31 results on '"Carla Vaz, Ferreira"'
Search Results
2. The BRAFV600E mutation analysis and risk stratification in papillary thyroid carcinoma
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Rafael Selbach Scheffel, Ana Patrícia de Cristo, Mirian Romitti, Carla Vaz Ferreira Vargas, Lucieli Ceolin, André B. Zanella, Jose Miguel Dora, and Ana Luiza Maia
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Papillary thyroid carcinoma ,BRAF mutation ,risk classification ,persistent disease ,Medicine ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
ABSTRACT Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively. The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients.
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- 2020
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3. An Undetectable Postoperative Calcitonin Level Is Associated with Long-Term Disease-Free Survival in Medullary Thyroid Carcinoma: Results of a Retrospective Cohort Study
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Marta Amaro da Silveira, Duval, Carla Vaz, Ferreira, Laura, Marmitt, José Miguel, Dora, Mateus, Espíndola, Antonio Felipe, Benini, Marli Viapiana, Camelier, Daniel, Bulzico, Fernanda Accioly de, Andrade, Paulo Alonso, Alves Júnior, Rossana, Corbo, Fernanda, Vaisman, André Borsatto, Zanella, Rafael Selbach, Scheffel, and Ana Luiza, Maia
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Endocrinology ,Endocrinology, Diabetes and Metabolism - Published
- 2023
4. Neoadjuvant Multikinase Inhibitor in Patients With Locally Advanced Unresectable Thyroid Carcinoma
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Carla Fernanda Nava, Rafael Selbach Scheffel, Ana Patrícia Cristo, Carla Vaz Ferreira, Shana Weber, André Borsatto Zanella, Francisco Costa Paixão, Alceu Migliavaca, José Ricardo Guimarães, Marcia Silveira Graudenz, José Miguel Dora, and Ana Luiza Maia
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thyroid carcinoma ,multikinase inhibitors ,neoadjuvant therapy ,unresectable thyroid tumors ,locally invasive thyroid tumors ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Background: Papillary thyroid carcinoma (PTC) is the most common and less aggressive thyroid cancer, but some patients may display locally advanced disease. Therapeutic options are limited in these cases, particularly for those patients with unresectable tumors. Neoadjuvant therapy is not part of the recommended work up.Methods: Report a case of an unresectable grossly locally invasive PTC successfully managed with neoadjuvant therapy and provide a systematic review (SR) using the terms “Neoadjuvant therapy” AND “Thyroid carcinoma.”Results: A 32-year-old man with a 7.8 cm (in the largest dimension) PTC was referred to total thyroidectomy, but tumor resection was not feasible due to extensive local invasion (trachea, esophagus, and adjacent structures). Sorafenib, a multikinase inhibitor (MKI), was initiated; a 70% tumor reduction was observed after 6 months, allowing new surgical intervention and complete resection. Radioactive iodine (RAI) was administered as adjuvant therapy, and whole body scan (WBS) shows uptake on thyroid bed. One-year post-surgery the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. The SR retrieved 123 studies on neoadjuvant therapy use in thyroid carcinoma; of them, 6 were extracted: 4 case reports and 2 observational studies. MKIs were used as neoadjuvant therapy in three clinical cases with 70–84% of tumor reduction allowing surgery.Conclusion: Our findings, along with other reports, suggest that MKIs is an effective neoadjuvant therapy and should be considered as a therapeutic strategy for unresectable grossly locally invasive thyroid carcinomas.
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- 2019
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5. Role of VEGF-A and Its Receptors in Sporadic and MEN2-Associated Pheochromocytoma
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Carla Vaz Ferreira, Débora Rodrigues Siqueira, Mírian Romitti, Lucieli Ceolin, Beatriz Assis Brasil, Luise Meurer, Clarissa Capp, and Ana Luiza Maia
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pheocromocytoma ,VEGF-A ,microvessel density ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%–80%) or as part of inherited syndromes (20%–24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38 ± 14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p = 0.027, p = 0.003 and p = 0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors.
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- 2014
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6. Advances and controversies in the management of medullary thyroid carcinoma
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Maia, Ana Luiza, Wajner, Simone Magagnin, and Vargas, Carla Vaz Ferreira
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- 2017
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7. Effect of 3'UTR RET Variants on RET mRNA Secondary Structure and Disease Presentation in Medullary Thyroid Carcinoma.
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Lucieli Ceolin, Mirian Romitti, Débora Rodrigues Siqueira, Carla Vaz Ferreira, Jessica Oliboni Scapineli, Beatriz Assis-Brazil, Rodolfo Vieira Maximiano, Tauanne Dias Amarante, Miriam Celi de Souza Nunes, Gerald Weber, and Ana Luiza Maia
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Medicine ,Science - Abstract
BACKGROUND:The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients. OBJECTIVE:To evaluate the frequency of the RET 3'UTR variants (rs76759170 and rs3026785) in MTC patients and to determine whether these variants are in LD with S836S polymorphism. METHODS:Our sample comprised 152 patients with sporadic MTC. The RET S836S and 3'UTR (rs76759170 and rs3026785) variants were genotyped using Custom TaqMan Genotyping Assays. Haplotypes were inferred using the phase 2.1 program. RET mRNA structure was assessed by Vienna Package. RESULTS:The mean age of MTC diagnosis was 48.5±15.5 years and 57.9% were women. The minor allele frequencies of RET polymorphisms were as follows: S836S, 5.6%; rs76759170, 5.6%; rs3026785, 6.2%. We observed a strong LD among S836S and 3'UTR variants (|D'| = -1, r2 = 1 and |D'| = -1, r2 = 0,967). Patients harboring the S836S/3'UTR variants presented a higher percentage of lymph node and distant metastasis (P = 0.013 and P
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- 2016
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8. The BRAFV600E mutation analysis and risk stratification in papillary thyroid carcinoma
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Ana Patrícia de Cristo, José Miguel Dora, André Borsatto Zanella, Rafael Selbach Scheffel, Lucieli Ceolin, Mirian Romitti, Ana Luiza Maia, and Carla Vaz Ferreira Vargas
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medicine.medical_specialty ,Multivariate analysis ,business.industry ,Endocrinology, Diabetes and Metabolism ,Thyroid ,persistent disease ,Généralités ,Disease ,RC648-665 ,Gastroenterology ,Diseases of the endocrine glands. Clinical endocrinology ,Thyroid carcinoma ,medicine.anatomical_structure ,BRAF mutation ,Internal medicine ,Papillary thyroid carcinoma ,Mutation (genetic algorithm) ,Risk stratification ,medicine ,Mutation testing ,Medicine ,business ,Lymph node ,risk classification - Abstract
Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively.The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients. Arch Endocrinol Metab. 2020;64(6):751-7., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2020
9. The BRAF
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Rafael Selbach, Scheffel, Ana Patrícia, de Cristo, Mirian, Romitti, Carla Vaz Ferreira, Vargas, Lucieli, Ceolin, André B, Zanella, Jose Miguel, Dora, and Ana Luiza, Maia
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Proto-Oncogene Proteins B-raf ,Thyroid Cancer, Papillary ,Carcinoma ,Mutation ,Humans ,Thyroid Neoplasms ,Prognosis ,Risk Assessment ,Carcinoma, Papillary - Abstract
Although the prognostic role of BRAFPTC patients attending a university-based hospital who had the analysis of the BRAFOf the 134 patients evaluated, 44 (32.8%) carried BRAFInclusion of BRAF
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- 2021
10. The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma
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Rafael Selbach Scheffel, Lucieli Ceolin, Antônio Felippe Benini, Carla Vaz Ferreira Vargas, Ana Luiza Maia, and Márcia Silveira Graudenz
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Male ,Pathology ,medicine.medical_specialty ,endocrine system diseases ,Medullary cavity ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Stem cell marker ,Metastasis ,Thyroid carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine ,Biomarkers, Tumor ,Humans ,Thyroid Neoplasms ,Tumor marker ,business.industry ,medicine.disease ,Primary tumor ,Immunohistochemistry ,digestive system diseases ,Carcinoma, Neuroendocrine ,030220 oncology & carcinogenesis ,CA19-9 ,Female ,business ,Neck - Abstract
Elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well-established tumor marker in pancreatic neoplasms, has been proposed as a prognostic marker of tumor aggressiveness in medullary thyroid carcinoma (MTC). A hypothesis of C-cell dedifferentiation has been raised. Here, we evaluated the expression of CA19.9 and CD133, a stem cell marker, in MTC tissues. MTC samples from patients attending a university-based hospital were evaluated for CA19.9 and CD133 expression by immunohistochemistry. Clinical data were retrieved from medical records. Tumor specimens from 70 MTC patients (57.1% hereditary) were evaluated. The age at diagnosis was 36.1 ± 16.3 years, and 58.6% were female; 53% of patients had cervical and 20% distant metastases. CA19.9 staining was detected in 87% of the samples, but no association was observed with biochemical markers, tumor size, local or distant metastases (All P > 0.05). Remarkable, CA19.9 expression was higher in the metastasis than in primary tumor samples (P = 0.0002). CD133 was expressed in 90.5% samples, but no correlation was found with CA19.9. Interestingly, we identified three distinct expression patterns to CA19.9: individual, focal, and diffuse cells. Sporadic MTC was associated with the individual cell pattern (70.6%), while the hereditary form with the focal expression pattern (63.9%; P = 0.04). Remarkably, the diffuse pattern was associated with larger tumor size and distant metastases (P = 0.032). The majority of samples stained for CA19.9, suggesting it is an MTC cell-intrinsic feature. Three distinct expression patterns were identified, which were associated with the hereditary or sporadic form, larger tumor size, and presence of metastases.
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- 2020
11. The brafv600e mutation analysis and risk stratification in papillary thyroid carcinoma
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Scheffel, Rafael Selbach, de Cristo, Ana Patrícia, Romitti, Mirian, Vargas, Carla Vaz Ferreira, Ceolin, Lucieli, Zanella, André Borsatto, Dora, Jose Miguel, Maia, Ana Luiza, Scheffel, Rafael Selbach, de Cristo, Ana Patrícia, Romitti, Mirian, Vargas, Carla Vaz Ferreira, Ceolin, Lucieli, Zanella, André Borsatto, Dora, Jose Miguel, and Maia, Ana Luiza
- Abstract
Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively.The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients. Arch Endocrinol Metab. 2020;64(6):751-7., SCOPUS: ar.j, info:eu-repo/semantics/published
- Published
- 2020
12. Global DNA methylation profile in medullary thyroid cancer patients
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Carla Vaz Ferreira, Mirian Romitti, Ana Luiza Maia, Ana Paula Palauro Goularte, and Lucieli Ceolin
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,endocrine system diseases ,Clinical Biochemistry ,medicine.disease_cause ,Pathology and Forensic Medicine ,Thyroid carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Leukocytes ,Humans ,Medicine ,Thyroid Neoplasms ,Neoplasm Metastasis ,Molecular Biology ,Thyroid cancer ,business.industry ,Global DNA Methylation Profile ,Medullary thyroid cancer ,Cancer ,Methylation ,DNA Methylation ,Middle Aged ,medicine.disease ,Carcinoma, Papillary ,Carcinoma, Neuroendocrine ,030104 developmental biology ,Thyroid Cancer, Papillary ,Case-Control Studies ,030220 oncology & carcinogenesis ,DNA methylation ,Female ,business ,Carcinogenesis - Abstract
Background Changes in global DNA methylation have been suggested to cause genomic instability leading to increased risk of cancer. The accumulation of epigenetic changes is believed to contribute to tumorigenesis and dedifferentiation, but the effects of such changes in thyroid cancer are still yet defined. Objective To evaluate the global DNA methylation levels in thyroid cancer patients. Methods Total DNA was extracted from peripheral blood leukocytes of the medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) patients and the methylation pattern was evaluated using the Imprint Methylated DNA Quantification kit (Sigma-Aldrich). Results A total of 42 patients were analyzed (24 MTC, 12 PTC, and 6 controls). For MTC, the mean age was 41 ± 20 years, 54% were women and 12 cases were sporadic. The median calcitonin level at diagnosis was 1692 (637–8865), 65% of the MTC patients had local metastases and 23% distant metastases. For PTC, the median age was 43 ± 15 years, 58% were women and 50% had local metastases. The percentage of overall methylation differed according to the tumor subtype. Patients with MTC had a higher level of DNA methylation when compared to individuals with PTC (35 (24–48) vs. 17 (6.5–20.5); P = 0.002, respectively). Interestingly, among patients with MTC, individuals with the sporadic form of the disease had a higher level of methylation when compared to the hereditary form (25 (16–37) vs. 43 (33–52); P = 0.025, respectively). No association was observed between global methylation levels and clinical and/or oncological characteristics of the disease. Conclusion Global methylation levels were higher in MTC as compared to PTC patients. These results suggest the overall DNA methylation profile may be influenced by the histological subtype of thyroid cancer.
- Published
- 2018
13. The BRAFV600E mutation analysis and risk stratification in papillary thyroid carcinoma
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Scheffel, Rafael Selbach, primary, Cristo, Ana Patrícia de, additional, Romitti, Mirian, additional, Vargas, Carla Vaz Ferreira, additional, Ceolin, Lucieli, additional, Zanella, André B., additional, Dora, Jose Miguel, additional, and Maia, Ana Luiza, additional
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- 2020
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14. Advances and controversies in the management of medullary thyroid carcinoma
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Simone Magagnin Wajner, Carla Vaz Ferreira Vargas, and Ana Luiza Maia
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Oncology ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Cabozantinib ,medicine.drug_class ,medicine.medical_treatment ,030209 endocrinology & metabolism ,Vandetanib ,Receptor tyrosine kinase ,Tyrosine-kinase inhibitor ,Targeted therapy ,Thyroid carcinoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Molecular Targeted Therapy ,Thyroid Neoplasms ,Protein Kinase Inhibitors ,biology ,business.industry ,Thyroid ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Carcinoma, Medullary ,030220 oncology & carcinogenesis ,biology.protein ,business ,Progressive disease ,medicine.drug - Abstract
Purpose of review Medullary thyroid carcinoma (MTC) comprises approximately 4% of all malignant thyroid neoplasms. Although the majority of patients have a good prognosis, a subgroup of patients develops progressive disease and requires systemic therapy. Here, we focused on the current MTC therapeutic approaches and discussed the advantages and disadvantages of molecular targeted therapies. Recent findings Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have been shown to improve progression-free survival in patients with advanced MTC. Two drugs, vandetanib and cabozantinib, have been approved for the treatment of progressive or symptomatic MTC, and several others have exhibited variable efficacy. No tyrosine kinase inhibitor has been shown to improve survival. Although no definitive recommendation can currently be made, cumulative data indicate that knowledge of the tumor mutational profile may facilitate improvements in targeted therapy for MTC. Summary Tyrosine kinase inhibitors are effective therapeutic agents for the treatment of progressive MTC. Nevertheless, it is not clear who will benefit the most from therapy, and the decision regarding when and how to initiate the treatment should be made based on the patient's medical history and tumor behavior. Hopefully, in the near future, molecular profiling of MTC can be used to determine the most effective molecular therapeutic target.
- Published
- 2017
15. Vascular White Matter Lesions in Young Adults: A Neurology Outpatient Clinic Registry
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Fernando Silva, Pedro Soares, Ana Amélia Nogueira Pinto, João Pedro Marto, Miguel Viana-Baptista, Vera Cruz-e-Silva, Teresa Pinho-e-Melo, Andreia Veiga, Carla Vaz Ferreira, Elsa Azevedo, Miguel Rodrigues, Cátia Carmona, João Martins, Francisco Javier Ros Forteza, Nuno Inácio, André Caetano, and Portywhite investigators
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Adult ,Male ,medicine.medical_specialty ,Pediatrics ,Neurology ,Adolescent ,Population ,Young Adult ,Leukoencephalopathies ,Risk Factors ,Medicine ,Outpatient clinic ,Humans ,Registries ,Young adult ,CADASIL ,education ,Stroke ,Aged ,education.field_of_study ,business.industry ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,Hyperintensity ,Etiology ,Female ,Neurology (clinical) ,business - Abstract
Introduction: Although frequently assumed to be age-related changes, vascular white matter lesions (WML) are sometimes found in young adults. Etiology is usually attributed to sporadic small vessel disease; nevertheless, genetic disorders may also be implicated. We aimed to characterize the population of young adults with vascular WML in Neurology outpatient clinics. Methods: Neurologists from 12 Portuguese hospitals were invited to include patients aged 18–55 years evaluated in consultation, with vascular WML on MRI, scoring II or III in the Fazekas scale. Central imaging validation was performed by 2 independent, blinded, Neuroradiologists. Demographic and clinical data were collected as well as results of investigations performed. Results: During 2 years, 77 patients were included (mean age 47.7 years). Vascular risk factors were present in 88.3% patients (hypertension in 53.2%) and previous history of stroke in 36.4%. Patients without history of stroke were younger (46.6 ± 7.2 vs. 49.6 ± 3.9 years, p = 0.045) and had fewer vascular risk factors (p < 0.001). They were more frequently females (87.8 vs. 46.4%, p < 0.001), and headache (30.6 vs. 3.6%, p = 0.007), contrary to focal symptoms (16.3 vs. 53.6%, p = 0.001), was the most frequent reason of referral. Etiological investigations performed differed between Neurologists. A genetic disorder was identified in 6 out of 58 patients (CADASIL n = 5; COL4A1 n = 1). Conclusion: Young adults with vascular WML evaluated in Neurology outpatient clinics concentrate in the oldest age groups. Vascular risk factors should be screened carefully in this population. Among patients without history of stroke, females largely outweigh males. Diagnostic investigations performed do not follow a standardized protocol.
- Published
- 2019
16. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives
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Carla Vaz Ferreira, Lucieli Ceolin, Antônio Felippe Benini, Marta Amaro da Silveira Duval, and Ana Luiza Maia
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0301 basic medicine ,Cancer Research ,endocrine system diseases ,Medullary cavity ,Cabozantinib ,Genotype ,Somatic cell ,Endocrinology, Diabetes and Metabolism ,Molecular target therapy ,Tyrosine kinase inhibitor ,Antineoplastic Agents ,Vandetanib ,Proto-Oncogene Mas ,Thyroid carcinoma ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Germline mutation ,Neoplasias da glândula tireóide ,medicine ,Humans ,Molecular Targeted Therapy ,Thyroid Neoplasms ,Protein Kinase Inhibitors ,Medullary thyroid cancer ,business.industry ,Thyroid ,Terapia de alvo molecular ,Imunoterapia ,Carcinoma, Neuroendocrine ,030104 developmental biology ,medicine.anatomical_structure ,Phenotype ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Immunotherapy ,Inibidores de proteínas quinases ,business ,medicine.drug ,Signal Transduction - Abstract
Medullary thyroid carcinoma (MTC) is a rare type of tumor that originates from thyroid C cells and accounts for 2–4% of all malignant thyroid neoplasms. MTC may occur sporadically or be inherited, as part of the MEN 2 syndrome. Germline mutations of the RET (REarranged during Transfection) proto-oncogene cause hereditary cancer, whereas somatic RET mutations and, less frequently, RAS mutations have been described in sporadic MTC samples. Since early surgery with complete resection of tumor mostly determines the likelihood of attaining cure for MTC, the broader use of RET genetic screening has dramatically changed the prognostic of gene carriers in hereditary MTC. Nevertheless, despite recent advances, the management of advanced, progressive MTC remains challenging. The multikinase inhibitors (MKI), vandetanib and cabozantinib, were approved for the treatment of progressive or symptomatic MTC, and several other compounds have exhibited variable efficacy. Although these drugs have been shown to improve progression-free survival, no MKI has been shown to increase the overall survival. As these drugs are nonselective, significant off-target toxicities may occur, limiting achievement of the required TK-specific inhibition. Recently, next-generation small-molecule TKI has been developed. These TKI are specifically designed for highly potent and selective targeting of oncogenic RET alterations, making them promising drugs for the treatment of advanced MTC. Here, we summarize the current understanding of the intracellular signaling pathways involved in MTC pathogenesis as well as the therapeutic approaches and challenges for the management of advanced MTC, focusing on targeted molecular therapies.
- Published
- 2019
17. Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study
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Léa Maria Zanini Maciel, Carla Vaz Ferreira, Sergio P. A. Toledo, Flávia O. F. Valente, Luciana A. Castroneves, Rui M. B. Maciel, Gisah Amaral de Carvalho, Rita V Weiss, Janete M. Cerutti, Henrique de Campos Reis Galvão, Tânia M B L Ferraz, Célia Regina Nogueira, Patrícia Künzle Ribeiro Magalhães, Francisco M de Castro, Shana de Souto Weber, Vera L.G. Leal, Cencita H. C. N. Pessoa, M Inez C França, Natassia Elena Bufalo, Gláucia Maria Ferreira da Silva Mazeto, Maria A. Sousa, Ji H. Yang, Bibiana Prada, Débora Rodrigues Siqueira, M Cecília Martins-Costa, Magnus R. Dias-da-Silva, Rossana Corbo, João Roberto Maciel Martins, Ana Luiza Maia, Ana O. Hoff, Delmar M. Lourenço, Laura Sterian Ward, Edenir Inêz Palmero, Hans Graf, Marcio W Lauria, Rodrigo A. Toledo, Alexander A. L. Jorge, Ligia V. M. Assumpção, Anelise I Impellizzeri, Ilda S. Kunii, Fernanda Vaisman, Lucieli Ceolin, Fausto Germano-Neto, André Lopes Carvalho, Susan C. Lindsey, and Cleber P. Camacho
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Genetics ,lcsh:RC648-665 ,business.industry ,Endocrinology, Diabetes and Metabolism ,Research ,Medullary thyroid cancer ,Multiple endocrine neoplasia type 2 ,Disease ,medicine.disease ,Genome ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,pheochromocytoma ,Thyroid carcinoma ,Exon ,Endocrinology ,Germline mutation ,Genotype-phenotype distinction ,medullary thyroid carcinoma ,Internal Medicine ,medicine ,multiple endocrine neoplasia ,business ,RET ,Brazil - Abstract
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.
- Published
- 2019
18. Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study
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Mariola Pęczkowska, Akihiro Sukurai, Anita Špehar Uroić, Andreas Machens, Laura Fugazzola, Tushar Bandgar, Carla Vaz Ferreira Vargas, Hartmut P. H. Neumann, Martin Schlumberger, Delphine Drui, Patricia Fainstein-Day, Francoise Borson Chazot, Amandine Berdelou, Tom R. Kurzawinski, Delphine Mirebeau-Prunier, Olivier Chabre, Dominique Maiter, Philippe Caron, Gabriella Sanso, Tsuneo Imai, Camilo Jimenez, Frederic Sebag, Márta Korbonits, Atila Patocs, Laura Valerio, Sarka Dvorakova, Claudio Letizia, Srivandana Akshintala, Christian Godballe, Regis Cohen, Eric Baudin, Caterina Mian, Jolanta Krajewska, Rossella Elisei, Laurence Leclerc, Tobias Else, Marc Klein, Kornelia Hasse-Lazar, Thierry Brue, Steven G. Waguespack, Petr Vlcek, Nuria Valdes, Thera P. Links, Ana Luisa Maia, Ana O. Hoff, Henning Dralle, Frederic Castinetti, André Lacroix, Xiao Ping Qi, Maria João Bugalho, Maralyn Druce, Nelson Wohllk, Barbara Jarzab, Birke Bausch, Delmar M. Lourenço, John Glod, Shinya Uchino, Caroline Brain, Letizia Canu, Charis Eng, Marta Barontini, Jes Sloth Mathiesen, Antoine Tabarin, Elizabeth G. Grubbs, Lucieli Ceolin, Sandrine Laboureau, Repositório da Universidade de Lisboa, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), University of Coimbra [Portugal] (UC), Endocrine Section, Hospital del Salvador, Département d'Endocrinologie [CHU Nantes] (Institut du Thorax), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut du Thorax [Nantes], Queen Mary University of London (QMUL), Centre de médecine nucléaire, Fédération d'endocrinologie-Groupement hospitalier Lyon-Est, Department of Internal Medicine and Medical Specialties, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Endocrinology and Diabetes Mellitus, Hôpital Delafontaine, CHU Bordeaux [Bordeaux], Endocrinology, Cliniques Universitaires Saint-Luc [Bruxelles], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Department of Medical and Surgical Sciences, Universita degli Studi di Padova, Department of Hypertension, Institute of Cardiology, Service de chirurgie générale et endocrinienne, Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Centro de Investigaciones Endocrinológicas, Hospital de Niños R. Gutiérrez, Genomic Medicine Institute, Cleveland Clinic, Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)-Fédération d'endocrinologie, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Università degli Studi di Firenze = University of Florence (UniFI), Università degli Studi di Padova = University of Padua (Unipd), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Male ,Pediatrics ,PHEOCHROMOCYTOMA ,MEDULLARY-THYROID CARCINOMA ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Medizin ,Adrenal Gland Neoplasms ,Multiple Endocrine Neoplasia Type 2b ,Internal Medicine ,Endocrinology ,surgery ,0302 clinical medicine ,DOMAIN ,030212 general & internal medicine ,Child ,MUTATION ,men2 ,Middle Aged ,Prognosis ,Penetrance ,CANCER ,3. Good health ,Diabetes and Metabolism ,Natural history ,Survival Rate ,Child, Preschool ,RET PROTOONCOGENE ,MANAGEMENT ,Cohort ,Thyroidectomy ,Female ,Multiple endocrine neoplasia type 2b ,Adult ,medicine.medical_specialty ,Adolescent ,030209 endocrinology & metabolism ,Pheochromocytoma ,03 medical and health sciences ,Young Adult ,medicine ,Humans ,Thyroid Neoplasms ,Survival rate ,Retrospective Studies ,adrenal gland ,business.industry ,Infant ,International Agencies ,Retrospective cohort study ,medicine.disease ,Carcinoma, Neuroendocrine ,MEN2b ,business ,Follow-Up Studies - Abstract
© 2019 Elsevier Ltd. All rights reserved., Background: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. Methods: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. Findings: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range
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- 2019
19. Neoadjuvant multikinase inhibitor in patients with locally advanced unresectable thyroid carcinoma
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Nava, Carla Fernanda, Scheffel, Rafael Selbach, Cristo, Ana Patrícia de, Vargas, Carla Vaz Ferreira, Weber, Shana de Souto, Zanella, André Borsatto, Paixão, Francisco Costa, Guimaraes, Jose Ricardo, Graudenz, Márcia Silveira, Dora, José Miguel Silva, and Maia, Ana Luiza Silva
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Terapia neoadjuvante ,Thyroid carcinoma ,Neoplasias da glândula tireóide ,Neoadjuvant therapy ,Unresectable thyroid tumors ,Locally invasive thyroid tumors ,Multikinase inhibitors ,Câncer papilífero da tireoide - Abstract
Background: Papillary thyroid carcinoma (PTC) is the most common and less aggressive thyroid cancer, but some patients may display locally advanced disease. Therapeutic options are limited in these cases, particularly for those patients with unresectable tumors. Neoadjuvant therapy is not part of the recommended work up. Methods: Report a case of an unresectable grossly locally invasive PTC successfully managed with neoadjuvant therapy and provide a systematic review (SR) using the terms “Neoadjuvant therapy” AND “Thyroid carcinoma.” Results: A 32-year-old man with a 7.8 cm (in the largest dimension) PTC was referred to total thyroidectomy, but tumor resection was not feasible due to extensive local invasion (trachea, esophagus, and adjacent structures). Sorafenib, a multikinase inhibitor (MKI), was initiated; a 70% tumor reduction was observed after 6 months, allowing new surgical intervention and complete resection. Radioactive iodine (RAI) was administered as adjuvant therapy, and whole body scan (WBS) shows uptake on thyroid bed. One-year post-surgery the patient is asymptomatic with a status of disease defined as an incomplete biochemical response. The SR retrieved 123 studies on neoadjuvant therapy use in thyroid carcinoma; of them, 6 were extracted: 4 case reports and 2 observational studies. MKIs were used as neoadjuvant therapy in three clinical cases with 70–84% of tumor reduction allowing surgery. Conclusion: Our findings, along with other reports, suggest that MKIs is an effective neoadjuvant therapy and should be considered as a therapeutic strategy for unresectable grossly locally invasive thyroid carcinomas.
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- 2019
20. MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma
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Carla Vaz Ferreira, Shana de Souto Weber, Simone Magagnin Wajner, Ana Luiza Maia, Edna Teruko Kimura, Mirian Romitti, Helena Cecin Rohenkohl, Cesar Seigi Fuziwara, Rafaela Vanin Pinto Ribeiro, Lucieli Ceolin, and Patrícia Luciana da Costa Lopez
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Proto-Oncogene Proteins B-raf ,0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,medicine.medical_specialty ,Cyclopamine ,Endocrinology, Diabetes and Metabolism ,Deiodinase ,MAP Kinase Kinase 1 ,Iodide Peroxidase ,p38 Mitogen-Activated Protein Kinases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Cyclin D1 ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Gene silencing ,Hedgehog Proteins ,RNA, Messenger ,Thyroid Neoplasms ,RNA, Small Interfering ,Cell Proliferation ,biology ,Oncogene ,Carcinoma ,Carcinoma, Papillary ,Hedgehog signaling pathway ,030104 developmental biology ,Oncology ,chemistry ,Thyroid Cancer, Papillary ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,biology.protein ,V600E ,Signal Transduction - Abstract
Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metastatic disease. The objective of this study is to investigate the signaling pathways involved inDIO3upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples.DIO3mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein.DIO3gene silencing was performed via siRNA transfection.DIO3mRNA levels and activity were readily detected in K1 (BRAFV600E) and, at lower levels, in TPC-1 (RET/PTC1) cells (PP=0.02 respectively). Similarly,DIO3mRNA levels were higher in PTC samples harboring theBRAFV600Emutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (PBRAFoncogene (PLX4032, 3 μM), MEK (U0126, 10–20 μM) or p38 (SB203580, 10–20 μM) signaling was associated with decreases inDIO3expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 μM) resulted in markedly decreases inDIO3mRNA levels. Interestingly, siRNA-mediatedDIO3silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels ofDIO3expression in PTC. Importantly,DIO3silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.
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- 2016
21. Papel do antigeno carboidrato 19.9 como marcador de agressividade no carcinoma medular de tireoide
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Vargas, Carla Vaz Ferreira and Maia, Ana Luiza Silva
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Proteínas tirosina quinases ,Neoplasias da glândula tireóide ,Carcinoma medular - Abstract
O carcinoma medular da tireoide (CMT) é um tumor maligno raro originário de células C parafoliculares da tireoide e corresponde a 4% das neoplasias malignas dessa glândula. O CMT apresenta-se como um tumor esporádico (75-80%) ou na forma hereditária (20-25%). O único tratamento curativo disponível no momento para o CMT é cirúrgico. No entanto, isso só é possível em casos em que o diagnóstico é realizado precocemente e a doença encontra-se restrita a glândula. Nos pacientes com doença avançada, onde as opções terapêuticas tradicionais como quimioterapia e radioterapia não são efetivas, os inibidores tirosino-quinase tem demonstrado eficácia na sobrevida livre de progessão da doença. Níveis de calcitonina sérica, um biomarcador específico para céluas C tireoideanas, e o antígeno-carcinoembrionário (CEA) são amplamente utilizados como marcadores no diagnóstico e seguimento dos pacientes com CMT. No entanto, estudos recentes têm indicado que níveis séricos elevados do antígeno carboidrato 19.9 (CA19.9), marcador tumoral bem estabelecido no em neoplasias pancreáticas, como um potencial marcador de agressividade e mortalidade em indivíduos com CMT avançado. O objetivo desse trabalho foi avaliar o papel do CA19.9 como marcador de agressividade tumoral em pacientes com CMT. Amostras tumorais de pacientes com CMT atendidos no Serviço de Endocrinologia do HCPA foram avaliados para expressão do CA19.9 por imunohistoquimica, através de anticorpo especifico. Para estudar a hipótese de os níveis de CA19.9 observados em pacientes com CMT estarem associados à desdiferenciação das células C, também avaliamos a expressão tecidual de CD133, um marcador para a identificação de células-tronco cancerígenas (CSC). A leitura das lâminas foi realizada por patologista, e quantificação da expressão foi inicialmente realizada pelo método de h-score. Adicionalmente as amostras foram classificadas de acordo com o padrão de expressão observado: células individuais, focos ou difuso. Setenta pacientes com CMT foram incluídos no estudo, 57,1% apresentavam a forma hereditária e 42,9% a forma esporádica. A idade média ao diagnóstico foi 36.1 (±16.3) anos e 58,6% foram do sexo feminino. A mediana dos níveis de calcitonina e CEA foram de 536pg/ml (49,35-1300,5) e 21,3ng/ml (3,6-52,6), respectivamente. Aproximadamente 53% dos pacientes apresentavam metástases locais e 20% à distância ao diagnóstico. Das 64 amostras de tumor primário disponíveis para analise, 56 (87,5%) apresentaram expressão do CA19.9, com mediana de h-score 14 (2-30). De forma semelhante, o CD133 estava expresso em 90.5% das amostras de tumor primário, no entanto não se observou nenhuma correlação entre os dois marcadores estudados (r=- 0.09; P=0.74). Não foram observadas diferenças na expressão de CA19.9 sobre idade, sexo, níveis 11 séricos calcitonina ou CEA (P>0,05). Curiosamente amostras de CMT hereditário tinham maior expressão de CA19.9 que amostras de CMT esporádico. Observamos três padrões de expressão distintos para o CA19.9: células individuais, focal e difuso. A maioria das amostras (64,3%) apresentaram o padrão de expressão focal. O padrão de células individuais foi observado em 17 (30,3%) das amostras e o padrão difuso em 3 (5,4%). As formas esporádica e hereditária da doença apresentaram diferentes padrões de expressão. De forma interessante, o CMT esporádico mostrouse associado ao padrão de células individuais (70,6%), enquanto a forma hereditária foi associada ao padrão focal de expressão (63,9%) (P=0,04). Adicionalmente, o padrão de células individuais foi associado a metástases local (P=0,055) enquanto que o padrão difuso, a metástases à distância (P=0,032). Nossos resultados demonstram expressão do CA19.9 na maioria das amostras de CMT. Diferenças nos níveis de expressão do CA19.9 não foram associadas às características clínicas ou oncológicas, sendo no entanto significativamente mais elevados em amostras de CMT hereditário. Três padrões de expressão distintos foram observados, sendo que o padrão difuso foi associado à presença de metástases à distância ao diagnóstico. Em conclusão, o CA19.9 é amplamente expresso no CMT e apresenta características distintas de outros marcadores atualmente utilizados. Estudos adicionais podem definir o papel desse marcador no manejo de pacientes de CMT. Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from parafollicular C-cell of the thyroid and corresponds to 4% of malignant neoplasms of this gland. MTC presents as a sporadic tumor (75-80%) or in hereditary form (20-25%). The only curative treatment currently available for MTC is surgical. However, this is only possible in cases of early diagnosis and the disease is restricted to the gland. In patients with advanced disease, where traditional therapeutic options such as chemotherapy and radiotherapy are not effective, tyrosine kinase inhibitors have demonstrated efficacy in disease-free survival. Levels of serum calcitonin, a specific biomarker for thyroid C-cells, and carcinoembryonic antigen (CEA) are widely used as markers in the diagnosis and follow-up of patients with MTC. However, recent studies have indicated that elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well established tumor marker in pancreatic neoplasms, are a potential marker of aggression and mortality in individuals with advanced MTC. The objective of this study was to evaluate the role of CA19.9 as a marker of tumor aggressiveness in patients with MTC. Tumor samples from MTC patients treated at the HCPA Endocrinology Service were evaluated for expression of CA19.9 by immunohistochemistry using a specific antibody. To study the hypothesis that CA19.9 levels observed in patients with MTC are associated with C-cell dedifferentiation, we also assessed the tissue expression of CD133, a marker for the identification of cancer stem cells (CSC). The reading of the slides was performed by a pathologist, and quantification of the expression was initially performed by the h-score method. Additionally, the samples were classified according to the observed expression pattern: individual cells, focal or diffuse. Seventy patients with MTC were included in the study, 57.1% presented the hereditary form and 42.9% presented sporadic form. The mean age at diagnosis was 36.1 (± 16.3) years and 58.6% were female. The median levels of calcitonin and CEA were 536pg/ml (49.35-1300.5) and 21.3ng/ml (3.6-52.6), respectively. Approximately 53% of the patients had local metastases and 20% at a distance at diagnosis. Of the 64 primary tumor samples available for analysis, 56 (87.5%) presented CA19.9 expression, with median h-score 14 (2-30). Similarly, CD133 was expressed in 90.5% of the primary tumor samples. However, no correlation was observed between the two markers studied (r=-0.09; P=0.74). No differences in CA19.9 expression were observed on age, sex, serum calcitonin or CEA levels (P>0.05). Curiously, samples of hereditary MTC had higher CA19.9 expression than sporadic MTC samples. We observed three distinct expression patterns for 13 CA19.9: individual cells, focal and diffuse. Most of the samples (64.3%) had the focal expression pattern. The individual cell pattern was observed in 17 (30.3%) of the samples and the diffuse pattern in 3 (5.4%). The sporadic and hereditary forms of the disease presented different patterns of expression. Interestingly, sporadic CMT was associated with the individual cell pattern (70.6%), while the hereditary form was associated with the focal expression pattern (63.9%) (P=0.04). In addition, the individual cell pattern was associated with local metastases (P=0.055) while the diffuse pattern, with distant metastases (P=0.032). Our results demonstrate expression of CA19.9 in the majority of MTC samples. Differences in CA19.9 expression levels were not associated with clinical or oncological features disease but it were significantly higher in hereditary MTC samples. Three distinct expression patterns were observed, and the diffuse pattern was associated with the presence of distant metastases at diagnosis. In conclusion, CA19.9 is widely expressed in MTC and presents distinct characteristics of other markers currently used. Additional studies may define the role of this marker in the management of MTC patients.
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- 2018
22. Additive effect of RET polymorphisms on sporadic medullary thyroid carcinoma susceptibility and tumor aggressiveness
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Lucieli, Ceolin, Débora Rodrigues, Siqueira, Carla Vaz, Ferreira, Mírian, Romitti, Silvana Cavalcante, Maia, Leonardo, Leiria, Daisy, Crispim, Patrícia, Ashton-Prolla, Patrícia Ashton, Prolla, and Ana Luiza, Maia
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Adult ,Male ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,Endocrinology ,Gene Frequency ,Risk Factors ,Internal medicine ,Genetic variation ,Humans ,Medicine ,Genetic Predisposition to Disease ,Neoplasm Invasiveness ,Thyroid Neoplasms ,Allele ,Genotyping ,Allele frequency ,business.industry ,Proto-Oncogene Proteins c-ret ,Haplotype ,Genetic Variation ,General Medicine ,Odds ratio ,Middle Aged ,Carcinoma, Neuroendocrine ,Minor allele frequency ,Haplotypes ,Disease Progression ,Female ,business - Abstract
Objective: RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of medullary thyroid carcinoma (MTC). Here, we investigated the influence of multiple RET variants (G691S, L769L, S836S, and S904S) on the risk of MTC and tumor behavior. Design and methods: One hundred and seven MTC patients and 308 cancer-unaffected control individuals were included. SNPs were analyzed using Custom TaqMan Genotyping Assays. Haplotypes based on the combination of allelic variants were inferred using a Bayesian statistical method. Results: The minor allele frequencies in MTC patients were as follows: L769L: 28.0%, S836S: 8.9%, and G691S/S904S: 22.2%. The RET L769L and S836S SNPs were associated with increased risk of MTC (odds ratio (OR)Z1.95, 95% CI: 1.2–3.1, PZ0.005 and ORZ2.29, 95% CI: 1.2–4.5, PZ0.017 respectively). The adjusted OR for individuals harboring haplotypes with three or more polymorphic alleles was 3.79 (95% CI: 1.5–9.5; PZ0.004), indicating an additive effect of these variants on the risk for MTC. Among MTC patients, no significant associations were observed between RET variants and age of diagnosis or tumor size but serum calcitonin levels increased according to the number of risk alleles (PZ0.003). Remarkably, patients carrying haplotypes with three or four risk alleles had increased risk for lymph node and distant metastases at diagnosis (ORZ5.84, 95% CI: 1.1–31.2, PZ0.039). Further analysis using Kaplan–Meier model demonstrated that metastatic disease occurred earlier in individuals harboring multiple risk alleles. Conclusion: Our results demonstrated an additive effect of RET polymorphic alleles on the estimated risk of developing aggressive MTC.
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- 2012
23. Molecular Basis of Medullary Thyroid Carcinoma: The Role of RET Polymorphisms
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Débora Rodrigues Siqueira, Carla Vaz Ferreira, Lucieli Ceolin, Ana Luiza Maia, and Mirian Romitti
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Pathology ,medicine.medical_specialty ,Medullary cavity ,endocrine system diseases ,Genotype ,Population ,Guanine Nucleotide Exchange Factors -- chemistry -- metabolism ,RET polymorphisms ,Single-nucleotide polymorphism ,Review ,Proto-Oncogene Mas ,Catalysis ,Thyroid Neoplasms -- genetics -- metabolism -- pathology ,Inorganic Chemistry ,Thyroid carcinoma ,lcsh:Chemistry ,medullary thyroid carcinoma ,Clinical heterogeneity ,Medicine ,Guanine Nucleotide Exchange Factors ,Humans ,In patient ,Thyroid Neoplasms ,Physical and Theoretical Chemistry ,education ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Genetic Association Studies ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,Organic Chemistry ,Thyroid ,Proto-Oncogene Proteins c-ret -- chemistry -- genetics -- metabolism ,Proto-Oncogene Proteins c-ret ,Molecular pathogenesis ,General Medicine ,Sciences bio-médicales et agricoles ,Computer Science Applications ,Carcinoma, Neuroendocrine ,medicine.anatomical_structure ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research ,prognosis ,business - Abstract
Medullary thyroid carcinoma is a rare malignant tumor originating in parafollicular C cells. It accounts for 5 to 8% of all thyroid cancers. MTC develops in either sporadic (75%) or hereditary form (25%). Genetic and molecular studies have demonstrated the involvement of the RET proto-oncogene in hereditary MTC and, less often, in its sporadic form. Although a strong genotype-phenotype correlation has been described, wide clinical heterogeneity is observed among families with the same RET mutation or even in carriers of the same kindred. In recent years, several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. Some studies have reported associations between the presence of polymorphisms and development or progression of MTC. Nonetheless, other studies failed to demonstrate any effect of the RET variants. Differences in the genetic background of distinct populations or methodological approaches have been suggested as potential reasons for the conflicting results. Here, we review current knowledge concerning the molecular pathogenesis of sporadic and hereditary MTC. In particular, we analyze the role of RET polymorphisms in the clinical presentation and prognosis of MTC based on the current literature., info:eu-repo/semantics/published
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- 2011
24. Effect of 3'UTR RET Variants on RET mRNA Secondary Structure and Disease Presentation in Medullary Thyroid Carcinoma
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Carla Vaz Ferreira, Tauanne D. Amarante, Rodolfo Vieira Maximiano, Lucieli Ceolin, Jessica Oliboni Scapineli, Ana Luiza Maia, Débora Rodrigues Siqueira, Beatriz Assis-Brazil, Miriam Celi de Souza Nunes, Gerald Weber, and Mirian Romitti
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0301 basic medicine ,Male ,Linkage disequilibrium ,3' Untranslated Regions -- genetics ,Heredity ,endocrine system diseases ,Haplotypes -- genetics ,lcsh:Medicine ,Kaplan-Meier Estimate ,Biochemistry ,Linkage Disequilibrium ,Metastasis ,0302 clinical medicine ,Gene Frequency ,Basic Cancer Research ,Medicine and Health Sciences ,Mutation -- genetics ,lcsh:Science ,3' Untranslated Regions ,Thyroid Neoplasms -- genetics -- pathology ,Genetics ,Multidisciplinary ,RNA mensageiro ,Messenger RNA ,Sciences bio-médicales et agricoles ,Proto-Oncogene Proteins c-ret -- genetics ,Middle Aged ,Immunohistochemistry ,Nucleic acids ,Proteínas proto-oncogênicas c-ret ,Proto-Oncogene Proteins c-ret ,Oncology ,030220 oncology & carcinogenesis ,Thermodynamics ,Female ,Regiões 3' não traduzidas ,Anatomy ,RNA, Messenger -- chemistry -- genetics -- metabolism ,Research Article ,Calcitonin ,endocrine system ,congenital, hereditary, and neonatal diseases and abnormalities ,Heterozygote ,Biology ,Gene Frequency -- genetics ,Lymphatic System ,03 medical and health sciences ,Germline mutation ,Predisposição genética para doença ,Neoplasias da glândula tireóide ,Linkage Disequilibrium -- genetics ,Humans ,Computer Simulation ,Genetic Predisposition to Disease ,RNA, Messenger ,Thyroid Neoplasms ,Allele ,Genotyping ,Allele frequency ,Alleles ,Evolutionary Biology ,Population Biology ,lcsh:R ,Haplotype ,Carcinoma neuroendócrino ,Genetic Variation ,Biology and Life Sciences ,Molecular biology ,digestive system diseases ,Hormones ,Carcinoma, Neuroendocrine ,Minor allele frequency ,030104 developmental biology ,Carcinoma, Neuroendocrine -- genetics -- pathology ,Haplotypes ,Genetic Loci ,Mutation ,Nucleic Acid Conformation ,RNA ,Somatic Mutation ,lcsh:Q ,Lymph Nodes ,Frequência do gene ,Population Genetics - Abstract
The RET S836S variant has been associated with early onset and increased risk for metastatic disease in medullary thyroid carcinoma (MTC). However, the mechanism by which this variant modulates MTC pathogenesis is still open to discuss. Of interest, strong linkage disequilibrium (LD) between RET S836S and 3'UTR variants has been reported in Hirschsprung's disease patients., info:eu-repo/semantics/published
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- 2015
25. Role of VEGF-A and its receptors in sporadic and MEN2-associated pheochromocytoma
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Clarissa Capp, Carla Vaz Ferreira, Mirian Romitti, Luise Meurer, Lucieli Ceolin, Ana Luiza Maia, Débora Rodrigues Siqueira, and Beatriz Maria de Azevedo Assis Brasil
- Subjects
Vascular Endothelial Growth Factor A ,Male ,Pathology ,Angiogenesis ,Adrenal Gland Neoplasms ,Multiple Endocrine Neoplasia Type 2a ,Adrenal Gland Neoplasms -- blood supply -- diagnosis ,VEGF-A ,Receptor 1 do fator de crescimento do endotélio vascular ,lcsh:Chemistry ,chemistry.chemical_compound ,microvessel density ,Pheochromocytoma -- blood supply -- diagnosis ,Vascular Endothelial Growth Factor A -- biosynthesis ,Receptor ,Adrenal Medulla -- blood supply -- cytology -- pathology ,lcsh:QH301-705.5 ,Spectroscopy ,Neovascularization, Pathologic ,pheocromocytoma ,General Medicine ,Sciences bio-médicales et agricoles ,Computer Science Applications ,Microvessels -- physiology ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,Feocromocitoma ,Pheocromocytoma ,cardiovascular system ,Immunohistochemistry ,Biomarkers, Tumor -- biosynthesis ,Female ,Adult ,medicine.medical_specialty ,endocrine system ,Vascular Endothelial Growth Factor Receptor-1 -- biosynthesis ,Adrenal Gland Neoplasm ,Microvessel density ,Pheochromocytoma ,Biology ,Catalysis ,Article ,Inorganic Chemistry ,medicine ,Biomarkers, Tumor ,Humans ,Receptor 2 do fator de crescimento do endotélio vascular ,Neoplasia endócrina múltipla tipo 2a ,Physical and Theoretical Chemistry ,Molecular Biology ,Vascular Endothelial Growth Factor Receptor-1 ,Organic Chemistry ,Kinase insert domain receptor ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Vascular Endothelial Growth Factor Receptor-2 -- biosynthesis ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Adrenal Medulla ,Microvessels - Abstract
Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%-80%) or as part of inherited syndromes (20%-24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38±14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p=0.027, p=0.003 and p=0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors., info:eu-repo/semantics/published
- Published
- 2014
26. Role of RET genetic variants in MEN2-associated pheochromocytoma
- Author
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Mirian Romitti, Ana Luiza Maia, Débora Rodrigues Siqueira, Lucieli Ceolin, Carla Vaz Ferreira, Silvana Cavalcante Maia, and Léa Maria Zanini Maciel
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Adrenal Gland Neoplasms ,Multiple Endocrine Neoplasia Type 2a ,Penetrance ,Multiple endocrine neoplasia type 2 ,Pheochromocytoma ,PROTEÍNAS PROTO-ONCOGÊNICAS ,Polymorphism, Single Nucleotide ,Young Adult ,Endocrinology ,Germline mutation ,Gene Frequency ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Allele frequency ,Germ-Line Mutation ,Proportional hazards model ,business.industry ,Proto-Oncogene Proteins c-ret ,Hazard ratio ,General Medicine ,Middle Aged ,medicine.disease ,Pedigree ,Female ,business - Abstract
Background: RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma.ObjectiveTo investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients. Methods: The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan–Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance.ResultsA total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5±13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all P>0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4–5.0; P=0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6±6.3 and 39.3±14.4 years respectively; P=0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24–16.03); PConclusionsRET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.
- Published
- 2014
27. Advanced medullary thyroid cancer: pathophysiology and management
- Author
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Carla Vaz Ferreira, Lucieli Ceolin, Débora Rodrigues Siqueira, and Ana Luiza Maia
- Subjects
Pathology ,medicine.medical_specialty ,biology ,endocrine system diseases ,business.industry ,Thyroid ,Cancer ,Medullary thyroid cancer ,Review ,medicine.disease ,Receptor tyrosine kinase ,Thyroid carcinoma ,medicine.anatomical_structure ,Oncology ,medullary thyroid carcinoma ,tyrosine kinase inhibitors ,Cancer research ,biology.protein ,Medicine ,business ,Multiple endocrine neoplasia ,Tyrosine kinase ,proto-oncogene RET ,Endocrine gland - Abstract
Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3%-4% of thyroid gland neoplasias. MTC may occur sporadically or be inherited. Hereditary MTC appears as part of the multiple endocrine neoplasia syndrome type 2A or 2B, or familial medullary thyroid cancer. Germ-line mutations of the RET proto-oncogene cause hereditary forms of cancer, whereas somatic mutations can be present in sporadic forms of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration, and survival. Nowadays, early diagnosis of MTC followed by total thyroidectomy offers the only possibility of cure. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in an attempt to control metastatic disease. Of these, small-molecule tyrosine kinase inhibitors represent one of the most promising agents for MTC treatment, and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs and about the tyrosine kinase inhibitor-associated side effects will help in choosing the best therapeutic approach to enhance their benefits.
- Published
- 2013
28. Advanced medullary thyroid cancer : pathophysiology and management
- Author
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Vargas, Carla Vaz Ferreira, Siqueira, Débora Rodrigues, Ceolin, Lucieli, and Maia, Ana Luiza Silva
- Subjects
Proteínas tirosina quinases ,Tyrosine kinase inhibitors ,Proteínas proto-oncogênicas c-ret ,Medullary thyroid carcinoma ,Proto-oncogene RET ,Carcinoma medular ,Glândula tireóide - Abstract
Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3%–4% of thyroid gland neoplasias. MTC may occur sporadically or be inherited. Hereditary MTC appears as part of the multiple endocrine neoplasia syndrome type 2A or 2B, or familial medullary thyroid cancer. Germ-line mutations of the RET proto-oncogene cause hereditary forms of cancer, whereas somatic mutations can be present in sporadic forms of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration, and survival. Nowadays, early diagnosis of MTC followed by total thyroidectomy offers the only possibility of cure. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in an attempt to control metastatic disease. Of these, small-molecule tyrosine kinase inhibitors represent one of the most promising agents for MTC treatment, and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs and about the tyrosine kinase inhibitor-associated side effects will help in choosing the best therapeutic approach to enhance their benefits.
- Published
- 2013
29. O papel dos marcadores de angiogênese no feocromocitoma
- Author
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Vargas, Carla Vaz Ferreira and Maia, Ana Luiza Silva
- Subjects
Tyrosine kinase inhibitors ,Indutores da angiogênese ,Feocromocitoma ,endocrine system diseases ,Endocrinologia ,Protooncogene RET ,Medullary Thyroid Carcinoma - Abstract
Medullary thyroid carcinoma (MTC) is a rare malignant tumor originating from thyroid parafollicular C cells. This tumor accounts for 3-4% of thyroid gland neoplasias. MTC may occur sporadically or inherited. The hereditary MTC is part of syndromes of multiple endocrine neoplasia (MEN) 2A and 2B, familial medullary thyroid carcinoma (FMTC). Germline mutations of the RET (REarranged during Transfection) protooncogene cause hereditary form of cancer, whereas somatic mutations can be present in sporadic form of the disease. The RET gene encodes a receptor tyrosine kinase involved in the activation of intracellular signaling pathways leading to proliferation, growth, differentiation, migration and survival. Nowadays, the only possibility of cure for MTC patients consists of total thyroidectomy associated with lymph node dissection. Based on the knowledge of the pathogenic mechanisms of MTC, new drugs have been developed in attempt to control metastatic disease. Of these, the small-molecule tyrosine kinase inhibitors (TKIs) represent one of the most promising agents for MTC treatment and clinical trials have shown encouraging results. Hopefully, the cumulative knowledge about the targets of action of these drugs as well as TKI-associated side effects will help on choosing the best therapeutic approach in order to enhance its benefits.
- Published
- 2013
30. Signaling pathways in follicular cell-derived thyroid carcinomas (review)
- Author
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Carla Vaz Ferreira, Débora Rodrigues Siqueira, Ana Luiza Maia, Mirian Romitti, Simone Magagnin Wajner, and Lucieli Ceolin
- Subjects
Oncology ,endocrine system ,Cancer Research ,medicine.medical_specialty ,endocrine system diseases ,Biology ,medicine.disease_cause ,Follicular cell ,Thyroid carcinoma ,Internal medicine ,Adenocarcinoma, Follicular ,medicine ,Animals ,Humans ,Thyroid cancer ,Thyroid ,Cancer ,medicine.disease ,Neoplasm Proteins ,medicine.anatomical_structure ,Cancer research ,Adenocarcinoma ,Carcinogenesis ,PAX8 ,Signal Transduction - Abstract
Thyroid carcinoma is the most common malignant endocrine neoplasia. Differentiated thyroid carcinomas (DTCs) represent more than 90% of all thyroid carcinomas and comprise the papillary and follicular thyroid carcinoma subtypes. Anaplastic thyroid carcinomas correspond to less than 1% of all thyroid tumors and can arise de novo or by dedifferentiation of a differentiated tumor. The etiology of DTCs is not fully understood. Several genetic events have been implicated in thyroid tumorigenesis. Point mutations in the BRAF or RAS genes or rearranged in transformation (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are observed in approximately 70% of papillary cancer cases. Follicular carcinomas commonly harbor RAS mutations and paired box gene 8 (PAX8)-peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Anaplastic carcinomas may have a wide set of genetic alterations, that include gene effectors in the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and/or β-catenin signaling pathways. These distinct genetic alterations constitutively activate the MAPK, PI3K and β-catenin signaling pathways, which have been implicated in thyroid cancer development and progression. In this context, the evaluation of specific genes, as well as the knowledge of their effects on thyroid carcinogenesis may provide important information on disease presentation, prognosis and therapy, through the development of specific tyrosine kinase targets. In this review, we aimed to present an updated and comprehensive review of the recent advances in the understanding of the genetic basis of follicular cell-derived thyroid carcinomas, as well as the molecular mechanisms involved in tumor development and progression.
- Published
- 2012
31. The BRAF V600E mutation analysis and risk stratification in papillary thyroid carcinoma.
- Author
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Scheffel RS, de Cristo AP, Romitti M, Vargas CVF, Ceolin L, Zanella AB, Dora JM, and Maia AL
- Subjects
- Humans, Mutation, Prognosis, Proto-Oncogene Proteins B-raf genetics, Risk Assessment, Thyroid Cancer, Papillary genetics, Carcinoma genetics, Carcinoma, Papillary genetics, Thyroid Neoplasms genetics
- Abstract
Objective: Although the prognostic role of BRAF
V600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification., Methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated., Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively. The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up., Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients.- Published
- 2021
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