Treatment Of Medullary Thyroid Cancer Research Articles

Diagnosis and treatment of medullary thyroid cancer in four Hungarian university centers (2000-2023)

Diagnosis and treatment of medullary thyroid cancer in four Hungarian university centers (2000-2023)

Complexities in diagnosis and treatment of medullary thyroid cancer. Clinical observation

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.

Trends in the incidence, organization of care, and treatment of medullary thyroid cancer in the netherlands over the last three decades: a population-based study

Trends in the incidence, organization of care, and treatment of medullary thyroid cancer in the netherlands over the last three decades: a population-based study

Biodistribution and Radiation Dosimetry for 68 Ga-DOTA-CCK-66, a Novel CCK 2 R-Targeting Compound for Imaging of Medullary Thyroid Cancer.

Cholecystokinin 2 receptor (CCK 2 R) is a promising target for imaging and treatment of medullary thyroid cancer due to its overexpression in over 90% of tumor cells. 68 Ga-DOTA-CCK-66 is a recently introduced PET tracer selective for CCK 2 R, which has shown favorable pharmacokinetics in vivo in preclinical experiments. In order to further investigate safety and suitability of this tracer in the human setting, whole-body distribution and radiation dosimetry were evaluated. Six patients with a history of medullary thyroid cancer were injected intravenously with 169 ± 19 MBq of 68 Ga-DOTA-CCK-66. Whole-body PET/CT scans were acquired at 10 minutes, 1 hour, 2 hours, and 4 hours after tracer injection. Time-activity curves per organ were determined, and mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM. Injection of a standard activity of 150 MBq of 68 Ga-DOTA-CCK-66 results in an effective dose of 4.5 ± 0.9 mSv. The highest absorbed organ doses were observed in the urinary bladder wall (40 mGy) and the stomach (15 mGy), followed by the kidneys (6 mGy), as well as the liver and the spleen (3 mGy each). CCK 2 R-expressing tumor manifestations could be detected in 2 of the 6 patients, including lymph node, bone, and liver metastases. 68 Ga-DOTA-CCK-66 exhibits a favorable dosimetry. Beyond physiologic receptor expression of the stomach, no other relevant tracer accumulation could be observed, rendering this organ at risk in case of subsequent radioligand therapy using 177 Lu-DOTA-CCK-66.

Sex differences and racial/ethnic disparities in the presentation and treatment of medullary thyroid cancer

BackgroundThis study assessed for disparities in the presentation and management of medullary thyroid cancer (MTC). MethodsPatients with MTC (2010–2020) were identified from the National Cancer Database. Differences in disease presentation and likelihood of guideline-concordant surgical management (total thyroidectomy and resection of ≥1 lymph node) were assessed by sex and race/ethnicity. ResultsOf 6154 patients, 68.2% underwent guideline-concordant surgery. Tumors >4 ​cm were more likely in men (vs. women: OR 2.47, p ​< ​0.001) and Hispanic patients (vs. White patients: OR 1.52, p ​= ​0.001). Non-White patients were more likely to have distant metastases (Black: OR 1.63, p ​= ​0.002; Hispanic: OR 1.44, p ​= ​0.038) and experienced longer time to surgery (Black: HR 0.66, p ​< ​0.001; Hispanic: HR 0.71, p ​< ​0.001). Black patients were less likely to undergo guideline-concordant surgery (OR 0.70, p ​= ​0.022). ConclusionsMale and non-White patients with MTC more frequently present with advanced disease, and Black patients are less likely to undergo guideline-concordant surgery.

Meta-Analysis of the Efficacy and Safety Evaluation of Vandetanib in the Treatment of Medullary Thyroid Cancer.

The aim of the work was to systematically evaluate the efficacy and safety of Vandetanib in the treatment of advanced medullary thyroid carcinoma (MTC). MeSH entries to search for randomized controlled trials and clinical research literature on the application of Vandetanib in the treatment of medullary thyroid cancer from PubMed, Chinese national knowledge infrastructure (CNKI), and Web of Science databases since their establishment until March 2023 were used. In terms of efficacy, the analysis results showed that Vandetanib had a significantly higher objective response rate compared to the control group using placebo (OR=2.13, 95% CI: 1.38, 3.29). In terms of side effects, Vandetanib significantly increases the incidence of hypertension, rash, and diarrhea, and has statistical significance (p+<+0.05). Vandetanib has a better therapeutic effect on MTC, but it also increases the incidence of hypertension, rash, and diarrhea. Attention should be paid to the relief of side effects when using it.

Precision medicine in endocrinology exemplified by medullary thyroid cancer

Medullary thyroid cancer (MTC) is a prime example for precision medicine in endocrinology and underlines the immediate benefits of basic, translational and healthcare research for patients with a rare disease in clinical . A mutation in the rearranged during transfection (RET) proto-oncogene that codes for a transmembrane receptor protein tyrosine kinase, leads to constitutive activation of the kinase, which is the decisive pathomechanism for the disease. The MTC occurs in a sporadic (somatic RET mutation) or hereditary form (RET germline mutation, multiple endocrine neoplasia types 2 and 3). For germline mutation carriers the timing of preventive thyroidectomy depends on the RET genotype. For advanced metastasized RET-mutant MTC, selective RET kinase inhibitors are available, which are currently considered to be game changers in the treatment. Based on the specific tumor marker calcitonin, MTC can be identified at an early stage during the differential diagnosis of thyroid nodules. The preoperative calcitonin level even enables statements on the degree of dissemination of the disease and on the probability of a cure through surgery. A new development is the consideration of desmoplasia as a histopathological biomarker for the metastatic potential of a MTC, which could possibly modify the operative approach as well as the future MTC nomenclature. Furthermore, the postoperative calcitonin level and the calcitonin doubling time are highly valid prognostic markers for tumor burden and biological aggressiveness of MTC and therefore decisive for patient follow-up. Biochemical, molecular and histological markers enable a risk-adapted surgical treatment and together with new targeted systemic treatments have contributed to a paradigm shift in the diagnostics, prognosis and treatment of MTC in recent years. Endocrine precision medicine for MTC therefore enabled a change from the previous purely symptom-oriented to a modern preventive and individualized treatment.

Innovations in the systemic treatment of medullary thyroid cancer with kinase inhibitors

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.&#x0D; Objective: The review and presentation of the current state of knowledge on the systemic treatment of medullary thyroid cancer with kinase inhibitors.&#x0D; Material and methods: Literature review based on available sources from PubMed database and Google Scholar.&#x0D; 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).

A rare case of medullary carcinoma

Medullary thyroid cancer (MTC) accounts for 5–10 % of all thyroid cancers. Most cases (75 %) are sporadic, but the proportion of patients with MTC and a familial predisposition syndrome is the highest among those with any hereditary cancer syndrome (about 25 %), and this possibility should be considered when examining a patient with MTC. Familial syndromes include multiple endocrine neoplasia (MEN) 2A, MEN 2B, and non-MEN familial MTC (familial MTC). Familial MTC syndromes occur in approximately one case per 30,000 of the population. Reduced penetrance and clinical variability are well-established features of many monogenic disorders, particularly phenotypes associated with the RET proto-oncogene. They require an individual assessment of the pathogenic effects and clinical significance of any identified new sequence of the RET va­riant as prerequisites for individual genetic counseling and planning of medical monitoring and treatment. Diagnostic criteria for the disease have been outlined, molecular and genetic aspects have been discussed, and the determination of treatment and further observation has been addressed. The article describes a clinical case of a rare variant of MTC. Treatment of this pathology with radical extrafascial thyroidectomy is under consideration. Given the ineffectiveness of radioiodine and chemotherapy, the main task in the treatment of MTC is early diagnosis, radical surgical intervention, and active monitoring aimed at early detection of disease recurrence. When planning prophylactic thyroidectomy, it is recommended to focus on the stratification of the level of RET gene mutations and the timing of prophylactic thyroidectomy proposed by the American Thyroid Association. The introduction of molecular genetic research into clinical practice for the purpose of diagnosing MTC allows for the objective assessment of the genetic lineage of the disease within a biological family. A timely diagnosis of MTC makes it possible to prescribe an adequate treatment at the stage of preclinical manifestations of the disease, which can significantly increase the quality and duration of life.

Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells.

RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDITonline web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-c]quinolines 6a-e and 7a-e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a-d as promising anticancer agents, with IC50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC.

Tumor lysis syndrome during neoadjuvant selpercatinib treatment for medullary thyroid cancer

Tumor lysis syndrome during neoadjuvant selpercatinib treatment for medullary thyroid cancer

CD276 as a Candidate Target for Immunotherapy in 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.

Validation of miRNAs as diagnostic and prognostic biomarkers, and possible therapeutic targets in medullary thyroid cancers.

Medullary 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. We 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. Silencing 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. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.

Draft of clinical guidelines for the diagnosis and treatment of medullary thyroid cancer in adult patients

The article presents a draft of clinical recommendations for the diagnosis and treatment of medullary thyroid cancer in adult patients, which provides a modern examination algorithm, discusses the basic principles of laboratory, instrumental diagnostics and treatment approaches.

Cabozantinib in patients with locally advanced or metastatic urothelial cell carcinoma who have progressed after cisplatin-based chemotherapy and anti-PD-1/PD-L1 therapy or after anti-PD-1/PD-L1 therapy only.

525 Background: Cabozantinib inhibits c-Met , AXL, RET, and VEGFR and has been FDA and EMA approved for the treatment of medullary thyroid cancer, hepatocellular carcinoma and renal cell carcinoma. In this trial (NCT04066595) we wanted to gain more insights about the potential of Cabozantinib in patients with advanced urothelial carcinoma (UC) ineligible for cisplatin-based chemotherapy and in patients with chemo and/or PD-1- and PD-L1 resistant UC. Methods: This investigator-sponsored Phase II multicenter single-arm trial assessed ORR to Cabozantinib in patients with locally advanced or metastatic UC, who have been pre-treated with checkpoint inhibitors only (cohort 1) or cisplatin-based chemotherapy and checkpoint inhibitors (cohort 2). Secondary outcome measurements were PFS, OS, CBR, DOR, and patient safety. All radiologic findings were determined using RECIST 1.1. Patients commenced treatment with Cabozantinib 60 mg given per os once per day continuously. Participants continued on trial as long as their cancer was not worsened and side effects were not too severe. For the assessment of side effects the severity was qualified in accordance with NCI CTCAE, version 5.0. The primary outcome measure of ORR was reported as percentages and associated 95% confidence interval for each cohort. For planning Simon's two-stage minimax design (Simon, 1989) was used. A total of 44 patients (total 88 patients) were planned to be included into each cohort. Results: Seven patients were included in cohort 2. The patients in cohort 2 (N = 7) had a median age of 69 y, 6 male patients and one female patient. All patients had an ECOG PS 0 (n=2) or 1 (n=5). All tumors were originated from the urinary bladder, two of them showing histological subtypes. PD-L1 status was available in two patients. Visceral metastases were evident in 3 patients. At December 20th 2021 data cutoff no patient was alive. The overall response rate was 0%. The median progression free survival was 2,9 months (range 1-5,4 months). The median overall survival was 3 months (range 1-18,3 months) 3 patients showed a stable disease. All patients (n=7) revealed TRAEs, 3 patients each (43%) showed endocrine disorders, metabolic and nutrition disorders and nervous system disorders. In 5 patients (71%) respiratory AEs and in 86% (n=6) gastrointestinal AEs were evident. In 86% of patients (n=6) SAEs led to treatment dose reduction or discontinuation. In 43% of patients (n=3) grade 5 SAEs were evident. Treatment-related SAEs were notified in 57% of patients (n=4). Conclusions: Cabozantinib was administered in 7 patients without clinical response. Due to low patient recruitment and no adequate response rates the study was discontinued early. Cabozantinib in this study does not reveal a clinical benefit for patients with metastatic UC with prior chemotherapy and IO. Clinical trial information: NCT04066595 .

RATIONALE FOR THE APPLICATION OF CALCITONIN LEVEL IN THE EARLY POSTOPERATIVE PERIOD TO EVALUATE THE EFFECTIVENESS OF SURGICAL TREATMENT OF MEDULLARY THYROID CANCER.

To determine the effectiveness of the basal calcitonin (CTb) determination in the early postoperative period to predict the possible recurrence (persistence) of medullary thyroid cancer (MTC). A retrospective study of the treatment results in 194 patients with MTC (148 (76.3%) primary - group 1 and 46 (23.8%) recurrent - group 2) according to the levels of CTb in the first week after surgery and one year later. All groups were analyzed by staging, the level of preoperative and postoperative basal calcitonin 5 days and 1 year after the primary surgery. Among all patients, women prevailed - 144 (74.2%), the average age was (48.7±15.2), the average follow-up period was 67.5 months. Basal calcitonin was studied in patients of all groups in the preoperative and serially in the postoperative periods: 5 days and 1 year after the most radical surgical volumes. To test the hypothesis about the possibility of using CTb indicators in the early postoperative period, the degree of compliance with normal calcitonin indicators (≤18 pg/mL) was assessed by observation groups 5 days and 1 year after surgery. 1. The CTb value 5 days after surgery is no less a reliable marker of the result of surgical treatment of MTC than the currently recommended CTb measurement 2-3 months after surgery. 2. The technique is applicable for both primary and reoperations used for recurrent forms of medullary thyroid cancer.

A Novel Green Micellar HPLC-UV Method for the Estimation of Vandetanib in Pure Form, Human Urine, Human Plasma and Human Liver Microsomes Matrices with Application to Metabolic Stability Evaluation.

Vandetanib (Caprelsa®; VNB) is a prescription medicine that is used for the treatment of medullary thyroid cancer that has disrupted other body parts or that cannot be removed by surgery. It is considered a tyrosine kinase inhibitor (TKI). Fast, sensitive and validated HPLC-UV was established for VNB quantification in pure human biological fluids (urine and plasma) and human liver microsomes (HLMs). This analytical methodology was applied also to the metabolic stability assessment of VNB. This method was performed using a phenyl column (250 mm × 4.6 mm id, 5 µm particle size). A sodium dodecyl sulphate solution (0.05 M, pH 3.0 using 0.02 M orthophosphoric acid) containing 0.3% triethylamine and 10% n-butanol was used as a mobile phase and was pumped isocratically at a flow rate of 0.7 mL/min and at a 260 nm detection wavelength. The total elution time was 6 min with an injection volume of 20 μL. The linearity of the established methodology ranged from 30 to 500 ng/mL in pure form and 50 to 500 ng/mL (r2 ≥ 0.9994) in human biological fluids and HLMs. No significant interference from the matrix components was observed. The proposed methodology revealed the benefits of being green, reliable and economic.

Improved Adherence to ATA Medullary Thyroid Cancer Treatment Guidelines.

The 2009 American Thyroid Association (ATA) guidelines for medullary thyroid cancer (MTC) were created to unify national practice patterns. Our aims were to (1) evaluate national adherence to ATA guidelines before and after 2009, (2) identify factors that are associated with concordance with guidelines, and (3) evaluate whether there is an association between survival and concordant treatment. Patients with MTC were identified from the 2009 to 2015 National Cancer Database. Adherence to ATA recommendations regarding extent of surgery (R61-R66) was analyzed. Logistic regression was used to determine predictors of discordance and propensity score matching was used to compare concordant treatment rates between time periods. Kaplan-Meier survival analysis was used to determine association between survival and concordant treatment. There were 3421 patients with MTC, and of these 3087 had M0 disease and 334 had M1 disease. We found that 72% of M0 cases adhered to R61-66, and 68% of M0 cases without advanced local disease were adherent to R61-63. Following propensity score matching, the adherence rate was 67% before 2009 and 74% after. Patient factors associated with discordant treatment were female gender, older age, treatment at a nonacademic facility, and living within 50 miles of the treatment facility. Adherence to guidelines was associated with improved overall survival (OS) (p < 0.01). Treatment of MTC was discordant from guidelines in 26% of cases from 2009 to 2015 compared with 33% prior to 2009 in a propensity matched analysis, and was most often in cases with localized, noninvasive disease. Improved adherence to guidelines may improve overall survival.

1656P Durable efficacy of selpercatinib in patients (pts) with medullary thyroid cancer (MTC): Update of the LIBRETTO-001 trial

Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-mutant MTC and RET fusion-positive thyroid and lung cancers. In the previous report, duration of response (DoR) and progression free survival (PFS) follow-up (f/u) was limited.

RREB1 promotes the development of parafollicular carcinogenesis through the Ras-Raf-1-ELK3 signaling pathway

Thyroid cancer (TC) is the most common endocrine malignancy. Medullary thyroid carcinoma (MTC) is derived from parathyroid follicle cells (C cells) secrete calcitonin, accounting for approximately 5-10% of all thyroid cancers. The malignancy is between differentiated and undifferentiated thyroid cancer and undifferentiated thyroid cancer and has a relatively poor prognosis. In MTC tumor cells, RREB1 regulates the differentiation of parathyroid cells via RAS-Raf-1-ELK3 signaling and induce calcitonin secretion. Therefore, it is easy to induce parathyroid parafollicular cells canceration and medullary thyroid carcinoma. Here, we investigated the correlation between RREB1, RAS-Raf-1-ELK3 signaling pathway and medullary thyroid carcinoma with various phases. Our results suggest that RREB1 promotes parafollicular carcinoma through the Ras-Raf1-elk3 signaling pathway, providing a rationale to further investigate the role of RREB1 in parafollicular carcinoma. It provides theoretical guidance for the clinical treatment of medullary thyroid cancer.