Summary Substantial developments have occurred in the past 5–10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET -PTC, RAS , and BRAFV600E ...mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine.
To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer (ATC) and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.
The ...genetic profiles of 583 advanced differentiated and 196 ATCs generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed.
ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared with other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated thyroid cancers and ATCs. Copy number losses and mutations of
and
, amplification of
, amplification of receptor tyrosine kinase genes
, and
, amplification of immune evasion genes
, and
, and activating point mutations in small GTPase
were associated with ATC. An association of
, and
amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown
Three genetically distinct types of ATCs are proposed.
This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed.
.
Many different drugs affect thyroid function. Most of these drugs act at the level of the thyroid in patients with normal thyroid function, or at the level of thyroid hormone absorption or metabolism ...in patients requiring exogenous levothyroxine. A small subset of medications including glucocorticoids, dopamine agonists, somatostatin analogues and rexinoids affect thyroid function through suppression of TSH in the thyrotrope or hypothalamus. Fortunately, most of these medications do not cause clinically evident central hypothyroidism. A newer class of nuclear hormone receptors agonists, called rexinoids, cause clinically significant central hypothyroidism in most patients and dopamine agonists may exacerbate ‘hypothyroidism’ in patients with non-thyroidal illness. In this review, we explore mechanisms governing TSH suppression of these drugs and the clinical relevance of these effects.
The treatment of differentiated thyroid cancer continues to move away from a ‘one size fits all’ approach to a process of tailored therapeutic decision-making that incorporates disease-specific ...factors and individual patient preferences. Management options range from active surveillance to thyroid lobectomy to total thyroidectomy with or without the use of postoperative radioactive iodine (RAI). RAI may be administered for one or more reasons: Thyroid remnant ablation, adjuvant therapy, or therapy for persistent structural disease. It is important to be cognizant of the therapeutic intent of RAI and weigh the risks and benefits of treatment for each individual patient. Risk stratification should be used to identify those patients who are most likely to benefit from RAI and guide therapeutic choices. Available data suggest that RAI can be safely deferred for most patients considered at low risk for structural recurrence, while adjuvant RAI is associated with improved disease-free survival in patients with higher-risk disease. Although progress has been made, many areas of uncertainty related to the use of RAI remain. These include: (1) The appropriate selection of intermediate-risk patients to receive adjuvant RAI, (2) the superiority or inferiority of different RAI dosing activities, (3) the optimal approach to the use of RAI in special populations, including patients with end-stage renal disease and children, and (4) the management of patients with RAI-refractory disease.
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.
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.
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.,
,
, or gene fusions). Mutations in the
promoter (83%) and
(71%) were highly prevalent. There were frequent alterations in
,
, 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 BRAF
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
heterozygous tumors was the most prominent event selected during
immortalization.
This cell line resource will help inform future preclinical studies exploring tumor-specific dependencies.
Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of ...these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.
The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research.
We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.
Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the ...management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines.
Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force.
The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease.
We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.
Context: Thyroid nodules are common in adults, but only a small fraction of them are malignant. Fine-needle aspiration (FNA) with cytological evaluation is the most reliable tool for cancer diagnosis ...in thyroid nodules. However, 10–40% of nodules are diagnosed as indeterminate by cytology, making it difficult to optimally manage these patients.
Objective: The aim of this study was to establish the feasibility and role of testing for tumor-specific mutations in improving the FNA diagnosis of thyroid nodules.
Design: The prospective study included 470 FNA samples of thyroid nodules from 328 patients. At the time of aspiration, a small portion of the material was collected and tested for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations. The mutational status was correlated with cytology and either surgical pathology diagnosis or follow-up (mean, 34 months).
Results: A sufficient amount of nucleic acids were isolated in 98% of samples. Thirty-two mutations were found, including 18 BRAF, eight RAS, five RET/PTC, and one PAX8/PPARγ. The presence of any mutation was a strong indicator of cancer because 31 (97%) of mutation-positive nodules had a malignant diagnosis after surgery. A combination of cytology and molecular testing showed significant improvement in the diagnostic accuracy and allowed better prediction of malignancy in the nodules with indeterminate cytology.
Conclusions: These results indicate that molecular testing of thyroid nodules for a panel of mutations can be effectively performed in a clinical setting. It enhances the accuracy of FNA cytology and is of particular value for thyroid nodules with indeterminate cytology.
Testing for a panel of mutations in thyroid fine needle aspiration samples improves cancer detection, particularly in thyroid nodules with indeterminate cytology.
The overall prognosis of thyroid cancer is excellent, but some patients have grossly invasive disease and distant metastases with limited responses to systemic therapies. Thus, relevant preclinical ...models are needed to investigate thyroid cancer biology and novel treatments. Different preclinical models have recently emerged with advances in thyroid cancer genetics, mouse modeling and new cell lines. Choosing the appropriate model according to the research question is crucial to studying thyroid cancer. This review will discuss the current preclinical models frequently used in thyroid cancer research, from cell lines to mouse models, and future perspectives on patient-derived and humanized preclinical models in this field.
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