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1.
Eur J Cancer ; 124: 161-169, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31790974

RESUMO

INTRODUCTION: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as ≤1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management. METHODS: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39-59 years) and a median follow-up time of 53 months (IQR, 25-93 months). RESULTS: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15-5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80-24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan-Meier recurrence-free survival curve in low-risk PTMC. CONCLUSIONS: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.

2.
Int J Cancer ; 146(2): 521-530, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31403184

RESUMO

It is critical to identify biomarkers and functional networks associated with aggressive thyroid cancer to anticipate disease progression and facilitate personalized patient management. We performed miRNome sequencing of 46 thyroid tumors enriched with advanced disease patients with a median follow-up of 96 months. MiRNome profiles correlated with tumor-specific histopathological and molecular features, such as stromal cell infiltration and tumor driver mutation. Differential expression analysis revealed a consistent hsa-miR-139-5p downexpression in primary carcinomas from patients with recurrent/metastatic disease compared to disease-free patients, sustained in paired local metastases and validated in publicly available thyroid cancer series. Exogenous expression of hsa-miR-139-5p significantly reduced migration and proliferation of anaplastic thyroid cancer cells. Proteomic analysis indicated RICTOR, SMAD2/3 and HNRNPF as putative hsa-miR-139-5p targets in our cell system. Abundance of HNRNPF mRNA, encoding an alternative splicing factor involved in cryptic exon inclusion/exclusion, inversely correlated with hsa-miR-139-5p expression in human tumors. RNA sequencing analysis revealed 174 splicing events differentially regulated upon HNRNPF repression in our cell system, affecting genes involved in RTK/RAS/MAPK and PI3K/AKT/MTOR signaling cascades among others. These results point at the hsa-miR-139-5p/HNRNPF axis as a novel regulatory mechanism associated with the modulation of major thyroid cancer signaling pathways and tumor virulence.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/genética , MicroRNAs/metabolismo , Neoplasias da Glândula Tireoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Perfilação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/genética , Taxa de Sobrevida , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia
3.
Oncogene ; 38(27): 5486-5499, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30967628

RESUMO

The global downregulation of microRNAs (miRNAs) is emerging as a common hallmark of cancer. However, the mechanisms underlying this phenomenon are not well known. We identified that the oncogenic miR-146b-5p attenuates miRNA biosynthesis by targeting DICER1 and reducing its expression. DICER1 overexpression inhibited all the miR-146b-induced aggressive phenotypes in thyroid cells. Systemic injection of an anti-miR-146b in mice with orthotopic thyroid tumors suppressed tumor growth and recovered DICER1 levels. Notably, DICER1 downregulation promoted proliferation, migration, invasion, and epithelial-mesenchymal transition through miRNA downregulation. Our analysis of The Cancer Genome Atlas revealed a general decrease in DICER1 expression in thyroid cancer that was associated with a worse clinical outcome. Administration of the small-molecule enoxacin to promote DICER1 complex activity reduced tumor aggressiveness both in vitro and in vivo. Overall, our data confirm DICER1 as a tumor suppressor and show that oncogenic miR-146b contributes to its downregulation. Moreover, our results highlight a potential therapeutic application of RNA-based therapies including miRNA inhibitors and restoration of the biogenesis machinery, which may provide treatments for thyroid and other cancers.


Assuntos
RNA Helicases DEAD-box/metabolismo , Regulação para Baixo , MicroRNAs/metabolismo , Ribonuclease III/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Animais , Proliferação de Células , RNA Helicases DEAD-box/genética , Inativação Gênica , Xenoenxertos , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Ribonuclease III/genética , Neoplasias da Glândula Tireoide/patologia
4.
J Clin Oncol ; 36(27): 2787-2795, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30070937

RESUMO

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.


Assuntos
Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Caracteres Sexuais , Câncer Papilífero da Tireoide/mortalidade
5.
J Clin Endocrinol Metab ; 103(2): 397-406, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165662

RESUMO

Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Metilação de DNA , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
6.
J Natl Cancer Inst ; 110(4): 362-370, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165667

RESUMO

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Papilar/patologia , Mutação , Recidiva Local de Neoplasia/patologia , Medicina de Precisão , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/patologia , Adulto , Carcinoma Papilar/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Medição de Risco , Taxa de Sobrevida , Neoplasias da Glândula Tireoide/genética
7.
J Clin Oncol ; 36(5): 438-445, 2018 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-29240540

RESUMO

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTC-specific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.


Assuntos
Proteínas Proto-Oncogênicas B-raf/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/mortalidade , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/mortalidade , Adulto , Fatores Etários , Idade de Início , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Medição de Risco , Fatores de Risco
8.
J Clin Endocrinol Metab ; 102(9): 3241-3250, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28582521

RESUMO

Context: Multifocality is often treated as a risk factor for papillary thyroid cancer (PTC), prompting aggressive treatments, but its prognostic value remains unestablished. Objective: To investigate the role of tumor multifocality in clinical outcomes of PTC. Methods: Multicenter study of the relationship between multifocality and clinical outcomes of PTC in 2638 patients (623 men and 2015 women) with median [interquartile range (IQR)] age of 46 (35 to 58) years and median (IQR) follow-up time of 58 (26 to 107) months at 11 medical centers in six countries. Surveillance, Epidemiology and End Results (SEER) data were used for validation. Results: Disease recurrence in multifocal and unifocal PTC was 198 of 1000 (19.8%) and 221 of 1624 (13.6%) (P < 0.001), with a hazard ratio of 1.55 [95% confidence interval (CI), 1.28 to 1.88], which became insignificant at 1.13 (95% CI, 0.93 to 1.37) on multivariate adjustment. Similar results were obtained in PTC variants: conventional PTC, follicular-variant PTC, tall-cell PTC, and papillary thyroid microcarcinoma. There was no association between multifocality and mortality in any of these PTC settings, whereas there was a strong association between classic risk factors and cancer recurrence or mortality, which remained significant after multivariate adjustment. In 1423 patients with intrathyroidal PTC, disease recurrence was 20 of 455 (4.4%) and 41 of 967 (4.2%) (P = 0.892) and mortality was 0 of 455 (0.0%) and 3 of 967 (0.3%) (P = 0.556) in multifocal and unifocal PTC, respectively. The results were reproduced in 89,680 patients with PTC in the SEER database. Conclusions: Tumor multifocality has no independent risk prognostic value in clinical outcomes of PTC; its indiscriminate use as an independent risk factor, prompting overtreatments of patients, should be avoided.


Assuntos
Carcinoma Papilar/patologia , Carcinoma/patologia , Linfonodos/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/métodos , Adulto , Carcinoma/mortalidade , Carcinoma/cirurgia , Carcinoma Papilar/mortalidade , Carcinoma Papilar/cirurgia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER , Taxa de Sobrevida , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/mortalidade , Resultado do Tratamento
9.
Eur J Endocrinol ; 175(5): R203-17, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27666535

RESUMO

Thyroid cancer is the most common endocrine malignancy giving rise to one of the most indolent solid cancers, but also one of the most lethal. In recent years, systematic studies of the cancer genome, most importantly those derived from The Cancer Genome Altas (TCGA), have catalogued aberrations in the DNA, chromatin, and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Cancer genomics is therefore providing new information on cancer development and behavior, as well as new insights into genetic alterations and molecular pathways. From this genomic perspective, we will review the main advances concerning some essential aspects of the molecular pathogenesis of thyroid cancer such as mutational mechanisms, new cancer genes implicated in tumor initiation and progression, the role of non-coding RNA, and the advent of new susceptibility genes in thyroid cancer predisposition. This look across these genomic and cellular alterations results in the reshaping of the multistep development of thyroid tumors and offers new tools and opportunities for further research and clinical development of novel treatment strategies.


Assuntos
Transformação Celular Neoplásica/genética , Mutação , Neoplasias da Glândula Tireoide/genética , Genômica , Humanos , Transdução de Sinais/genética
10.
Oncotarget ; 7(31): 49435-49449, 2016 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-27384483

RESUMO

Mutations in ß-catenin are traditionally described as late events in thyroid cancer progression. However, the functional implications of ß-catenin dysregulation in the context of tumor initiating events remain unclear. The aim of this work was to investigate whether the two main oncogenic drivers in thyroid cancer, RAS and BRAF, could activate the Wnt/ß-catenin pathway. Expression of HRASV12 but not BRAFV600E in thyroid cells induced ß-catenin nuclear localization, increased ß-catenin-dependent transcriptional activity and inhibited GSK3ß. In a panel of human thyroid cancer cell lines representative of the main genetic events in thyroid cancer, ß-catenin activation was highly dependent on PI3K/AKT activity through its phosphorylation at S552, but not on MAPK. Silencing of ß-catenin expression in cell lines led to a dramatic reduction in proliferation due to an induction of senescence, which was concordant with a reduction in tumor size in nude mice. Moreover, ß-catenin silencing suppressed the expression of EMT-related genes and reduced the invasive capacity of the tumor cells. In conclusion, this work demonstrates that RAS-driven tumors induce PI3K/AKT-dependent ß-catenin activation.


Assuntos
Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias da Glândula Tireoide/patologia , beta Catenina/metabolismo , Proteínas ras/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Senescência Celular , Ativação Enzimática , Feminino , Inativação Gênica , Células HEK293 , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Invasividade Neoplásica , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Via de Sinalização Wnt
11.
Endocrinol. nutr. (Ed. impr.) ; 63(4): e17-e24, abr. 2016. tab
Artigo em Inglês | IBECS | ID: ibc-150565

RESUMO

Background: Approximately one third of the patients with differentiated thyroid cancer (DTC) who develop structurally-evident metastatic disease are refractory to radioactive iodine (RAI). Most deaths from thyroid cancer occur in these patients. The main objective of this consensus is to address the most controversial aspects of management of these patients. Methods: On behalf of the Spanish Society of Endocrinology & Nutrition (SEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI), the Spanish Task Force for Thyroid Cancer, consisting of endocrinologists and oncologists, reviewed the relevant literature and prepared a series of clinically relevant questions related to management of advanced RAI-refractory DTC. Results: Ten clinically relevant questions were identified by the task force. In answering to these 10 questions, the task force included recommendations regarding the best definition of refractoriness; the best therapeutic options including watchful waiting, local therapies, and systemic therapy (e.g. kinase inhibitors), when sodium iodide symporter (NIS) restoration may be expected; and how recent advances in molecular biology have increased our understanding of the disease. Conclusions: In response to our appointment as a task force by the SEEN and GHETI, we developed a consensus to help in clinical management of patients with advanced RAI-refractory DTC. We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care (AU)


Antecedentes: Alrededor de un tercio de los pacientes con cáncer diferenciado de tiroides (CDT) que desarrollan enfermedad metastásica estructural son refractarios al yodo radiactivo. Desafortunadamente, la mayoría de las muertes debidas al cáncer de tiroides ocurren en pacientes con CDT avanzado refractario al yodo radiactivo. El principal objetivo de este consenso es abordar los aspectos más controvertidos del manejo de estos pacientes. Métodos: En nombre de la Sociedad Española de Endocrinología y Nutrición (SEEN) y del Grupo Español de Tumores Raros e Infrecuentes (GETHI), el grupo de trabajo para el Cáncer de Tiroides, compuesto por endocrinólogos y oncólogos, revisó la literatura más destacada y desarrolló una serie de preguntas clínicamente relevantes concernientes al manejo de los pacientes con CDT refractario. Resultados: Diez preguntas clínicamente relevantes fueron identificadas por el grupo de trabajo. En las respuestas el grupo incluyó recomendaciones sobre la mejor definición de la refractariedad, las mejores opciones terapéuticas, entre las cuales se incluyen la actitud expectante, las terapias locales y la terapia sistémica (por ejemplo inhibidores de tirosín-cinasa), cuándo esperar la recaptación de yodo radiactivo mediada por NIS y cómo los recientes avances en genética molecular han ayudado a comprender mejor la enfermedad. Conclusión: En respuesta a nuestro compromiso como grupo de trabajo de la SEEN y GETHI hemos creado un consenso para asistir al manejo clínico de los pacientes con CDT avanzado refractario al yodo radiactivo. Pensamos que este consenso proporcionará unas recomendaciones útiles y actualizadas que ayuden a los pacientes con esta enfermedad a tener un cuidado óptimo (AU)


Assuntos
Humanos , Neoplasias da Glândula Tireoide/terapia , Radioisótopos do Iodo , Neoplasias da Glândula Tireoide
12.
J Clin Endocrinol Metab ; 101(1): 264-74, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26529630

RESUMO

CONTEXT: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. OBJECTIVE: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). METHODS: This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo). RESULTS: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. CONCLUSION: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC.


Assuntos
Carcinoma/patologia , Recidiva Local de Neoplasia , Neoplasias da Glândula Tireoide/patologia , Adulto , Carcinoma/epidemiologia , Carcinoma/genética , Carcinoma Papilar , Estudos de Coortes , Feminino , Seguimentos , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/patologia , Prevalência , Prognóstico , Radioterapia/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética
13.
Endocrinol Nutr ; 63(4): e17-24, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26601805

RESUMO

BACKGROUND: Approximately one third of the patients with differentiated thyroid cancer (DTC) who develop structurally-evident metastatic disease are refractory to radioactive iodine (RAI). Most deaths from thyroid cancer occur in these patients. The main objective of this consensus is to address the most controversial aspects of management of these patients. METHODS: On behalf of the Spanish Society of Endocrinology & Nutrition (SEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI), the Spanish Task Force for Thyroid Cancer, consisting of endocrinologists and oncologists, reviewed the relevant literature and prepared a series of clinically relevant questions related to management of advanced RAI-refractory DTC. RESULTS: Ten clinically relevant questions were identified by the task force. In answering to these 10 questions, the task force included recommendations regarding the best definition of refractoriness; the best therapeutic options including watchful waiting, local therapies, and systemic therapy (e.g. kinase inhibitors), when sodium iodide symporter (NIS) restoration may be expected; and how recent advances in molecular biology have increased our understanding of the disease. CONCLUSIONS: In response to our appointment as a task force by the SEEN and GHETI, we developed a consensus to help in clinical management of patients with advanced RAI-refractory DTC. We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Consenso , Humanos
14.
Cancer Res ; 75(19): 4119-30, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26282166

RESUMO

The presence of differentiated thyroid cells in thyroid cancer is critical for the antitumor response to radioactive iodide treatment, and loss of the differentiated phenotype is a key hallmark of iodide-refractory metastatic disease. The role of microRNAs (miRNA) in fine-tuning gene expression has become a major regulatory mechanism by which developmental and pathologic processes occur. In this study, we performed next-generation sequencing and expression analysis of eight papillary thyroid carcinomas (PTC) to comprehensively characterize miRNAs involved in loss of differentiation. We found that only a small set of abundant miRNAs is differentially expressed between PTC tissue and normal tissue from the same patient. In addition, we integrated computational prediction of potential targets and mRNA sequencing and identified a master miRNA regulatory network involved in essential biologic processes such as thyroid differentiation. Both mature products of mir-146b (miR-146b-5p and -3p) were among the most abundantly expressed miRNAs in tumors. Specifically, we found that miR-146b-3p binds to the 3'-untranslated region of PAX8 and sodium/iodide symporter (NIS), leading to impaired protein translation and a subsequent reduction in iodide uptake. Furthermore, our findings show that miR-146b and PAX8 regulate each other and share common target genes, thus highlighting a novel regulatory circuit that governs the differentiated phenotype of PTC. In conclusion, our study has uncovered the existence of a miR-146b-3p/PAX8/NIS regulatory circuit that may be exploited therapeutically to modulate thyroid cell differentiation and iodide uptake for improved treatment of advanced thyroid cancer.


Assuntos
Carcinoma Papilar/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Iodetos/metabolismo , MicroRNAs/fisiologia , Proteínas de Neoplasias/fisiologia , Fatores de Transcrição Box Pareados/fisiologia , RNA Neoplásico/fisiologia , Simportadores/fisiologia , Neoplasias da Glândula Tireoide/metabolismo , Regiões 3' não Traduzidas , Transporte Biológico , Carcinoma Papilar/patologia , Diferenciação Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Humanos , MicroRNAs/genética , Fator de Transcrição PAX8 , Fatores de Transcrição Box Pareados/antagonistas & inibidores , Fatores de Transcrição Box Pareados/genética , Fenótipo , RNA/metabolismo , Interferência de RNA , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Transfecção
15.
J Med Genet ; 52(10): 647-56, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26269449

RESUMO

BACKGROUND: Nowadays, 65-80% of pheochromocytoma and paraganglioma (PPGL) cases are explained by germline or somatic mutations in one of 22 genes. Several genetic testing algorithms have been proposed, but they usually exclude sporadic-PPGLs (S-PPGLs) and none include somatic testing. We aimed to genetically characterise S-PPGL cases and propose an evidence-based algorithm for genetic testing, prioritising DNA source. METHODS: The study included 329 probands fitting three criteria: single PPGL, no syndromic and no PPGL family history. Germline DNA was tested for point mutations in RET and for both point mutation and gross deletions in VHL, the SDH genes, TMEM127, MAX and FH. 99 tumours from patients negative for germline screening were available and tested for RET, VHL, HRAS, EPAS1, MAX and SDHB. RESULTS: Germline mutations were found in 46 (14.0%) patients, being more prevalent in paragangliomas (PGLs) (28.7%) than in pheochromocytomas (PCCs) (4.5%) (p=6.62×10(-10)). Somatic mutations were found in 43% of those tested, being more prevalent in PCCs (48.5%) than in PGLs (32.3%) (p=0.13). A quarter of S-PPGLs had a somatic mutation, regardless of age at presentation. Head and neck PGLs (HN-PGLs) and thoracic-PGLs (T-PGLs) more commonly had germline mutations (p=2.0×10(-4) and p=0.027, respectively). Five of the 29 metastatic cases harboured a somatic mutation, one in HRAS. CONCLUSIONS: We recommend prioritising testing for germline mutations in patients with HN-PGLs and T-PGLs, and for somatic mutations in those with PCC. Biochemical secretion and SDHB-immunohistochemistry should guide genetic screening in abdominal-PGLs. Paediatric and metastatic cases should not be excluded from somatic screening.


Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Testes Genéticos , Mutação em Linhagem Germinativa , Neoplasias de Cabeça e Pescoço/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias Torácicas/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Criança , Prática Clínica Baseada em Evidências , Feminino , Predisposição Genética para Doença , Neoplasias de Cabeça e Pescoço/diagnóstico , Humanos , Masculino , Mutação , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Neoplasias Torácicas/diagnóstico
16.
Endocrinol. nutr. (Ed. impr.) ; 62(4): e37-e46, abr. 2015. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-135131

RESUMO

Background In Spain medullary thyroid carcinoma (MTC) would not exceed 80 new cases per year and less than half of them would be good candidates for systemic treatment with novel agents. Methods Relevant literature was reviewed, including PubMed searches supplemented with additional articles. Results The consensus summarizes the clinical outcomes in terms of activity and toxicity of each of the available drugs. A brief summary of the minimum requirements in terms of follow up and genetic counselling around MTC is also included. Conclusions Only those patients with objective imaging progression in the last 12–14 months with large volume of disease are clear candidates to start systemic treatment. However, those patients with low disease volume should be considered for ‘wait and see’ strategy until symptoms of the disease appear. Multidisciplinary approach for the management of MTC patient is mandatory nowadays (AU)


Contexto Se calcula que la incidencia de cáncer medular de tiroides (MTC) en España no supera los 80 nuevos casos por año y menos de la mitad podrán ser buenos candidatos para recibir tratamiento sistémico con nuevas terapias. Métodos Se ha revisado la información científica pertinente a través de búsquedas en PubMed y otras fuentes adicionales. Resultados Este consenso compendia los resultados clínicos en términos de actividad y toxicidad de los fármacos actualmente disponibles. También se aborda un breve resumen con los requerimientos mínimos para el seguimiento y el consejo genético en el CMT. Conclusiones Los pacientes candidatos para iniciar tratamientos sistémicos son únicamente aquellos con gran carga tumoral en los que se objetiva, mediante pruebas de imagen, una progresión en los últimos 12-14 meses. En aquellos pacientes con escasa carga de enfermedad se debe considerar la observación hasta que aparezcan síntomas de enfermedad. Hoy en día es preceptivo manejar al paciente con MTC por un equipo multidisciplinar (AU)


Assuntos
Humanos , Carcinoma Medular/diagnóstico , Carcinoma Medular/terapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/terapia , Padrões de Prática Médica , Seleção de Pacientes , Carga Tumoral , Biomarcadores Tumorais/análise , Calcitonina/análise , Antígeno Carcinoembrionário/análise
17.
Endocrinol Nutr ; 62(4): e37-46, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25732322

RESUMO

BACKGROUND: In Spain medullary thyroid carcinoma (MTC) would not exceed 80 new cases per year and less than half of them would be good candidates for systemic treatment with novel agents. METHODS: Relevant literature was reviewed, including PubMed searches supplemented with additional articles. RESULTS: The consensus summarizes the clinical outcomes in terms of activity and toxicity of each of the available drugs. A brief summary of the minimum requirements in terms of follow up and genetic counseling around MTC is also included. CONCLUSIONS: Only those patients with objective imaging progression in the last 12-14 months with large volume of disease are clear candidates to start systemic treatment. However, those patients with low disease volume should be considered for 'wait and see' strategy until symptoms of the disease appear. Multidisciplinary approach for the management of MTC patient is mandatory nowadays.


Assuntos
Carcinoma Medular/terapia , Neoplasias da Glândula Tireoide/terapia , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Calcitonina/sangue , Antígeno Carcinoembrionário/análise , Carcinoma Medular/epidemiologia , Carcinoma Medular/genética , Terapia Combinada , Diagnóstico por Imagem/métodos , Gerenciamento Clínico , Doxorrubicina/uso terapêutico , Estudos de Associação Genética , Humanos , Metástase Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-ret/genética , Piridinas/uso terapêutico , Radioterapia/métodos , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/genética
18.
Endocrinol. nutr. (Ed. impr.) ; 62(3): e15-e22, mar. 2015. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-134089

RESUMO

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumour known and is a rare but highly lethal form of thyroid cancer that requires a multidisciplinary team approach. No Spanish consensus exists for management of patients with ATC. The Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the GETHI (Grupo Español de Enfermedades Huérfanas e Infrecuentes) of the Spanish Society of Oncology, in agreement with the Boards of these Societies, commissioned an independent task force to develop a wide consensus on ATC. The relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The consensus includes the characteristics, diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active treatment), approaches to advanced/metastatic disease, palliative care options, monitoring, and long-term follow-up of ATC. For operable disease, a combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin, cisplatin and paclitaxel, is the best treatment strategy. Cytotoxic drugs are poorly effective for advanced/metastatic ATC. On the other hand, targeted agents may represent a viable therapeutic option. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for clinical trials or (..) (AU)


El cáncer anaplásico de tiroides (CAT) es el tumour sólido más agresivo conocido y es una forma rara pero muy letal de cáncer de tiroides que requiere un enfoque multidisciplinario. No existe ningún consenso español para definir la conducta a seguir en los pacientes con CAT. El Grupo de Cáncer de Tiroides de la Sociedad Española de Endocrinología y Nutrición y el GETHI (Grupo Español de Enfermedades Huérfanas e Infrecuentes) de la Sociedad Española de Oncología, de acuerdo con las Juntas Directivas de estas Sociedades decidieron que un grupo de trabajo independiente desarrollaran un amplio consenso sobre el CAT. Se revisó la literatura relevante, incluyendo la búsqueda en PubMed de las series más relevantes. En el consenso se incluyen las características, el diagnóstico, la evaluación inicial, el establecimiento de los objetivos del tratamiento, la actitud a seguir ante la enfermedad locorregional (cirugía, radioterapia, terapia sistémica, la atención de apoyo durante el tratamiento activo), acerca a la enfermedad avanzada/metastásica, las opciones de cuidados paliativos, la vigilancia y el seguimiento a largo plazo del CAT. Para la enfermedad operable, la combinación de la cirugía radical con radioterapia o quimioterapia adyuvante, utilizando agentes tales como doxorrubicina, cisplatino y paclitaxel, es la mejor estrategia de tratamiento. Los fármacos citotóxicos para los casos avanzados/metastásicos de CAT son poco eficaces. Por otra parte, los agentes dirigidos a dianas específicas pueden representar una opción terapéutica viable. Los pacientes con enfermedad resecable en estadio IVA/IVB tienen el mejor pronóstico, sobre todo si se utiliza un enfoque multimodal, y algunos pacientes no resecables etapa IVB pueden responder a una terapia agresiva. En los pacientes con enfermedad en estadio IVC (..) (AU)


Assuntos
Humanos , Neoplasias da Glândula Tireoide/terapia , Anaplasia/terapia , Metástase Linfática , Predisposição Genética para Doença , Biópsia/métodos , Tireoidectomia/métodos
19.
Mod Pathol ; 28(6): 748-57, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25720323

RESUMO

MicroRNA deregulation could be a crucial event in thyroid carcinogenesis. However, current knowledge is based on studies that have used inherently biased methods. Thus, we aimed to define in an unbiased way a list of deregulated microRNAs in well-differentiated thyroid cancer in order to identify diagnostic and prognostic markers. We performed a microRNA deep-sequencing study using the largest well-differentiated thyroid tumor collection reported to date, comprising 127 molecularly characterized tumors with follicular or papillary patterns of growth and available clinical follow-up data, and 17 normal tissue samples. Furthermore, we integrated microRNA and gene expression data for the same tumors to propose targets for the novel molecules identified. Two main microRNA expression profiles were identified: one common for follicular-pattern tumors, and a second for papillary tumors. Follicular tumors showed a notable overexpression of several members of miR-515 family, and downregulation of the novel microRNA miR-1247. Among papillary tumors, top upregulated microRNAs were miR-146b and the miR-221~222 cluster, while miR-1179 was downregulated. BRAF-positive samples displayed extreme downregulation of miR-7 and -204. The identification of the predicted targets for the novel molecules gave insights into the proliferative potential of the transformed follicular cell. Finally, by integrating clinical follow-up information with microRNA expression, we propose a prediction model for disease relapse based on expression of two miRNAs (miR-192 and let-7a) and several other clinicopathological features. This comprehensive study complements the existing knowledge about deregulated microRNAs in the development of well-differentiated thyroid cancer and identifies novel markers associated with recurrence-free survival.


Assuntos
Adenocarcinoma Folicular/genética , Carcinoma/genética , MicroRNAs/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/mortalidade , Adolescente , Adulto , Idoso , Carcinoma/mortalidade , Carcinoma Papilar , Análise por Conglomerados , Intervalo Livre de Doença , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/mortalidade , Transcriptoma , Adulto Jovem
20.
Endocrinol Nutr ; 62(3): e15-22, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25583658

RESUMO

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumour known and is a rare but highly lethal form of thyroid cancer that requires a multidisciplinary team approach. No Spanish consensus exists for management of patients with ATC. The Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the GETHI (Grupo Español de Enfermedades Huérfanas e Infrecuentes) of the Spanish Society of Oncology, in agreement with the Boards of these Societies, commissioned an independent task force to develop a wide consensus on ATC. The relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The consensus includes the characteristics, diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active treatment), approaches to advanced/metastatic disease, palliative care options, monitoring, and long-term follow-up of ATC. For operable disease, a combination of radical surgery with adjuvant radiotherapy or chemotherapy, using agents such as doxorubicin, cisplatin and paclitaxel, is the best treatment strategy. Cytotoxic drugs are poorly effective for advanced/metastatic ATC. On the other hand, targeted agents may represent a viable therapeutic option. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for clinical trials or for hospice/palliative care depending on their preference. This is the first Spanish consensus for ATC, and provides recommendations for management of this extremely aggressive malignancy. Novel systemic therapies are being tested, and more effective combinations are needed to improve patient outcomes. Although more aggressive radiotherapy has reduced locoregional recurrence, mean overall survival has not improved in the past 50 years.


Assuntos
Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Algoritmos , Humanos , Espanha
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