piperidines and Thyroid-Neoplasms

This manuscript investigates cabozantinib, vandetanib, pralsetinib, and selpercatinib, four tyrosine kinase inhibitors (TKIs), which are used to treat advanced and/or metastatic medullary thyroid cancer (MTC). Data on efficacy and safety are presented with the main focus on treatment-related hypertension, a well-known adverse effect (AE) of these TKIs. Taken together, TKI-induced hypertension is rarely a dose-limiting side effect. However, with increasing survival times of patients under treatment, hypertension-associated complications can be expected to be on the rise without proper medication.

Topics: Carcinoma, Neuroendocrine; Humans; Hypertension; Piperidines; Protein Kinase Inhibitors; Thyroid Neoplasms

Vandetanib is an anti-cancer drug called an antineoplastic kinase inhibitor. The FDA authorized vandetanib on April6, 2011 for the treatment of nonresectable, locally progressed, or metastatic medullary thyroid carcinoma in adults. Because Vandetanib can make the Q-T interval last longer, it shouldn't be given to people with serious heart problems like congenital long QT syndrome or heart failure that hasn't been fixed yet. This chapter provides an overview of Vandetanib's physical and molecular properties, mode of action, pharmacokinetics, and common applications. In furthermore, a detailed summary of the reported techniques of Vandetanib measurement will be provided to assist analysts in selecting the most practical approach for its estimation in routine analysis. This chapter will also explain the synthesis methods developed in the preparation of vandetanib as well as pharmacology of its. In addition, this section summarizes the analytical and characterization techniques utilized to characterize vandetanib row material.

Topics: Adult; Antineoplastic Agents; Carcinoma, Neuroendocrine; Humans; Piperidines; Protein Kinase Inhibitors; Thyroid Neoplasms

The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile.. Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity.. Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective.. Clinical trial identification: NCT02925234.

Topics: Antineoplastic Agents; Azetidines; Humans; Piperidines; Proto-Oncogene Proteins B-raf; Skin Neoplasms; Thyroid Neoplasms; Vemurafenib

Vandetanib is indicated for adults with advanced medullary thyroid cancer (MTC).. To describe the efficacy and toxicity profile of vandetanib treatment with a maximal follow-up of 11 years at Institut Gustave Roussy/France.. A review of the clinical files of the 76 MTC patients treated with vandetanib. Efficacy was estimated by markers and imaging.. A total of 76 patients received vandetanib. Nine were excluded from efficacy analysis because lack of morphological data. The overall (N = 76) median treatment duration was 17.6 (range: 0.7-130.6) months and the median progression-free survival (PFS) was 22.7 (95% CI, 13.9-37.3) months. In total, 21/76 (27.6%) patients were classified as long-term users because have received vandetanib for more than 48 months, with a median treatment duration of 68.1 (range: 49.1-130.6) months. For long-term vandetanib users, the objective response rate was 85.7%, the median time to best response was 27.8 (11.6.1-110) months and the median duration of response was 70.4 (38.3-127.5) (95% CI 49.5-102.8) months with a median PFS of 73.2 (95% CI, 53.1-105.6) months. Duration of response had a significant negative correlation with patient age at diagnosis (p = 0.03) and was significantly higher in patients that did not have confirmed tumor progression before treatment onset (p = 0.007). After 48 months of vandetanib use, renal failure took place in two patients and heart failure, cholecystitis, acute pancreatitis, posterior encephalopathy, and skin cancer first occurred in one patient, each.. Our findings suggest that a substantial number of patients receiving first-/second-line vandetanib may sustain long clinical benefit and that a younger age at diagnosis and the absence of progression before treatment could be considered as predictors of durable response.

Topics: Acute Disease; Adult; Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease-Free Survival; Follow-Up Studies; France; Humans; Pancreatitis; Piperidines; Quinazolines; Thyroid Neoplasms

The tyrosine kinase inhibitors (TKIs) sorafenib, lenvatinib, vandetanib, and cabozantinib are currently used for thyroid cancer treatment; however, the differences in their clinical efficacy and toxicity remain unclear. This meta-analysis assessed the efficacy and toxicity of these four TKIs based on 34 studies. The pooled incidence of partial response (PR), stable disease (SD), TKI-related adverse events (AEs), and pooled median progression-free survival (PFS) were calculated with 95% confidence intervals (CI). Complete response to TKIs was extremely rare (0.3%). The highest PR rate and longest PFS were observed for lenvatinib in differentiated thyroid cancer (69%, 95% CI: 57-81 and 19 months, 95% CI: 9-29, respectively) and vandetanib in medullary thyroid cancer (40%, 95% CI: 25-56 and 31 months, 95% CI: 19-43, respectively). Although the discontinuation rate due to AEs was similar for each TKI, there was a difference in the most frequently observed AE for each TKI (hand-foot syndrome for sorafenib, hypertension and proteinuria for lenvatinib, and QTc prolongation for vandetanib). The identified differences in the TKI efficacy and AE profiles may provide a better understanding of thyroid cancer treatment. Although TKIs are promising agents for thyroid cancer treatment, they are unlikely to lead to a cure. Thus, even in the TKI era, a multimodal treatment including surgery, radioiodine therapy, external beam radiotherapy, and TKIs is required to optimize patient chances of improved survival.

Topics: Antineoplastic Agents; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms; Treatment Outcome

Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq. (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England.. Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions.. A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model.. The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population.. The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained.. (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL.. This study is registered as PROSPERO CRD42016050403.. The National Institute for Health Research Health Technology Assessment programme.. Medullary thyroid carcinoma (MTC) is a rare form of cancer that presents as a mass of tumours in the thyroid gland of the neck. MTC affects both patients’ health-related quality of life and survival. Targeted therapies (cabozantinib and vandetanib) are currently used to treat unresectable progressive and symptomatic MTC. The evidence for the use of cabozantinib and vandetanib in patients with unresectable locally advanced or metastatic MTC was reviewed, and two clinical trials were identified. The trials suggest that both drugs improve progression-free survival. Neither trial demonstrated significant survival benefits for cabozantinib or vandetanib. Both drugs produced frequent adverse events, often leading to dose interruption or reduction. Whether or not these therapies represent good value for money for the NHS was also assessed. Analyses indicate that the incremental cost-effectiveness ratios (ICERs) (a measure of cost-effectiveness) for cabozantinib and vandetanib versus best supportive care (BSC) in patients with symptomatic and progressive MTC are > £138,000 per quality-adjusted life-year (QALY) gained. Within a subgroup of patients with symptomatic and progressive MTC and carcinoembryonic antigen and/or calcitonin doubling times of ≤ 24 months, the ICER for vandetanib versus BSC remains > £66,000 per QALY gained.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cost-Benefit Analysis; England; Humans; Models, Economic; Piperidines; Pyridines; Quality-Adjusted Life Years; Quinazolines; Technology Assessment, Biomedical; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is a rare malignancy with a poor prognosis. First line therapy is surgery, which is the only curative method of the disease. However, in non-operable cases or with tumor progression and metastases, a systemic treatment is necessary. This form of cancer is often insensitive to conventional chemotherapy, but the use of tyrosine kinase inhibitors (TKIs), such as pazopanib, cabozantinib, and vandetanib, has shown promising results with an increase in progression-free survival and prolonged lifetime. Therefore, we focused on the pharmacological characteristics of TKIs, their mechanism of action, their application as a secondary treatment option for MTC, their efficacy as a cancer drug treatment, and reviewed the ongoing clinical trials. TKIs also act systemically causing various adverse events (AEs). One common AE of this treatment is hypertension, known to be associated with cardiovascular disease and can therefore potentially worsen the well-being of the treated patients. The available treatment strategies of drug-induced hypertension were discussed. The mechanism behind the development of hypertension is still unclear. Therefore, the treatment of this AE remains symptomatic. Thus, future studies are necessary to investigate the link between tumor growth inhibition and hypertension. In addition, optimized, individual treatment strategies should be implemented.

Topics: Anilides; Carcinoma, Neuroendocrine; Cardiotoxicity; Humans; Hypertension; Indazoles; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Sulfonamides; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) represents 3-5% of thyroid cancers. 75% is sporadic and 25% is the dominant component of the hereditary multiple endocrine neoplasia (MEN) type 2 syndromes. Three different subtypes of MEN2, such as MEN2A, MEN2B, and Familial MTC (FMTC) have been defined, based on presence or absence of hyperparathyroidism, pheocromocytoma and characteristic clinical features. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC, but there are many other mutational patterns involved. In MEN2A, Codon 634 in exon 11 (Cys634Arg), corresponding to a cysteine in the extracellular cysteine-rich domain, is the most commonly altered codon. Many other mutations include codons 611, 618, 620. In the genetical testing of RET mutations in MTCs, Next-Generation Sequencing (NGS) is taking an increasingly important role. One of the most important benefit is the comprehensive analysis of molecular alterations in MTC, which allows rapidly to select patients with different risk levels. There is a difference in miRNA expression pathway between sporadic and hereditary MTCs. Among sporadic cases, expression of miR-127 was significantly lower in those who harbor somatic RET mutations than those with wild-type RET. CDKN1B mutations are associated with many clinical pictures of cancers, such as MEN4. V109G polymorphism is associated with sporadic MTCs negative for RET mutations, and might influence the clinical course of the patients affected by MTC. Although surgery (i.e. total thyroidectomy with neck lymph node dissection) is the elective treatment for MTCs, about 80% of patients have distant metastases at diagnosis and in this cases surgery is not enough and an additional treatment is needed. Interesting results come from two large phase III clinical trials with two targeted tyrosine kinase inhibitors (TKIs), vandetanib and cabozantinib.. New genetical testings and therapeutical approaches open new perspectives in MTC management.

Topics: Anilides; Carcinoma, Medullary; Codon; Exons; Humans; Male; Middle Aged; Multiple Endocrine Neoplasia Type 2a; Mutation; Piperidines; Polymorphism, Genetic; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms; Thyroidectomy

Medullary thyroid carcinoma (MTC) is a hyperplasia of thyroid C-cells, accounting for 5-10% of all thyroid cancers. MTCs may appear as sporadic or hereditary forms, and several molecules and signaling pathways have been found to function defectively in MTC cells. Tyrosine kinases are the most well-studied molecules that have abnormal function in these tumor cells. Due to their limited response, chemotherapeutic agents and radiation therapy are not effective in treating patients with advanced metastatic MTC. In the past decade, significant attention has been given to the utilization of multikinase inhibitors as targeted therapeutic agents for treating MTC patients, with the most promising results arising from the study of tyrosine kinase inhibitors, which generally bind to the ATP binding sites of these kinases. Two drugs-vandetanib and cabozantinib-are approved for the treatment of aggressive advanced MTC; however, the potential for toxicities and adverse effects of these agents on patient quality of life need to be considered against any therapeutic gain. According to recent data, it appears that inhibition of only one receptor or molecule in a pathway is not as effective as simultaneous inhibition of different pathways, indicating the need to use combination therapy. The main purpose of this review is to describe the clinical characteristics, molecular mechanisms, and current molecular and targeted therapeutic strategies active in clinical trials for advanced MTC treatment.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials as Topic; High-Throughput Nucleotide Sequencing; Humans; Molecular Targeted Therapy; Mutation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms

Medullary thyroid cancer (MTC) represents 3% of all clinical thyroid cancers and arises from thyroid C cells that produce calcitonin. Locally advanced or metastatic MTC requires a careful work-up including measurement of serum calcitonin and carcinoembryonic antigen, determination of their doubling time and comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for treatment. Cytotoxic chemotherapy can control tumor burden in some patients with response rates of around 20% in old series. For the last 10 years, systemic therapy for MTC patients with large tumor burden and documented progression of the disease has involved the use of tyrosine kinase inhibitors targeting VEGFR and ret. Progression-free survival benefits have been demonstrated for both vandetanib and cabozantinib, as compared to placebo. Although these molecules are effective, they also have specific toxicity profiles which require a thorough clinical management in specialized centers. In the present review, we describe the work-up and treatment modalities of patients with advanced or metastatic medullary thyroid cancer with a focus on chemotherapy and targeted therapy results.

Topics: Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Disease-Free Survival; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

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Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; 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Background CD30+ lymphoproliferative disorders are rare and may feature a wide variety of presentations that mimic other conditions. Purpose A man with metastatic papillary thyroid carcinoma to skin who subsequently developed cutaneous anaplastic large cell lymphoma is described. Methods The PubMed medical database was used to search the following terms separately and in combination: ALCL, anaplastic large cell lymphoma ALCL, cutaneous anaplastic large cell lymphoma CALCL, cutaneous t-cell lymphoma CTCL, large t-cell lymphoma LTCL, lymphoproliferative, lymphomatoid papulosis LyP, mimic, papillary, thyroid cancer. Results CD30+ cutaneous anaplastic large cell lymphoma was diagnosed in a man with metastatic papillary thyroid carcinoma based on the temporal, histologic, and immunochemical features of an enlarging lesion. To the best of our knowledge, this is the initial description of a CD30+ lymphoproliferative disorder occurring in a patient with primary carcinoma of the thyroid. Conclusion Cutaneous lesions may present with various morphologies. Our patient had a previous history of metastatic papillary thyroid carcinoma to skin. His new chest lesion was originally suspected to be either an infection or a cutaneous metastasis. Multiple biopsies, not only for microscopic evaluation but also cultures for infectious organisms, were performed. Unexpectedly, a CD30+ lymphoproliferative disorder was diagnosed; subsequently the tumor spontaneously resolved. Therefore, when skin lesions appear that have more than one clinical presentation, it may be prudent for the clinician to collect representative samples of each distinct morphology to assure that an accurate diagnosis is established.

Topics: Aged; Carcinoma; Carcinoma, Papillary; Humans; Immunohistochemistry; Ki-1 Antigen; Lymphoma, Large-Cell, Anaplastic; Lymphoproliferative Disorders; Male; Neoplasms, Multiple Primary; Piperidines; Quinazolines; Skin Neoplasms; Thoracic Wall; Thyroid Cancer, Papillary; Thyroid Neoplasms

Medullary thyroid cancer arises from calcitonin-producing C-cells and accounts for 3-5% of all thyroid cancers. The discovery of a locally advanced medullary thyroid cancer that is not amenable to surgery or of distant metastases needs careful work-up, including measurement of serum calcitonin and carcinoembryonic antigen (and their doubling times), in addition to comprehensive imaging to determine the extent of the disease, its aggressiveness, and the need for any treatment. In the past, cytotoxic chemotherapy was used for treatment but produced little benefit. For the past 10 years, tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors and RET (rearranged during transfection) have been used when a systemic therapy is indicated for large tumour burden and documented disease progression. Vandetanib and cabozantinib have shown benefits on progression-free survival compared with placebo in this setting, but their toxic effect profiles need thorough clinical management in specialised centres. This Review describes the management and treatment of patients with advanced medullary thyroid cancer with emphasis on current targeted therapies and perspectives to improve patient care. Most treatment responses are transient, emphasising that mechanisms of resistance need to be better understood and that the efficacy of treatment approaches should be improved with combination therapies or other drugs that might be more potent or target other pathways, including immunotherapy.

Topics: Anilides; Antineoplastic Agents; Biomarkers; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Disease-Free Survival; Humans; Molecular Targeted Therapy; Piperidines; Pyridines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms; Treatment Outcome

The tyrosine kinase inhibitor vandetanib was approved for use in 2012 for aggressive and symptomatic medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease. As the first effective systemic therapy for MTC, vandetanib is a major step forward and the phase III study suggests an important role for this agent. Trials have also been performed for its use in differentiated thyroid cancer (DTC) though it is not yet approved for use for this indication.. The efficacy and safety of vandetanib is discussed. Studies suggest improvement in progression-free survival (PFS) without clear overall survival benefit but with manageable low grade toxicities and improved quality of life on therapy.. Vandetanib has an important role in the management of patients with progressive metastatic MTC. The use in patients with stable or asymptomatic disease has no proven benefit. The side effects can usually be managed with dose reduction, interruption, and/or specific symptomatic therapy.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease-Free Survival; Humans; Piperidines; Protein Kinase Inhibitors; Quality of Life; Quinazolines; Survival Rate; Thyroid Neoplasms

Traditional therapies for advanced or metastatic progressive medullary thyroid cancer (pMTC) are poor effective. Several TKIs have been tested in clinical trials in pMTC patients. Areas covered: This paper reviews efficacy and safety of vandetanib in the treatment of pMTC. Expert commentary: Vandetanib (trade name CAPRELSA® [Vandetanib]) has been shown to improve progression-free survival (30.5 vs 19.3 months in controls) in pMTC patients. Vandetanib is approved by FDA and EMA for metastatic MTC in adults; in adolescents and children with metastatic or locally advanced MTC, vandetanib seems to be effective. The most common adverse events in vandetanib-treated patients are: diarrhea, rash, folliculitis, nausea, QTc prolongation, hypertension and fatigue. In patients with aggressive differentiated thyroid cancer, vandetanib has shown promising results. Further research is needed to determine the ideal targeted therapy, based on tumor molecular characterization and host factors, to obtain the best response in terms of survival and quality of life.

Topics: Adolescent; Adult; Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Child; Disease Progression; Disease-Free Survival; Humans; Piperidines; Protein Kinase Inhibitors; Quality of Life; Quinazolines; Thyroid Neoplasms

Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Chemotherapy, Adjuvant; Genotype; Humans; Molecular Targeted Therapy; Phenotype; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Receptors, Fibroblast Growth Factor; Thyroid Neoplasms; Thyroidectomy; Vascular Endothelial Growth Factor Receptor-2

Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC).

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Humans; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms

During the past two decades, several key somatic mutations associated with development and progression of differentiated thyroid cancer (DTC) have been revealed. Historically, the treatment for advanced DTC is challenging after patients become refractory to radioactive iodine. The response to doxorubicin, the only chemotherapy agent approved by the US Food and Drug Administration, is disappointing either as monotherapy or combination therapy. Because of the lack of effective systemic treatment coupled with increased understanding of molecular and cellular pathogenesis, multiple kinase inhibitors (MKIs) as an alternative therapy for the treatment of advanced DTC has generated much interest, enthusiasm, and, most excitingly, promising results. After the encouraging results of these agents in earlier trials, the Food and Drug Administration approved sorafenib for the treatment of locally recurrent, progressive, or metastatic DTC refractory to radioactive iodine treatment based on the results of a multicenter DECISION trial. Sorafenib therefore became the first MKI approved for this indication in more than 20 years. However, even more impressive responses and progression-free survival benefits were seen in the phase III SELECT trial with lenvatinib, giving even higher hopes for the future management of what was considered just a decade ago an orphan disease. Given the role of MKIs, a new era in the treatment of advanced DTC has begun. We review the key therapeutic targets, oncogenic pathways, and promising clinical results of these agents in refractory disease, as well as their roles after failure of first line kinase inhibitors.

Topics: Antineoplastic Agents; Clinical Trials, Phase II as Topic; Humans; Iodine Radioisotopes; Mutation; Neoplasm Metastasis; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Signal Transduction; Sorafenib; Thyroid Neoplasms; Treatment Failure

In the last few years, three new drugs for targeted systemic therapies have been approved for advanced and progressive thyroid cancer, namely vandetanib and cabozantinib for medullary and sorafenib for radioiodine refractory differentiated thyroid cancer. Patient selection by an interdisciplinary team and education of patients by the treating physicians play a major role when such a treatment is considered and initiated. Only patients with significant tumor burden and/or symptomatic disease or progression, which cannot be controlled by local therapies, should be treated. In order to preserve quality of life, the management of adverse effects is of utmost importance. Due to the mechanism of action of these tyrosine kinase inhibitors, the reliability of serum tumour markers, calcitonin and thyroglobulin, is limited for the assessment of response and follow-up, therefore morphological and metabolic imaging is of great importance. Minor or localized progression should not automatically trigger the termination of treatment or change of drug. In the near future, it is expected that additional drugs become available.

Topics: Anilides; Antineoplastic Agents; Drug Monitoring; Evidence-Based Medicine; Humans; Piperidines; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms; Tomography, Emission-Computed; Treatment Outcome

Vandetanib is a once-daily orally available tyrosine kinase inhibitor that works by blocking RET (REarranged during Transfection), vascular endothelial growth factor receptor (VEGFR-2, VEGFR-3), and epidermal growth factor receptor and to a lesser extent VEGFR-1, which are important targets in thyroid cancer (TC). It is emerging as a potentially effective option in the treatment of advanced medullary thyroid cancer (MTC) and in dedifferentiated papillary thyroid cancer not responsive to radioiodine. The most important effect of vandetanib in aggressive MTC is a prolongation of progression-free survival and a stabilization of the disease. Significant side effects have been observed with the vandetanib therapy (as fatigue, hypertension, QTc prolongation, cutaneous rash, hand-and-foot syndrome, diarrhea, etc), and severe side effects can require the suspension of the drug. Several studies are currently under way to evaluate the long-term efficacy and tolerability of vandetanib in MTC and in dedifferentiated papillary TC. The efficacy of vandetanib in patients with MTC in long-term treatments could be overcome by the resistance to the drug. However, the effectiveness of the treatment could be ameliorated by the molecular characterization of the tumor and by the possibility to test the sensitivity of primary TC cells from each subject to different tyrosine kinase inhibitor. Association studies are evaluating the effect of the association of vandetanib with other antineoplastic agents (such as irinotecan, bortezomib, etc). Further research is needed to determine the ideal therapy to obtain the best response in terms of survival and quality of life.

Topics: Animals; Antineoplastic Agents; Disease-Free Survival; Humans; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Thyroid Neoplasms; Treatment Outcome

Advanced thyroid cancer is not amenable to therapy with conventional cytotoxic chemotherapy. However, newer advances in the understanding of the molecular pathogenesis of different subtypes of thyroid cancer have provided new opportunities for the evaluation of molecularly targeted therapies. This has led to multiple clinical trials using various multi-kinase inhibitors and the subsequent US FDA approval of sorafenib for differentiated thyroid cancer and vandetanib and cabozantinib for medullary thyroid carcinoma. This review provides a summary of the current literature for the treatment of advanced thyroid carcinoma and future directions in this disease.

Topics: Anilides; Antineoplastic Agents; Axitinib; Carcinoma, Neuroendocrine; DNA Mutational Analysis; Drug Approval; Humans; Imidazoles; Indazoles; Indoles; MAP Kinase Signaling System; Molecular Targeted Therapy; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phosphatidylinositol 3-Kinases; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Sorafenib; Sulfonamides; Sunitinib; Thyroid Neoplasms; United States; United States Food and Drug Administration; Vascular Endothelial Growth Factor A

To review the place in therapy of vandetanib for medullary thyroid carcinoma (MTC).. Literature searches were performed in Ovid MEDLINE, EMBASE, and Google Scholar using the search terms ZD6474 OR vandetanib OR Caprelsa combined with medullary thyroid carcinoma.. Two phase 2 trials and 1 phase 3 trial were identified.. Vandetanib is approved for the treatment of unresectable, locally advanced or metastatic MTC in patients with symptomatic or progressive disease. In the phase 3 randomized, double-blind, placebo-controlled trial, vandetanib 300 mg daily (n = 231) was compared with placebo (n = 100). Vandetanib-treated patients experienced a significant improvement in progression-free survival (PFS; hazard ratio [HR] = 0.46; 95% CI = 0.31-0.69; P < .001). No difference in overall survival (OS) was seen at the time of publication. Most adverse effects were grade 1 or 2 and managed by dose interruptions or reductions. The most common grade 3/4 adverse effects were diarrhea, hypertension, QT prolongation, fatigue, and rash. Because of the potential for QT prolongation, torsades de pointes, and sudden death, vandetanib is restricted via a Risk Evaluations and Mitigation Strategy program.. Vandetanib prolongs PFS but has not been shown to improve OS. Vandetanib can be considered for patients with unresectable locoregional disease. It is a first-line option for patients with unresectable symptomatic distant metastases as well as an option for advanced disseminated symptomatic metastatic disease. Vandetanib is expected to be an important addition to the formulary of health plans that provide prescription drug benefits.

Topics: Antineoplastic Agents; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease-Free Survival; Drug Interactions; Drug Labeling; Humans; Neoplasm Metastasis; Piperidines; Quinazolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms

Thyroid cancer represents over 90% of all endocrine malignancies, with medullary thyroid carcinoma (MTC) accounting for 5 - 9% of them. Patients with early-stage disease have a favorable prognosis, but once distant metastasis develops, survival drops to 50% or less. Although surgery remains effective for early-stage disease, patients with advanced disease pose a challenge as traditional therapies have not provided long-term benefits. Vandetanib, initially developed to target other receptors, demonstrated anti-rearranged during transfection (anti-RET) kinase activity. This led to preclinical studies followed by recent human clinical trials, culminating in its FDA approval in April 2011 for application in the treatment of symptomatic or progressive MTC in patients with surgically unresectable, locally advanced or metastatic disease.. The authors provide a review of the discovery strategy and preclinical development of vandetanib. The authors also provide some insight into the clinical development and the drug's post-launch situation.. Vandetanib has been shown to improve progression-free survival in MTC patients, but its impact on overall survival is still inconclusive. Further data analysis will be needed to answer the question of whether it impacts overall survival in MTC. Despite its advancements, vandetanib still lacks durable efficacy, carries moderate toxicity and has issues with drug resistance over time, not to mention issues of cost. There is a significant need for additional research to discover and develop improved therapeutic strategies for this difficult disease.

Topics: Disease-Free Survival; Drug Discovery; Humans; Piperidines; Quinazolines; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) is a rare endocrine malignancy accounting for a significant percentage of thyroid cancer-related fatal events. Traditional treatment modalities used in the other types of thyroid carcinomas have been proved largely ineffective in advanced MTC. Better understanding of the molecular pathways implicated in the pathogenesis of MTC has led to the development of new drugs, which are implicated in the disruption of these molecular cascades.. This review provides the latest information regarding vandetanib , a new tyrosine kinase inhibitor mainly in the treatment of MTC. A collection of available data was conducted using the PubMed database as well as the ClinicalTrials.gov website, searching for vandetanib and thyroid cancer.. Vandetanib targets multiple cell-signaling pathways involved in the molecular pathogenesis of thyroid cancer, namely vascular endothelial growth factor receptor-2, epidermal growth factor receptor and rearranged during transfection receptor. It is an effective approach in treating advanced MTC. However, treatment toxicity issues, as well as individual patient parameters, including disease burden and progression, should be taken into consideration before initiating vandetanib treatment.

Topics: Animals; Carcinoma, Neuroendocrine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Epidermal Growth Factor; Humans; Piperidines; Protein Kinase Inhibitors; Quinazolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms; Transfection; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2

Up until now there have been no promising drugs for the treatment of advanced thyroid cancer, but the development of novel therapeutic agents is now anticipated as a result of the advent of molecular targeted drugs that inhibit tumor growth signals or angiogenesis. Against a background in which the development of numerous molecular targeted drugs for advanced thyroid cancer is being pursued worldwide, the development of sorafenib, vandetanib, and lenvatinib is currently also under way in Japan. All three of these compounds are undergoing phase 3 trials or have been approved abroad, and because they are in the final stage of development in Japan, they are expected to be introduced in clinical settings in the near future. After they have been introduced, it will be necessary to understand the differences between these compounds and to administer them to patients appropriately.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Japan; Molecular Targeted Therapy; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Piperidines; Quinazolines; Quinolines; Sorafenib; Thyroid Neoplasms

Since chemotherapy has been shown to be unsuccessful in case of advanced thyroid carcinomas, the research for new therapies is fundamental. Clinical trials of many tyrosine kinase inhibitors as well as anti-angiogenic inhibitors suggest that patients with thyroid cancer could have an advantage with new target therapy. Recently, Food and Drug Administration approved two targeted therapies, vandetanib and cabozantinib for the treatment of metastatic thyroid carcinomas with acceptable outcome. We summarized the results and the toxic effects associated with these treatments reported in clinical trials. Future trials should aim at combinations of targeted agents with or without other treatment modalities to obtain a more effective result in thyroid carcinoma treatment.

Topics: Anilides; Antineoplastic Agents; Boronic Acids; Bortezomib; Cell Differentiation; Cell Proliferation; ErbB Receptors; Genetic Therapy; Histone Deacetylase Inhibitors; Humans; Immunotherapy; Lithium; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyridines; Quinazolines; Stilbenes; Thalidomide; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is a rare cancer. Vandetanib, a RET tyrosine-kinase inhibitor, significantly increased progression free survival and is the first treatment approved in France for unresectable, locally advanced or metastatic MTC that is symptomatic or progressive. Most frequents adverse events are diarrhea, folliculitis and asthenia. The prolongation of the QT interval on electrocardiogram is frequent but in the most of cases not clinically relevant. A good selection of the patients who could benefit from this treatment and management of side effect are important for the risk-benefit assessment.

Topics: Antineoplastic Agents; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Humans; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Rare Diseases; Thyroid Neoplasms

New therapeutic options for both differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) have opened up during the past few years, as the key role of tyrosine kinases in the pathogenesis of thyroid carcinoma has been proved. Recently, two tyrosine kinase inhibitors (TKIs) targeting VEGFR vandetanib (Caprelsa) and cabozantinib (Cometriq) have been approved for advanced MTC, whereas, sorafenib (Nexavar) has been accepted to treat late-stage of DTC. Their efficacy was demonstrated in Phase III studies, compared to placebo; each of them significantly prolonged the progression-free survival.. Common adverse reactions related to VEGFR blockade are hypertension, proteinuria, impaired wound healing, hemorrhage and thrombosis, and congestive heart failure. Fatigue, different gastrointestinal disturbances with diarrhea, appetite decrease and weight loss are observed in the majority of patients. Another frequent TKI side effect is thyroid-stimulating hormone increase secondary to inhibition of MCT8-dependent T3 and T4 uptake in pituitary.. So far, no direct comparison of both treatment outcomes and toxicity between particular drugs has been carried out. The evidence-based medicine guidelines are necessary to precisely indicate what drug to use: more effective or less toxic and when to start the treatment.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Diarrhea; Humans; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Quinolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

Among the 35 new molecular entities approved by the FDA in 2011, 17 were particularly notable for their significant contributions to the health of patients, including abiraterone acetate, vandetanib, belatacept and fidaxomicin. Thus, abiraterone acetate, namely Zytiga®, was included as the first in a new class of drugs to treat late-stage prostate cancer. The ability of Zytiga® to prolong survival in these patients was considered as significant because they have few other treatments options and the benefits of Zytiga® outweighed the risks of reported side-effects. Vandetanib, namely Caprelsa®, was also considered as a relevant drug since it represents the first drug approved to treat particularly aggressive medullary thyroid cancer, an orphan disease. Despite huge progress in transplantation, renal transplantation remains a serious problem since patients treated with the calcineurin inhibitors cyclosporine and tacrolimus are at high risk of developing renal injury. With longer follow-up, the novel immunosuppressant belatacept continued to show better renal function compared with a cyclosporine-based regimen, as well as a consistent safety profile and comparable efficacy. It was approved by the Food and Drug Administration in June 2011 for the prophylaxis of organ rejection in adult recipients of a kidney transplant acting by a selective T-cell costimulation blocker given as an infusion. Clostridium difficile is currently the most important cause of infectious diarrhea in the United States. Fidaxomicin, a macrolide antibiotic, was recently approved for treatment of these infections (CDIs). It could be an alternative treatment for infection with C. difficile, with similar efficacy and safety to vancomycin. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile.

Topics: Abatacept; Aminoglycosides; Androstenes; Androstenols; Anti-Bacterial Agents; Antineoplastic Agents; Clostridioides difficile; Clostridium Infections; Enzyme Inhibitors; Fidaxomicin; Humans; Immunoconjugates; Immunosuppressive Agents; Male; Piperidines; Prostatic Neoplasms; Quinazolines; Thyroid Neoplasms

Medullary thyroid cancer (MTC) is frequently diagnosed in a locally advanced or metastatic stage, and 10-year survival rates in these cases are below 20 %. Cytotoxic chemotherapy has no significant impact on overall or progression-free survival. Vandetanib (Caprelsa(®), AstraZeneca) is a once-daily oral tyrosine kinase inhibitor that selectively inhibits signalling mediated by growth-factor receptor tyrosine kinase RET (constitutively activated in roughly 60 % of all MTCs), vascular endothelial growth-factor receptors 2 and 3, and epidermal growth-factor receptors. It is the first systemic drug with demonstrated anti-tumor benefits in advanced MTC, and it has recently been approved for locally advanced or metastatic MTC by the United States Food and Drug Administration (April 2011) and the European Medicines Agency (February 2012). This review, starting from the phases II and III efficacy and safety data that led to these approvals, explores important issues related to dosing, patient selection, and strategies for managing the substantial risk of toxicity associated with the drug (including life-threatening cardiac events that are the subject of a black-box warning in the United States). All these issues still remain to be defined. Vandetanib is becoming a standard of care for symptomatic, progressive, metastatic MTCs, to be used selectively in those patients who are likely to benefit from it.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease Progression; Drugs, Investigational; Humans; Medical Oncology; Piperidines; Professional Practice; Quinazolines; Thyroid Neoplasms; Treatment Outcome

The pharmacology, pharmacokinetics, efficacy, safety and tolerability, drug and food interactions, cost, and place in therapy of vandetanib are reviewed.. Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and receptor tyrosine kinase signaling pathways, which are involved in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Vandetanib was evaluated in a randomized, placebo-controlled, double-blind Phase III study comparing vandetanib with placebo in adult patients with unresectable locally advanced or metastatic hereditary or sporadic MTC. Vandetanib demonstrated a statistically significant longer progression-free survival (predicted median of 30.5 months) compared with placebo (median of 19.3 months) (hazard ratio, 0.46; 95% confidence interval, 0.31-0.69; p = 0.0001). The most commonly observed adverse effects of vandetanib include nausea, diarrhea, headache, rash, prolongation of the Q-T interval, and hypertension. Because it can prolong the Q-T interval, vandetanib is contraindicated for use in patients with serious cardiac complications, including congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, and a history of torsades de pointes.. Vandetanib has been shown to be more effective than placebo in the treatment of advanced MTC; however, it has not been compared with radiation, resection, or embolization. Vandetanib also has significant and fairly common cardiac toxicities. The cost, benefits, and risks of vandetanib for patients with MTC should be weighed, as alternative treatments remain an option for most patients.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Disease-Free Survival; ErbB Receptors; Fees, Pharmaceutical; Humans; Piperidines; Quinazolines; Thyroid Neoplasms

Thyroid neoplasias represent among the fastest growing cancers. While surgery has become the treatment of choice for most thyroid tumors, many require chemotherapy. In this review, we examine the contributions of work in the fruit fly Drosophila toward multiple endocrine neoplasia type 2 (MEN2), a Ret-based disease to which recent Drosophila models have proven useful both for understanding disease mechanism as well as helping identify new generation therapeutics.

Topics: Animals; Antineoplastic Agents; Disease Models, Animal; Drosophila; Drug Evaluation, Preclinical; Humans; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms

Vandetanib has recently demonstrated clinically meaningful benefits in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). Given the potential for long-term vandetanib therapy in this setting, in addition to treatment for disease-related symptoms, effective management of related adverse events (AEs) is vital to ensure patient compliance and maximize clinical benefit with vandetanib therapy.. This expert meeting-based review aims to summarize published data on AEs associated with vandetanib therapy and to provide clinicians with specific practical guidance on education, monitoring, and management of toxicities induced in patients treated with vandetanib in advanced and metastatic MTC. The content of this review is based on the expert discussions from a multidisciplinary meeting held in October 2012.. Characteristics, frequency, and risk data are outlined for a number of dermatological, cardiovascular, gastrointestinal, and general AEs related to vandetanib treatment. Preventive strategies, practical treatment suggestions, and points for clinical consideration are provided.. Good patient and team communication is necessary for the prevention, early detection, and management of AEs of vandetanib. Physicians, nurses, and other healthcare providers play a critical role in providing AE management and patient support to optimize outcomes with vandetanib in MTC.

Topics: Carcinoma, Neuroendocrine; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Eruptions; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Neoplasm Invasiveness; Neoplasm Staging; Patient Selection; Piperidines; Prognosis; Quinazolines; Risk Assessment; Thyroid Neoplasms; Treatment Outcome

A better understanding of molecular mechanisms responsible for tumorigenesis has allowed the development of targeted drugs designed to improve the outcome of cancer. In endocrine tumors, several molecules have demonstrated efficacy in terms of progression free survival during phase III trials such as vandetanib and cabozantinib in medullary thyroid carcinoma, sorafenib in differentiated thyroid carcinoma and everolimus or sunitinib for pancreatic neuroendocrine tumors. Rare cancer network has allowed ongoing phase III trials in malignant pheochromocytoma and adrenocortical carcinoma. However, to date no specific predictive biomarker has yet been identified for a personalized cancer medicine. We review recent advances in endocrine oncology concerning molecular targets identification, targeted therapies and predictive or prognostic markers.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials, Phase III as Topic; Disease-Free Survival; Endocrine Gland Neoplasms; Everolimus; Humans; Indoles; Molecular Targeted Therapy; Neuroendocrine Tumors; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Piperidines; Prognosis; Pyrroles; Quinazolines; Sirolimus; Sorafenib; Sunitinib; Thyroid Neoplasms; Treatment Outcome

Vandetanib is a small molecule tyrosine kinase inhibitor that has been recently approved as an 'orphan drug' for the treatment of patients with unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC).. MTC is a neuroendocrine malignancy frequently associated with mutations to the RET proto-oncogene. Vandetanib selectively targets RET, vascular endothelial growth factor receptor-2, and epidermal growth factor receptor dependent signaling. Vandetanib has been shown to improve progression-free survival in patients with advanced MTC. In general, vandetanib is well tolerated, but QTc prolongation remains a potential concern demanding careful patient selection and monitoring.. Vandetanib has emerged as one of the more promising small molecule tyrosinse kinase inhibitors, providing durable rates of disease stabilization, with an acceptable adverse event profile in patients with advanced MTC.

Topics: Antineoplastic Agents; Carcinoma, Medullary; Clinical Trials as Topic; Humans; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Quinazolines; Thyroid Neoplasms

Vandetanib (ZD6474, Caprelsa, AstraZeneca), an oral small-molecule tyrosine kinase inhibitor (TKI) that targets the rearranged during transfection receptor (RET), VEGF receptor (VEGFR2-3), and EGF receptor (EGFR), is the first systemic therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of symptomatic or progressive advanced medullary thyroid cancer (MTC). In a randomized phase III trial of patients with unresectable, locally advanced, or metastatic MTC, vandetanib improved progression-free survival compared with placebo [HR, 0.46; 95% confidence interval (CI), 0.31-0.69; P < 0.001]. However, the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities, including diarrhea, hypertension, and QTc prolongation. Here, we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in MTC.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Humans; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms; Treatment Outcome

The incidence of thyroid cancer continues to increase and this neoplasia remains the most common endocrine malignancy. No effective systemic treatment currently exists for iodine-refractory differentiated or medullary thyroid carcinoma, but recent advances in the pathogenesis of these diseases have revealed key targets that are now being evaluated in the clinical setting. RET (rearranged during transfection)/PTC (papillary thyroid carcinoma) gene rearrangements, B-Raf gene mutations, and vascular endothelial growth factor receptor 2 (VEGFR-2) angiogenesis pathways are some of the known genetic alterations playing a crucial role in the development of thyroid cancer. Several novel agents have demonstrated promising responses. Of the treatments studied, multi-kinase inhibitors such as axitinib, sorafenib, motesanib, and XL-184 have shown to be the most effective by inducing clinical responses and stabilizing the disease process. Randomized clinical trials are currently evaluating these agents, results that may soon change the management of thyroid cancer.

Topics: Angiogenesis Inhibitors; Anilides; Antineoplastic Agents; Axitinib; Benzamides; Benzenesulfonates; Benzoquinones; Bibenzyls; Boronic Acids; Bortezomib; Depsipeptides; ErbB Receptors; Gefitinib; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Imatinib Mesylate; Imidazoles; Indazoles; Indoles; Lactams, Macrocyclic; Lenalidomide; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Quinolines; Receptor Protein-Tyrosine Kinases; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib; Thalidomide; Thyroid Neoplasms; Valproic Acid; Vorinostat

Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and RET tyrosine kinases that has demonstrated clinical benefits in patients with medullary thyroid cancer (MTC). By identifying patients who are in greatest need of therapy, the risks of vandetanib can be balanced against the potential benefits in patients for whom there had been no effective therapy until now. This review discusses the development of vandetanib in patients with MTC and the benefits and risks in this patient population.

Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; ErbB Receptors; Humans; Piperidines; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Topics: Carcinoma, Neuroendocrine; Drug Costs; Drug Interactions; Humans; Piperidines; Quinazolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms

This review will focus on the recent advances in molecular pathogenesis and targeted therapies for medullary thyroid carcinoma (MTC). Unlike hereditary MTC in which rearranged during transfection (RET) mutations are the most important precipitating events, in sporadic MTC the genetic or molecular biomarkers are yet to be established.. Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC and are under investigation. In addition, the recent findings of H-RAS mutations in 56% of RET-negative sporadic MTC and the activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway in hereditary MTC suggests that additional or alternative genetic events are important for MTC pathogenesis.. Recently, vandetanib (ZD6474), an inhibitor of vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR 3, RET, and epidermal growth factor receptor (EGFR), was approved for the treatment of adults with symptomatic or progressive MTC. Significant advantages for vandetanib over placebo were seen in terms of response rate, disease control rate, and biochemical response in a phase III study. Furthermore, cabozantinib (XL184), an inhibitor of VEGFR 1 and VEGFR 2, hepatocyte growth factor receptor (MET), and RET, was associated with partial response and stable disease in 29 and 41%, respectively.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Clinical Trials, Phase III as Topic; Female; Humans; Male; Molecular Targeted Therapy; Mutation; Piperidines; Prognosis; Quinazolines; Signal Transduction; Thyroid Neoplasms; Time Factors; TOR Serine-Threonine Kinases

Vandetanib is an oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection tyrosine kinases. It is approved for the treatment of unresectable or metastatic medullary thyroid cancer. Its use may be hindered due to adverse events, including rash. The reported incidence and risk of rash to vandetanib varies widely and has not been more closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing a rash.. Databases from PubMed from 1996 through July 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through July 2011 were searched for relevant studies.. Eligible studies were prospective trials that described side effects of all-grade or high-grade rash for patients who received vandetanib 300 mg as a single agent. The incidence of all-grade and high-grade rash and relative risk were calculated using random-effects or fixed-effects models.. Of 63 studies initially identified, nine met the selection criteria and were included for the study. A total of 2961 patients were included for analysis. The summary incidences of all-grade and high-grade rash were 46.1% [95% confidence interval (CI), 40.6-51.8%] and 3.5% (95% CI, 2.5-4.7%), respectively. From randomized controlled trials, patients who received vandetanib 300 mg had a significantly increased risk of developing all-grade rash in comparison with controls, with a relative risk of 2.43 (95% CI, 1.37-4.29; P = 0.002).. There is a significant risk of developing rash in cancer patients receiving vandetanib. Awareness and treatment of this adverse event is critical to ensure adherence and maximize dosing, guaranteeing the best possible clinical benefit.

Topics: Antineoplastic Agents; Breast Neoplasms; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Eruptions; ErbB Receptors; Female; Humans; Incidence; Lung Neoplasms; Male; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Risk; Severity of Illness Index; Small Cell Lung Carcinoma; Thyroid Neoplasms

Thyroid cancers represent the largest group of pediatric carcinomas. Unlike other cancers of childhood, they have not been prospectively studied; instead adult data has been extrapolated to childhood and adolescent treatment. In this article we review the treatment of both well differentiated thyroid cancer (WDTC), as well as medullary thyroid cancer (MTC). The approach to both cancers relies on a low threshold of suspicion, and a willingness to biopsy suspicious lesions. Surgery remains the primary method of curing these patients, although radioactive iodine (RAI) may offer some benefit in WDTC for selected patients. For patients with MTC new medications, such as Vandetanib, may offer some adjuvant benefit following surgery. Lastly, suppression of thyroid stimulating hormone (TSH) may be one of the most beneficial treatments for WDTC.

Topics: Adolescent; Age Factors; Child; Child, Preschool; Female; Humans; Iodine Isotopes; Male; Piperidines; Quinazolines; Thyroid Neoplasms; Thyrotropin; Young Adult

The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

Topics: Antineoplastic Agents; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Humans; Molecular Targeted Therapy; Patient Selection; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

The addition of vandetanib to chemotherapy has been shown to have a marked effect on patients with advanced cancers who had failed previous chemotherapy. We carried out a meta-analysis to determine the efficacy and safety of vandetanib compared with chemotherapy in patients with advanced cancers. For this meta-analysis, we selected randomized clinical trials that compared vandetanib-based therapy (VBT) with the matched chemotherapy or placebo alone in patients with advanced cancers. The outcomes included overall survival (OS), progression-free survival (PFS), the objective response rate, and toxicities. Hazard ratios (HRs) and odds ratios were reported with 95% confidence intervals (CIs). A total of 14 eligible trials were included for the meta-analysis, with 2995 patients in the VBT group and 2479 patients in the control group. A significant improvement was observed in PFS (HR 0.76, 95% CI 0.68-0.86 in all cancers, HR 0.80, 95% CI 0.70-0.90 in lung cancer, HR 0.54, 95% CI 0.40-0.74 in thyroid cancer) and in objective response rate (odds ratio 2.09, 95% CI 1.42-3.07) in the VBT group. However, no significant difference was found in OS (HR 0.96, 95% CI 0.90-1.03). The subgroups of patients with non-small-cell lung cancer who benefited from vandetanib therapy were identified as those with a history of smoking (HR 0.87, 95% CI 0.80-0.95) and an adenocarcinoma histology (HR 0.85, 95% CI 0.77-0.94). In addition, patients who received VBT had an increased incidence of adverse events such as rash, diarrhea, and neutropenia. The addition of vandetanib to chemotherapy significantly improves PFS in patients with locally advanced or metastatic cancers, especially lung and thyroid cancer.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Humans; Lung Neoplasms; Neoplasms; Piperidines; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Vandetanib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor, demonstrates potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR) and the rearranged during transfection (RET) tyrosine kinase receptor. The large (n=331), randomized, double-blind, multinational ZETA trial compared vandetanib at a dosage of 300 mg once daily with placebo in patients with unresectable, locally advanced or metastatic, hereditary or sporadic, medullary thyroid cancer. During a median follow-up period of 2 years, vandetanib demonstrated statistically significant clinical benefits over placebo with respect to the primary endpoint, namely progression-free survival (PFS), and a range of secondary endpoints, which included objective response rate, disease control rate, time to worsening of pain and calcitonin biochemical response rate. The PFS benefit with vandetanib was mostly consistent across patient subgroups based on baseline characteristics and disease status. Although the correlation between RET mutation status and clinical outcome could not be clearly evaluated in this trial, it is notable that, among patients with sporadic disease, vandetanib not only demonstrated a PFS benefit in the subgroup confirmed as having a RET mutation, but also in the subgroup for whom the RET mutation status was unknown. Vandetanib was generally well tolerated in the ZETA trial; the majority of adverse events were manageable according to standard clinical practice alone or in combination with vandetanib dose reductions. The adverse event of most concern is corrected QT interval prolongation, particularly in view of the long terminal elimination half-life of the drug.

Topics: Administration, Oral; Antineoplastic Agents; Carcinoma, Neuroendocrine; Disease-Free Survival; Humans; Molecular Structure; Neoplasm Metastasis; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Randomized Controlled Trials as Topic; Thyroid Neoplasms

Vandetanib (Caprelsa™) provides an acceptable treatment option in patients with advanced medullary thyroid cancer for whom, historically, there have been no effective therapies. Vandetanib, an orally active, multitargeted tyrosine kinase inhibitor, improves progression-free survival and tumor response in patients with unresectable, locally advanced or metastatic medullary thyroid cancer. It has an acceptable tolerability profile in this patient population, although it does have the potential to prolong the corrected QT interval.

Topics: Carcinoma, Neuroendocrine; Disease-Free Survival; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidines; Practice Guidelines as Topic; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Quinazolines; Thyroid Neoplasms

The U.S. Food and Drug Administration (FDA) approved vandetanib in April 2011 for the treatment of unresectable, locally advanced or metastatic medullary thyroid cancer (MTC). In Europe it was approved in March 2012, but only for the treatment of aggressive and symptomatic MTC. This small molecule is a tyrosine kinase inhibitor of several growth factors involved in cellular proliferation and angiogenesis, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptors 2 and 3 (VEGFR-2, VEGFR-3). In addition, vandetanib is an inhibitor of the RET (rearranged during transfection) gene, a proto-oncogene often mutated in familial MTC. Since MTC is a rare disease, for which no previous medical therapies are approved, vandetanib is the first drug shown to be effective in a large phase III trial treating patients with metastatic or locally advanced MTC. Common adverse events are diarrhea, nausea, hypertension, headache and QT prolongation that are manageable and are commonly outweighed by the benefits of vandetanib in terms of delaying disease progression and inducing tumor response.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Drug Interactions; ErbB Receptors; Humans; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

The prognosis of almost all thyroid cancers is good, but some patients have indications for these molecularly targeted drugs. Some of these drugs, i.e., vandetanib, XL-184, sorafenib, motesanib, axitinib, and pazopanib, are clearly useful clinically.

Topics: Anilides; Benzenesulfonates; Disease Progression; Humans; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Sorafenib; Thyroid Neoplasms

Protein tyrosine kinase inhibitors (TKIs) have emerged as significant targets for novel cancer therapies. For patients with differentiated or medullary carcinomas unresponsive to conventional treatments, multiple novel therapies primarily targeting angiogenesis have entered clinical trials. Partial response rates up to 30% have been reported in single-agent studies, but prolonged disease stabilisation is more commonly seen. The most successful agents target the vascular endothelial growth factor receptors. Sorafenib and sunitinib have had promising preliminary results reported and are being used selectively for patients who do not qualify for clinical trials. Treatment for patients with metastatic or advanced thyroid carcinoma now emphasises clinical trial opportunities for novel agents with considerable promise. Adverse effects on thyroid function and thyroid hormone metabolism have also been seen with several TKIs, necessitating prospective thyroid function testing for all patients starting therapy.

Topics: Axitinib; Benzenesulfonates; Clinical Trials as Topic; Gefitinib; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Oligonucleotides; Pharmaceutical Preparations; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins B-raf; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Sulfonamides; Sunitinib; Thyroid Gland; Thyroid Neoplasms

Thyroid cancer incidence has significantly increased in the last three decades and many patients seek medical attention for its treatment every year. Among follicular cell-derived tumors, the majority are differentiated thyroid carcinomas (DTC), whose prognosis is very good with only 15% of the cases presenting disease persistence or recurrence after initial treatment. Medullary thyroid carcinoma has a worse prognosis, especially in patients with diffused cancers at the time of initial surgery. Traditional treatment options for persistent or recurrent disease include additional surgery, radioiodine treatment and TSH-suppression in DTC patients; external beam radiotherapy, and cytotoxic chemotherapy, often have low efficacy and many patients with advanced disease ultimately die. In the last two decades many of the molecular events involved in cancer formation have been uncovered. This knowledge has prompted the development of novel therapeutic strategies mainly based on the inhibition of key molecular mediators of the tumorigenic process. In particular the class of small-molecule tyrosine kinase inhibitors was enriched by many compounds that have reached clinical trials and in some cases have had approval for clinical use in specific cancers. Many of these compounds entered clinical trials also for locally advanced or metastatic thyroid carcinomas showing very promising results.

Topics: Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Medullary; Carcinoma, Papillary; Humans; Imidazoles; Indazoles; Indoles; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thyroid Neoplasms

Historically, systemic therapies for advanced, metastatic thyroid carcinomas have been poorly effective. However, as a result of a confluence of increasing knowledge of the biologic basis for thyroid cancer development and progression, identification of therapeutic agents that could target these biologic abnormalities, and enthusiasm for research by both funding agencies as well as patients, multiple clinical trials have been initiated and successfully completed during the past several years. This article focuses on findings from key studies that reflect the new paradigms for treatment.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Benzamides; Benzenesulfonates; Carcinoma; Clinical Trials as Topic; Drug Delivery Systems; Gefitinib; Humans; Imatinib Mesylate; Imidazoles; Indazoles; Indoles; Niacinamide; Oligonucleotides; Phenylurea Compounds; Piperazines; Piperidines; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Quinazolines; Sorafenib; Thyroid Neoplasms

Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced. We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety.. A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.. Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with

Topics: Antineoplastic Agents; Disease Progression; Humans; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms

Vandetanib at a dose of 300 mg orally every day plus bortezomib 1.3 mg/m. The proto-oncogene RET (. Patients with advanced solid tumors were treated with escalating doses of bortezomib or vandetanib to assess the safety and tolerability of daily oral vandetanib and intravenous (IV) bortezomib administered on days 1, 4, 8, and 11 of a 28-day cycle. The MTD of the combination was established as bortezomib, 1.3 mg/m

Topics: Antineoplastic Agents; Bortezomib; Carcinoma, Neuroendocrine; Female; Humans; Male; Piperidines; Proto-Oncogene Mas; Quinazolines; Thyroid Neoplasms

Vandetanib is an oral tyrosine kinase inhibitor approved for treatment of advanced symptomatic or progressive medullary thyroid cancer (MTC). The current study (Nbib1496313) evaluated the benefit-risk of two starting doses of vandetanib in patients with symptomatic or progressive MTC. Patients were randomized 1:1 to receive vandetanib 150 or 300 mg daily and followed for a maximum of 14 months (Part A), with the option to then enter an open-label phase (Part B) investigating vandetanib 100, 150, 200 and 300 mg daily doses. Efficacy was assessed in Part A, and safety and tolerability during Parts A and B up to 2 years post randomization. Eighty-one patients were randomized in Part A and 61 patients entered Part B, of whom 37 (60.7%) received 2 years of treatment. Overall, 25% of patients experienced an objective response (OR) at 14 months (OR rate, 0.29 (95% CI, 0.176-0.445) for 300 mg, and 0.20 (95% CI, 0.105-0.348) for 150 mg; one-sided P value approximately 0.43). The most common adverse events (AEs) included diarrhea, hypocalcemia, asthenia, QTc prolongation, hypokalemia and keratopathy, all at generally higher incidence with 300 vs 150 mg (Part A). Part B safety and tolerability was consistent with Part A. OR was observed with both vandetanib doses; the 300 mg dose showed a more favorable trend vs 150 mg as initial dose. Thus, for most patients, 300 mg vandetanib is the most appropriate starting dose; dose reductions to manage AEs and lower initial doses for patients with particular comorbidities can be considered.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Neuroendocrine; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms; Young Adult

Cutaneous immune-related adverse events (irAEs) are a known consequence of immune checkpoint inhibitor (ICI) therapy and may exhibit a spectrum of morphologic features both clinically and histologically. Lichenoid dermatitis associated with ICI therapy (LD-ICI) is the most frequently encountered histopathologic type of irAE biopsied by dermatologists. There is frequent clinical and histologic overlap between irAEs and several reactive and neoplastic dermatologic disorders; thus, clinical information is essential. LD-ICI with histologic, immunohistochemical, and molecular features typical of mycosis fungoides (MF) are unique. Here, we report a patient who developed LD-ICI with MF-like morphologic features with monoclonal T-cell receptor gene rearrangement on consecutive biopsies during ICI therapy. The development of monoclonal LD-ICI is important for clinicians and pathologists to recognize in patients receiving ICI therapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Drug Eruptions; Humans; Lichenoid Eruptions; Male; Piperidines; Skin; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Vemurafenib

Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.. Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.. LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.. These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Topics: Adult; Brain Neoplasms; Carbazoles; Carcinoma, Neuroendocrine; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Oncogene Proteins, Fusion; Piperidines; Proof of Concept Study; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Thyroid Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

In a phase III trial, Western patients with medullary thyroid cancer (MTC) treated with the oral multikinase inhibitor vandetanib showed significantly improved progression-free survival (PFS) and objective response rate (ORR) compared with placebo. The biology of MTC and pharmacokinetics (PK) are similar for Japanese and Western patients; therefore, similar clinical benefit is anticipated in the Japanese population. This study evaluated the safety and tolerability of vandetanib in Japanese patients with unresectable locally advanced or metastatic MTC.. This was a phase I/II, open-label, nonrandomized study. Patients received vandetanib (300 mg daily) until objective disease progression. The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and PK. Final data analysis was conducted once all patients with measurable baseline disease had been followed to progression, or for 56 weeks.. Fourteen patients received vandetanib. All patients experienced at least one adverse event (AE), and 7 patients (50%) experienced grade ≥3 AEs. Common AEs included diarrhea (79%), hypertension (64%), and rash (43%). Four patients reported a total of five serious AEs (SAEs). Eleven patients (79%) had dose interruptions, and 8 patients (57%) had dose reductions. One patient discontinued treatment because of an SAE (interstitial lung disease). No patients met the prespecified criterion for QTc prolongation. The ORR was 38% and PFS at 12 months was 85%.. Safety and efficacy data were comparable to those previously reported, and AEs were generally manageable by standard clinical practice or dose modifications. Overall, vandetanib was considered to be beneficial for Japanese MTC patients.. AE = adverse event CI = confidence interval C

Topics: Adult; Aged; Antineoplastic Agents; Asian People; Carcinoma, Neuroendocrine; Disease-Free Survival; ErbB Receptors; Female; Humans; Male; Middle Aged; Piperidines; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Novel targeted agents have been increasingly developed and tested in clinical trials over the past 5-10 years, many with unknown and unanticipated side effects. We describe here a case of a patient with a history of metastatic follicular thyroid carcinoma that we believe developed vandetanib-associated photoallergic dermatitis while enrolled on a phase 1 clinical trial.. A 51-year-old Caucasian female with poorly differentiated, metastatic follicular thyroid carcinoma presented with a cutaneous eruption that developed over 3 to 4 days while treated on phase 1 clinical trial with vandetanib-based therapy. Given the concern for photoallergic dermatitis, vandetanib was discontinued and supportive care provided including topical and oral steroid administration. Her cutaneous eruption improved and she was successfully re-challenged with vandetanib.. Tyrosine kinase inhibitors, such as typo-vandetinib, with various therapeutic targets have come to the forefront of oncologic therapy in recent years. It is important to have a better understanding of the side effect profile and management in order to anticipate adverse events and maintain patient safety in future clinical trials.

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dermatitis, Photoallergic; Everolimus; Female; Humans; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Thyroid Neoplasms

This study was designed to investigate whether stepwise tapering of remifentanil at the end of surgery could decrease postoperative pain scores and requirements of rescue analgesics after remifentanil-desflurane anesthesia in patients with thyroidectomy.. Sixty two patients undergoing thyroidectomy under general anesthesia were randomly allocated into two groups. All patients were anesthetised with desflurane and high-dose remifentanil. Remifentnail was infused at the rate of 0.3 μg/kg/min until the end of surgery in patients of the control group (group A) whereas remifentanil was tapered gradually from 0.3 to 0.1 μg/kg/min until the end of surgery for at least 30 minutes in patients with group B. Pain scores (0-100 numerical rating scale, NRS), rescue analgesic requirements and adverse events were assessed at 30 min, 2 h, 6 h, 12 h, and 24 h after operation.. There was a significant decrease in pain scores at 30 min (20 [0-80] vs. 50 [0-100], P = 0.002) and 2 h (30 [10-60] vs. 40 [20-80], P = 0.018) after surgery in group B compared with group A. In addition, rescue analgesics are less required in group B than in group A postoperatively (2 [1-3] vs. 3 [2,3], P = 0.039). There were no significant differences in adverse events between the two groups.. Tapering of remifentanil at the end of surgery decreased postoperative pain scores immediately after thyroidectomy with desflurane and high-dose remifentanil anesthesia.. Clinical Research information Service (CRiS, registration number KCT0000589).

Topics: Adult; Aged; Analgesics; Anesthesia Recovery Period; Anesthetics, Combined; Anesthetics, Inhalation; Anesthetics, Intravenous; Desflurane; Female; Humans; Infusions, Intravenous; Isoflurane; Male; Middle Aged; Pain Measurement; Pain, Postoperative; Piperidines; Prospective Studies; Remifentanil; Single-Blind Method; Thyroid Neoplasms; Thyroid Nodule; Thyroidectomy; Young Adult

To investigate whether the type of anesthetic agent administered affects the antitussive effect of remifentanil.. Prospective randomized study.. Operating room of a university hospital.. 78 ASA physical status 1 and 2 women, aged 20 to 65 years, who were scheduled to undergo a thyroidectomy.. Patients were randomly assigned to three groups to receive anesthesia with propofol (Group P), sevoflurane (Group S), or desflurane (Group D). The main anesthetics were titrated to maintain a target Bispectral Index for hypnosis of 40 to 60. Remifentanil was administered via effect-site target-controlled infusion (TCI). To determine the effective remifentanil effect-site concentration (Ce) to suppress coughing in each group, the up-and-down sequential allocation design was used.. The half maximal effective concentration (EC50) values of remifentanil for preventing coughing in the groups were estimated using isotonic regression and compared among the groups.. The EC50 of remifentanil for cough suppression in Group P [1.60 ng/mL (98.3% CI, 0.92-1.75 ng/mL)] was statistically lower than in Group D [1.96 ng/mL (98.3% CI, 1.81-2.50 ng/mL)]. The EC50 in Group S was 1.75 ng/mL (98.3% CI, 1.39-2.13 ng/mL), which was higher than in Group P and lower than in Group D, but did not differ significantly from either group.. Remifentanil administration for cough suppression during emergence should be customized to the anesthetic agent.

Topics: Adult; Aged; Anesthesia Recovery Period; Anesthetics, General; Antitussive Agents; Cough; Desflurane; Female; Humans; Intubation, Intratracheal; Isoflurane; Methyl Ethers; Middle Aged; Piperidines; Postoperative Complications; Propofol; Prospective Studies; Remifentanil; Sevoflurane; Thyroid Neoplasms; Thyroidectomy; Young Adult

Vandetanib was approved by the U.S. Food and Drug Association for the treatment of advanced medullary thyroid cancer (MTC). Because body weight (BW) loss is observed in MTC and because low skeletal muscle mass (SM) is associated with drug toxicity, this study assessed effects of vandetanib on SM and adipose tissue (AT) and explored the association between SM, toxicity, and serum concentration of vandetanib.. Thirty-three patients with MTC received vandetanib (n = 23) or placebo (n = 10) in the ZETA study. Visceral AT (VAT), sc AT (SAT), and SM were assessed with computed tomography imaging by measuring tissue cross-sectional areas (square centimers per square meter). Dose-limiting toxicities (DLTs) were prospectively recorded.. Early at 3 months, compared with placebo group who lost BW, muscle, and SAT, patients treated with vandetanib gained 1.5 kg BW (P = 0.02), 1.3 cm(2)/m(2) (∼0.7 kg) of SM (P = 0.009), and 4.5 cm(2)/m(2) (∼0.5 kg) of SAT (P = 0.004) and gained more VAT, 5.1 cm(2)/m(2) (∼0.7 kg) (P = 0.02). Patients with DLT had lower SM index (37.2 vs 44.3 cm(2)/m(2), P = 0.003) and a higher vandetanib serum concentration (1091 vs 739 ng/mL, P = 0.03). Patients with SM index <43.1 cm(2)/m(2) had a higher probability of DLT (73% vs 14%, P = 0.004) and a higher vandetanib serum concentration (1037 vs 745 ng/mL, P = 0.04). Patients with the highest compared with the intermediate and lower levels of vandetanib serum concentration experienced more DLT, respectively, 78% vs 40% vs 20% (P = 0.04).. Muscle and adipose tissues are restored after only 3 months of vandetanib treatment. Patients with low muscle mass had high vandetanib serum concentration and high incidence of toxicities.

Topics: Adult; Aged; Body Composition; Carcinoma, Neuroendocrine; Cross-Over Studies; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC.. We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit.. Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects.. Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

Topics: Adolescent; Carcinoma, Medullary; Carcinoma, Neuroendocrine; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Gene Expression Regulation, Neoplastic; Germ-Line Mutation; Humans; Multiple Endocrine Neoplasia Type 2b; Neoplasm Metastasis; Neoplasm Recurrence, Local; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms

Targeted biologic agents showed clinically meaningful efficacy as front-line therapy for advanced radioiodine-refractory and medullary thyroid cancer. The clinical benefit of these agents beyond the front line has yet to be established.. We assessed the clinical benefit of targeted agents in patients with advanced differentiated and medullary thyroid cancer treated at a single academic cancer center. We determined efficacy and compared front-line and second-line benefit using biochemical and anatomic response, time to treatment failure, and progression-free survival (PFS). Statistical differences were assessed by t test and chi-square test. Survival curves were generated by the Kaplan-Meier method. Differences in survival were assessed using the log-rank test, and a p value <.05 was considered significant.. We identified 39 patients with advanced differentiated and medullary thyroid cancer treated with targeted biologic agents. Median age was 56.3 years. Overall, 25 men and 14 women participated. Histology showed 23% medullary and 77% differentiated cancer. Nineteen patients progressed on front-line therapy and subsequently received second-line therapy. Targeted agents conferred clinically meaningful benefit in the second-line setting in terms of biochemical response (13.3%), clinical benefit (83.3%), median time to treatment failure (4.0 months; 95% confidence interval: 2.6-8.2), and median PFS (4.6 months; 95% confidence interval: 3.2-8.2). Second-line benefit (median PFS) was more modest in comparison to the front-line setting in both genders (women: 3 months vs. 12.2 months; men: 6 months vs. 19.7 months), in differentiated cancers (4.1 months vs. 15.7 months), and with vascular targeting agents (4.4 months vs. 20.1 months).. Patients with advanced thyroid cancer derived meaningful clinical benefit from additional therapy with a biologic agent following disease progression on front-line targeted therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Disease-Free Survival; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Piperidines; Quinazolines; Retrospective Studies; Sirolimus; Sorafenib; Thyroid Neoplasms; Treatment Outcome

There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC.. Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments.. Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%).. Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).

Topics: Carcinoma, Neuroendocrine; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Piperidines; Placebos; Quinazolines; Thyroid Neoplasms

On April 6, 2011, the U.S. Food and Drug Administration approved vandetanib (Caprelsa tablets; AstraZeneca Pharmaceuticals LP) for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. Vandetanib is the first drug approved for this indication, and this article focuses on the basis of approval. Approval was based on the results of a double-blind trial conducted in patients with medullary thyroid carcinoma. Patients were randomized 2:1 to vandetanib, 300 mg/d orally (n = 231), or to placebo (n = 100). The primary objective was demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Other endpoints included evaluation of overall survival and objective response rate. The PFS analysis showed a marked improvement for patients randomized to vandetanib (hazard ratio = 0.35; 95% confidence interval, 0.24-0.53; P < 0.0001). The objective response rate for the vandetanib arm was 44% compared with 1% for the placebo arm. The most common grade 3 and 4 toxicities (>5%) were diarrhea and/or colitis, hypertension and hypertensive crisis, fatigue, hypocalcemia, rash, and corrected QT interval (QTc) prolongation. This approval was based on a statistically significant and clinically meaningful improvement in PFS. Given the toxicity profile, which includes prolongation of the QT interval and sudden death, only prescribers and pharmacies certified through the vandetanib Risk Evaluation Mitigation Strategy Program are able to prescribe and dispense vandetanib. Treatment-related risks should be taken into account when considering the use of vandetanib in patients with indolent, asymptomatic, or slowly progressing disease.

Topics: Carcinoma, Neuroendocrine; Disease-Free Survival; Drug Approval; Humans; Piperidines; Quinazolines; Thyroid Neoplasms; United States; United States Food and Drug Administration

No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting.. In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095.. Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group).. Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted.. AstraZeneca.

Topics: Adenocarcinoma, Follicular; Adolescent; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Papillary; Diarrhea; Disease-Free Survival; Double-Blind Method; Electrocardiography; ErbB Receptors; Female; Heart Conduction System; Humans; Kaplan-Meier Estimate; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Skin Neoplasms; Survival Analysis; Thyroid Cancer, Papillary; Thyroid Neoplasms; Young Adult

Topics: Adult; Aged; Aged, 80 and over; Female; Folliculitis; Hand-Foot Syndrome; Humans; Hyperpigmentation; Male; Middle Aged; Photosensitivity Disorders; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

The purpose of the study was to assess the endocrine effects of vandetanib, a multikinase inhibitor targeting RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor, in 39 patients with progressive thyroid cancer included in two randomized placebo-controlled trials using vandetanib 300 mg/d.. Endocrine samplings were performed at baseline and then every 6 months. We compared differences in endocrine parameters between baseline and on vandetanib therapy or placebo.. During vandetanib treatment, several changes were observed. 1) Calcium (P = 0.0004) and vitamin D (P = 0.001) mean replacement doses were increased; calcium level remained unchanged, but serum 25(OH) vitamin D level decreased (P = 0.001); and serum PTH (P = 0.01) and 1,25(OH)(2) vitamin D (P = 0.01) levels increased, suggesting a decreased intestinal absorption of vitamin D or lack of sun exposure as a result of photosensitization. 2) l-T(4) doses were increased (P < 0.0001) to maintain serum TSH within the normal range. 3) In male patients, total testosterone (P = 0.048), bioavailable testosterone (P = 0.03), and SHBG (P = 0.02) levels increased. Serum inhibin B decreased (P = 0.02) and stimulated FSH increased (P = 0.006), suggesting a Sertoli cells insufficiency. 4) Cortisol level increased (P = 0.007) as well as ACTH level (P = 0.03) and cortisol-binding globulin (P = 0.02), but free urinary cortisol levels remained in the normal range. None of these changes were observed in patients randomized to the placebo arm.. In patients with locally advanced or metastatic thyroid cancer, the tyrosine kinase inhibitor vandetanib has several endocrine effects. Thyroid hormone, calcium, and vitamin D analog requirements increased, but consequences of the biological alterations on phosphocalcic metabolism and gonadotrope and adrenal functions are unknown.

Topics: Adenocarcinoma, Follicular; Adenocarcinoma, Papillary; Adult; Aged; Aged, 80 and over; Blood Glucose; Calcium; Cross-Over Studies; Enzyme Inhibitors; ErbB Receptors; Female; Humans; Male; Middle Aged; Parathyroid Hormone; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Testosterone; Thyroid Neoplasms; Treatment Outcome; Vitamin D

PURPOSE There is no effective therapy for patients with distant metastasis of medullary thyroid carcinoma (MTC). Activating mutations in the RET proto-oncogene cause hereditary MTC, which provides a strong therapeutic rationale for targeting RET kinase activity. This open-label, phase II study assessed the efficacy of vandetanib, a selective oral inhibitor of RET, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, in patients with advanced hereditary MTC. METHODS Patients with unresectable locally advanced or metastatic hereditary MTC received initial treatment with once-daily oral vandetanib 300 mg. The dose was adjusted additionally in some patients on the basis of observed toxicity until disease progression or any other withdrawal criterion was met. The primary assessment was objective tumor response (by RECIST [Response Evaluation Criteria in Solid Tumors]). Results Thirty patients received initial treatment with vandetanib 300 mg/d. On the basis of investigator assessments, 20% of patients (ie, six of 30 patients) experienced a confirmed partial response (median duration of response at data cutoff, 10.2 months). An additional 53% of patients (ie, 16 of 30 patients) experienced stable disease at >/= 24 weeks, which yielded a disease control rate of 73% (ie, 22 of 30 patients). In 24 patients, serum calcitonin levels showed a 50% or greater decrease from baseline that was maintained for at least 4 weeks; 16 patients showed a similar reduction in serum carcinoembryonic antigen levels. The most common adverse events were diarrhea (70%), rash (67%), fatigue (63%), and nausea (63%). CONCLUSION In this study, vandetanib demonstrated durable objective partial responses and disease control with a manageable adverse event profile. These results demonstrate that vandetanib may provide an effective therapeutic option in patients with advanced hereditary MTC, a rare disease for which there has been no effective therapy.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Medullary; Disease-Free Survival; Drug Administration Schedule; Female; France; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pedigree; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Quinazolines; Risk Factors; Thyroid Neoplasms; Time Factors; Treatment Outcome; United States; Young Adult

Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor tyrosine kinases that also inhibits rearranged during transfection kinase activity. Vandetanib (300 mg/d) has previously demonstrated antitumor activity in patients with advanced hereditary medullary thyroid cancer (MTC). This study investigated the efficacy and safety of 100 mg/d vandetanib in patients with advanced hereditary MTC.. Eligible patients with unresectable, measurable, locally advanced, or metastatic hereditary MTC received 100 mg/d vandetanib. Upon disease progression, eligible patients could enter postprogression treatment with 300 mg/d vandetanib until a withdrawal criterion was met. The primary objective was to assess the objective response rate by response evaluation criteria in solid tumors.. The study comprised 19 patients (13 males, six females; mean age 45 yr). Confirmed objective partial responses were observed in three patients, yielding an objective response rate of 16% (95% confidence interval 3.4-39.6). Stable disease lasting 24 wk or longer was reported in a further 10 patients (53%); the disease control rate was therefore 68% (95% confidence interval 43.4-87.4). Serum levels of calcitonin and carcinoembryonic antigen showed a sustained 50% or greater decrease from baseline in 16% (three of 19) and 5% (one of 19) of patients, respectively. Adverse events were predominantly grade 1 or 2 and consistent with previous vandetanib monotherapy studies.. Vandetanib at a once-daily dose of 100 mg has clinically relevant antitumor activity in patients with locally advanced or metastatic hereditary MTC and an overall acceptable safety profile.

Topics: Adult; Aged; Antineoplastic Agents; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Medullary; Codon; Double-Blind Method; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms; Tomography, X-Ray Computed; Young Adult

MTC has varying clinical course. In cases with metastatic disease (meta-MTC) further therapeutic modalities (locoregional and/or Tyrosine-Kinase-Inhibitors, TKIs) are needed. Clinical features, disease progression, response to therapy and possible factors predisposing to TKIs response-resistance in meta-MTCs were investigated.. Out of 338 MTC patients 54 had meta-MTC and were followed for 0.7-46 years (median 10.5); therapeutic interventions and response to therapy were recorded retrospectively.. Of 54 meta-MTC patients, 34/54 were men, 44/54 sporadic (age-at-diagnosis 47 ± 17.4 years, range: 5-78). Distant metastases at diagnosis were present in 12/54 (≥2 loci in 8/12), 7/12 received TKIs; During follow-up metastases occurred in 42/54 (within 0.6-25 years from diagnosis, median 5 yrs). Locoregional therapies were administered to 44/54 (81.5%) and TKIs to 40/54 (74.1%). Vandetanib was administered in 30 patients (24 as first-line therapy). The median progression-free-survival, PFS) was 48 months (range 4-120), partial response (PR): 26.7%, stable disease (SD): 23.3%, progressive disease (PD): 50.0%, cancer-specific survival: 44.8%, (16 in ongoing-therapy). More favorable disease course was recorded in familial-MTC compared to sporadic (p = 0.02) and in those patients with serious-adverse-events (SAEs) under treatment (p = 0.027). Those with biochemical progression under vandetanib, later showed more frequently structural progression (p = 0.007). Ten patients received cabozantinib (8/10 as second-line therapy, median PFS:11 months (3-36 months), 8/10 died). Three RET-mutant patients received selpercatinib; all showed PR. Within the total follow-up period, the response to therapy was: PR: 8/54 (14.8%), SD: 15/54 (27.8%), PD: 31/54 (57.4%), cancer-specific survival 46.3%. Mortality was higher in older patients (≥60 years) compared to younger ones (<60 yrs) (83.3 vs 45.2%, p = 0.021). Outcome was better in familial-MTC vs sporadic (PR: 50 vs 6.8%, SD: 20 vs 29.5%, PD: 30 vs 59.1%, p = 0.007).. Meta-MTCs treatment results in disease stabilization in 42.6% during a median 10.5 year follow-up. Combination of locoregional and systemic therapies may result in more favorable PFS. Family history, younger age, SAEs may predict better response; biochemical escape under TKI needs to be followed-up closely as it may indicate disease progression.

Topics: Adolescent; Adult; Aged; Carcinoma, Neuroendocrine; Child; Child, Preschool; Disease Progression; Drug Resistance; Female; Humans; Male; Middle Aged; Piperidines; Retrospective Studies; Thyroid Neoplasms; Young Adult

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.

Topics: Apoptosis Regulatory Proteins; Biomarkers; Humans; MicroRNAs; Piperidines; Prognosis; RNA-Binding Proteins; RNA, Messenger; Thyroid Neoplasms

Not required for Clinical Vignette.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Humans; Piperidines; Quinazolines; Thyroid Neoplasms

Tyrosine kinase inhibitors have been a breakthrough in the treatment of advanced medullary thyroid cancer (MTC), and they can prolong progression-free survival (PFS).. A patient with MTC and metastatic spread to the lymph nodes, lungs, bones, breast, and cerebellum started treatment with vandetanib. During treatment, she developed secondary adrenal insufficiency and hypogonadotropic hypogonadism. After 9 years of vandetanib therapy, the disease has not progressed and the patient maintains a complete response of the breast metastases and a partial response of the other metastatic lesions.. To our knowledge, this is the first reported case of secondary adrenal insufficiency and hypogonadotropic hypogonadism related to therapy with vandetanib. Moreover, the prolonged PFS and the complete disappearance of some of the metastatic lesions in this patient are truly unusual.

Topics: Carcinoma, Neuroendocrine; Female; Humans; Hypopituitarism; Piperidines; Quinazolines; Thyroid Neoplasms

Topics: Anilides; Antineoplastic Agents; Carcinoma, Medullary; Drug Approval; Humans; Mutation; Phenylurea Compounds; Piperidines; Precision Medicine; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Quinazolines; Quinolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

The tyrosine kinase inhibitors (TKI) vandetanib and cabozantinib are approved as targeted therapies in advanced medullary thyroid carcinoma (MTC) with symptoms or high tumour burden. Only recently, toxicity in long-time TKI usage was analysed. However, little is known about the impact of TKI discontinuation on MTC disease course after longer-term therapy. Here, we report our experience in a series of 7 MTC patients with vandetanib treatment of up to 87 months followed by discontinuation for concerns of toxicity or due to side-effects. The discontinuation of TKI therapy is a relevant clinical scenario. To our knowledge we present the largest single center series on an important aspect of TKI management.. Retrospective analysis of MTC patients with continued discontinuation of vandetanib treatment in a tertiary referral endocrine tumour centre. Analysis included a review of patients' records for TKI indication, and treatment response as well indications for continued TKI discontinuation and follow-up by clinical assessment, calcitonin and CEA doubling times as well as imaging (ultrasound, CT).. Seven MTC patients [6 sporadic MTC, 1 Multiple Endocrine Neplasie Type 2a (MEN2a)] with previous vandetanib treatment (median: 41 months; range 7-87 months) and continued TKI discontinuation were identified out of 161 analysed MTC files. TKI treatment was initiated due to high tumour burden and symptoms or RECIST (Response Evaluation Criteria In Solid Tumors) progression in all patients. Two patients (29%) remained stable after discontinuation of vandetanib until now (follow-up of 47 and 61 months). Both patients had been on TKI therapy for 73 and 58 months. Five patients (71%) developed progressive disease after TKI discontinuation. In 2 patients, vandetanib was restarted after 45 and 52 months resulting again in disease control. One patient was enrolled in a new RET kinase inhibitor trial after 45 months of vandetanib discontinuation. Two patients declined restart of treatment due to mental health issues leading to discontinuation of vandetanib in the first place (after 7 and 38 months of treatment) and both patients died of rapidly progressive disease. At time points of tumour progression, calcitonin-doubling time (CDT) was < 2 years in all patients.. This case series suggests that discontinuation of long-term vandetanib treatment with documented stable disease does not automatically result in rapid disease progression but may be followed by prolonged "TKI free" stable disease in individual patients. Analysis of calcitonin and CDT during discontinuation is indicated as it will unmask tumour progression earlier than imaging. Restart with the same TKI is possible in case of progression.

Topics: Adult; Carcinoma, Neuroendocrine; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperidines; Prognosis; Protein Kinase Inhibitors; Quinazolines; Retrospective Studies; Thyroid Neoplasms; Withholding Treatment; Young Adult

Medullary thyroid cancer (MTC) is infrequently found among all thyroid nodules in previously iodine deficient regions. Measurement of serum calcitonin is an important tool for early identification of MTC among the large number of thyroid nodules. With the use of modern laboratory assays and sex-specific reference intervals, clinical diagnostic specificity has considerably improved. While the prognosis of MTC confined to the thyroid (stage I/II tumors) is favorable with a disease specific survival similar to the general population, biochemical cure rates by surgery decreases in extensive disease. Few patients present with aggressive tumours that show rapid progression or advanced disease at diagnosis. Oncogenic mutations in the RET protooncogene occur in ~25 % of patients as part of the multiple endocrine neoplasia type 2 syndromes and are present as somatic mutations in 60 % of all MTC and up to 90 % of metastatic cases.The multi-tyrosine kinase inhibitors vandetanib and cabozantinib have been approved for progressive advanced disease but have low specificity for the RET tyrosine kinase. With the advent of highly selective RET inhibitors selpercatinib and pralsetinib, the treatment landscape has profoundly changed. Selpercatinib is approved in the EU for treatment in the second and later lines of treatment. They have demonstrated a favorable safety profile and high objective response rates also in previously treated MTC patients. The use of selective RET inhibitors in the first line setting is currently the subject of clinical trials.. Calcitonin ist ein sensitiver und spezifischer Tumormarker zur Früherkennung und Verlaufskontrolle des MTC. Daneben kommt dem Ultraschall der Schilddrüse eine entscheidende Rolle zu.. Das medulläre Schilddrüsenkarzinom (MTC) nimmt seinen Ursprung aus den parafollikulären Calcitonin-produzierenden C-Zellen. Es macht nur ca. 3–8 % aller Schilddrüsenkarzinome aus. Aktivierende Mutationen im RET (rearranged during transfection)-Gen liegen bei etwa 25 % der Patienten in der Keimbahn vor, werden aber auch beim sporadischen MTC als somatische Mutationen in ca. 60 % der Fälle beobachtet. Bei metastasierter Erkrankung findet sich in 90 % eine RET-Mutation. RET-Mutationen gelten als Treibermutationen und schließen weitere Treibermutationen weitestgehend aus. Seltener sind somatische Mutationen der RAS-Gene.. Die chirurgische Resektion ist bis heute der einzige kurative Therapieansatz. Entscheidend für eine frühzeitige Diagnosestellung ist die Bestimmung des Serum-Calcitonins bei Nachweis von Schilddrüsenknoten. Die chirurgische Therapie steht auch bei der Behandlung lokoregionärer Rezidive oder lokal angehbarer Metastasen im Zentrum.. Bei irresektabel fortgeschrittener und progredienter Erkrankung mit signifikanter Tumorlast kann eine systemische Therapie erforderlich werden. Neuerdings ist die Kenntnis einer RET-Mutation im Tumorgewebe therapeutisch relevant, da mit den selektiven RET-Inhibitoren Selpercatinib und zukünftig Pralsetinib neue, effektive und gut verträgliche Systemtherapien zur Verfügung stehen. Ihr Einsatz ist nach Vortherapie mit einem der Multityrosinkinase-Inhibitoren Vandetanib oder Cabozantinib zugelassen und wird derzeit in der Erstlinientherapie in klinischen Studien untersucht.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Humans; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms

Few cases of immunoallergic tubulointerstitial nephritis associated with tyrosine kinase inhibitors have been described. We describe the first report case associated with vandetanib, a tyrosine kinase inhibitor indicated for the treatment of aggressive and symptomatic medullary thyroid cancer (CMT) in patients with locally advanced or metastatic non-resectable disease.

Topics: Aged; Humans; Male; Nephritis, Interstitial; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

Cases of neurofibromatosis type 1 (

Topics: Adolescent; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Germ-Line Mutation; Homozygote; Humans; Male; Neurofibromatosis 1; Neurofibromin 1; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Female; Germany; Humans; Male; Middle Aged; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyridines; Quinazolines; Registries; Retrospective Studies; Thyroid Neoplasms; Time Factors; Young Adult

Medullary thyroid carcinoma (MTC) is a tumor deriving from the thyroid C cells. Vandetanib (VAN) and cabozantinib (CAB) are two tyrosine kinase inhibitors targeting REarranged during Transfection (RET) and other kinase receptors and are approved for the treatment of advanced MTC. We aim to compare the in vitro and in vivo anti-tumor activity of VAN and CAB in MTC. The effects of VAN and CAB on viability, cell cycle, and apoptosis of TT and MZ-CRC-1 cells are evaluated in vitro using an MTT assay, DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, respectively. In vivo, the anti-angiogenic potential of VAN and CAB is evaluated in

Topics: Angiogenesis Inhibitors; Anilides; Animals; Apoptosis; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Embryo, Nonmammalian; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms; Zebrafish

Vandetanib is an important treatment option for advanced metastatic medullary thyroid cancer. The aims of this study were to evaluate the predictors of both a longer response to vandetanib and the outcome. Medical records of 79 medullary thyroid cancer patients treated with vandetanib at our center were analysed. Twenty-five patients were treated for <12 months, 54 were treated for ≥12 months and 24 of these latter were treated for ≥48 months (short-, long- and very long-term). The median progression free survival of the long and very long-term treated patients was significantly longer than in the ZETA trial. When comparing the groups of short - and long-term treated patients the only significant difference was that these latter were less frequently previously treated with a tyrosine kinase inhibitor. However, the long-term treated patients had a younger age, both at diagnosis and enrolment, which was statistically significant in the very long-term treated patients. In the long-term treated group, younger age, enrolment for symptoms and development of adverse events were significantly correlated with a better outcome. The enrolment for symptoms remained the only statistically significant predictor of a good outcome in the very long-term treated patients. In conclusion, early treatment with vandetanib, when patients are younger, with a good ECOG performance status and symptomatic disease, not necessarily progressing for RECIST, seem to be the best predictors of a longer and durable response. Further studies are needed to confirm these results

Topics: Adolescent; Adult; Aged; Carcinoma, Neuroendocrine; Female; Humans; Male; Middle Aged; Piperidines; Quinazolines; Thyroid Neoplasms; Young Adult

Medullary thyroid cancer (MTC) is the third most common thyroid cancer.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Female; Gene Silencing; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Mutation; Piperidines; Proto-Oncogene Proteins c-ret; Quinazolines; Signal Transduction; Thyroid Neoplasms; Transcription Factors; Xenograft Model Antitumor Assays; YAP-Signaling Proteins

Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.

Topics: Anilides; Animals; Carcinoma, Neuroendocrine; Chemoradiotherapy; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Piperidines; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms; Xenograft Model Antitumor Assays

We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients.. Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated.. Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64;. Vandetanib demonstrated clinical benefit-specifically, increased PFS-in patients with symptomatic and progressive MTC.

Topics: Adult; Carcinoma, Neuroendocrine; Disease Progression; Female; Humans; Male; Middle Aged; Piperidines; Quinazolines; Survival Analysis; Thyroid Neoplasms

Anaplastic thyroid cancer (ATC) is a rare, but nearly uniformly fatal disease that is typically resistant to chemotherapy and radiation. Alternative strategies to target this cancer at a molecular level are necessary in order to improve dismal outcomes for ATC patients. We examined the effects of flavopiridol, a CDK inhibitor, in a panel of ATC cell lines. When cell lines were treated over a ten-point concentration range, CAL62, KMH2 and BHT-101 cell lines had a sub micromolar half-maximal inhibitory concentration, while no effect was seen in the non-cancerous cell line IMR-90. Flavopiridol treatment resulted in decreased levels of the cell cycle proteins CDK9 and MCL1, and induced cell cycle arrest. Flavopiridol also decreased the in vitro ability of ATC cells to form colonies and impeded migration using a transwell migration assay. In vivo, flavopiridol decreased tumor weight and tumor volume over time in a patient-derived xenograft model of ATC. Given the observed in vitro and in vivo activity, flavopiridol warrants further investigation for treatment of ATC.

Topics: Animals; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin-Dependent Kinase 9; Flavonoids; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Piperidines; Protein Kinase Inhibitors; RNA Interference; RNA, Small Interfering; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transplantation, Heterologous

Vandetanib is the most widely used tyrosine kinase inhibitor for the treatment of patients with advanced medullary thyroid cancer (MTC). However, only limited data regarding its use outside clinical trials are available. We aimed to evaluate the efficacy and safety of vandetanib in patients with advanced MTC in routine clinical practice.. In this multicenter retrospective study, 12 patients with locally advanced or metastatic MTC treated with vandetanib at four tertiary hospitals were included. The primary outcome was the objective response rate (ORR) based on the Response Evaluation Criteria in Solid Tumors. The progression-free survival (PFS), overall survival (OS), and toxicities were also evaluated.. Eleven patients (92%) had distant metastasis and 10 (83%) had disease progression at enrollment. Partial response was observed in five patients (ORR, 42%) and stable disease lasting ≥24 weeks was reported in an additional five patients (83%). During the median 31.7 months of follow-up, disease progression was seen in five patients (42%); of these, two died due to disease progression. The median PFS was 25.9 months, while the median OS was not reached. All patients experienced adverse events (AEs) which were generally consistent with the known safety profile of vandetanib. Vandetanib was discontinued in two patients due to skin toxicity.. Consistent with the phase III trial, this study confirmed the efficacy of vandetanib for advanced MTC in terms of both ORR and PFS in the real-world setting. Vandetanib was well tolerated in the majority of patients, and there were no fatal AEs.

Topics: Carcinoma, Neuroendocrine; Disease-Free Survival; Female; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Quinazolines; Republic of Korea; Retrospective Studies; Thyroid Neoplasms

Thyroid cancer is becoming increasingly common worldwide, but little is known about the epidemiology of medullary thyroid carcinoma (MTC). This study investigated the current status of the incidence and treatment of MTC using Korean National Health Insurance Service (NHIS) data for the entire Korean population from 2004 to 2016.. This study included 1,790 MTC patients identified from the NHIS database.. The age-standardized incidence rate showed a slightly decreasing or stationary trend during the period, from 0.25 per 100,000 persons in 2004 to 0.19 in 2016. The average proportion of MTC among all thyroid cancers was 0.5%. For initial surgical treatment, 65.4% of patients underwent total thyroidectomy. After surgery, external-beam radiation therapy (EBRT) was performed in 10% of patients, a proportion that increased from 6.7% in 2004 to 11.0% in 2016. Reoperations were performed in 2.7% of patients (n=49) at a median of 1.9 years of follow-up (interquartile range, 1.2 to 3.4). Since November 2015, 25 (1.4%) patients with MTC were prescribed vandetanib by December 2016.. The incidence of MTC decreased slightly with time, and the proportion of patients who underwent total thyroidectomy was about 65%. EBRT, reoperation, and tyrosine kinase inhibitor therapy are additional treatments after initial surgery for advanced MTC in Korea.

Topics: Adolescent; Adult; Age Distribution; Aged; Aged, 80 and over; Carcinoma, Neuroendocrine; Child; Child, Preschool; Databases, Factual; Disease-Free Survival; Female; Forecasting; Humans; Infant; Infant, Newborn; Male; Middle Aged; National Health Programs; Piperidines; Quinazolines; Radiotherapy; Reoperation; Republic of Korea; Retrospective Studies; Sex Distribution; Thyroid Neoplasms; Thyroidectomy; Young Adult

Aloperine, an alkaloid isolated from

Topics: Autophagic Cell Death; Cell Cycle Checkpoints; Cell Line, Tumor; Humans; MAP Kinase Signaling System; Neoplasm Proteins; Piperidines; Quinolizidines; Thyroid Neoplasms

Vandetanib has been shown to improve progression-free survival in adults with advanced medullary thyroid cancer. This article describes a pediatric patient with metastatic medullary thyroid cancer secondary to sporadic multiple endocrine neoplasia 2B, treated with vandetanib. At presentation, he had an inoperable primary tumor, with carotid encasement, and pulmonary metastases. Vandetanib induced a significant response: calcitonin and carcinoembryonic antigen levels both fell considerably, primary tumor maximal diameter decreased by 68%, and pulmonary metastases became no longer detectable. This allowed surgical resection of the primary tumor. The patient remains well after over 6 years of vandetanib therapy, with no treatment toxicity.

Topics: Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Child; Humans; Lung Neoplasms; Male; Piperidines; Quinazolines; Thyroid Neoplasms; Treatment Outcome; Tumor Burden

Two tyrosine kinase inhibitors (TKIs), lenvatinib and vandetanib, are often used to treat advanced radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) and medullary thyroid cancer (MTC), respectively. Fatigue is a common adverse event during treatment with these and other TKIs and a common cause of drug discontinuation or dosage reduction.. We evaluated the basal and stimulated adrenal function in 12 patients with advanced RAI-R DTC and MTC treated with lenvatinib or vandetanib, respectively. Ten patients complaining of fatigue showed a progressive ACTH increase with normal cortisol levels. Moreover, six of 10 patients had a blunted cortisol response after ACTH stimulation, thus confirming the diagnosis of primary adrenal insufficiency (PAI). The causal relationship between TKIs and PAI onset was also demonstrated by the repeated testing of adrenal function before and during treatment. Patients with PAI received cortisone acetate replacement therapy, with a substantial and prompt improvement in the degree of fatigue, as assessed by the Common Terminology Criteria for Adverse Events version 4.03, thus supporting the major impact of impaired adrenal function in the genesis of this adverse event.. We show that the occurrence of PAI may be a common cause of fatigue during lenvatinib and vandetanib treatment, and we therefore recommend testing adrenal function for a prompt start of replacement therapy to avoid treatment discontinuation, dosage reduction, and potentially severe PAI complications.

Topics: Addison Disease; Adult; Aged; Carcinoma, Neuroendocrine; Child; Cortisone; Dose-Response Relationship, Drug; Fatigue; Female; Follow-Up Studies; Humans; Male; Middle Aged; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Thyroid Neoplasms; Treatment Outcome; Young Adult

Tyrosine kinase inhibitors (TKIs) aid in prolonging life in patients with advanced locoregional thyroid malignancy. Such patients may undergo total laryngectomy for local disease control and tracheoesophageal puncture (TEP) for speech rehabilitation. Enlargement of TEP fistulas is usually attributed to wound healing issues and leads to major complications. Four laryngectomies with TEP were performed between 2015 and 2016 and subsequently placed on a TKI. Three patients developed a complication after TKI treatment, and 2 patients had a tracheoesophageal fistula. Patients should be counseled about possible wound healing risks associated with TKIs.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Esophagus; Female; Humans; Laryngectomy; Male; Middle Aged; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Punctures; Quinazolines; Quinolines; Speech Disorders; Surgical Wound; Thyroid Neoplasms; Trachea; Wound Healing

Vandetanib is effective for treating symptomatic or progressive medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease, but its toxicity such as photosensitivity reactions should be considered. It is a rare adverse effect of this drug but might cause severe morbidity and even mortality.. A 26-year man with MTC developed phototoxic rashes on the sun-exposed areas of his shin after 15 days from the initiation of vandetanib treatment. Grade II skin toxicity was evaluated based on the Common Terminology Criteria for Adverse Events standard.. Drug-induced phototoxic rash.. The vandetanib dose was reduced by 30%, and the application of topical steroids and sunscreen was adopted.. After dose reduction of vandetanib, the symptoms of vandetanib-induced phototoxic rash resolved, although residual pigmentation was observed.. Close attention should be paid to the adverse effect of vandetanib, phototoxic rash, and patients should be advised on the prevention and treatment measures.

Topics: Adult; Antineoplastic Agents; Dermatitis, Phototoxic; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

Topics: Adolescent; Carcinoma, Medullary; Child; Disease Progression; Disease-Free Survival; Female; Germ-Line Mutation; Humans; Male; Multiple Endocrine Neoplasia Type 2a; Outcome Assessment, Health Care; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

Topics: Antineoplastic Agents; Apoptosis; Biomarkers; Caspases; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Flow Cytometry; Humans; Piperidines; Proto-Oncogene Proteins c-akt; Quinolizidines; Signal Transduction; Thyroid Neoplasms

Topics: Anilides; Humans; Mitochondria; Piperidines; Pyridines; Quinazolines; Thyroid Neoplasms

Topics: Adult; Carcinoma, Neuroendocrine; Female; Humans; Multiple Endocrine Neoplasia Type 2a; Mutation, Missense; Neoplasm Metastasis; Piperidines; Pregnancy; Quinazolines; Thyroid Neoplasms; Young Adult

The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC‑cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 µM) was tested by WST‑1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose‑dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF‑A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclin D1; Dose-Response Relationship, Drug; ErbB Receptors; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Quinazolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cyclic N-Oxides; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Drug Synergism; Enhancer Elements, Genetic; Gene Expression Regulation, Neoplastic; Humans; Indolizines; Introns; Molecular Targeted Therapy; Oncogene Addiction; Piperazines; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyridines; Pyridinium Compounds; Quinazolines; Thyroid Gland; Thyroid Neoplasms; Tissue Array Analysis; Transcription, Genetic

Topics: Administration, Oral; Carcinoma, Neuroendocrine; Clinical Trials, Phase III as Topic; Europe; Humans; Medical Oncology; Piperidines; Placebos; Practice Guidelines as Topic; Progression-Free Survival; Quinazolines; Randomized Controlled Trials as Topic; Societies, Medical; Thyroid Neoplasms

The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital.. Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment.. During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment.. About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma; Carcinoma, Medullary; Female; Follow-Up Studies; Heart Failure; Humans; Intestinal Perforation; Kaplan-Meier Estimate; Male; Middle Aged; Oophoritis; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Quinolines; Retrospective Studies; Risk Factors; Sorafenib; Thrombocytopenia; Thyroid Neoplasms; Time Factors; Young Adult

Topics: Anilides; Animals; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Membrane Potential, Mitochondrial; Mice; Mitochondria; Mitochondrial Dynamics; Piperidines; Protein Kinase Inhibitors; Pyridines; Quinazolines; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Cabozantinib is an oral multiple tyrosine kinase receptor inhibitor (ITK): VEGFR2, c-MET and RET. Inhibition of VEGFR and c-MET decrease resistance of VEGFR inhibitor via c-MET axis. Cabozantinib improve progression-free survival (PFS) in progressive metastatic medullary thyroid cancer (MTC): 4 months in the placebo group and 11.2 months in the cabozantinib group (P<0.001) in all patient subgroups including those with or without prior ITK and RET mutation status. Cabozantinib increased overall survival (OS) compared with everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR ITK treatment: 21.4 months in cabozantinib group and 16.5 months in everolimus group (P<0.0003). Cabozantinib obtained the AMM for the treatment of progressive metastatic MTC and advanced renal cell carcinoma. Cabozantinib is a new option in the treatment of MTC by inclusion in therapeutic trials (no payment in this indication) and advanced renal cell carcinoma (hospital delivery). Its tolerance is similar to anti-angiogenic therapies and justifies an optimal management of the secondary effect.

Topics: Anilides; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease-Free Survival; Everolimus; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Piperidines; Prostatic Neoplasms; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, which encodes a receptor tyrosine kinase, is often associated with the development of medullary thyroid carcinoma (MTC). The proximal promoter region of the RET gene consists of a guanine-rich sequence containing five runs of three consecutive guanine residues that serve as the binding site for transcriptional factors. As we have recently shown, this stretch of nucleotides in the promoter region is highly dynamic in nature and tend to form non-B DNA secondary structures called G-quadruplexes, which suppress the transcription of the RET gene. In the present study, ellipticine and its derivatives were identified as excellent RET G-quadruplex stabilizing agents. Circular dichroism (CD) spectroscopic studies revealed that the incorporation of a piperidine ring in an ellipticine derivative, NSC311153 improves its binding with the G-quadruplex structure and the stability induced by this compound is more potent than ellipticine. Furthermore, this compound also interfered with the transcriptional mechanism of the RET gene in an MTC derived cell line, TT cells and significantly decreased the endogenous RET protein expression. We demonstrated the specificity of NSC311153 by using papillary thyroid carcinoma (PTC) cells, the TPC1 cell line which lacks the G-quadruplex forming sequence in the promoter region due to chromosomal rearrangement. The RET downregulation selectively suppresses cell proliferation by inhibiting the intracellular Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways in the TT cells. In the present study, we also showed that the systemic administration of a water soluble NSC311153 analog in a mouse MTC xenograft model inhibited the tumor growth through RET downregulation.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carbazoles; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Cell Proliferation; Ellipticines; G-Quadruplexes; Humans; Male; Mice; Mice, SCID; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Pyridines; Signal Transduction; Thyroid Cancer, Papillary; Thyroid Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies.. The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753T>C) somatic mutation was identified in a lymph node metastasis.. Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.

Topics: Calcitonin; Carcinoma, Neuroendocrine; Cushing Syndrome; Cytoreduction Surgical Procedures; Humans; Hydrocortisone; Male; Middle Aged; Neck Dissection; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms; Thyroidectomy

The oncogenic activation of the rearranged during transfection (RET) proto-oncogene has a main role in the pathogenesis of medullary thyroid cancer (MTC). Several lines of evidence suggest that RET function could be influenced by cyclic AMP (cAMP)-dependent protein kinase A (PKA) activity. We evaluated the in vitro anti-tumor activity of 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP) and PKA type I-selective cAMP analogs [equimolar combination of the 8-piperidinoadenosine-3',5'-cyclic monophosphate (8-PIP-cAMP) and 8-hexylaminoadenosine-3',5'-cyclic monophosphate (8-HA-cAMP) in MTC cell lines (TT and MZ-CRC-1)]. 8-Cl-cAMP and the PKA I-selective cAMP analogs showed a potent anti-proliferative effect in both cell lines. In detail, 8-Cl-cAMP blocked significantly the transition of TT cell population from G2/M to G0/G1 phase and from G0/G1 to S phase and of MZ-CRC-1 cells from G0/G1 to S phase. Moreover, 8-Cl-cAMP induced apoptosis in both cell lines, as demonstrated by FACS analysis for annexin V-FITC/propidium iodide, the activation of caspase-3 and PARP cleavage. On the other hand, the only effect induced by PKA I-selective cAMP analogs was a delay in G0/G1-S and S-G2/M progression in TT and MZ-CRC-1 cells, respectively. In conclusion, these data demonstrate that cAMP analogs, particularly 8-Cl-cAMP, significantly suppress in vitro MTC proliferation and provide rationale for a potential clinical use of cAMP analogs in the treatment of advanced MTC.

Topics: 2-Chloroadenosine; 8-Bromo Cyclic Adenosine Monophosphate; Amines; Antineoplastic Agents; Apoptosis; Carcinoma, Neuroendocrine; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Humans; MAP Kinase Signaling System; Piperidines; Proto-Oncogene Mas; Thyroid Neoplasms

We describe a child with advanced, metastatic, inoperable medullary carcinoma of thyroid associated with multiple endocrine neoplasia 2B and rearranged during transfection mutation with a positive response to vandetanib treatment. He responded well with a fall in calcitonin levels and a reduction in size of the thyroid malignancy, lymph nodes, and pulmonary metastases. He has been on vandetanib for 4 years with good clinical and biochemical response. Vandetanib has a role in the treatment of patients including children with inoperable locally advanced and metastatic medullary carcinoma of thyroid. More information is needed on its use in children and long-term outcome.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Child; Humans; Male; Multiple Endocrine Neoplasia Type 2a; Piperidines; Quinazolines; Thyroid Neoplasms

Aberrant RET kinase signaling plays critical roles in several human cancers such as thyroid carcinoma. The gatekeeper mutants (V804L or V804M) of RET are resistant to currently approved RET inhibitors such as cabozantinib and vandetanib. We, for the first time, report a highly selective and extremely potent RET inhibitor, 6i rationally designed. Compound 6i inhibits strongly RET gatekeeper mutants and other clinically relevant RET mutants as well as wt-RET. This substance also significantly suppresses growth of thyroid cancer-derived TT cell lines and Ba/F3 cells transformed with various RET mutants. Docking studies reveal that the isoxazole moiety in 6i is responsible for binding affinity improvement by providing additional site for H-bonding with Lys758. Also, 6i not only substantially blocks cellular RET autophosphorylation and its downstream pathway, it markedly induces apoptosis and anchorage-independent growth inhibition in TT cell lines while having no effect on normal thyroid Nthy ori-3-1 cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Drug Design; Drug Resistance, Neoplasm; Humans; Models, Molecular; Molecular Docking Simulation; Mutation; Phosphorylation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Structure-Activity Relationship; Substrate Specificity; Thyroid Neoplasms

The analysis of adverse events plays an important role in the benefit assessment of drugs. Consequently, results on adverse events are an integral part of reimbursement dossiers submitted by pharmaceutical companies to health policy decision-makers. Methods applied in the analysis of adverse events commonly include simple standard methods for contingency tables. However, the results produced may be misleading if observations are censored at the time of discontinuation due to treatment switching or noncompliance, resulting in unequal follow-up periods. In this paper, we present examples to show that the application of inadequate methods for the analysis of adverse events in the reimbursement dossier can lead to a downgrading of the evidence on a drug's benefit in the subsequent assessment, as greater harm from the drug cannot be excluded with sufficient certainty. Legal regulations on the benefit assessment of drugs in Germany are presented, in particular, with regard to the analysis of adverse events. Differences in safety considerations between the drug approval process and the benefit assessment are discussed. We show that the naive application of simple proportions in reimbursement dossiers frequently leads to uninterpretable results if observations are censored and the average follow-up periods differ between treatment groups. Likewise, the application of incidence rates may be misleading in the case of recurrent events and unequal follow-up periods. To allow for an appropriate benefit assessment of drugs, adequate survival time methods accounting for time dependencies and duration of follow-up are required, not only for time-to-event efficacy endpoints but also for adverse events. © 2016 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.

Topics: Adverse Drug Reaction Reporting Systems; Androstenes; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Drug Industry; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Germany; Humans; Male; Piperidines; Prostatic Neoplasms; Quinazolines; Survival Rate; Thyroid Neoplasms

Surgery is the mainstay of treatment for medullary thyroid cancer. Cytotoxic chemotherapy is generally ineffective in patients with progressive, inoperable, advanced-stage or metastatic tumours. Vandetanib is also authorised in this setting, but it has more harms than benefits. Cabozantinib, like vandetanib, inhibits several tyrosine kinases involved in angiogenesis. Cabozantinib has been authorised in the European Union for use in this setting. In a randomised, placebo-controlled trial in 330 patients, adding cabozantinib to tailored symptomatic treatment did not prolong survival or improve symptoms, despite a favourable effect on tumour imaging and certain laboratory parameters. On the contrary, cabozantinib appeared to undermine quality of life and aggravate diarrhoea. The known adverse effects of cabozantinib are numerous and often severe: diarrhoea, hand-foot syndrome, hypertension, venous and arterial thrombosis, bleeding and fistulae. Deaths unrelated to tumour progression were more frequent with cabozantinib than with placebo. Cabozantinib carries a risk of multiple pharmacokinetic interactions by interfering with cytochrome P450 isoenzyme CYP3A4 and P-glycoprotein. In animals, cabozantinib is teratogenic and also impairs male and female fertility. Contraception is required for women, and also for the partners of treated men, who must use condoms. These precautions must be maintained for at least 4 months after the end of treatment. In practice, in mid-2015, cabozantinib, like vandetanib, has an unfavourable harm-benefit balance in medullary thyroid cancer. The focus should remain on tailored symptomatic care.

Topics: Anilides; Antineoplastic Agents; Carcinoma, Neuroendocrine; Female; Humans; Male; Piperidines; Protein Kinase Inhibitors; Pyridines; Quality of Life; Quinazolines; Thyroid Neoplasms

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Cell Line; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; MicroRNAs; Middle Aged; Piperidines; Quinazolines; RNA Interference; Thyroid Neoplasms; Vesicular Transport Proteins

The aim of this study was to determine the genomic alterations of cancer-related genes in advanced medullary thyroid carcinoma during the course of clinical care.. Hybrid-capture-based comprehensive genomic profiling was performed on 34 consecutive medullary thyroid carcinoma cases to identify all four classes of genomic alterations, and outcome for an index patient was collected.. RET was mutated in 88% (30/34) of cases, with RET M918T being responsible for 70% (21/30) of the RET alterations. The other RET alterations were RET E632_L633del, C634R, C620R, C618G/R/S, V804M, and RET amplification. Two of the four RET wild-type patients harbored mutations in KRAS or HRAS (1/34 each). The next most frequent genomic alterations were amplifications of CCND1, FGF3, and FGF19 and alterations in CDKN2A (3/34 each). One case with a RET M918T mutation developed acquired resistance to progressively dose-escalated vandetanib. When the mTOR inhibitor everolimus was added to continued vandetanib treatment, the patient achieved a second 25% reduction of tumor volume (RECIST 1.1) for 8 months.. Comprehensive genomic profiling identified the full breadth of RET alterations in metastatic medullary thyroid carcinoma and possible cooperating oncogenic driver alterations. This approach may refine the use of targeted therapy for these patients.

Topics: Aged; Anilides; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p16; Drug Resistance, Neoplasm; Everolimus; Female; Fibroblast Growth Factor 3; Fibroblast Growth Factors; Gene Amplification; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Methionine; Middle Aged; Molecular Targeted Therapy; Mutation; Piperidines; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Pyridines; Quinazolines; Threonine; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.. Clinical courses of 32 patients with sporadic MTC (n=10 pN0cM0, n=8 pN1cM0, n=14 pN1cM1) were compared with genetic profiles of the patients' primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis.. Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P=0.019), FGFR2 (P=0.007), FGFR3 (P=0.044) and VEGFC (P=0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P=0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P=0.039), FLT4 (P=0.025) and VEGFB (P=0.042) was significantly higher in therapy responders.. In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Medullary; Female; Humans; Male; Middle Aged; Mutation; Piperidines; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Medullary thyroid carcinoma (MTC) is a rare cancer during childhood. MTC is sporadic in approximately 80% of cases and hereditary in 20%. When hereditary, it can be associated with other endocrine neoplasias and/or typical nonendocrine diseases, thus configuring the multiple endocrine neoplasia (MEN) syndromes. Children with clinically obvious MTC belong to MEN 2A or 2B families, related to RET mutations. The standard treatment is total thyroidectomy and central neck dissection. However, treatment of advanced MTC has not yet been standardized, even if a new tyrosine kinase inhibitor specific to RET mutation has changed the outcome of such patients. Vandetanib plays a role in the treatment of children with metastatic, locally advanced and nonoperable MTC, with good tolerance. We report the 5-year treatment of an 11-year-old patient, with vandetanib and without thyroid surgery.

Topics: Carcinoma, Neuroendocrine; Child; Female; Humans; Lung Neoplasms; Multiple Endocrine Neoplasia Type 2b; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

Recently platelet derived growth factor receptor-alpha (PDGFRα) was recognized as a potential target to treat aggressive papillary thyroid cancer given its strong association with lymph node metastases. However, it is unclear how PDGFRα potentiates metastases and if it works through the canonical MAPK pathway traditionally linked to PTC oncogenesis. We explored the phenotypic changes driven by PDGFRα activation in human papillary thyroid cancer (PTC) cells and the downstream signalling cascades through which they are effected. We demonstrate that PDGFRα drives an impressive phenotypic change in PTC cell lines as documented by significant cytoskeletal rearrangement, increased migratory potential, and the formation of invadopodia. Cells lacking PDGFRα formed compact and dense spheroids, whereas cells expressing active PDGFRα exhibited invadopodia in three-dimensional culture. To achieve this, active PDGFRα provoked downstream activation of the MAPK/Erk, PI3K/Akt and STAT3 pathways. We further confirmed the role of PDGFRα as a transformative agent promoting the epithelial to mesenchymal transition of PTC cells, through the augmentation of Snail and Slug expression. Crenolanib, a small molecule inhibitor of PDGFRα, suppressed the levels of Snail and Slug and almost completely reversed all the phenotypic changes. We demonstrate that PDGFRα activation is an essential component that drives aggressiveness in PTC cells, and that the signaling pathways are complex, involving not only the MAPK/Erk but also the PI3K/Akt and STAT3 pathways. This argues for upstream targeting of the PDGFRα given the redundancy of oncogenic pathways in PTC, especially in patients whose tumors over-express this tyrosine kinase receptor.

Topics: Antineoplastic Agents; Benzimidazoles; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Cytoskeleton; Epithelial-Mesenchymal Transition; Extracellular Signal-Regulated MAP Kinases; Humans; Lymphatic Metastasis; Phenotype; Phosphatidylinositol 3-Kinase; Piperidines; Podosomes; Proto-Oncogene Proteins c-akt; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Snail Family Transcription Factors; STAT3 Transcription Factor; Thyroid Cancer, Papillary; Thyroid Neoplasms; Time Factors

Topics: Adult; Alopecia Areata; Carcinoma, Neuroendocrine; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

A randomized phase III trial demonstrated that vandetanib treatment is effective in patients with metastatic medullary thyroid cancer (MTC), leading to regulatory approval, but its use may be associated with toxicities that require specific monitoring and management. The objective of the present study performed in France was to describe the toxicity profile and efficacy of vandetanib treatment when given outside any trial.. Sixty-eight patients were treated with vandetanib in the frame of a temporary use authorization (ATU) in France from August 2010 to February 2012, when the drug was available on request for patients with locally advanced or metastatic MTC. Patients were registered by the French health authorities, and characteristics, treatment parameters, toxicity profile, and efficacy were retrospectively reviewed. Eight patients were excluded from the analysis because vandetanib treatment was not administered (n=3), had been given in a trial before ATU (n=3), or was given for a non-MTC cancer (n=2).. Data from the 60 MTC patients were analyzed. Mean age was 58 years (range 11-83 years), 39 patients were male, and six had hereditary MTC. Fifty-six (93%) had metastatic disease in the mediastinum (82%), bones (65%), liver (53%), or lung (53%), and four had only locally advanced disease. At the time of study evaluation, with a median follow-up of 20 months and a median duration of treatment of 9.7 months (range 0.3-36 months), 15 patients were continuing vandetanib treatment (range 18-36 months). Median progression-free survival was 16.1 months. Twenty-five patients discontinued treatment for disease progression (range 0.3-29 months). Best tumor response was a complete response in one patient, a partial response in 12 (20%), stable disease in 33 (55%), and progression in seven patients (12%). All patients had at least one adverse event (AE) during treatment. The main AEs were skin toxicity, diarrhea, and asthenia. Sixteen patients (27%) discontinued treatment for toxicity, and one patient died from vandetanib-induced cardiac toxicity.. Vandetanib is an effective option for patients with advanced MTC. AEs should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Neuroendocrine; Child; Female; France; Humans; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Quinazolines; Retrospective Studies; Risk Factors; Thyroid Neoplasms; Time Factors; Treatment Outcome; Young Adult

Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of follow-up developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up.

Topics: Adult; Carcinoma, Neuroendocrine; Cushing Syndrome; Disease Progression; Female; Humans; Neoplasm Staging; Piperidines; Quinazolines; Thyroid Neoplasms; Treatment Outcome

Clinical evidence shows that dual inhibition of kinases as well angiogenesis provides ideal therapeutic option in the treatment of medullary thyroid carcinoma (MTC) than inhibiting either of these with the events separately. Although treatment with dual inhibitors has shown good clinical responses in patients with MTC, it has been associated with serious side effects. Some inhibitors are active agents for both angiogenesis or kinase activity. Owing to narrow therapeutic window of established inhibitors, the present study aims to identify high affinity dual inhibitors targeting RET and VEGFR2 respectively for kinase and angiogenesis activity. Established inhibitors like Vandetanib, Cabozantinib, Motesanib, PP121, RAF265 and Sunitinib served as query parent compounds for identification of structurally similar compounds by Tanimoto-based similarity searching with a threshold of 95% against the PubChem database. All the parent inhibitors and respective similar compounds were docked against RET and VEGFR2 in order to retrieve high affinity compounds with these two proteins. AGN-PC-0CUK9P PubCID: 59320403 a compound related to PPI21 showed almost equal affinity for RET and VEGFR2 and unlike other screened compounds with no apparent bias for either of the receptors. Further, AGN- PC-0CUK9P demonstrated appreciable interaction with both RET and VEGFR2 and superior kinase activity in addition to showed optimal ADMET properties and pharmacophore features. From our in silico investigation we suggest AGN-PC-0CUK9P as a superior dual inhibitor targeting RET and VEGFR2 with high efficacy which should be proposed for pharmacodynamic and pharmacokinetic studies for improved treatment of MTC.

Topics: Angiogenesis Inhibitors; Anilides; Carcinoma, Neuroendocrine; Databases, Chemical; Drug Discovery; Humans; Imidazoles; Indoles; Molecular Docking Simulation; Molecular Structure; Niacinamide; Oligonucleotides; Piperidines; Protein Binding; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Quinazolines; Sunitinib; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

Tyrosine kinase inhibitors (TKIs) such as vandetanib have shown clinical effectiveness in advanced medullary thyroid cancer (MTC). During TKI treatment, fluctuations in the tumor markers carcinoembryonic antigen (CEA) and calcitonin (CTN) are frequently observed. Their role for treatment monitoring and the decision-making process has not been fully elucidated yet.Twenty-one patients (male, 16, female, 5; mean age, 49 ± 13 years) with progressive MTC receiving vandetanib (300 mg orally per day) were considered. Tumor restaging was performed every 3 months including contrast-enhanced computed tomography (CT). Response was assessed according to recent criteria (Response Evaluation Criteria in Solid Tumors, RECIST 1.1). Additionally, CEA and CTN were measured at the day of CT imaging and alterations observed in tumor markers were compared to respective imaging findings (partial response, PR; stable disease, SD; progressive disease, PD).During long-term follow-up (510 ± 350 days [range, 97-1140 days]), CTN and CEA levels initially dropped in 71.4% and 61.9% of the patients followed by fluctuations in serum marker levels. A rise in CTN ≥39.5% between 2 subsequent measurements (defined by ROC analysis) had a sensitivity of 70.6% and a specificity of 83.2% in predicting PD with an accuracy of 82.0% (area under the curve (AUC), 0.76). Oscillations in CEA levels were not predictive for PD.Whereas tumor marker fluctuations in MTC patients undergoing TKI treatment are a frequent phenomenon, a significant rise in CTN ≥40% turns out to as an early indicator of tumor progression.

Topics: Adult; Aged; Antineoplastic Agents; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Piperidines; Prognosis; Protein-Tyrosine Kinases; Quinazolines; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) is a rare tumor that is caused by activating mutations in the proto-oncogene RET. Vandetanib, a tyrosine-kinase inhibitor, has been recently approved to treat adult patients with metastatic MTC. The aim of this study was to investigate changes in signaling pathways induced by vandetanib treatment in preclinical MTC models, using the reverse-phase protein array method (RPPA).. The human TT cell line was used to assess in vitro and in vivo activity of vandetanib. Protein extracts from TT cells or TT xenografted mice, treated by increasing concentrations of vandetanib for different periods of time, were probed with a set of 12 antibodies representing major signaling pathways, using RPPA. Results were validated using two distinct protein detection methods: Western immunoblotting and immunohistochemistry.. Vandetanib displays antiproliferative and antiangiogenic activities and inhibits RET autophosphorylation. The MAPK and AKT pathways were the two major signaling pathways inhibited by vandetanib. Interestingly, phosphorylated levels of NFκB-p65 were significantly increased by vandetanib. Comparable results were obtained in both the in vitro and in vivo approaches, as well as for the protein detection methods. However, some discrepancies were observed between RPPA and Western immunoblotting, possibly due to lack of specificity of the primary antibodies used.. Overall, our results confirmed the interest of RPPA for screening global changes induced in signaling pathways by kinase inhibitors. MAPK and AKT were identified as the main pathways involved in vandetanib response in MTC models. Our results also suggest alternative routes for controlling the disease, and provide a rationale for the development of therapeutic combinations based on the comprehensive identification of molecular events induced by inhibitors.

Topics: Adult; Animals; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Proliferation; Humans; MAP Kinase Signaling System; Mice; Piperidines; Proto-Oncogene Mas; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; Thyroid Neoplasms

Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers.. THERE WERE 62 PATIENTS (37 MEN, MEAN AGE: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints.. Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.. This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.

Topics: Adenocarcinoma; Adenocarcinoma, Follicular; Adenoma, Oxyphilic; Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Disease-Free Survival; Female; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Niacinamide; Phenylurea Compounds; Piperidines; Pleural Neoplasms; Protein-Tyrosine Kinases; Pyrroles; Quinazolines; Retrospective Studies; Sorafenib; Sunitinib; Thyroid Cancer, Papillary; Thyroid Neoplasms; Treatment Outcome

Ectopic Cushing syndrome due to ACTH secretion from metastatic medullary thyroid cancer (MTC) is associated with significant morbidity and mortality.. The aim of the study was to describe the first case of Cushing syndrome associated with MTC in a pediatric patient and the successful reversal of Cushing syndrome with tyrosine kinase inhibitor (vandetanib) therapy.. A 17-year-old Brazilian adolescent presented with metastatic MTC and associated ACTH-dependent ectopic Cushing syndrome in the context of multiple endocrine neoplasia type 2B. When the patient was treated with the tyrosine kinase inhibitor vandetanib, rapid decrease in serum cortisol and improvement of clinical symptoms were observed.. We describe the first pediatric case of clinical and biochemical improvement of paraneoplastic MTC-related Cushing syndrome after treatment with vandetanib. Vandetanib and possibly other tyrosine kinase inhibitors may be a novel beneficial option in patients with neuroendocrine tumor-related ectopic Cushing syndrome.

Topics: Adolescent; Adrenocorticotropic Hormone; Carcinoma, Neuroendocrine; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Cushing Syndrome; Humans; Male; Multiple Endocrine Neoplasia Type 2b; Neoplasms, Second Primary; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Thyroid Neoplasms

Topics: Aged; Biopsy, Needle; Carcinoma, Medullary; Erythema Multiforme; Follow-Up Studies; Humans; Immunohistochemistry; Male; Neoplasm Staging; Photosensitivity Disorders; Piperidines; Quinazolines; Risk Assessment; Thyroid Neoplasms; Thyroidectomy

Medullary thyroid cancer (MTC) is a rare form of thyroid cancer comprising approximately 4% of all thyroid cancers. The majority of patients have a relatively good prognosis; however, a subgroup of patients will require systemic therapy. Large phase III randomized trials led to the approval of two drugs--vandetanib and cabozantinib--for progressive or symptomatic MTC. The decision regarding which drug to initiate first is not entirely clear and is a common concern amongst treating physicians.. A review of the literature in English was conducted, and data were summarized and integrated into a decision matrix.. The decision regarding which drug to initiate first for progressive MTC should be based on a careful review of the medical history, physical examination findings, medication list, electrocardiogram, laboratory results, and tumor characteristics. It is necessary to consider the relative contraindications when choosing which drug to initiate first.

Topics: Anilides; Carcinoma, Neuroendocrine; DNA Mutational Analysis; Humans; Male; Middle Aged; Piperidines; Precision Medicine; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Thyroid Neoplasms; Thyroidectomy

Topics: Biopsy, Fine-Needle; Calcitonin; Carcinoma, Neuroendocrine; Diagnosis, Differential; Female; Humans; Lymph Nodes; Lymphatic Diseases; Middle Aged; Neck; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Gland; Thyroid Neoplasms; Thyroid Nodule; Thyrotropin; Tomography, X-Ray Computed; Ultrasonography

Medullary thyroid carcinoma (MTC) accounts for 3-4% of all malignant thyroid neoplasias. Vandetanib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor 2, epidermal growth factor receptor, and RET, has been approved by the FDA for the treatment of locally advanced or metastatic MTC. The heart seems to be particularly susceptible to adverse effects associated with TKI therapy, and virtually all TKIs have been associated with cardiovascular events.. We report the case of a patient with metastatic MTC who was enrolled in the Phase III clinical study (NCT00410761) and presented a favorable response to vandetanib therapy, displaying marked decrease in the level of serologic tumor markers and shrinkage of metastatic lesions. After 14 months of therapy, the patient developed a fatal cardiac failure. Myocardial infarction was excluded by serial measurements of specific cardiac markers (serial troponin-T measurements varied from 0.037 to 0.042 ng/ml) and serologic tests for Chaga's disease were negative. Postmortem examination of the heart revealed cardiomyocyte hypertrophy and marked myocyte degeneration in the subendocardial zones and papillary muscles of the myocardium. These pathological changes are similar to those observed in TKI-treated rats and are suggestive of drug-induced cardiotoxicity.. This case illustrates a previously unreported serious vandetanib-related adverse effect and highlights the need for close monitoring of patients under TKI therapy in order to identify early signs of congestive heart failure or myocardium damage.

Topics: Adult; Carcinoma, Neuroendocrine; Cardiomyopathies; Clinical Trials, Phase III as Topic; Fatal Outcome; Female; Heart Failure; Humans; Male; Piperidines; Protein Kinase Inhibitors; Quinazolines; Thyroid Neoplasms

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor mainly caused by mutations in the RET proto-oncogene. For MTC therapy, the U.S. Food and Drug Administration recently approved vandetanib and cabozantinib, multikinase inhibitors targeting RET and other tyrosine kinase receptors of vascular endothelial growth factor, epidermal growth factor, or hepatocyte growth factor. Nevertheless, not all patients with the progressive MTC respond to these drugs, requiring the development of additional therapeutic modalities that have distinct activity.. We aimed to evaluate mitochondria-targeted carboxy-proxyl (Mito-CP), a mitochondria-targeted redox-sensitive agent, for its tumor-suppressive efficacy against MTC.. In vitro cultures of 2 human MTC cell lines, TT and MZ-CRC-1, and TT xenografts in mice were treated with Mito-CP in comparison with vandetanib. The effects on cell survival/death, RET expression, mitochondrial integrity, and oxidative stress were determined.. Contrary to vandetanib, Mito-CP induced RET downregulation and strong cytotoxic effects in both cell lines in vitro, including caspase-dependent apoptosis. These effects were accompanied by mitochondrial membrane depolarization, decreased oxygen consumption, and increased oxidative stress in cells. Intriguingly, Mito-CP-induced cell death, but not RET downregulation, was partially inhibited by the reactive oxygen species scavenger, N-acetyl-cysteine, indicating that Mito-CP mediates tumor-suppressive effects via redox-dependent as well as redox-independent mechanisms. Orally administered Mito-CP effectively suppressed TT xenografts in mice, with an efficacy comparable to vandetanib and relatively low toxicity to animals.. Our results suggest that Mito-CP can effectively suppress MTC cell growth/survival via a mechanism distinct from vandetanib effects. Mitochondrial targeting may be a potential strategy for MTC therapy.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Cell Line, Tumor; Cell Survival; Cyclic N-Oxides; Drug Delivery Systems; Female; Humans; Mice; Mice, Nude; Mitochondria; Nitrogen Oxides; Organophosphorus Compounds; Piperidines; Proto-Oncogene Mas; Quinazolines; Thyroid Neoplasms; Xenograft Model Antitumor Assays

Despite various attempts at modifying usual treatment modalities, anaplastic thyroid cancer (ATC) is still associated with unfavorable prognosis. Results of preclinical investigations are often of limited transferability to clinical tumor biology. Individualized multimodal treatment regimens, including novel growth-inhibiting drugs, might be a future option.. Tumor tissue, freshly prepared from a patient operated for ATC, was xenotransplanted to nude mice. While the patient obtained a hyperfractionated external beam radiation, mice carrying xenotransplanted tumors were randomized (n = 6) and treated by multikinase inhibitors (sorafenib [S]: vascular endothelial growth factor receptor [VEGF-R], platelet derived growth factor receptor, RET; vandetanib [V]: VEGF-R, endothelial growth factor receptor [EGF-R]; and MLN8054 [M]: Aurora kinases [AK]). Antiproliferative, antiangiogenic, and proapoptotic effects were evaluated.. Treatment of successfully xenotransplanted fresh ATC tumor tissue by multikinase inhibitors and aurora kinase inhibitor reduced the tumor volume up to 61% depending on the drug and time of application (3 wk of treatment: 46% [M], 34% [V], 30% [S]; 5 wk of treatment: 61% [S]). Tumor cell proliferation (BrdU) was reduced between 34% and 58% [S] and [V]. Reduction of tumor vascularity was between 67% [V] and 33% [S] and was accompanied by decreased EGF-R/VEGF-R2 receptor activity [V/V,S]. Tumor cell apoptosis (caspase 3 activity) increased up to 2.4-fold [S].. Successful in vivo evaluation of novel drugs in xenotransplanted fresh tumor tissue allows in-time (while patient receives standard treatment) prospective analysis for possible additional clinical application. However, technical specifications have to be taken into account to obtain stable in vivo tumor growth. Based on the individual results, a tailored clinical drug application seems possible.

Topics: Animals; Apoptosis; Benzazepines; Cell Proliferation; Drug Evaluation, Preclinical; Humans; Male; Mice; Mice, Nude; Middle Aged; Neovascularization, Pathologic; Niacinamide; Phenylurea Compounds; Piperidines; Protein Kinase Inhibitors; Quinazolines; Random Allocation; Receptors, Vascular Endothelial Growth Factor; Sorafenib; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

Topics: Adrenocorticotropic Hormone; Calcitonin; Carcinoma, Neuroendocrine; Cushing Syndrome; Deamino Arginine Vasopressin; Humans; Lymphatic Metastasis; Male; Middle Aged; Paraneoplastic Syndromes; Piperidines; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms

Topics: Anilides; Biomarkers, Tumor; Calcitonin; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Disease Progression; Humans; Piperidines; Proto-Oncogene Proteins c-ret; Pyridines; Quinazolines; Thyroid Neoplasms

Topics: Carcinoma, Neuroendocrine; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

Topics: Carcinoma, Neuroendocrine; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

Topics: Carcinoma, Neuroendocrine; Humans; Male; Middle Aged; Neoplasm Metastasis; Piperidines; Quinazolines; Thyroid Neoplasms

Topics: Female; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

Treatment modalities for progressive iodine-refractory poorly differentiated thyroid carcinomas are not yet well defined. Molecular targeted therapy with multikinase inhibitors has recently shown promising results, and cytotoxic chemotherapy is generally considered of low efficacy.. We report the case of a 57-yr-old woman with an advanced iodine-refractory poorly differentiated thyroid cancer who was treated sequentially between October 2006 and March 2011 with two different regimens of cytotoxic chemotherapy and three lines of multikinase inhibitors.. Efficacy and adverse effects of the consecutive treatment modalities, i.e. vandetanib, doxorubicin-cisplatin combination, sorafenib, paclitaxel-carboplatin combination, and sunitinib, are reported.. The patient presented a complete tumor response to a doxorubicin-cisplatin combination lasting 10 months and to a paclitaxel-carboplatin regimen lasting 5 months and had no or limited response to kinase inhibitors, i.e. progression after 3 months of vandetanib, progression after 4 months of sorafenib, and stable disease for 8 months with sunitinib treatment.. When tumor progresses with kinase inhibitors, cytotoxic chemotherapy may be an alternative in selected cases of advanced iodine-refractory poorly differentiated thyroid cancer. For those rare cases, clinical management should benefit from a multidisciplinary team approach through specialized networks.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Cisplatin; Combined Modality Therapy; Doxorubicin; Fatal Outcome; Female; Fluorodeoxyglucose F18; Humans; Indoles; Iodine Radioisotopes; Lung Neoplasms; Middle Aged; Niacinamide; Paclitaxel; Phenylurea Compounds; Piperidines; Pyridines; Pyrroles; Quinazolines; Radiopharmaceuticals; Sorafenib; Sunitinib; Thyroid Neoplasms; Thyroidectomy; Tomography, X-Ray Computed

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Adenocarcinoma, Follicular; Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Female; Humans; Male; Piperidines; Quinazolines; Thyroid Cancer, Papillary; Thyroid Neoplasms

Topics: Anticoagulants; Antineoplastic Agents; Benzimidazoles; beta-Alanine; Carcinoma, Neuroendocrine; Clinical Trials as Topic; Dabigatran; Drug Approval; Efficiency, Organizational; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Patient Safety; Piperidines; Propylene Glycols; Quinazolines; Risk; Sphingosine; Stroke; Thyroid Neoplasms; Time Factors; United States; United States Food and Drug Administration

Treatment of medullary thyroid cancer is mainly based on surgery. Life expectancy exceeds 10 years in almost half of patients with inoperable advanced or metastatic disease. Cytotoxic chemotherapy is generally ineffective when this malignancy progresses. Vandetanib (Caprelsa, AstraZeneca), a multiple kinase inhibitor, is authorised in the European Union for use in this setting. Its clinical evaluation is mainly based on a double-blind, randomised, placebo-controlled trial in 331 patients, 70% of whom had progressed within the previous 6 months. Median follow-up (2 years) is too short to detect an impact on overall survival (about 85% in both groups). Analyses based on other outcomes (progression-free survival and pain) are unreliable, due to the large amount of missing data. The adverse effect profile of vandetanib is unfavourable: it includes diarrhoea and other gastrointestinal disorders, cardiovascular disorders, and cutaneous, neuropsychological, haemorrhagic and metabolic disorders. Visual disturbances have also been observed. Vandetanib also prolongs the QT interval: 3 cases of torsades de pointes and 9 sudden deaths have already been reported. Renal failure increases this risk. Numerous pharmacokinetic interactions are likely to occur, notably via cytochrome P450 isoenzyme CYP 3A4. Vandetanib reduces the effectiveness of levothyroxine. Vandetanib should not be combined with other drugs that prolong the QT interval. The long half-life of vandetanib (about 3 weeks) must be taken into account when managing interactions and adverse effects. There is no firm evidence that vandetanib has a favourable harm-benefit balance in patients with inoperable advanced or metastatic medullary thyroid cancer.

Topics: Antineoplastic Agents; Carcinoma, Neuroendocrine; Evidence-Based Medicine; Humans; Patient Safety; Piperidines; Protein Kinase Inhibitors; Quinazolines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Thyroid Neoplasms; Treatment Outcome

Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.

Topics: Carcinoma, Medullary; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Humans; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Signal Transduction; Thyroid Neoplasms; Transforming Growth Factor alpha; Vascular Endothelial Growth Factor Receptor-2

Anaplastic thyroid carcinoma (ATC) is one of the most lethal human cancers with a median survival of 6 months. The inhibition of epidermal growth factor receptor (EGFR) alone, or with VEGF receptor 2 (VEGFR2), represents an attractive approach for treatment of ATC. Several reports have examined agents that target these receptors. However, with the misidentification of as many as 60% of all commonly used ATC cell lines, the significance of these past findings is unclear.. Cell lines authenticated by short tandem repeat profiling were selected to establish xenograft tumors in an orthotopic murine model of ATC. These mice were then treated with vandetanib to evaluate its effects on ATC tumor growth. Dynamic contrast-enhanced (DCE) MRI was utilized to measure the impact of vandetanib on tumor vasculature.. Vandetanib inhibited tumor growth of the ATC cell lines Hth83 and 8505C in vivo by 69.3% (P < 0.001) and 66.6% (P < 0.05), respectively, when compared with control. Significant decreases in vascular permeability (P < 0.01) and vascular volume fraction (P < 0.05) were detected by DCE-MRI in the orthotopic xenograft tumors after 1 week of treatment with vandetanib as compared with control.. The inhibition of EGFR and VEGFR2 by vandetanib and its tremendous in vivo antitumor activity against ATC make it an attractive candidate for further preclinical and clinical development for the treatment of this particularly virulent cancer, which remains effectively untreatable. Vandetanib disrupts angiogenesis and DCE-MRI is an effective method to quantify changes in vascular function in vivo.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Humans; Immunoblotting; In Situ Nick-End Labeling; Magnetic Resonance Imaging; Male; Mice; Mice, Nude; Neovascularization, Pathologic; Phosphorylation; Piperidines; Platelet Endothelial Cell Adhesion Molecule-1; Quinazolines; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

The RET (rearranged-during-transfection protein) protooncogene triggers multiple intracellular signaling cascades regulating cell cycle progression and cellular metabolism. We therefore hypothesized that metabolic imaging could allow noninvasive detection of response to the RET inhibitor vandetanib in vivo.. The effects of vandetanib treatment on the full-genome expression and the metabolic profile were analyzed in the human medullary thyroid cancer cell line TT. In vitro, transcriptional changes of pathways regulating cell cycle progression and glucose, dopa, and thymidine metabolism were correlated to the results of cell cycle analysis and the uptake of (3)H-deoxyglucose, (3)H-3,4-dihydroxy-L-phenylalanine, and (3)H-thymidine under vandetanib treatment. In vivo, the tumor metabolism under vandetanib was monitored by small-animal PET of tumor-bearing mice.. Vandetanib treatment resulted in the transcriptional downregulation of various effector pathways with consecutive downregulation of cyclin expression and a G(0)/G(1) arrest. In vitro, vandetanib treatment resulted in the decreased expression of genes regulating glucose, 3,4-dihydroxy-L-phenylalanine, and thymidine metabolism, with a subsequent reduction in the functional activity of the corresponding pathways. In vivo, metabolic imaging with PET was able to assess changes in the tumoral glucose metabolism profile as early as 3 d after initiation of vandetanib treatment.. We describe a metabolic imaging approach for the noninvasive detection of successful vandetanib treatment. Our results suggest that PET may be useful for identifying patients who respond to vandetanib early in the course of treatment.

Topics: Aged; Animals; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cyclins; Dihydroxyphenylalanine; Down-Regulation; Female; Fluorodeoxyglucose F18; G1 Phase; Glucose; Humans; Male; Mice; Mice, SCID; Microarray Analysis; Piperidines; Positron-Emission Tomography; Proto-Oncogene Proteins c-ret; Quality Control; Quinazolines; Radiopharmaceuticals; Resting Phase, Cell Cycle; RNA, Neoplasm; Signal Transduction; Thymidine; Thyroid Neoplasms; Tomography, Emission-Computed

Topics: Antineoplastic Agents; Benzenesulfonates; Humans; Indoles; Niacinamide; Phenylurea Compounds; Piperidines; Pyridines; Pyrroles; Quinazolines; Sorafenib; Sunitinib; Thyroid Neoplasms

Topics: Carcinoma, Neuroendocrine; Contraindications; Humans; Multiple Endocrine Neoplasia; Mutation; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Quinazolines; Research; Syndrome; Thyroid Neoplasms

Vandetanib is an orally active antagonist of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR or HER1 or ErbB1) and RET kinase, and is now available in the US for the treatment of metastatic medullary thyroid cancer (MTC). Regulatory submissions for this indication have been filed in the EU and Canada, with clinical development in malignant MTC ongoing in several other countries. Vandetanib is being developed by AstraZeneca, and is also in phase II development for biliary, breast and prostate cancer. Earlier, AstraZeneca withdrew regulatory filings for non-small cell lung cancer (NSCLC) in the US and EU, and later discontinued development. This article summarizes the milestones in the development of vandetanib leading to this first approval in malignant MTC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Drug Approval; Drug Design; Humans; Neoplasm Metastasis; Piperidines; Quinazolines; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

Topics: Female; Humans; Male; Piperidines; Quinazolines; Thyroid Neoplasms

The active components of Cannabis sativa and their derivatives produce a wide spectrum of effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids as agents capable of controlling the decision of cells to survive or die. We analysed the effects exerted by 2-methyl-2'-F-anandamide (Met-F-AEA), a metabolically stable analogue of anandamide, and observed a growth inhibition in cell lines derived from thyroid carcinomas. Growth inhibition was associated with a high level of CB1 receptor expression, suggesting that the cytotoxic effect is due to interaction with the CB1 receptor. This phenomenon was associated with activation of the protein, p53, an increased apoptotic rate, and expression of p21(CIP1/WAF1). This study provides new insights into the mechanism of Met-F-AEA action, and could have significance in providing a basis for the management of thyroid carcinoma.

Topics: Apoptosis; Arachidonic Acids; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Drug Screening Assays, Antitumor; Endocannabinoids; Humans; Molecular Weight; Piperidines; Poly(ADP-ribose) Polymerases; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant; Thyroid Neoplasms; Tumor Suppressor Protein p53

RET/papillary thyroid carcinoma (PTC), TRK-T, or activating mutations of Ras and BRaf are frequent genetic alterations in PTC, all leading to the activation of the extracellular-regulated kinase (Erk) cascade. The aim of this study was to investigate the role of calmodulin-dependent kinase II (CaMKII) in the signal transduction leading to Erk activation in PTC cells. In normal thyroid cells, CaMKII and Erk were in the inactive form in the absence of stimulation. In primary PTC cultures and in PTC cell lines harboring the oncogenes RET/PTC-1 or BRaf(V600E), CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C (PLC) attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRaf(V600E), or Ras(V12) induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in thyroid papillary carcinoma (TPC-1), a cell line harboring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, PTCs contain an active PLC/Ca(2+)/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRaf(V600E), oncogenic Ras, and by RET/PTC. CaMKII participates to the activation of the Erk pathway by oncogenic Ras and RET/PTC and contributes to their signal output, thus modulating tumor cell proliferation.

Topics: Amino Acid Sequence; Animals; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calmodulin; Carcinoma, Papillary; Cell Division; Enzyme Activation; Estrenes; Extracellular Signal-Regulated MAP Kinases; Humans; MAP Kinase Signaling System; Molecular Sequence Data; Mutation; Neoplasm Proteins; Oncogene Protein p21(ras); Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-ret; Pyrrolidinones; Quinazolines; Rats; Thyroid Neoplasms; Type C Phospholipases

Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.

Topics: Aged; Animals; Calcitonin; Carcinoma, Medullary; Cell Line, Tumor; Cell Transformation, Neoplastic; Chromogranin A; Disease Models, Animal; ErbB Receptors; Humans; Karyotyping; Male; Mice; Mice, Nude; Mutation; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Quinazolines; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-1; Xenograft Model Antitumor Assays

RET (rearranged during transfection) is a transmembrane tyrosine kinase and acts as co-receptor of glial-derived neurotrophic factor (GDNF) family neurothrofic factors in complex with GFRalpha family proteins; RET is important for development of enteric nervous system and renal organogenesis during embryonal life. Alterations in Ret gene are related to several neoplasias: point mutations are identified in medullary thyroid carcinoma (MTC) and multiple endocrine neoplasias 2A and B (MEN2A and B), while translocations and chromosomal inversions cause papillary thyroid carcinoma (PTC). We expressed recombinant RET kinase domain (rRET) containing the active site, the ATP binding pocket, and the activation loop with regulatory activity, with the Baculovirus expression system. RET was purified by a two-step procedure consisting of an anion exchange chromatography followed by nickel affinity chromatography. Moreover a biochemical characterization of the recombinant product was performed in order to verify its activity (by ELISA) and physical state (dynamic light scattering). We used rRET to validate an ELISA-based kinase assay, by testing inhibitors reported in literature such as PP1 and PP2. This method represents an easy system to screen potential inhibitors found by computational methods. We also produced V804M mutants to identify inhibitors that can overcome resistance to PP1 and ZD6474. The catalytic domain of RET can be used also for X-ray diffraction to obtain information about the three-dimensional structure, necessary for a rational design of selective inhibitors: it represents an important tool to understand the molecular mechanisms causing thyroid cancer and to care it.

Topics: Amino Acid Substitution; Animals; Cell Line; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Piperidines; Point Mutation; Protein Structure, Tertiary; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyrimidines; Quinazolines; Recombinant Proteins; Spodoptera; Thyroid Neoplasms

In thyroid cancer (TC), endothelial growth factor (EGF) has been associated with dedifferentiation, tumor cell proliferation, and angiogenesis. Vascular endothelial growth factor (VEGF) has been documented to be the main stimulator of angiogenesis in the thyroid gland. Patients with undifferentiated thyroid cancer are in desperate need of new therapeutic strategies because common protocols of therapy usually fail. The aim of this study, therefore, was to evaluate two tyrosine-kinase inhibitors (TKI, ZD 1839 gefitinib and ZD 6474 vandetanib), directed against the EGF/VEGF receptor for possible antitumor therapy in thyroid cancer.. EGF/VEGF-R was documented in anaplastic (Hth74, C643), follicular (FTC133), and papillary (TPC1) thyroid cancer cell lines by Western blot analysis. The antiproliferative effect of two TKI (0.1-10 microM) on thyroid cancer cell lines in vitro was quantified by MTT assay, the antiangiogenic effect by assessing secretion of VEGF by enzyme-linked immunosorbent assay (R&D Systems). ZD 1839 is mainly directed against EGF-R and ZD 6474 against VEGF-R (AstraZeneca, UK), single applications and combinations of compounds were evaluated.. EGF-R and VEGF-R as well as the phosphorylated receptor were documented in all of the cell lines. Administration of ZD1839 led to an up to 90% reduction of cell number in Hth74, 80% in C643, 50% in FTC133, and 90% in TPC1 (p < 0.05). ZD1839 induced a decrease of VEGF secretion between 30% in C643 and 90% in Hth74. Administration of ZD6474 led to an up to 95% reduction of cell number in Hth74, 85% in C643, 90% in FTC133, and 90% in TPC1 (p < 0.05). The ZD6474 induced decrease of VEGF secretion ranged between 20% (FTC133) and 60% (TPC1). Combinations of IC50 concentrations of TKI showed synergistic effects, resulting in additional inhibition of proliferation between 50 and 90% compared to single drug administration.. The EGF/EGF-R system resembles a powerful VEGF-stimulating pathway in all histiotypes of TC and can be inhibited by TKI. TKI directed against EGF-R as well as VEGF-R inhibit tumor cell proliferation and VEGF secretion in vitro. Combinations of TKI are more effective than strategies using single agents. It is suggested that targeting EGF-R/VEGF-R-mediated pathways may have therapeutic potential in some undifferentiated thyroid cancers.

Topics: Carcinoma; Cell Culture Techniques; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Gefitinib; Humans; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Thyroid Neoplasms; Vascular Endothelial Growth Factor A

Patients with hereditary medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC (FMTC) have mutations in the RET proto-oncogene. Approximately 40 percent of patients with papillary thyroid carcinoma (PTC) typically have either intrachromosomal or extrachromosomal rearrangements that join the promoter and NH(2)-terminal domains of unrelated genes to the COOH-terminal fragment of RET. The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK). RET kinase inhibitors are likely to be beneficial for patients with hereditary MTC, where currently there is no effective chemotherapy or radiation therapy. Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines. We have developed a Drosophila model for MEN2A and MEN2B diseases by targeting oncogenic forms of RET to the developing Drosophila eye. Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model. Importantly, ZD6474 showed high efficacy and very low toxicity. This compound failed to significantly suppress an activated form of another RTK, the Drosophila epidermal growth factor receptor, nor did it suppress the activity of downstream components of the RET/Ras pathway. Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of RET is a useful treatment strategy for RET-dependent carcinomas.

Topics: Animals; Carcinoma, Papillary; Disease Models, Animal; Drosophila; Drosophila Proteins; ErbB Receptors; Eye Abnormalities; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Piperidines; Protein Isoforms; Proto-Oncogene Proteins c-ret; Quinazolines; raf Kinases; ras Proteins; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms

We show that treatment of a panel of thyroid carcinoma cell lines naturally harboring the RET/PTC1 oncogene, with the RET kinase inhibitors PP1 and ZD6474, results in reversible G(1) arrest. This is accompanied by interruption of Shc and mitogen-activated protein kinase (MAPK) phosphorylation, reduced levels of G(1) cyclins, and increased levels of the cyclin-dependent kinase inhibitor p27Kip1 because of a reduced protein turnover. MAP/extracellular signal-regulated kinase 1/2 inhibition by U0126 caused G(1) cyclins down-regulation and p27Kip1 up-regulation as well. Forced expression of RET/PTC in normal thyroid follicular cells caused a MAPK- and proteasome-dependent down-regulation of p27Kip1. Reduction of p27Kip1 protein levels by antisense oligonucleotides abrogated the G(1) arrest induced by RET/PTC blockade. Therefore, in thyroid cancer, RET/PTC-mediated MAPK activation contributes to p27Kip1 deregulation. This pathway is implicated in cell cycle progression and in response to small molecule kinase inhibitors.

Topics: Cell Cycle Proteins; Cell Line, Tumor; Cyclin D; Cyclin E; Cyclin-Dependent Kinase Inhibitor p27; Cyclins; Cysteine Endopeptidases; Enzyme Inhibitors; Gene Rearrangement; Humans; MAP Kinase Signaling System; Multienzyme Complexes; Oncogene Proteins, Fusion; Piperidines; Proteasome Endopeptidase Complex; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Thyroid Neoplasms; Tumor Suppressor Proteins; Up-Regulation

We have recently demonstrated that the pyrazolopyrimidines PP1 and PP2 and the 4-anilinoquinazoline ZD6474 display a strong inhibitory activity (IC(50)< or =100 nM) towards constitutively active oncogenic RET kinases. Here, we show that most oncogenic MEN2-associated RET kinase mutants are highly susceptible to PP1, PP2 and ZD6474 inhibition. In contrast, MEN2-associated swap of bulky hydrophobic leucine or methionine residues for valine 804 in the RET kinase domain causes resistance to the three compounds. Substitution of valine 804 with the small amino- acid glycine renders the RET kinase even more susceptible to inhibition (ZD6474 IC(50): 20 nM) than the wild-type kinase. Our data identify valine 804 of RET as a structural determinant mediating resistance to pyrazolopyrimidines and 4-anilinoquinazolines.

Topics: Carcinoma, Medullary; Catalytic Domain; Cell Line; Drug Resistance; Enzyme Inhibitors; Mitogens; Piperidines; Point Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyrimidines; Quinazolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Thyroid Neoplasms; Valine

Endocannabinoid signaling has been shown to be enhanced in several cancer tissues and malignant cells, and studies in cell lines have shown that this up-regulation might serve the purpose of providing transformed cells with a further means to inhibit their proliferation. Here we investigated the effect of inhibitors of endocannabinoid degradation on the growth of rat thyroid tumor xenografts induced in athymic mice. VDM-11, a selective inhibitor of endocannabinoid cellular re-uptake, and arachidonoyl-serotonin (AA-5-HT), a selective blocker of endocannabinoid enzymatic hydrolysis, both inhibited the growth in vivo of tumor xenografts induced by the subcutaneous injection of rat thyroid transformed (KiMol) cells. This effect was accompanied by significantly enhanced endocannabinoid concentrations in the tumors excised at the end of the in vivo experiments. Endocannabinoids, as well as VDM-11 and AA-5-HT, inhibited the growth in vitro of the transformed rat thyroid cells used to induce the tumors in vivo, and their effect was reversed at least in part by the cannabinoid CB1 receptor antagonist SR141716A. This compound, however, when administered alone, did not enhance, but instead slightly inhibited, the growth of rat thyroid transformed cells both in vitro and in tumor xenografts induced in vivo. These findings indicate that endocannabinoids tonically control tumor growth in vivo by both CB1-mediated and non-CB1-mediated mechanisms and that, irrespective of the molecular mechanism of their anti-proliferative action, inhibitors of their inactivation might be used for the development of novel anti-cancer drugs.

Topics: Animals; Arachidonic Acids; Biodegradation, Environmental; Cannabinoid Receptor Modulators; Cell Proliferation; Endocannabinoids; Mice; Mice, Nude; Piperidines; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Rimonabant; Serotonin; Thyroid Neoplasms; Xenograft Model Antitumor Assays

The RET gene is frequently mutated in papillary thyroid carcinoma and in medullary thyroid carcinoma. We have identified three different anti-RET drugs: two pyrazolo-pyrimidines, PP1 and PP2 and an anilinoquinazoline, ZD6474 (AstraZeneca). These compounds are able to inhibit RET kinase activity in vitro (IC50 dose 100 nM) and in vivo and they can prevent RET mediated transformation. Finally, mutation of RET V804 to methionine or leucine, found in MTC patients, induces resistance to the three drugs.

Topics: Carcinoma, Medullary; Carcinoma, Papillary; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Mutation; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Quinazolines; Receptor Protein-Tyrosine Kinases; Sensitivity and Specificity; Thyroid Neoplasms; Treatment Outcome

RET/papillary thyroid carcinoma (PTC) oncogenes, generated by recombination of the tyrosine kinase-encoding domain of RET with different heterologous genes, are prevalent in papillary carcinomas of the thyroid. Point mutations of RET cause multiple endocrine neoplasia type 2 (MEN2) familial cancer syndrome and are found in sporadic medullary thyroid carcinomas. Here, we show that ZD6474, a low molecular weight tyrosine kinase inhibitor, blocks the enzymatic activity of RET-derived oncoproteins at a one-half maximal inhibitory concentration of 100 nM. ZD6474 blocked in vivo phosphorylation and signaling of the RET/PTC3 and RET/MEN2B oncoproteins and of an epidermal growth factor (EGF)-activated EGF-receptor/RET chimeric receptor. RET/PTC3-transformed cells-treated ZD6474 lost proliferative autonomy and showed morphological reversion. ZD6474 prevented the growth of two human PTC cell lines that carry spontaneous RET/PTC1 rearrangements. Finally, it blocked anchorage-independent growth of RET/PTC3-transformed NIH3T3 fibroblasts and the formation of tumors after injection of NIH-RET/PTC3 cells into nude mice. Thus, targeting RET oncogenes with ZD6474 might offer a potential treatment strategy for carcinomas sustaining oncogenic activation of RET.

Topics: 3T3 Cells; Animals; Carcinoma, Papillary; Cell Transformation, Neoplastic; Drosophila Proteins; Enzyme Inhibitors; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Piperidines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Quinazolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Thyroid Neoplasms; Vascular Endothelial Growth Factor Receptor-2

We investigated the effect of 2-methyl-arachidonyl-2'-fluoro-ethylamide (Met-F-AEA), a stable analog of the endocannabinoid anandamide, on a rat thyroid epithelial cell line (FRTL-5) transformed by the K-ras oncogene, and on epithelial tumors derived from these cells. Met-F-AEA effect in vivo was evaluated in a nude mouse xenograft model, where K-ras-transformed (KiMol) cells were implanted subcutaneously. Met-F-AEA (0.5 mg/kg/dose) induced a drastic reduction in tumor volume. This effect was inhibited by the CB1 receptor antagonist SR141716A (0.7 mg/kg/dose) and was accompanied by a strong reduction of K-ras activity. Accordingly, KiMol cells and tumors express CB1 receptors. Met-F-AEA inhibited (IC50 ~5 mM) the proliferation in vitro and the transition to the S phase of KiMol cells and it reduced K-ras activity; these effects were antagonized by SR141716A. Met-F-AEA cytostatic action was significantly smaller in nontransformed FRTL-5 cells than in KiMol cells. Met-F-AEA treatment exerted opposite effects on the expression of CB1 receptors in KiMol and FRTL-5 cells, with a strong up-regulation in the former case and a suppression in nontransformed cells. The data suggest that: 1) Met-F-AEA inhibits ras oncogene-dependent tumor growth in vivo through CB1 cannabinoid receptors; and 2) responsiveness of FRTL-5 cells to endocannabinoids depends on whether or not they are transformed by K-ras.

Topics: Animals; Arachidonic Acids; Blotting, Western; Cannabinoid Receptor Modulators; Cannabinoids; Cell Cycle; Cell Division; Cell Line; Cell Line, Transformed; Dose-Response Relationship, Drug; Endocannabinoids; Genes, ras; Mice; Mice, Nude; Neoplasms, Experimental; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Receptors, Cannabinoid; Receptors, Drug; Rimonabant; RNA, Messenger; Thyroid Neoplasms; Xenograft Model Antitumor Assays

In medullary carcinoma of the thyroid (MTC), drug resistance remains the major obstacle to effective chemotherapy. In this work, we studied the effect of S9788 on doxorubicin (DOX) efficiency in a MTC cell line (TT cells) injected in nude mice. After two passages, TT cells were injected in 40 nude mice divided into four groups [controls and groups receiving DOX alone (10 mg/kg), S9788 alone (50 mg/kg) or both DOX + S9788]. The weight of the mice, tumoral volume (TV), doubling time (DT) of the tumor and survival time of mice were evaluated in each group. In addition, the efficiency of DOX with or without S9788 was assessed by the inhibition of tumoral growth and specific growth delay. In vitro, glycoprotein P 170 (P-gp) was detected on tissular sections and on tumoral cells by immunocytochemistry or flow cytometry with several monoclonal antibodies: JSB1, MRK 16, C219 and UIC2. In vivo the weight of the mice decreased slightly with DOX and dropped dramatically with DOX + S9788. The DT of the tumors increased with DOX over controls (22.5 +/- 8.5/12.7 +/- 3.9 days) and showed a higher value with DOX + S9788 (29.2 +/- 11.4 days). Inhibition of tumoral growth, 89% with DOX, fell to 47.6% with DOX + S9788. Specific growth delay increased with the double treatment (130 versus 75% with DOX alone). In vitro, P-gp was not detected on tissular sections and cells whatever the method and the antibody used. In conclusion, S9788 potentiates the efficiency of DOX treatment in vivo. The absence of P-gp may result from the absence of translation of the MDR1 gene. The reversal effect of S9788 may involve another resistance mechanism such as the MDR Sister of MRP.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma; Doxorubicin; Drug Synergism; Female; Humans; Mice; Mice, Nude; Piperidines; Thyroid Neoplasms; Triazines; Tumor Cells, Cultured

Multidrug resistance was investigated in TT cells, a human medullary thyroid carcinoma (MTC) cell line and in normal thyrocytes. MDR1 mRNA was revealed by polymerase chain reaction (PCR) analysis both in normal and neoplastic cells despite the absence of glycoprotein P (Pgp) by immunohistochemistry using JSB-1 monoclonal antibody. Glutathione-S-transferase mRNA was undetectable by Northern blotting in TT cells. Doxorubicin-induced cytotoxicity was evaluated in TT cells with MTT, lacticodehydrogenase (LDH), glutathione (GSH) assays and neutral red uptake. IC50 values obtained for MTT assays were higher than those obtained with the three other tests. Cyclosporin A (CSA) (3 microM), verapamil (10 microM) and S9788 (5 microM) partially reversed the resistance to doxorubicin after a 48 h co-incubation (followed by a 24 h post-incubation for the S9788). Under these conditions, GSH levels were altered by verapamil and S9788, whereas CSA decreased LDH activity. CSA and verapamil had no effect on MTT assay. In conclusion this MTC cell line exhibited over-expression of the MDR1 gene and its resistance to doxorubicin can be partially reversed by CSA, verapamil and S9788.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Carcinoma, Medullary; Cyclosporine; Doxorubicin; Drug Resistance, Multiple; Drug Synergism; Glutathione; Glutathione Transferase; Humans; Neoplasm Proteins; Piperidines; Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Thyroid Neoplasms; Triazines; Verapamil