curative surgery whereas metastatic patients were offered palliative treatment. Acceptance of palliative treatment was less due to financial burden. The five year overall survival for nonmetastatic disease was 89.4 % and for patients with metastatic disease at presentation was 54.7 %. Conclusion: The incidence of medullary thyroid carcinoma is low compared to the differentiated thyroid carcinoma. The main treatment is surgery and other treatment options are limited. [ABSTRACT FROM AUTHOR]

ABSTRACT 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.

A clinical case of examination and treatment of a 29-year-old female patient with type 1 multiple endocrine neoplasia with calcitonin-secreting pancreatic tumors is presented. The difficulties of modern complex diagnostics are shown, as well as the effectiveness of multi-stage surgical tactics involving specialists of various profiles. The conducted laboratory and instrumental examination, which included the entire arsenal of high-tech methods, made it possible to timely diagnose a combined lesion of several endocrine organs. Based on the assessment of the functional activity of the identified tumors, the order of the stages of surgical treatment was substantiated. The implementation of the proposed surgical tactics contributed to the normalization of the patient’s hormonal status and improved quality of life.

Background: Medullary thyroid cancer (MTC) is a challenging malignancy. The survival outcome of MTC based on AJCC staging system does not render a discriminant classifier among early stages. Methods: 3601 MTC patients from 2000 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Smooth curve fitting, Cox proportional hazard regression and competing risk analysis were applied. Results: A linear correlation between age and log RR (relative risk of overall death) was detected. Overlaps were observed between K-M curves representing patients aged 45-50, 50-55, and 55-60. The study cohort was divided into 3 subgroups with 2 age cutoffs set at 45 and 60. Each further advanced age cutoff population resulted in a roughly "5%" increase in MTC-specific death risks and an approximately "3 times" increase in non-MTC-specific death risks. Conclusions: The survival outcome disparity across age cutoffs at 45 and 60 for MTC has been well defined. [ABSTRACT FROM AUTHOR]

Context Medullary thyroid cancer (MTC) is a rare disease. Objective The main objective of our study was to analyze the incidence evolution of MTC with a follow-up of more than 40 years. Further, a descriptive and survival analysis was performed according to the Kaplan–Meier analysis. Design, Setting, and Patients This is a retrospective epidemiological study using data from the Marne-Ardennes registry from 1975 to 2018. Two hundred sixty patients with MTC were included. Main Outcome Measures The incidence was calculated in the territory of the register (Marne and Ardennes departments of France) and standardized on the demographic structure of France. Patient and tumor characteristics were described. An analysis in a subgroup comparing hereditary and sporadic forms was performed. An analysis of survival was performed. Results The standardized incidence shows an increasing trend over time. The incidence increased significantly from 0.41 to 0.57/100 000 person-years between 1986 and 1996 and 2008 and 2018. The MTC was hereditary in 21.2% of cases. The sex ratio (males:females) was 0.73. The average age at diagnosis was 53 years. Ninety-seven patients (37.3%) were N1, 26 (10%) were M1, and 56 (21.5%) developed metastases during the follow-up. Complete remission was obtained in 58.5% of patients. The disease was refractory for 18.1% of patients. The 5-year survival rate was 88.4%. Sporadic cases had a poorer prognosis than hereditary MTC. Conclusion Our study demonstrates a moderate increase in the incidence of MTC between 1975 and 2018. The prognosis remains worse for sporadic MTC than for hereditary MTC. [ABSTRACT FROM AUTHOR]

Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

Objective: The treatment landscape for thyroid cancers has changed rapidly with the availability of kinase inhibitors against VEGFR, BRAF, MEK, NTRK, and RET. We provide an up-to-date review of the role of kinase inhibitors in thyroid cancer and discuss upcoming trials. Design & Methods: A comprehensive review of the available literature describing kinase inhibitors in thyroid cancer was performed. Results and Conclusions: Kinase inhibitors have become the standard of care for patients with metastatic radioactive iodine-refractory thyroid cancer. Short-term treatment can re-sensitize differentiated thyroid cancer to radioactive iodine, thereby potentially improving outcomes and sparing toxicities associated with the long-term use of kinase inhibitors. The approval of cabozantinib as salvage therapy for progressive radioactive iodine-refractory differentiated thyroid cancer following failure with sorafenib or lenvatinib adds to the available armamentarium of active agents. Vandetanib and cabozantinib have become mainstay treatments for metastatic medullary thyroid cancer regardless of RET mutation status. Selpercatinib and pralsetinib, potent and selective receptor kinase inhibitors with activity against RET, have revolutionized the treatment paradigm for medullary thyroid cancers and other cancers with driver mutations in RET. Dabrafenib plus trametinib for BRAF mutated anaplastic thyroid cancer provides an effective treatment option for this aggressive cancer with a dismal prognosis. In order to design the next generation of agents for thyroid cancer, fut ure efforts will need to focus on developing a better understanding of the mechanisms of resistance to kinase inhibition including bypass signaling and escape mutations.

Objective: This study aimed to describe real-world patient and physician characteristics, rearranged during transfection (RET) mutation testing and results, treatment patterns and patient-reported outcomes (PROs) in advanced or metastatic medullary thyroid cancer (aMTC) across five populous European countries. Methods: Cross-sectional physician and patient surveys were used to collect quantitative and qualitative data in France, Germany, Italy, Spain and the UK from July to December 2020, prior to the introduction of selective RET inhibitors in Europe. Physicians completed patient record forms and a survey about their specialty and practice site. Patients were asked to provide PRO data using four validated instruments, including the EuroQol 5 Dimension (EQ-5D) questionnaire. Results: The physician-reported sample included 275 patients with aMTC, including 79 patients with RET mutation-positive disease; median age was 60 and 56 years, respectively. Overall, 75% were tested for RET mutation (35% germline only, 21% somatic only and 44% both). Common physician-cited barriers to RET mutation testing included high cost, difficulty accessing the latest tests and time delay for results. First-line systemic therapy (most commonly vandetanib or cabozantinib) was prescribed for 69% of patients overall and 82% of the RET mutation-positive subgroup. Second-line therapy was prescribed for 12% of patients who received first-line therapy; most patients remained on first-line therapy at data capture. PROs revealed a substantial disease/treatment burden. Conclusion: Patients with aMTC report a substantial disease/treatment burden. Outcomes could be improved by identifying patients eligible for treatment with selective RET inhibitors through more optimal RET mutation testing.

Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.

Background: The current possible treatments of advanced medullary carcinoma (MTC) include different drugs belonging to the class of tyrosine kinase inhibitors (TKIs): vandetanib, cabozantinb, and selpercatinib. Although the effects of these TKIs have been well described in clinical trials, the real-practice evidence of the effectiveness and safety of these treatment is scant. This real-world case series aims to describe a niche of patients with advanced MTC treated with more than one TKI by focusing on treatment responses and any reported adverse events (AEs) and to provide additional insight on the individualized approach to the management of metastatic MTC. Methods: Five patients with a diagnosis of metastastic MTC, treated with at least two different molecules of TKIs, were retrospectively selected. Results: Three patients obtained a partial response (one with cabozantinb, one with selpercatinib, and one with vandetanib), and two patients obtained disease stability (both of them treated with all three TKIs, the first two lines discontinued for AEs). The AE profile agreed with the known clinical trials AEs except for non-neoplastic ascites related to selpercatinib and lung cavitations of non-neoplastic tissue related to cabozantinb. The latter was an AE never described so far in patients receiving TKIs. Conclusions: The best management of MTC relies on an individualized approach, keeping in mind and dealing with the potential toxicity in order to minimize the treatment withdrawal.

Neuroendocrine tumor (NET) metastasis to the thyroid is rare, and its presentation as the first manifestation of primary malignancy elsewhere is even more uncommon. We present a case of a 41-year-old female who underwent biopsy of enlarging thyroid nodules with findings suspicious for medullary thyroid cancer (MTC). Subsequent thyroidectomy demonstrated NET of unknown primary in the left lower lobe. Immediate workup with 68Ga-DOTATATE-PET/CT revealed abnormal somatostatin receptor (SR) expressing lesions in the liver, right cervical nodes, thoracic paravertebral soft tissue, precoccygeal soft tissue, and right acetabulum concerning for sites of neuroendocrine malignancy. Due to disease progression while on octreotide injections, a decision was made at the multidisciplinary NET board for the patient to receive peptide receptor radionuclide therapy (PRRT) which includes 4 cycles of 77Lu-DOTATATE (Lutathera). The patient had no side effects nor toxicities during the 8 months of PRRT and achieved a partial treatment response in the early post-treatment scan at 6 weeks. This case illustrates the importance of distinguishing NET metastasis to the thyroid from MTC to ensure appropriate workup and treatment as well as predict the response of neuroendocrine malignancies to PRRT based on the visualized overexpression of SR in the SR-PET scans, despite the organ of origin.

Background: Papillary thyroid carcinoma (PTC) is the most common type of differentiated TC, while medullary TC (MTC) accounts for 4%. The concomitant presence of PTC and MTC is rare. Methods: This is a retrospective, single-center observational study conducted over 16 years (2001–2017). The data were collected from the clinical records of patients who underwent total thyroidectomy at the Endocrine Unit-Department of Medicine of the University Hospital of Pisa, Italy. Results: Over 690 analyzed cases, 650 (94.2%) were exclusive DTC, 19 exclusive MTC (2.75%) and 5 PTC/MTC (0.7%). No case of mixed medullary/follicular TC or hereditary MTC (familial MTC/multiple endocrine neoplasia type 2) was found. Among the five PTC/MTC cases, there was a male prevalence (M:F = 3:2), and all PTC components were at stage I, whereas 40% of MTC were at stage I and III and 20% of MTC were at stage II; microPTC (mPTC) was prevalent (80%) and also microMTCs were frequent (40%); 60% of MTC patients recovered, while 40% of patients developed metastatic disease. The search for germline mutations of the RET gene resulted in being negative in all cases. Conclusions: The incidence of PTC/MTC has been increasing over the past 30 years. The etiology of PTC/MTC forms is still unknown, and although this simultaneous occurrence could be only a coincidence, we cannot exclude the hypothesis of a shared genetic origin.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have changed considerably the management of type 2 diabetes (T2D). However, recently published data from retrospective cohort studies suggest that chronic exposure to GLP-1RAs in T2D may increase the risk of papillary and medullary thyroid cancer. In this perspective, the role of the incretin system in thyroid carcinogenesis has been reviewed and critically commented on, aiming to understand if the time has arrived to be concerned about the risk. Although evidence suggested, speculative hypotheses should be verified, and further studies are urgently needed to clarify the issue.

Metastatic lung neuroendocrine carcinomas provide diagnostic challenges in identifying the cell of origin. High level calcitonin expression is not pathognomonic for medullary thyroid cancer. Tumor mutation analysis may provide essential clues regarding tissue origin and treatment targets. Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non- medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic MTC. Patients who receive radiation for the treatment of other cancers have an increased risk of developing a second malignancy, including a neuroendocrine carcinoma. Herein, we present a case of calcitonin-rich neuroendocrine carcinoma emerging on a background of prior radiation and chemotherapy for the treatment of Hodgkin's disease. Identification of a RET gene rearrangement (KIF5B-RET) led to initial successful treatment with selpercatinib, with eventual resistance associated with an activating mutation involving the MEK1 protein (MAP2K1 p. E102-I103 del) that led to relapse and progression of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Medullary thyroid cancer is a rare neuroendocrine tumor, which is inherited in 25% of cases. Medical progress has made it easier to find thyroid tumors before they spread to the neck nodes, which makes a surgical cure harder to achieve. Removing only the tumor-bearing thyroid lobe causes fewer surgical complications than removing the whole thyroid gland or neck nodes. When the remaining thyroid lobe produces enough thyroid hormone, patients are spared the need to take one thyroid hormone tablet daily for life. This literature review confirms that the removal of the tumor-bearing thyroid lobe alone clears all of the tumor in patients who are not gene carriers and whose thyroid tumors showed no 'desmoplasia' under the microscope on a rapid 'frozen section' examination. Gene carriers, who can be detected by a simple blood test, still need to have the whole thyroid gland removed so that no other thyroid tumors can form from the thyroid tissue left behind. (1) Background: The wider adoption of a preoperative ultrasound and calcitonin screening complemented by an intraoperative frozen section has increased the number of patients with occult sporadic medullary thyroid cancer (MTC). These advances offer new opportunities to reduce the extent of the initial operations, minimizing operative morbidity and the risk of postoperative thyroxin supplementation without compromising the cure. (2) Methods: This systematic review of the international literature published in the English language provides a comprehensive update on the latest progress made in the risk-adapted surgery for sporadic and hereditary MTC guided by an intraoperative frozen section. (3) Results: The current evidence confirms the viability of a hemithyroidectomy for desmoplasia-negative sporadic MTC. To add an extra safety margin, the hemithyroidectomy may be complemented by a diagnostic ipsilateral central node dissection. Despite the limited extent of the surgery, all the patients with desmoplasia-negative sporadic tumors achieved a biochemical cure with excellent clinical outcomes. A hemithyroidectomy decreases the need for postoperative thyroxine substitution, but a total thyroidectomy may be required for bilateral nodular thyroid disease. Hereditary MTC is a different issue. Because each residual thyroid C cell carries its own risk of malignant progression, a total thyroidectomy remains mandatory for hereditary MTC. (4) Conclusion: In experienced hands, a hemithyroidectomy, which minimizes morbidity without compromising the cure, is an adequate therapy for desmoplasia-negative sporadic MTC. [ABSTRACT FROM AUTHOR]

Background The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for medullary thyroid cancer (MTC) was implemented in 2018. However, its ability to predict prognosis remains controversial. Patients and Methods Patient data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database and multicenter datasets. Overall survival was the primary end-point of the present study. The concordance index (C-index) was used to assess the efficacy of various models to predict prognostic outcomes. Results A total of 1450 MTC patients were selected from the SEER databases and 349 in the multicenter dataset. According to the AJCC staging system, there were no significant survival differences between T4a and T4b categories (P =.299). The T4 category was thus redefined as T4a' category (≤3.5 cm) and T4b' category (>3.5 cm) based on the tumor size, which was more powerful for distinguishing the prognosis (P =.003). Further analysis showed that the T category was significantly associated with both lymph node (LN) location and count (P <. 001). Therefore, the N category was modified by combining the LN location and count. Finally, the above-mentioned novel T and N categories were adopted to modify the 8th AJCC classification using the recursive partitioning analysis principle, and the modified staging system outperformed the current edition (C-index, 0.811 vs. 0.792). Conclusions The 8th AJCC staging system was improved based on the intrinsic relationship among the T category, LN location, and LN count, which would have a positive impact on the clinical decision-making process and appropriate surveillance. [ABSTRACT FROM AUTHOR]

BackgroundIn cancers with a chronic phase, patients and family caregivers face difficult decisions such as whether to start a novel therapy, whether to enroll in a clinical trial, and when to stop treatment. These decisions are complex, require an understanding of uncertainty, and necessitate the consideration of patients' informed preferences. For some cancers, such as medullary thyroid carcinoma, these decisions may also involve significant out-of-pocket costs and effects on family members. Providers have expressed a need for web-based interventions that can be delivered between consultations to provide education and prepare patients and families to discuss these decisions. To ensure that these tools are effective, usable, and understandable, studies are needed to identify patients', families', and providers' decision-making needs and optimal design strategies for a web-based patient decision aid.ObjectiveFollowing the international guidelines for the development of a web-based patient decision aid, the objectives of this study are to engage potential users to guide development; review the existing literature and available tools; assess users' decision-making experiences, needs, and design recommendations; and identify shared decision-making approaches to address each need.MethodsThis study used the decisional needs assessment approach, which included creating a stakeholder advisory panel, mapping decision pathways, conducting an environmental scan of existing materials, and administering a decisional needs assessment questionnaire. Thematic analyses identified current decision-making pathways, unmet decision-making needs, and decision support strategies for meeting each need.ResultsThe stakeholders reported wide heterogeneity in decision timing and pathways. Relevant existing materials included 2 systematic reviews, 9 additional papers, and multiple educational websites, but none of these met the criteria for a patient decision aid. Patients and family members (n=54) emphasized the need for plain language (46/54, 85%), shared decision making (45/54, 83%), and help with family discussions (39/54, 72%). Additional needs included information about uncertainty, lived experience, and costs. Providers (n=10) reported needing interventions that address misinformation (9/10, 90%), foster realistic expectations (9/10, 90%), and address mistrust in clinical trials (5/10, 50%). Additional needs included provider tools that support shared decision making. Both groups recommended designing a web-based patient decision aid that can be tailored to (64/64, 100%) and delivered on a hospital website (53/64, 83%), focuses on quality of life (45/64, 70%), and provides step-by-step guidance (43/64, 67%). The study team identified best practices to meet each need, which are presented in the proposed decision support design guide.ConclusionsPatients, families, and providers report multifaceted decision support needs during the chronic phase of cancer. Web-based patient decision aids that provide tailored support over time and explicitly address uncertainty, quality of life, realistic expectations, and effects on families are needed.

Metastatic lung neuroendocrine carcinomas provide diagnostic challenges in identifying the cell of origin. High level calcitonin expression is not pathognomonic for medullary thyroid cancer. Tumor mutation analysis may provide essential clues regarding tissue origin and treatment targets. Oncogenic RET gene fusions have been identified in non-small cell lung cancer and non-medullary thyroid cancers, whereas RET point mutations are the key genetic finding in both inherited and sporadic MTC. Patients who receive radiation for the treatment of other cancers have an increased risk of developing a second malignancy, including a neuroendocrine carcinoma. Herein, we present a case of calcitonin-rich neuroendocrine carcinoma emerging on a background of prior radiation and chemotherapy for the treatment of Hodgkin’s disease. Identification of a RET gene rearrangement (KIF5B-RET) led to initial successful treatment with selpercatinib, with eventual resistance associated with an activating mutation involving the MEK1 protein (MAP2K1 p. E102-I103 del) that led to relapse and progression of the disease.

Introduction: Medullary thyroid carcinoma is a primary thyroid neoplasm originating from thyroid C cells. It can be familial or sporadic. The familial form is associated with multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and is caused by a mutation in the RET gene, which encodes a tyrosine kinase receptor. Treatment of medullary thyroid cancer is mainly based on surgical resection of the thyroid gland, usually a total thyroidectomy. It can be followed-up by a chemotherapy, which has limited efficacy. Hence, there is a growing interest in new molecular therapies, such as tyrosine kinase inhibitors, which include vandetanib, cabozantinib, selpercatinib, pralsetinib, sorafenib and lenvatinib. Objective: The review and presentation of the current state of knowledge on the systemic treatment of medullary thyroid cancer with kinase inhibitors. Material and methods: Literature review based on available sources from PubMed database and Google Scholar. Conclusions: Though systemic treatment options for medullary thyroid cancer continue to improve, patients with advanced neoplasms still have limited therapeutic options. Hence, further development of targeted treatment with kinase inhibitors, particularly those selective for the RET receptor is crucial. Molecular studies of mutations and signaling pathways involved in the oncopathogenesis of medullary thyroid cancer could contribute to the discovery of new therapeutic mechanisms, and drugs that target them, could potentially further improve disease progression-free survival (PFS) and overall survival (OS). [ABSTRACT FROM AUTHOR]

Background: Papillary thyroid carcinoma (PTC) is the most common type of differentiated TC, while medullary TC (MTC) accounts for 4%. The concomitant presence of PTC and MTC is rare. Methods: This is a retrospective, single-center observational study conducted over 16 years (2001–2017). The data were collected from the clinical records of patients who underwent total thyroidectomy at the Endocrine Unit-Department of Medicine of the University Hospital of Pisa, Italy. Results: Over 690 analyzed cases, 650 (94.2%) were exclusive DTC, 19 exclusive MTC (2.75%) and 5 PTC/MTC (0.7%). No case of mixed medullary/follicular TC or hereditary MTC (familial MTC/multiple endocrine neoplasia type 2) was found. Among the five PTC/MTC cases, there was a male prevalence (M:F = 3:2), and all PTC components were at stage I, whereas 40% of MTC were at stage I and III and 20% of MTC were at stage II; microPTC (mPTC) was prevalent (80%) and also microMTCs were frequent (40%); 60% of MTC patients recovered, while 40% of patients developed metastatic disease. The search for germline mutations of the RET gene resulted in being negative in all cases. Conclusions: The incidence of PTC/MTC has been increasing over the past 30 years. The etiology of PTC/MTC forms is still unknown, and although this simultaneous occurrence could be only a coincidence, we cannot exclude the hypothesis of a shared genetic origin. [ABSTRACT FROM AUTHOR]

Background: There remains uncertainty regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer (MTC). We aim to describe the patterns of disease recurrence and outcomes of the reoperative surgery in a cohort of consecutively treated patients at a specialized tertiary referral center. Patients and Methods: A retrospective cohort study of 235 surgically treated patients with MTC at a tertiary referral center was performed using prospectively collected data. Results: In the study period 1986-2022, 235 patients underwent surgery for MTC. Of these, 45 (19%) patients had reoperative surgery for cervical nodal recurrence at a median (range) 2.1 (0.3-16) years following the index procedure. After a median follow-up of 4 years, 38 (84%) patients remain free of structural cervical recurrence, although 15 (33%) underwent 2 or more reoperative procedures. No long-term complications occurred after reoperative surgery. Local cervical recurrence was independently predicted by pathologically involved nodal status (OR 5.10, P = .01) and failure to achieve biochemical cure (OR 5.0, P = .009). Local recurrence did not adversely affect overall survival and was not associated with distant recurrence (HR 0.93, P = .83). Overall survival was independently predicted by high pathological grade (HR 10.0, P = .002) and the presence of metastatic disease at presentation (HR 8.27, P = 0018). Conclusion: Loco-regional recurrence in MTC does not impact overall survival, or the development of metastatic disease, demonstrating the safety of the staged approach to the clinically node-negative lateral neck. When recurrent disease is technically resectable, reoperative surgery can be undertaken with minimal morbidity in a specialized center and facilitates structural disease control. Uncertainty remains regarding the optimal extent of initial surgery and management of recurrent disease in medullary thyroid cancer. This article reports patterns of disease recurrence and outcomes of reoperative surgery in a cohort of consecutively treated patients. [ABSTRACT FROM AUTHOR]

Objective: To determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study. Methods: Retrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups. Results: Genetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases, 56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01). Conclusion: This is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity. [ABSTRACT FROM AUTHOR]

Epidemiology of medullary thyroid cancer is presented in the literature review. Thyroid cancer is the most common form of endocrine oncological pathology. It accounts for 96–97 % of all malignant tumors of endocrine organs. According to the Surveillance, Epidemiology, and End Results Program (USA), the incidence of thyroid cancer in 1975–2009 increased approximately threefold, from 4.9 to 14.3 cases per 100,000 population. At the same time, the mortality rate remained low, approximately at the same level, 0.5 cases per 100,000. Such a situation can be explained to some extent by the improvement of diagnostic capabilities of the early, often preclinical, stage of thyroid tumors. Medullary thyroid cancer ranks third after papillary and follicular cancer, but surpasses them in terms of aggressiveness. It is a re­latively rare disease. This type of tumor makes up 1–9 % of all thyroid cancers. Against the background of the general tendency to increase the incidence of thyroid cancer, the absolute number of cases of medullary cancer according to various data remains relatively stable. Epidemiological characteristics of medullary thyroid cancer deserve attention in the age aspect, as well as when considering the frequency of detecting these tumors at autopsy of people who had no signs during their lifetime. In clinical practice, medullary thyroid cancer occurs in two main forms — sporadic and hereditary. The latter is represented as part of the combined syndrome of multiple endocrine neoplasia type 2 (MEN-2), which, in turn, is divided into two subtypes: MEN-2A and MEN-2B syndromes. MEN-2 syndrome is a rare combined hereditary pathology. Sporadic medullary thyroid cancer accounts for approximately 70–80 % of such tumors. It is accompanied by other types of endocrinopathies. Most cases of medullary thyroid cancer occur in the fifth decade of life. The presented data on the epidemiology of medullary thyroid cancer allow for a more detailed and in-depth study of this pathology and contain a certain amount of useful and necessary information.

Abstract Purpose To investigate the value of ultrasound and serum marker tests in detecting lateral lymph node metastasis in medullary thyroid cancer (MTC). Methods Data of 105 patients diagnosed with MTC and admitted to the Department of General Surgery in Peking Union Medical College Hospital from June 2010 to August 2020 were collected and retrospectively analyzed. Results Ultrasound examination alone had a sensitivity of 89.36% and a specificity of 70.69%. For surveillance of postoperative carcinoembryonic antigen and calcitonin, cut‐off values of 7.115 ng/mL and 13.185 pg/mL, respectively, were shown to discriminate the presence of cervical lymph node metastasis. Combining ultrasound and postoperative serum levels of both carcinoembryonic antigen and calcitonin as serial tests increased the specificity to 91.38% and 87.93%, with a sensitivity of 95.45%. Multivariate logistic analysis identified the following risk factors for lateral lymph node metastasis in MTC: suspicious lymph nodes detected by ultrasound and postoperative calcitonin above 13.185 pg/mL. Conclusion The combination of ultrasound and serological tests achieved higher sensitivity and specificity to identify MTC cases with potential occult lateral cervical lymph node metastasis compared with single tests.

Introduction: Serum calcitonin (CT) and carcinoembryonic antigen (CEA) are valuable tumour markers in patients with medullary thyroid carcinoma (MTC). Both markers most often evolve in parallel after treatment. Selpercatinib (LOXO-292) is a highly selective RET kinase inhibitor indicated in advanced RET-mutant MTC patients. Cases presentation: In this study, we report two observations of RET-mutant progressive metastatic and symptomatic MTC patients who were treated with selpercatinib. Patient 1, a 61-year-old man, presented dyspnoea and diarrhoea at selpercatinib initiation with large neck lymph nodes and lung metastases. Patient 2, a 76-year-old man, had acute discomfort with flush and diarrhoea, with small but diffuse bone and liver disease. Both patients had an objective tumour response with rapid clinical improvement and RECIST 1.1 response (−90%) in patient 1. A rapid dramatic decrease in CT level was observed in both patients (−99% in both patients), while CEA levels gradually and sustainably increased after selpercatinib initiation (+207% at cycle 15 in patient 1 and + 835% at cycle 14 in patient 2). In both patients, 18FDG PET/CT did not show any abnormal uptake that could explain the CEA increase. Colonoscopy and oesogastric fibr oscopy showed colonic polyposis with mild oesophagitis and gastritis in patient 1 and were normal in patient 2. Conclusion: These observations show an unusual and lasting increase in serum CEA in two MTC patients who exhibited an objective tumour response to selpercatinib. The mechanism behind this unexpected rise in CEA level remains unknown. The frequency of this evolving profile will be determined in further phase III studies.

Introduction: Medullary thyroid cancer (MTC) is a rare endocrine tumor, which can be sporadic or familial, as a component of multiple endocrine neoplasia 2 (MEN2). Overall, 10% of MTC cases have already developed at presentation or will develop metastasis during follow-up. Testicular metastases are exceptional and only one case of unilateral testis involvement by metastatic MTC has been already reported in literature. We described the first known case of asymptomatic bilateral testicu lar MTC metastases, discovered incidentally at testicular ultrasound (US) performed for unrelated reasons. Case presentation: A Latin American 32-year-old man with MEN 2A syndrome and metastatic MTC underwent andrological and urological examination due to premature ejaculation. US imaging showed two symmetrical hypoechoic lesions involving both testes. Suspecting a bilateral testicular cancer, the patient underwent excision biopsy of both testicular lesions. Histopathology and immunohistochemical examinations documented metastatic MTC of both testicular lesions. Conclusion: Beyond its rarity, testis should be considered as a potential metastatic site of MTC, especially in patients with advanced disease.

Objectives: Liver metastases occur in 45% of patients with advanced metastatic medullary thyroid cancer (MTC). Transarterial radioembolization (TARE) has been proposed to treat liver metastases (LM), especially in neuroendocrine tumors. The aim of this study was to investigate the biochemical (calcitonin and carcino-embryonic antigen) and objective response of liver metastases from MTC to TARE. Methods: TARE is an internal radiotherapy in which microspheres loaded with β-emitting yttrium-90 (90Y) are delivered into the hepatic arteries that supply blood to LM. Eight patients with progressive multiple LM underwent TARE and were followed prospectively. They were clinically, biochemically and radiologically evaluated at 1, 4, 12 and 18 months after TARE. Results: Two patients were excluded from the analysis due to severe liver injury and death due to extrahepatic disease progression, respectively. One month after TARE, a statistically significant (P = 0.02) reduction of calcitonin was observed in all patients and remained clinically relevant during follow-up; reduction of CEA , although not significant, was found in all patients. Significant reduction of liver tumor mass was observed 1, 4 and 12 months after TARE (P = 0.007, P = 0.004, P = 0.002, respectively). After 1 month, three of six patients showed partial response (PR) and three of six stable disease (SD) according to RECIST 1.1, while five of six patients had a PR and one of six a SD according to mRECIST. The clinical response remained relevant 18 months after TARE. Excluding one patient, all others showed only a slight and transient increase in liver enzymes. Conclusions: TARE is effective in LM treatment of MTC. The absence of severe complications and the good tolerability make TARE a valid therapeutic strategy when liver LM are multiple and progressive.

The endocrine secretions of carcinomas can be life-threatening. Medullary thyroid carcinoma (MTC) is a rare cancer that is often associated with cortisol secretion, leading to paraneoplastic Cushing’s syndrome. Mutations of the proto-oncogene RET are driver molecular events in 70% of MTC cases. Here, we report a case of a woman, born in 1956, who was diagnosed with sporadic MTC in 2005, with subsequent relapses treated with focal treatments. In April 2019, she presented with severe and rapidly progressive paraneoplastic Cushing’s syndrome associated with lymph node, lung, liver and bone metastases. A supraclavicular lymph node biopsy revealed a somatic p.M918T (c.2753T>C) mutation in exon 16 of the RET proto-oncogene. The patient began treatment with selpercatinib in September 2019. Clinical efficacy was immediate. Chronic diarrhea disappeared within a few days. Clinical hypercorticism quickly disappeared, with quick improvements in muscle and skin conditions and fatigue. Two months after treatment initiation, urinary free cortisol normalized to 42 μg/24 h. Levels of the tumor markers carcinoembryonic antigen (CEA) and calcitonin also greatly decreased from baseline. After 34 months of treatment, selpercatinib elicits sustained clinical, biological and morphological responses. In summary, this case report illustrates the rapid and long-lasting antisecretory effect of selpercatinib associated with tumor control. As Cushing’s syndrome associated with medullary thyroid cancer is associated with poor prognosis, this case report is very encouraging. In addition, this suggests the potential benefit of molecular testing in all cases of medullary thyroid c ancer.

Cabozantinib is a tyrosine kinase inhibitor that has been approved as therapy for several solid tumors, including metastatic renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid cancer. To prepare this review, we comprehensively searched various websites, including the United States Food and Drug Administration, the European Medicine Agency Drug Manual, PubMed, Science Direct, and UpToDate using the search terms, “cabozantinib,” “renal cell carcinoma,” “hepatocellular carcinoma,” “differentiated thyroid cancer,” and “medullary thyroid cancer.” We shortlisted all the full-text articles published between 2011 and 2022. Out of a total of 788 manuscripts identified, we included 52. This review of cabozantinib details the pharmacodynamics, pharmacokinetics, clinical indications, adverse effects, safety, and the key research trials that investigated the use of cabozantinib. We have discussed the available clinical trial data and real-world outcomes, both with respect to the efficacy and safety of cabozantinib.

Multiple endocrine neoplasia (MEN) syndromes are rare and potentially malignant hereditary entities. Clinical manifestations of MEN 2B include medullary thyroid cancer, pheochromocytoma, gastrointestinal ganglioneuromatosis, and musculoskeletal and ophthalmologic lesions. Metastases to the prostate from the cancers of other organs are extremely rare. There are only a few cases of metastases to the prostate gland, originating from medullary thyroid cancer, found in literature, especially associated with MEN 2B syndrome. In this case report, we present the extremely rare case of a 28-year-old patient, diagnosed with MEN 2B syndrome, with medullary thyroid cancer metastasis to the prostate. Although a few reports of medullary thyroid cancer metastasis into the prostate gland can be found in the literature, to our knowledge, this is the first case of a laparoscopic radical prostatectomy procedure performed as a metastasectomy to treat the prostatic metastasis. Laparoscopic radical prostatectomy, performed as a metastasectomy, for the treatment of metastatic cancer, is an extremely rare surgical indication with distinctive requirements and difficulties. The extraperitoneal access enables the realization of the laparoscopic radical prostatectomy procedure even in the cases of patients with a history of multiple intra-abdominal operations.

Introduction: Medullary thyroid carcinoma is a primary thyroid neoplasm originating from thyroid C cells. It can be familial or sporadic. The familial form is associated with multiple endocrine neoplasia (MEN) syndrome types 2A and 2B and is caused by a mutation in the RET gene, which encodes a tyrosine kinase receptor. Treatment of medullary thyroid cancer is mainly based on surgical resection of the thyroid gland, usually a total thyroidectomy. It can be followed-up by a chemotherapy, which has limited efficacy. Hence, there is a growing interest in new molecular therapies, such as tyrosine kinase inhibitors, which include vandetanib, cabozantinib, selpercatinib, pralsetinib, sorafenib and lenvatinib. Objective: The review and presentation of the current state of knowledge on the systemic treatment of medullary thyroid cancer with kinase inhibitors. Material and methods: Literature review based on available sources from PubMed database and Google Scholar. Conclusions: Though systemic treatment options for medullary thyroid cancer continue to improve, patients with advanced neoplasms still have limited therapeutic options. Hence, further development of targeted treatment with kinase inhibitors, particularly those selective for the RET receptor is crucial. Molecular studies of mutations and signaling pathways involved in the oncopathogenesis of medullary thyroid cancer could contribute to the discovery of new therapeutic mechanisms, and drugs that target them, could potentially further improve disease progression-free survival (PFS) and overall survival (OS).

Background: This case report provides detailed experiences of a patient with Multiple Endocrine Neoplasia type 2A (MEN-2A) who underwent surgery for pheochromocytoma and medullary thyroid cancer (MTC). Case Report: A 58-year-old male patient with resistant hypertension, despite triple anti-hypertensive drug therapy, was diagnosed with pheochromocytoma after investigation into the underlying etiology. Although the adrenalectomy performed was unilateral rather than bilateral, and there were no signs of Cushing's syndrome or adrenal insufficiency before the operation, temporary adrenal insufficiency developed after the excision of the large adrenal mass. Additionally, the biochemical diagnosis of MTC was primarily established using a calcium stimulation test (CST) rather than basal calcitonin levels. Conclusion: In cases where unilateral adrenalectomy is performed for a large adrenal mass, postoperative hypotension resistant to conservative therapy should raise suspicion of adrenal insufficiency. Furthermore, when basal calcitonin levels fall within the gray zone, a CST may be necessary for the diagnosis of MTC. [ABSTRACT FROM AUTHOR]