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1.
Best Pract Res Clin Endocrinol Metab ; 37(1): 101678, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35668021

RESUMO

Anaplastic thyroid cancer (ATC) is one of the most lethal of all cancers. It is more common in women and occurs primarily in older patients. ATC has a median overall survival of 3-5 months and a nearly 100% disease-specific mortality. It is known to spread rapidly to locoregional structures as well as outside the neck to distant sites, hence ATC is always considered stage IV. With better understanding of the disease at a molecular level, the introduction of newer treatment strategies has been possible and is part of the multimodal (surgery, radiation, and systemic therapy) therapeutic approach. However, there is extensive work needed to achieve better survival outcomes.


Assuntos
Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Feminino , Idoso , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tireoidectomia
2.
Expert Rev Anticancer Ther ; 22(11): 1239-1247, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36283091

RESUMO

INTRODUCTION: Anaplastic thyroid cancer (ATC) is one of the most lethal diseases known to humans with a median survival of 5 months. The American Thyroid Association (ATA) recently published guidelines for the treatment of this dreadful thyroid malignancy. AREAS COVERED: This review presents the current therapeutic landscape of this challenging disease. We also present the results from trials published over the last five years and summarize currently active clinical trials. EXPERT OPINION: Recent attempts to improve the prognosis of these tumors are moving toward personalized medicine, basing the treatment decision on the specific genetic profile of the individual tumor. The positive results of dabrafenib and trametinib for ATC harboring the BRAF V600E mutation have provided a useful treatment option. For the other genetic profiles, different drugs are available and can be used to individualize the treatment, likely using drug combinations. Combinations of drugs act on different molecular pathways and achieve inhibition at separate areas. With new targeted therapies, average survival has improved considerably and death from local disease progression or airway compromise is less likely with improvement in quality of life. Unfortunately, the results remain poor in terms of survival.


Assuntos
Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/patologia , Qualidade de Vida , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Prognóstico , Medicina de Precisão , Proteínas Proto-Oncogênicas B-raf/genética , Mutação
3.
Endocrine ; 74(3): 592-602, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34089480

RESUMO

PURPOSE: To compare cardiovascular outcomes and rates of fractures and falls among patients with persistent brand-name versus generic L-thyroxine use. METHODS: Retrospective, 1:1 propensity-matched longitudinal study using a national administrative claims database to examine adults (≥18 years) who initiated either brand or generic L-thyroxine between 2008 and 2018, censored at switch or discontinuation of L-thyroxine formulation or disenrollment from the health plan. Main outcome measures included rates of hospitalization for atrial fibrillation, myocardial infarction, congestive heart failure, stroke, spine and hip fractures, and rate of falls in the outpatient or inpatient setting. Hospitalizations for pneumonia were used as a negative control. RESULTS: 195,046 adults initiated treatment with L-thyroxine between 2008 and 2017: 87% generic and 13% brand formulations. They were mostly women (76%), young (94.6% under age 65), white (66%), and 47% had baseline thyroid stimulating hormone levels between 4.5 and 9.9 mIU/L. Among 35,667 propensity-matched patients, there were no significant differences between patients treated with brand versus generic L-thyroxine in atrial fibrillation (HR 0.96, 0.58-1.60), myocardial infarction (HR 0.66, 0.39-1.14), congestive heart failure (HR 1.30, 0.78-2.16), stroke (0.72, 0.49-1.06), spine (HR 0.87, 0.38-1.99) and hip fractures (HR 0.86, 0.26-2.82), or fall outcomes (HR 1.02, 0.14-7.32). Hospitalization rates for pneumonia (used as negative control) did not differ between groups (HR 0.85, 0.61-1.19). There were no interactions between brand versus generic L-thyroxine, these outcomes, and thyroid cancer, age, or L-thyroxine dose subgroups. CONCLUSIONS: We found no significant differences in cardiovascular outcomes and rates of falls and fractures for patients who filled brand versus generic L-thyroxine.


Assuntos
Medicamentos Genéricos , Tiroxina , Idoso , Feminino , Humanos , Estudos Longitudinais , Estudos Retrospectivos , Hormônios Tireóideos , Tiroxina/uso terapêutico
4.
Cancer ; 127(11): 1770-1778, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33449369

RESUMO

BACKGROUND: Factors associated with receiving initial care for thyroid cancer (TC) at academic centers (ACs) versus nonacademic centers (NACs) and their impact on patient outcomes have not been reported. METHODS: The National Cancer Database with TC cases from 2004 to 2013 was evaluated for association of type of center for initial care with socioeconomic factors and disease and treatment characteristics, as well as overall survival (OS; all-cause mortality). RESULTS: The patients with TC (n = 200,824) included were predominantly women (74%), non-Hispanic Whites (85%), and from metro areas (84%). Sixty percent received initial care at a NAC. There were no significant differences between treatment groups by age or gender. Among those treated at an AC, a higher proportion belonged to racial/ethnic minorities (16.5%) versus at a NAC (11.6%). Hormone therapy was used more in an AC versus a NAC (60% vs 47%). Patients with all TC pathologies combined had a lower likelihood of death when they received initial care at an AC (hazard ratio [HR], 0.948; P = .0006). Among individual pathologic subtypes, a lower likelihood of death was noted when initial care was received at an AC for follicular (HR, 0.828, P = .0010) and Hurthle cell cancers (HR, 792; P = .0008), as well as stage II papillary thyroid cancer (HR, 0.828; P = .0026), but not for other histopathologic subtypes. CONCLUSIONS: Initial care at an AC was associated with lower likelihood of death for patients with TC, especially for those with follicular or Hurthle cell subtypes. Optimal resource use with consideration of patients' socioeconomic and demographic factors is imperative to ensure the most appropriate management of patients with TC in various treatment settings.


Assuntos
Centros Médicos Acadêmicos , Institutos de Câncer , Neoplasias da Glândula Tireoide , Centros Médicos Acadêmicos/estatística & dados numéricos , Institutos de Câncer/estatística & dados numéricos , Minorias Étnicas e Raciais/estatística & dados numéricos , Feminino , Humanos , Masculino , Fatores Socioeconômicos , Neoplasias da Glândula Tireoide/etnologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/terapia , Resultado do Tratamento , Estados Unidos/epidemiologia
5.
Thyroid ; 30(9): 1254-1262, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32538690

RESUMO

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.


Assuntos
Indazóis/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Tireoglobulina/imunologia , Neoplasias da Glândula Tireoide/imunologia , Idoso , Anticorpos/química , Biomarcadores Tumorais , Diferenciação Celular , Análise Mutacional de DNA , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Radioisótopos do Iodo/farmacologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Estudos Prospectivos , Inibidores de Proteínas Quinases/uso terapêutico , Terapia de Salvação , Neoplasias da Glândula Tireoide/terapia , Resultado do Tratamento
6.
J Clin Endocrinol Metab ; 105(7)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421817

RESUMO

CONTEXT: Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. OBJECTIVES, DESIGN, AND SETTING: We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. PATIENT CONTEXT: Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. INTERVENTION: The intervention was Foundation One tumor interrogation. MAIN OUTCOME MEASURES: Main outcome measures included genomic alterations, patient characteristics, and overall survival. RESULTS: Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine-refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)-but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. CONCLUSIONS: Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.


Assuntos
Metástase Neoplásica/genética , Metástase Neoplásica/terapia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/terapia , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sobrevida , Resultado do Tratamento
7.
Semin Intervent Radiol ; 36(5): 381-385, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31798211

RESUMO

Differentiated thyroid cancer often metastasizes to cervical lymph nodes, characteristically with slow growth rate and low-level aggressiveness. Cervical lymph node resection is the treatment of choice, but ethanol ablation offers a therapeutic option for patients with few nodes unresponsive to radioiodine therapy and who are poor surgical candidates. The ethanol ablation procedure is minimally invasive, guided sonographically, easily and safely repeated, and easily implemented with minimal technology and cost. Transient nerve injury is infrequent and virtually the only important complication. Current experience indicates that ethanol ablation has the safest therapeutic profile compared to surgery and thermal ablation, and the effectiveness is comparable to thermal ablation and approaches that of surgery. Well-designed clinical trials are lacking.

8.
Clin Cancer Res ; 25(10): 3141-3151, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30737244

RESUMO

PURPOSE: Thyroid cancer cell lines are valuable models but have been neglected in pancancer genomic studies. Moreover, their misidentification has been a significant problem. We aim to provide a validated dataset for thyroid cancer researchers. EXPERIMENTAL DESIGN: We performed next-generation sequencing (NGS) and analyzed the transcriptome of 60 authenticated thyroid cell lines and compared our findings with the known genomic defects in human thyroid cancers. RESULTS: Unsupervised transcriptomic analysis showed that 94% of thyroid cell lines clustered distinctly from other lineages. Thyroid cancer cell line mutations recapitulate those found in primary tumors (e.g., BRAF, RAS, or gene fusions). Mutations in the TERT promoter (83%) and TP53 (71%) were highly prevalent. There were frequent alterations in PTEN, PIK3CA, and of members of the SWI/SNF chromatin remodeling complex, mismatch repair, cell-cycle checkpoint, and histone methyl- and acetyltransferase functional groups. Copy number alterations (CNA) were more prevalent in cell lines derived from advanced versus differentiated cancers, as reported in primary tumors, although the precise CNAs were only partially recapitulated. Transcriptomic analysis showed that all cell lines were profoundly dedifferentiated, regardless of their derivation, making them good models for advanced disease. However, they maintained the BRAFV600E versus RAS-dependent consequences on MAPK transcriptional output, which correlated with differential sensitivity to MEK inhibitors. Paired primary tumor-cell line samples showed high concordance of mutations. Complete loss of p53 function in TP53 heterozygous tumors was the most prominent event selected during in vitro immortalization. CONCLUSIONS: This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.


Assuntos
Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Telomerase/genética , Neoplasias da Glândula Tireoide/genética , Proteína Supressora de Tumor p53/genética , Animais , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias da Glândula Tireoide/classificação , Neoplasias da Glândula Tireoide/patologia , Estudos de Validação como Assunto
9.
J Natl Compr Canc Netw ; 16(12): 1429-1440, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30545990

RESUMO

The NCCN Guidelines for Thyroid Carcinoma provide recommendations for the management of different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, medullary, and anaplastic carcinomas. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for differentiated thyroid carcinoma, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and the addition of a new targeted therapy option for BRAF V600E-mutated anaplastic thyroid carcinoma.


Assuntos
Carcinoma/terapia , Oncologia/normas , Neoplasias da Glândula Tireoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma/diagnóstico , Carcinoma/mortalidade , Carcinoma/patologia , Ensaios Clínicos como Assunto , Humanos , Biópsia Guiada por Imagem/métodos , Biópsia Guiada por Imagem/normas , Estadiamento de Neoplasias , Prognóstico , Inibidores de Proteínas Quinases/normas , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Sociedades Médicas/normas , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/patologia , Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia/métodos , Tireoidectomia/normas , Resultado do Tratamento , Estados Unidos
10.
J Clin Endocrinol Metab ; 103(9): 3169-3182, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29846633

RESUMO

Objective: To investigate the molecular underpinnings of thyroid cancer, preclinical cell line models are crucial; however, ∼40% of these have been proven to be either duplicates of existing thyroid lines or even nonthyroid-derived lines or are not derived from humans at all. Therefore, we set out to establish procedures and guidelines that should proactively avoid these problems, which facilitated the creation of criteria to make valid preclinical models for thyroid cancer research. Design: Based on our recommendations, we systematically characterized all new cell lines that we generated by a standardized approach that included (1) determination of human origin, (2) exclusion of lymphoma, (3) DNA fingerprinting and histological comparisons to establish linkage to presumed tissue of origin, (4) examining thyroid differentiation by screening two to three thyroid markers, (5) examination of biological behavior (growth rate, tumorigenicity), and (6) presence of common thyroid cancer genetic changes (TP53, BRAF, PTEN, PIK3CA, RAS, TERT promoter, RET/PTC, PAX8/PPARγ, NF1, and EIF1AX). Results: We established seven new thyroid cell lines (LAM136, EAM306, SDAR1, SDAR2, JEM493, THJ529, and THJ560) out of 294 primary culture attempts, and 10 patient-derived tumor xenografts (PDTXs; MC-Th-95, MC-Th-374, MC-Th-467, MC-Th-491, MC-Th-493, MC-Th-504, MC-Th-524, MC-Th-529, MC-Th-560, and MC-Th-562) out of 67 attempts. All were successfully validated by our protocols. Conclusions: This standardized approach for cell line and PDTX characterization should prevent (or detect) future cross-contamination and ensure that only valid preclinical models are used for thyroid cancer research.


Assuntos
Neoplasias da Glândula Tireoide/patologia , Idoso , Idoso de 80 Anos ou mais , Animais , Diferenciação Celular , Divisão Celular , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Impressões Digitais de DNA/métodos , DNA de Neoplasias/genética , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Mutação , Transplante de Neoplasias , Neoplasias da Glândula Tireoide/genética , Células Tumorais Cultivadas
11.
Int J Mol Sci ; 19(2)2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29443941

RESUMO

Anaplastic thyroid carcinoma (ATC) is almost universally fatal. Elevated keratin-8 (KRT8) protein expression is an established diagnostic cancer biomarker in several epithelial cancers (but not ATC). Several keratins, including KRT8, have been suggested to have a role in cell biology beyond that of structural cytoskeletal proteins. Here, we provide evidence that KRT8 plays a direct role in the growth of ATCs. Genomic and transcriptomic analysis of >5000 patients demonstrates that KRT8 mutation and copy number amplification are frequently evident in epithelial-derived cancers. Carcinomas arising from diverse tissues exhibit KRT8 mRNA and protein overexpression when compared to normal tissue levels. Similarly, in a panel of patient-derived ATC cell lines and patient tumors, KRT8 expression shows a similar pattern. sh-RNA-mediated KRT8 knockdown in these cell lines increases apoptosis, whereas forced overexpression of KRT8 confers resistance to apoptosis under peroxide-induced cell stress conditions. We further show that KRT8 protein binds to annexin A2, a protein known to mediate apoptosis as well as the redox pathway.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma/metabolismo , Queratina-8/genética , Neoplasias da Glândula Tireoide/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anexina A2/metabolismo , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma/genética , Carcinoma/patologia , Linhagem Celular Tumoral , Feminino , Dosagem de Genes , Humanos , Queratina-8/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Ligação Proteica , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima
12.
Rare Tumors ; 9(2): 6834, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28975018

RESUMO

We previously reported an extremely rare case of follicular dendritic cell sarcoma (FDCS) presented as a thyroid mass. Given the rarity of this disease, there are no personalized and molecularly targeted treatment options due to the lack of knowledge in the genomic makeup of the tumor. A 44-year-old white woman was diagnosed with an extranodal FDCS in thyroid. The patient underwent a total thyroidectomy, central compartment dissection, parathyroid re-implantation, and adjuvant radiation therapy. Tumor DNA sequencing of 236 genes by FoundationOne panel found truncating mutations in PTEN and missense mutations in RET and TP53. However, patient-matched germline DNA was not sequenced which is critical for identification of true somatic mutations. Furthermore, the FoundationOne panel doesn't measure genomic rearrangements which have been shown to be abundant in sarcomas and are associated with sarcoma tumorigenesis and progression. In the current study, we carried out comprehensive genomic sequencing of the tumor, adjacent normal tissues, and patient-matched blood, in an effort to understand the genomic makeup of this rare extranodal FDCS and to identify potential therapeutic targets. Eighty-one somatic point mutations were identified in tumor but not in adjacent normal tissues or blood. A clonal truncating mutation in the CLTCL1 gene, which stabilizes the mitotic spindle, was likely a driver mutation of tumorigenesis and could explain the extensive copy number aberrations (CNAs) and genomic rearrangements in the tumor including a chr15/chr17 local chromothripsis resulted in 6 expressed fusion genes. The fusion gene HDGFRP3→SHC4 led to a 200-fold increase in the expression of oncogene SHC4 which is a potential target of the commercial drug Dasatinib. Missense mutations in ATM and splice-site mutation in VEGFR1 were also detected in addition to the TP53 missense mutation reported by FoundationOne.

13.
J Clin Endocrinol Metab ; 102(12): 4506-4514, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29029287

RESUMO

Context: Historical outcomes in anaplastic thyroid cancer (ATC) have been dismal. Objective: To determine whether an initial intensive multimodal therapy (MMT) is associated with improved ATC survival. Design: MMT was offered to all patients with newly diagnosed ATC treated at the Mayo Clinic from 2003 through 2015; MMT vs care with palliative intent (PI) was individualized considering clinical status and patient preferences. Outcomes were retrospectively analyzed by American Joint Committee on Cancer stage and treatments compared with patient cohort data from 1949 through 1999. Patients: Forty-eight patients (60% male; median age, 62 years); 18 treated with PI, 30 with MMT. Main Outcome Measure: Overall survival (OS) and progression-free survival determined by Kaplan-Meier method. Results: Median OS and 1-year survival for the later cohort were 9 months [95% confidence interval (CI), 4 to 22 months] and 42% (95% CI, 28% to 56%) vs 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT vs PI groups for the later cohort [hazard ratio (HR), 0.32; P = 0.0006]. Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 vs 4 months (HR, 0.12; 95% CI, 0.03 to 0.44; P = 0.0001), with 68% vs 0% alive at 1 year (MMT vs PI). Among patients with stage IVC cancer, OS did not differ by therapy. Conclusion: MMT appears to convey longer survival in ATC among patients with stage IVA/B disease.


Assuntos
Carcinoma/terapia , Neoplasias da Glândula Tireoide/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/tratamento farmacológico , Carcinoma/radioterapia , Quimiorradioterapia , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Estudos Retrospectivos , Análise de Sobrevida , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapia , Tireoidectomia , Resultado do Tratamento
14.
Endocr Pract ; 22(5): 602-11, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26799628

RESUMO

OBJECTIVE: The dramatic increase in papillary thyroid carcinoma (PTC) is primarily a result of early diagnosis of small cancers. Active surveillance is a promising management strategy for papillary thyroid microcarcinomas (PTMCs). However, as this management strategy gains traction in the U.S., it is imperative that patients and clinicians be properly educated, patients be followed for life, and appropriate tools be identified to implement the strategy. METHODS: We review previous active surveillance studies and the parameters used to identify patients who are good candidates for active surveillance. We also review some of the challenges to implementing active surveillance protocols in the U.S. and discuss how these might be addressed. RESULTS: Trials of active surveillance support nonsurgical management as a viable and safe management strategy. However, numerous challenges exist, including the need for adherence to protocols, education of patients and physicians, and awareness of the impact of this strategy on patient psychology and quality of life. The Thyroid Cancer Care Collaborative (TCCC) is a portable record keeping system that can manage a mobile patient population undergoing active surveillance. CONCLUSION: With proper patient selection, organization, and patient support, active surveillance has the potential to be a long-term management strategy for select patients with PTMC. In order to address the challenges and opportunities for this approach to be successfully implemented in the U.S., it will be necessary to consider psychological and quality of life, cultural differences, and the patient's clinical status.


Assuntos
Carcinoma Papilar/epidemiologia , Carcinoma Papilar/terapia , Atenção à Saúde/organização & administração , Vigilância da População/métodos , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/terapia , Carcinoma Papilar/economia , Análise Custo-Benefício , Atenção à Saúde/economia , Implementação de Plano de Saúde/economia , Implementação de Plano de Saúde/organização & administração , Humanos , Guias de Prática Clínica como Assunto/normas , Qualidade de Vida , Neoplasias da Glândula Tireoide/economia , Estados Unidos/epidemiologia
16.
J Natl Compr Canc Netw ; 13(9): 1140-50, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26358798

RESUMO

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma focuses on anaplastic carcinoma because substantial changes were made to the systemic therapy recommendations for the 2015 update. Dosages and frequency of administration are now provided, docetaxel/doxorubicin regimens were added, and single-agent cisplatin was deleted because it is not recommended for patients with advanced or metastatic anaplastic thyroid cancer.


Assuntos
Carcinoma Anaplásico da Tireoide/diagnóstico , Carcinoma Anaplásico da Tireoide/terapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Docetaxel , Doxorrubicina/administração & dosagem , Humanos , Paclitaxel/administração & dosagem , Radioterapia de Intensidade Modulada , Taxoides/administração & dosagem , Carcinoma Anaplásico da Tireoide/secundário , Neoplasias da Glândula Tireoide/patologia , Tireoidectomia
17.
Endocr Relat Cancer ; 22(5): 777-92, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26206775

RESUMO

Anaplastic thyroid carcinoma is a highly aggressive undifferentiated carcinoma with a mortality rate near 100% due to an assortment of genomic abnormalities which impede the success of therapeutic options. Our laboratory has previously identified that RhoB upregulation serves as a novel molecular therapeutic target and agents upregulating RhoB combined with paclitaxel lead to antitumor synergy. Knowing that histone deacetylase 1 (HDAC1) transcriptionally suppresses RhoB, we sought to extend our findings to other HDACs and to identify the HDAC inhibitor (HDACi) that optimally synergize with paclitaxel. Here we identify HDAC6 as a newly discovered RhoB repressor. By using isoform selective HDAC inhibitors (HDACi) and shRNAs, we show that RhoB has divergent downstream signaling partners, which are dependent on the HDAC isoform that is inhibited. When RhoB upregulates only p21 (cyclin kinase inhibitor) using a class I HDACi (romidepsin), cells undergo cytostasis. When RhoB upregulates BIMEL using class II/(I) HDACi (belinostat or vorinostat), apoptosis occurs. Combinatorial synergy with paclitaxel is dependent upon RhoB and BIMEL while upregulation of RhoB and only p21 blocks synergy. This bifurcated regulation of the cell cycle by RhoB is novel and silencing either p21 or BIMEL turns the previously silenced pathway on, leading to phenotypic reversal. This study intimates that the combination of belinostat/vorinostat with paclitaxel may prove to be an effective therapeutic strategy via the novel observation that class II/(I) HDACi antagonize HDAC6-mediated suppression of RhoB and subsequent BIMEL, thereby promoting antitumor synergy. These overall observations may provide a mechanistic understanding of optimal therapeutic response.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Histona Desacetilase 1/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/química , Carcinoma Anaplásico da Tireoide/patologia , Proteína rhoB de Ligação ao GTP/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteína 11 Semelhante a Bcl-2 , Western Blotting , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Sinergismo Farmacológico , Citometria de Fluxo , Desacetilase 6 de Histona , Humanos , Ácidos Hidroxâmicos/farmacologia , Técnicas Imunoenzimáticas , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Paclitaxel/farmacologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonamidas/farmacologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/metabolismo , Ativação Transcricional , Células Tumorais Cultivadas , Regulação para Cima , Vorinostat , Proteína rhoB de Ligação ao GTP/genética
18.
Oncotarget ; 6(11): 9073-85, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25940539

RESUMO

Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies that currently has no effective therapy. We performed quantitative high-throughput screening (qHTS) in three ATC cell lines using 3,282 clinically approved drugs and drug candidates, and identified 100 active agents. Enrichment analysis of active compounds showed that inhibitors of EGFR and histone deacetylase (HDAC) were most active. Of these, the first-in-class dual inhibitor of EGFR, HER2 and HDACs, CUDC-101, had the highest efficacy and lower IC50 than established drugs. We validated that CUDC-101 inhibited cellular proliferation and resulted in cell death by inducing cell cycle arrest and caspase-dependent apoptosis. CUDC-101 also inhibited cellular migration in vitro. Mechanistically, CUDC-101 inhibited MAPK signaling and histone deacetylation in ATC cell lines with multiple driver mutations present in human ATC. The anticancer effect of CUDC-101 was associated with increased expression of p21 and E-cadherin, and reduced expression of survivin, XIAP, ß-catenin, N-cadherin, and Vimentin. In an in vivo mouse model of metastatic ATC, CUDC-101 inhibited tumor growth and metastases, and significantly prolonged survival. Response to CUDC-101 treatment in vivo was associated with increased histone 3 acetylation and reduced survivin expression. Our findings provide a preclinical basis to evaluate CUDC-101 therapy in ATC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Ácidos Hidroxâmicos/uso terapêutico , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma/genética , Carcinoma/secundário , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA de Neoplasias/genética , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Mutação , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Clin Endocrinol Metab ; 100(5): E697-709, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25675381

RESUMO

CONTEXT: Currently there are no efficacious therapies for patients with anaplastic thyroid carcinoma (ATC) that result in long-term disease stabilization or regression. OBJECTIVE: We sought to identify pathways critical for ATC cell progression and viability in an effort to develop new therapeutic strategies. We investigated the effects of targeted inhibition of stearoyl-CoA desaturase 1 (SCD1), a constituent of fatty acid metabolism overexpressed in ATC. DESIGN: A gene array of ATC and normal thyroid tissue was performed to identify gene transcripts demonstrating altered expression in tumor samples. Effects of pharmacological and the genetic inhibition of SCD1 on tumor cell viability as well as cell signaling responses to therapy were evaluated in in vitro and in vivo models of this rare, lethal malignancy. RESULTS: The gene array analysis revealed consistent distortion of fatty acid metabolism and overexpression of SCD1 in ATC and well-differentiated thyroid carcinomas. SCD1 is critical for ATC cell survival and proliferation, the inhibition of which induced endoplasmic reticulum stress, activation of the unfolded protein response, and apoptosis. Combined suppression of endoplasmic reticulum-associated degradation, a prosurvival component of the unfolded protein response, using proteasome inhibitors resulted in a synergistic decrease in tumor cell proliferation and increased cell death. CONCLUSIONS: SCD1 is a novel oncogenic factor specifically required for tumor cell viability in ATC. Furthermore, the expression of SCD1 appears to be correlated with thyroid tumor aggressiveness and may serve as a prognostic biomarker. These findings substantiate SCD1 as a novel tumor-specific target for therapy in patients with ATC and should be further investigated in a clinical setting.


Assuntos
Metabolismo dos Lipídeos/genética , Estearoil-CoA Dessaturase/metabolismo , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Humanos , Estearoil-CoA Dessaturase/genética , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Análise Serial de Tecidos
20.
J Clin Endocrinol Metab ; 100(4): E611-5, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25625803

RESUMO

CONTEXT AND OBJECTIVE: Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation, and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management. DESIGN AND PATIENTS: Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line, and five Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene. RESULTS: Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors. CONCLUSION: Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of MEN1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis, and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.


Assuntos
Mutação , Proteínas Proto-Oncogênicas/genética , Neoplasias da Glândula Tireoide/genética , Adenoma Oxífilo , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Estudos de Coortes , Análise Mutacional de DNA , Dosagem de Genes , Humanos , Metástase Linfática , Análise por Pareamento , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia
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