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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.

BackgroundMedullary 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.Methods3601 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.ResultsA 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.ConclusionsThe survival outcome disparity across age cutoffs at 45 and 60 for MTC has been well defined.

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.

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.

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: 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.

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.

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.

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.

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.

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 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.

ObjectiveTo determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study.MethodsRetrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups.ResultsGenetic 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).ConclusionThis 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.

Background Pediatric medullary thyroid cancer (MTC) is one of the rare pediatric endocrine neoplasms. Derived from C cells of thyroid glands, MTC is more aggressive and more prompt to metastasis than other types of pediatric thyroid cancer. The mechanism remains unclear. Methods We performed single-cell transcriptome sequencing on the samples of the primary tumor and metastases lymph nodes from one patient diagnosed with MTC, and it is the first single-cell transcriptome sequencing data of pediatric MTC. In addition, whole exome sequencing was performed and peripheral blood was regarded as a normal reference. All cells that passed quality control were merged and analyzed in R to discover the association between tumor cells and their microenvironment as well as tumor pathogenesis. Results We first described the landscape of the single-cell atlas of MTC and studied the interaction between the tumor cell and its microenvironment. C cells, identified as tumor cells, and T cells, as the dominant participant in the tumor microenvironment, were particularly discussed in their development and interactions. In addition, the WES signature of tumor cells and their microenvironment were also described. Actively immune interactions were found, indicating B cells, T cells and myeloid cells were all actively participating in immune reaction in MTC. T cells, as the major components of the tumor microenvironment, proliferated in MTC and could be divided into clusters that expressed proliferation, immune effectiveness, and naive markers separately.

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.

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.

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.

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.

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.

In this paper we describe the current status of sentinel node mapping (SNM) in thyroid tumors and its potential perspectives. SNM in thyroid cancer has been tested since the end of the twentieth century, mainly in papillary thyroid cancer (PTC) and in medullary thyroid cancer (MTC). In PTC, it has been employed to find occult lymph node metastases in the central compartment of the neck as an alternative or indication for prophylactic dissection, by several methods. All of them have proven effective in spotting sentinel nodes, but the results have been somewhat diminished by uncertainty about the clinical significance of occult metastases in differentiated thyroid cancer. SNM in MTC has also been used to find occult lymph node metastases in the lateral compartments of the neck, also with excellent results hindered by a similar doubt about the real clinical significance of MTC micrometastases. Well designed, adequately sized randomized controlled trials are lacking, so SNM in thyroid tumors remains an interesting yet experimental methodology. New technology is emerging that could facilitate such studies, which could add solid information about the clinical significance of occult neck metastases in thyroid cancer.

IntroductionMedullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor that produces a hormone called calcitonin (CT). Thyroidectomy is the preferred treatment for MTC, as chemotherapy has been shown to have limited effectiveness. Targeted therapy approaches are currently being used for patients with advanced, metastatic MTC. Several studies have identified microRNAs, including miR-21, as playing a role in the development of MTC. Programmed cell death 4 (PDCD4) is a tumor suppressor gene that is an important target of miR-21. Our previous research has shown that high levels of miR-21 are associated with low PDCD4 nuclear scores and high CT levels. The aim of this study was to investigate the potential of this pathway as a novel therapeutic target for MTC.MethodsWe used a specific process to silence miR-21 in two human MTC cell lines. We studied the effect of this anti-miRNA process alone and in combination with cabozantinib and vandetanib, two drugs used in targeted therapy for MTC. We analyzed the effect of miR-21 silencing on cell viability, PDCD4 and CT expression, phosphorylation pathways, cell migration, cell cycle, and apoptosis.ResultsSilencing miR-21 alone resulted in a reduction of cell viability and an increase in PDCD4 levels at both mRNA and protein levels. It also led to a reduction in CT expression at both mRNA and secretion levels. When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis.ConclusionSilencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.

Abstract 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 0.05, for all). However, long-axis and short-axis diameter, hilum and calcifications were statistically different between these two groups (P

Abstract 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.

Background. Coronavirus disease 2019 (COVID-19) is a pandemic of the new millennium. COVID-19 can cause both pulmonary and systemic infammation, and can rapidly progress to multiple organ failure. Data on the relationship between COVID-19 and the thyroid gland have been available since March 2020. The thyroid gland and viral infection as well as associated infammatory-immune reactions participate in a complex interaction. The most common autoimmune disease is chronic autoimmune thyroiditis (chronic lymphocytic thyroiditis, Hashimoto thyroiditis). The majority of medullary thyroid cancers present as a thyroid nodule. Cervical lymph nodes and distant metastases are often detected at the time of diagnosis. The development of autoantibodies may be part of a more complex protective antitumor mechanism, the purpose of which is to eliminate the precursors of future tumor cells.The purpose of the study was to describe a clinical case of diagnosing medullary thyroid cancer in the patient who had COVID-19.Case description. We present the case of a 43-year-old woman who had coronavirus pneumonia (COVID-19), which was accompanied by an increase in serum procalcitonin (PC) level, which required additional examination. Since 2020, she had been observed for autoimmune thyroiditis, which was manifested by a thyroid nodular of a small size. After discharge from the COVID hospital, an ultrasound examination of the thyroid gland revealed an increase in the left lobe thyroid nodule up to 15 mm. The level of calcitonin was 681 pg/ml. Fine needle aspiration (FNA) biopsy of the thyroid gland showed suspicion for medullary thyroid cancer. Thyroidectomy with central lymph node dissection (level VI) was performed. A planned histological examination of the surgical specimen confrmed medullary thyroid cancer.Conclusion. In the present clinical case, medullary thyroid cancer was detected in the patient who had COVID-19 with elevated PC level, which was the basis for a diagnostic search.

ABSTRACT Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians’ Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results/conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II–V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; “berry node picking” is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer.

Key Clinical Message Diarrhea is a common symptom in medical practice that often gets overlooked. This article is intended to increase the awareness of physicians and other providers on a subtle but important cause of chronic diarrhea.

The incidence of thyroid cancer is increasing worldwide with the disease burden in Europe second only to that in Asia. In the last several decades, molecular pathways central to the pathogenesis of thyroid cancer have revealed a spectrum of targetable kinases/kinase receptors and oncogenic drivers characteristic of each histologic subtype, such as differentiated thyroid cancer, including papillary, follicular, and medullary thyroid cancer. Oncogenic alterations identified include B-Raf proto-oncogene (BRAF) fusions and mutations, neurotrophic tyrosine receptor kinase (NTRK) gene fusions, and rearranged during transfection (RET) receptor tyrosine kinase fusion and mutations. Multikinase inhibitors (MKIs) targeting RET in addition to multiple other kinases, such as sorafenib, lenvatinib and cabozantinib, have shown favourable activity in advanced radioiodine-refractory differentiated thyroid cancer or RET-altered medullary thyroid cancer; however, the clinical utility of MKI RET inhibition is limited by off-target toxicity resulting in high rates of dose reduction and drug discontinuation. Newer and selective RET inhibitors, selpercatinib and pralsetinib, have demonstrated potent efficacy and favourable toxicity profiles in clinical trials in the treatment of RET-driven advanced thyroid cancer and are now a therapeutic option in some clinical settings. Importantly, the optimal benefits of available specific targeted treatments for advanced RET-driven thyroid cancer require genetic testing. Prior to the initiation of systemic therapy, and in treatment-naïve patients, RET inhibitors may be offered as first-line therapy if a RET alteration is found, supported by a multidisciplinary team approach.

Background and Objectives The purpose of this study is to evaluate the relationship between lymph node status (the number of resected lymph nodes; the number of metastatic lymph nodes, LNM, and lymph node ratio, LNR) and biochemical recurrence, disease-free survival (DFS), as well as overall survival (OS) in medullary thyroid carcinoma (MTC). Methods This study enrolled MTC patients at Tianjin Medical University Cancer Institute and Hospital between 2011 and 2019. We used Logistic regression analysis, Cox regression models and Kaplan-Meier test to identify risk factors influencing biochemical recurrence, DFS, and OS. Results We identified 160 patients who satisfied the inclusion criteria from 2011 to 2019. We used ROC analysis to define the cut-off value of LNR with 0.24. Multifocality, preoperative calcitonin levels, pathologic N stage, resected lymph nodes, LNM, LNR, and the American Joint Committee on Cancer (AJCC) clinical stage were significant (P < 0.05) prognostic factors influencing biochemical cure. In univariable analyses, gross extrathyroidal extension, preoperative calcitonin levels, pathologic T classification, pathologic N stage, resected lymph nodes, LNM, LNR, AJCC clinical stage, and biochemical cure were significant (P < 0.05) factors of DFS. When the multivariable analysis was performed, LNR was identified as predictor of DFS (HR = 4.818, 95% CI [1.270–18.276]). Univariable Cox regression models reflected that tumor size, pathologic N stage, and LNR were predictor of OS. Furthermore, multivariable analysis manifested that LNR was predictor of OS (HR = 10.061, 95% CI [1.222–82.841]). Conclusions This study illustrated that LNR was independent prognostic factor of DFS and OS in MTC. In addition, LNR influenced biochemical cure. Further investigations are needed to determine the optimal cut-off value for predicting prognosis.

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.

Background. The urgency of the study is due to the need to find effective methods for the diagnosis and treatment of medullary thyroid cancer. Basal calcitonin is a biomarker that determines both the presence of this disease and the level of metastasis. Howe­ver, above-threshold calcitonin levels have a low prognostic value of the positive result. The study was aimed to analyze the importance of additional factors (besides calcitonin) in predicting the medullary thyroid cancer metastasis: age, sex, tumor focus, tumor volume (total volume). Materials and me­thods. A retrospective monocenter analysis was performed using the records of 194 patients treated for medullary thyroid cancer. The study involved 143 patients with primary forms of the di­sease. The required characteristics of the tumor were assessed in the postoperative period based on the pathomorphological exa­mination. Results. The association between age and metastasis was not found, but a moderate relationship between sex and metastasis has been shown. The ratio of the chances of metastases detected in male patients is estimated at 3 : 1. It is proved that in the presence of tumor multifocality, the likelihood of metastasis detection increa­ses. With an odds ratio of 2.368, the multifocal factor shows a weak but statistically significant strong association with the presence of metastases. Total tumor size is associated with metastasis. More than half (54.5 %) of cases are in the range of tumor sizes smaller than the selected cut-off threshold, with 16.7% metastasi­zing. On the other hand, the share of cases of exceeding the cut-off threshold (Cut-off = 1.9 cm; AUC = 0.703, Se = 0.745, Sp = 0.680) is 45.5 %, and metastasis is observed in 53.8 % of patients in this range. Conclusions. No association was found between age and metastasis. Male gender is a risk factor for metastasis. Multifocality is a risk factor for metastasis with a weak connection. The total size of the tumor is associated with metastasis with medium strength.

Background: Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer that occasionally occurs as part of MEN2A. The universal treatment of MTC is total thyroidectomy with central lymph node dissection. For disease progression, carcinoembryonic antigen (CEA) and calcitonin (CTN) need to be followed. Our aim was to study the presence and patterns of the above-mentioned characteristics of MTC in our population. Methodology: This retrospective study was conducted in a tertiary care hospital of Pakistan in which data of thirty-two medullary thyroid cancer patients over the past 20 years were reviewed and analysed after fulfilment of inclusion criteria. Their clinical, pathological, biochemical and treatment modalities were recorded through a retrospective review of their medical record files. Results: The mean age of patients was 42.88 ± 2.67 years in our study, with a male-to-female ratio of 2:1. Patients with sporadic MTC were 68.8%, while 31.2% were familial. The rates of metastasis were highest in bones followed by lungs and liver. Total thyroidectomy was performed in 26 (81.2%) patients and among those chemotherapy and XRT were performed in one and two patients, respectively. Histologically, the mean tumour size was 7.62 ± 3.64 cm. Median pre-surgery calcitonin was 5756 pg/ml that decreased to 29.3 pg/ml post-surgery. Median pre-surgery CEA level was 246.5 ng/ml that decreased to 6.39 ng/ml post-surgery. Two patients were RET positive. Conclusion: MTC usually presents in the fourth decade of life with male predominance and mostly sporadic occurrence. Total thyroidectomy with subsequent serial calcitonin and CEA levels thereafter are the mainstay of treatment and follow-up.

IntroductionCalcitonin is the most specific marker for medullary thyroid carcinoma, thus, low detectable calcitonin values after surgery can conceal persistent disease. The present study aimed to explore the prognostic role of pre-operative and early calcitonin levels in patients without distant metastases at diagnosis.MethodsA retrospective cohort of patients suffering from medullary thyroid carcinoma was considered (N=55). The final disease status, i.e. complete response (undetectable calcitonin levels and negative radiological assessments) or persistent disease (detectable calcitonin levels and/or positive radiological assessments), was deduced from the last available follow-up. Pre-operative and early calcitonin levels (i.e. six months after surgery) have been correlated to several clinical and histological features, according to the final disease status.ResultsPersistent disease patients showed higher pre-operative and early calcitonin values (p=0.028 and p

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

PurposeClinical guidelines presently recommend total thyroidectomy for the treatment of medullary thyroid cancer (MTC). This study was aimed to investigate whether lobectomy could be the initial treatment for stage I MTC patients.MethodsThe retrospective study was based on data from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015. The risk factors of survival were estimated by the univariate and multivariate Cox proportional-hazards model. The effect of age on death risk was estimated using restricted cubic splines. Survival curves were constructed according to the Kaplan–Meier method.ResultsA total of 988 stage I MTC patients was included in the study. Among them, 506 (51.2%) MTC patients received lobectomy and 482 (48.8%) received total thyroidectomy. The only independent prognostic factor for overall survival (OS) and disease-specific survival (DSS) was age, according to univariate and multivariate Cox regression analysis. The hazard ratio (HR) increased relatively slowly with age growing under the age of approximately 60 years. However, the death risk of MTC patients began to rise sharply with increasing age above 60 years. For patients under the age of 60, a significant survival difference for OS and DSS was observed between the lobectomy group and total thyroidectomy group (p < 0.05). However, for patients aged above 60, no significant survival difference was observed for OS or DSS (p > 0.05).ConclusionTotal thyroidectomy was an appropriate treatment for stage I MTC patients under the age of 60, which was consistent with the recommendation of the clinical guidelines. However, for those over the age of 60, lobectomy may be explored as a better surgical option. The findings may provide the evidence base for improving the clinical management of stage I MTC patients. Further prospective multicenter clinical studies are needed including information regarding RET status as well as calcitonin and CEA levels.

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.

Medullary thyroid cancer (MTC) is a rare malignancy, and the treatment of metastatic MTC is challenging. In previous work, immune profiling (RNA-Seq) of MTC identified CD276 as a potential target for immunotherapy. CD276 expression was 3-fold higher in MTC cells than in normal tissues. Paraffin blocks from patients with MTC were analyzed by immunohistochemistry to confirm the results of RNA-Seq. Serial sections were incubated with anti-CD276 antibody, and scored according to staining intensity and the percentage of immunoreactive cells. The results showed that CD276 expression was higher in MTC tissues than in controls. A lower percentage of immunoreactive cells correlated with the absence of lateral node metastasis, lower levels of calcitonin after surgery, no additional treatments, and remission. There were statistically significant associations of intensity of immunostaining and percentage of CD276 immunoreactive cells with clinical factors and the course of the disease. These results suggest that targeting this immune checkpoint molecule CD276 could be a promising strategy for the treatment of MTC.

BackgroundMedullary 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).MethodsWe 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.ResultsIn 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).ConclusionHigher 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 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.

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

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.

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.

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.