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Front Endocrinol (Lausanne) ; 15: 1354750, 2024.
Article in English | MEDLINE | ID: mdl-38756996

ABSTRACT

At the beginning of the eighteenth century, most physicians recognized cancer as an aggressive process that gradually spreads, leading to cachexia and death. Thyroid malignancies had long been underestimated because the majority of the population of West Europe suffered from diffuse goiters that masked malignant processes in the neck. Moreover, the life expectancy at that time was very low (about 37-40 years), so the majority of people died of other causes before metastatic thyroid cancer could develop and manifest. Nevertheless, in 1817, French dermatologist Jean Louis Alibert described the first case of a malignant tumor involving the thyroid gland. From the 1820s the number of case reports describing thyroid cancer increased. Even though Jean Claude Recamier described metastases in 1829, secondary lesions on various organs in patients with thyroid malignancies were not themselves considered malignant until 1876.


Subject(s)
Goiter , Thyroid Neoplasms , Thyroid Neoplasms/pathology , Thyroid Neoplasms/history , Humans , History, 19th Century , History, 18th Century , Goiter/history , Goiter/pathology , Neoplasm Metastasis , History, 20th Century
3.
J Clin Med ; 11(24)2022 Dec 16.
Article in English | MEDLINE | ID: mdl-36556093

ABSTRACT

Osteoporosis (OP) is a major global health concern, with aging being one of the most important risk factors. Osteoarthritis (OA) is also an age-related disorder. Patients with OP and/or OA may be treated surgically for fractures or when their quality of life is impaired. Poor bone quality due to OP can seriously complicate the stability of a bone fixation construct and/or surgical fracture treatment. This review summarizes the current knowledge on the pathophysiology of normal and osteoporotic bone healing, the effect of a bone fracture on bone turnover markers, the diagnosis of a low bone mineral density (BMD) before surgical intervention, and the effect of available anti-osteoporosis treatment. Interventions that improve bone health may enhance the probability of favorable surgical outcomes. Fracture healing and the treatment of atypical femoral fractures are also discussed.

4.
Cancers (Basel) ; 14(3)2022 Jan 22.
Article in English | MEDLINE | ID: mdl-35158824

ABSTRACT

The prevalence of obesity is progressively increasing along with the potential high risk for insulin resistance and development of type 2 diabetes mellitus. Obesity is associated with increased risk of many malignancies, and hyperinsulinemia has been proposed to be a link between obesity and cancer development. The incidence of thyroid cancer is also increasing, making this cancer the most common endocrine malignancy. There is some evidence of associations between obesity, insulin resistance and/or diabetes with thyroid proliferative disorders, including thyroid cancer. However, the etiology of such an association has not been fully elucidated. The goal of the present work is to review the current knowledge on crosstalk between thyroid and glucose metabolic pathways and the effects of obesity, insulin resistance, diabetes, and anti-hyperglycemic medications on the risk of thyroid cancer development.

5.
J Endocr Soc ; 5(2): bvaa191, 2021 Feb 01.
Article in English | MEDLINE | ID: mdl-33442570

ABSTRACT

CONTEXT: Lipodystrophy syndromes cause hypertriglyceridemia that improves with leptin treatment using metreleptin. Mechanisms causing hypertriglyceridemia and improvements after metreleptin are incompletely understood. OBJECTIVE: Determine relationship of circulating lipoprotein lipase (LPL) modulators with hypertriglyceridemia in healthy controls and in patients with lipodystrophy before and after metreleptin. METHODS: Cross-sectional comparison of patients with lipodystrophy (generalized lipodystrophy n = 3; partial lipodystrophy n = 11) vs age/sex-matched healthy controls (n = 28), and longitudinal analyses in patients before and after 2 weeks and 6 months of metreleptin. The study was carried out at the National Institutes of Health, Bethesda, Maryland. Outcomes were LPL stimulators apolipoprotein (apo) C-II and apoA-V and inhibitors apoC-III and angiopoietin-like proteins (ANGPTLs) 3, 4, and 8; ex vivo activation of LPL by plasma. RESULTS: Patients with lipodystrophy were hypertriglyceridemic and had higher levels of all LPL stimulators and inhibitors vs controls except for ANGPTL4, with >300-fold higher ANGPTL8, 4-fold higher apoC-III, 3.5-fold higher apoC-II, 1.9-fold higher apoA-V, 1.6-fold higher ANGPTL3 (P < .05 for all). At baseline, all LPL modulators except ANGPLT4 positively correlated with triglycerides. Metreleptin decreased apoC-II and apoC-III after 2 weeks and 6 months, and decreased ANGPTL8 after 6 months (P < 0.05 for all). Plasma from patients with lipodystrophy caused higher ex vivo LPL activation vs hypertriglyceridemic control plasma (P < .0001), which did not change after metreleptin. CONCLUSION: Elevations in LPL inhibitors apoC-III and ANGPTL8 may contribute to hypertriglyceridemia in lipodystrophy, and may mediate reductions in circulating and hepatic triglycerides after metreleptin. These therefore are strong candidates for therapies to lower triglycerides in these patients.

6.
Clin Cancer Res ; 26(8): 2022-2036, 2020 04 15.
Article in English | MEDLINE | ID: mdl-31937621

ABSTRACT

PURPOSE: Most aggressive thyroid cancers are commonly associated with a BRAF V600E mutation. Preclinical and clinical data in BRAF V600E cancers suggest that combined BRAF and MEK inhibitor treatment results in a response, but resistance is common. One mechanism of acquired resistance is through persistent activation of tyrosine kinase (TK) signaling by alternate pathways. We hypothesized that combination therapy with BRAF and multitargeting TK inhibitors (MTKI) might be more effective in BRAF V600E thyroid cancer than in single-agent or BRAF and MEK inhibitors. EXPERIMENTAL DESIGN: The combined drug activity was analyzed to predict any synergistic effect using high-throughput screening (HTS) of active drugs. We performed follow-up in vitro and in vivo studies to validate and determine the mechanism of action of synergistic drugs. RESULTS: The MTKI ponatinib and the BRAF inhibitor PLX4720 showed synergistic activity by HTS. This combination significantly inhibited proliferation, colony formation, invasion, and migration in BRAF V600E thyroid cancer cell lines and downregulated pERK/MEK and c-JUN signaling pathways, and increased apoptosis. PLX4720-resistant BRAF V600E cells became sensitized to the combination treatment, with decreased proliferation at lower PLX4720 concentrations. In an orthotopic thyroid cancer mouse model, combination therapy significantly reduced tumor growth (P < 0.05), decreased the number of metastases (P < 0.05), and increased survival (P < 0.05) compared with monotherapy and vehicle control. CONCLUSIONS: Combination treatment with ponatinib and PLX4720 exhibited significant synergistic anticancer activity in preclinical models of BRAF V600E thyroid cancer, in addition to overcoming PLX4720 resistance. Our results suggest this combination should be tested in clinical trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Evaluation, Preclinical/methods , Drug Synergism , Mutation , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Thyroid Neoplasms/drug therapy , Animals , Apoptosis , Cell Line, Tumor , Cell Proliferation , High-Throughput Screening Assays/methods , Humans , Imidazoles/administration & dosage , Indoles/administration & dosage , Mice , Mice, Inbred NOD , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Pyridazines/administration & dosage , Sulfonamides/administration & dosage , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology , Xenograft Model Antitumor Assays
7.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Article in English | MEDLINE | ID: mdl-31588494

ABSTRACT

CONTEXT: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN: Single-arm, open-label study of liothyronine. SETTING: National Institutes of Health. PARTICIPANTS: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.


Subject(s)
Antigens, CD/genetics , Biomarkers/analysis , Blood Glucose/analysis , Hyperglycemia/drug therapy , Mutation , Receptor, Insulin/genetics , Thyroid Hormones/pharmacology , Adipose Tissue, Brown/drug effects , Adipose Tissue, White/drug effects , Adolescent , Adult , Aged , Child , Female , Follow-Up Studies , Glycated Hemoglobin/analysis , Humans , Hyperglycemia/genetics , Hyperglycemia/metabolism , Hyperglycemia/pathology , Male , Middle Aged , Non-Randomized Controlled Trials as Topic , Prognosis , Prospective Studies , Young Adult
8.
J Thyroid Res ; 2019: 1893047, 2019.
Article in English | MEDLINE | ID: mdl-31360432

ABSTRACT

Medullary thyroid carcinoma (MTC), arising from the parafollicular C cells of the thyroid, accounts for 1-2% of thyroid cancers. MTC is frequently aggressive and metastasizes to cervical and mediastinal lymph nodes, lungs, liver, and bones. Although a number of new imaging modalities for directing the management of oncologic patients evolved over the last two decades, the clinical application of these novel techniques is limited in MTC. In this article, we review the biology and molecular aspects of MTC as an important background for the use of current imaging modalities and approaches for this tumor. We discuss the modern and currently available imaging techniques-advanced magnetic resonance imaging (MRI)-based techniques such as whole-body MRI, dynamic contrast-enhanced (DCE) technique, diffusion-weighted imaging (DWI), positron emission tomography/computed tomography (PET/CT) with 18F-FDOPA and 18F-FDG, and integrated positron emission tomography/magnetic resonance (PET/MR) hybrid imaging-for primary as well as metastatic MTC tumor, including its metastatic spread to lymph nodes and the most common sites of distant metastases: lungs, liver, and bones.

9.
Pediatr Endocrinol Rev ; 16(3): 311-334, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30888124

ABSTRACT

Many hereditary and sporadic tumor and other syndromes are associated with endocrine functional and or structural abnormalities. The last few decades have yielded advancements in the field with improvements in diagnostic testing, screening guidelines and novel treatment options. In general, endocrine functional abnormalities and neoplasms share an early age of onset. There remains room for improvement as limited literature exists regarding clinical course, prognosis, and screening for earlier cancer detection. This should allow for more timely intervention, and possibly improved outcomes. The aim of this article is to summarize the current knowledge about prevalence, clinical course, and prognosis of functional and structural pituitary, thyroid, adrenal, and gonadal abnormalities in patients with 17 known syndromic, mostly tumor-predisposing, diseases, wherever possible, we review screening recommendations.


Subject(s)
Adrenal Gland Neoplasms , Thyroid Neoplasms , Genetic Testing , Humans
10.
J Clin Endocrinol Metab ; 104(6): 2216-2228, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30657911

ABSTRACT

CONTEXT: Insulin and leptin may increase growth and proliferation of thyroid cells, underlying an association between type 2 diabetes and papillary thyroid cancer (PTC). Patients with extreme insulin resistance due to lipodystrophy or insulin receptor mutations (INSR) are treated with high-dose insulin and recombinant leptin (metreleptin), which may increase the risk of thyroid neoplasia. OBJECTIVE: The aim of this study was to analyze thyroid structural abnormalities in patients with lipodystrophy and INSR mutations and to assess whether insulin, IGF-1, and metreleptin therapy contribute to the thyroid growth and neoplasia in this population. DESIGN: Thyroid ultrasound characteristics were analyzed in 81 patients with lipodystrophy and 11 with INSR (5 homozygous; 6 heterozygous). Sixty patients were taking metreleptin. RESULTS: The prevalence of thyroid nodules in children with extreme insulin resistance (5 of 30, 16.7%) was significantly higher than published prevalence for children (64 of 3202; 2%), with no difference between lipodystrophy and INSR. Body surface area-adjusted thyroid volume was larger in INSR homozygotes vs heterozygotes or lipodystrophy (10.4 ± 5.1, 3.9 ± 1.5, and 6.2 ± 3.4 cm2, respectively. Three patients with lipodystrophy and one INSR heterozygote had PTC. There were no differences in thyroid ultrasound features in patients treated vs not treated with metreleptin. CONCLUSION: Children with extreme insulin resistance had a high prevalence of thyroid nodules, which were not associated with metreleptin treatment. Patients with homozygous INSR mutation had thyromegaly, which may be a novel phenotypic feature of this disease. Further studies are needed to determine the etiology of thyroid abnormalities in patients with extreme insulin resistance.


Subject(s)
Insulin Resistance , Lipodystrophy/pathology , Mutation , Receptor, Insulin/genetics , Thyroid Gland/pathology , Adolescent , Adult , Aged , Child , Cysts/pathology , Female , Humans , Insulin-Like Growth Factor I/analysis , Insulin-Like Growth Factor II/analysis , Leptin/analogs & derivatives , Leptin/pharmacology , Leptin/therapeutic use , MAP Kinase Signaling System/physiology , Male , Middle Aged , Receptor, Insulin/physiology , Syndrome , Thyroid Gland/drug effects , Thyroid Gland/physiology , Young Adult
11.
Surgery ; 165(1): 50-57, 2019 01.
Article in English | MEDLINE | ID: mdl-30327187

ABSTRACT

BACKGROUND: There are conflicting reports on whether familial nonmedullary thyroid cancer is more aggressive than sporadic nonmedullary thyroid cancer. Our aim was to determine if the clinical and pathologic characteristics of familial nonmedullary thyroid cancer are different than nonmedullary thyroid cancer. METHODS: We compared patients with familial nonmedullary thyroid cancer to a cohort of 53,571 nonmedullary thyroid cancer patients from the Surveillance, Epidemiology, and End Results database. RESULTS: A total of 78 patients with familial nonmedullary thyroid cancer from 31 kindreds presented at a younger age (P = .04) and had a greater rate of T1 disease (P = .019), lymph node metastasis (P = .002), and the classic variant of papillary thyroid cancer on histology (P < .001) compared with the Surveillance, Epidemiology, and End Results cohort. Patients with ≥3 affected family members presented at a younger age (P = .04), had a lesser female-to-male ratio (P = .04), and had a greater rate of lymph node metastasis (P = .009). Compared with the Surveillance, Epidemiology, and End Results cohort, we found a higher prevalence of lymph node metastasis in familial nonmedullary thyroid cancer index cases (P = .003) but not in those diagnosed by screening ultrasonography (P = .58). CONCLUSION: Patients with familial nonmedullary thyroid cancer present at a younger age and have a greater rate of lymph node metastasis. The treatment for familial nonmedullary thyroid cancer should be more aggressive in patients who present clinically and in those who have ≥3 first-degree relatives affected.


Subject(s)
Carcinoma, Medullary/congenital , Multiple Endocrine Neoplasia Type 2a/pathology , Thyroid Cancer, Papillary/pathology , Thyroid Neoplasms/pathology , Adult , Age Distribution , Carcinoma, Medullary/epidemiology , Carcinoma, Medullary/pathology , Carcinoma, Medullary/surgery , Cohort Studies , Female , Humans , Lymphatic Metastasis , Male , Middle Aged , Multiple Endocrine Neoplasia Type 2a/epidemiology , Multiple Endocrine Neoplasia Type 2a/surgery , Neck Dissection/statistics & numerical data , SEER Program , Sex Distribution , Thyroid Cancer, Papillary/epidemiology , Thyroid Cancer, Papillary/surgery , Thyroid Neoplasms/epidemiology , Thyroid Neoplasms/surgery , Thyroidectomy/statistics & numerical data , United States/epidemiology
12.
Insights Imaging ; 9(6): 1035-1056, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30484079

ABSTRACT

Fibrous dysplasia (FD) is a congenital disorder arising from sporadic mutation of the α-subunit of the Gs stimulatory protein. Osseous changes are characterised by the replacement and distortion of normal bone with poorly organised, structurally unsound, fibrous tissue. The disease process may be localised to a single or multiple bones. In McCune-Albright syndrome (MAS), fibrous dysplasia is associated with hyperfunction of endocrine organs and overproduction of melanin in the skin, while Mazabraud syndrome FD is associated with intramuscular myxomas. In radiology, FD is very often automatically associated with the term "ground glass matrix". However, FD is a complex disease, and knowledge of its unique pathogenesis and course are crucial to understanding imaging findings and potential complications. This article aims to not only summarise the spectrum of radiological findings of osseous and extra-osseous abnormalities associated with FD but also to highlight the pathological base of the disease evolution, corresponding imaging changes and complications based on the disease distribution. We also have provided current recommendations for clinical management and follow-up of patients with FD. TEACHING POINTS: • FD is often a part of complex disease, involving not only bone but also multiple other organs. • FD lesions are characterised by age-related histological, radiographical and clinical transformations. • Radiologists play a crucial role in the identification of osseous complications associated with FD. • The craniofacial form of the disease is the most common type of FD and the most difficult form to manage. • Patients with McCune-Albright syndrome may have different extra-skeletal abnormalities, which often require follow-up.

14.
Endocr Relat Cancer ; 24(3): 147-156, 2017 03.
Article in English | MEDLINE | ID: mdl-28137980

ABSTRACT

The HIV protease inhibitor Nelfinavir (NFV) inhibits PI3K/AKT and MAPK/ERK signaling pathways, emerging targets in thyroid cancers. We examined the effects of NFV on cancer cells that derived from follicular (FTC), papillary (PTC) and anaplastic (ATC) thyroid cancers. NFV (1-20 µM) was tested in FTC133, BCPAP and SW1736 cell lines. The effects of NFV on cell proliferation were determined in vitro using real-time microscopy and by flow cytometry. DNA damage, apoptotic cell death and expression of molecular markers of epithelial-mesenchymal transition (EMT) were determined by Western blot and real-time PCR. Real-time imaging demonstrated that NFV (10 µM) increased the time required for the cell passage through the phases of cell cycle and induced DNA fragmentation. Growth inhibitory effects of NFV were associated with the accumulation of cells in G0/G1 phase, downregulation of cyclin D1 and cyclin-dependent kinase 4 (CDK4). NFV also induced the expression of γH2AX and p53BP1 indicating DNA damage. Treatment with NFV (20 µM) resulted in caspase-3 cleavage in all examined cells. NFV (20 µM) decreased the levels of total and p-AKT in PTEN-deficient FTC133 cells. NFV had no significant effects on total ERK and p-ERK in BRAF-positive BCPAP and SW1736 cells. NFV had no effects on the expression of EMT markers (Twist, Vimentin, E- and N-Cadherin), but inhibited the migration and decreased the abilities of thyroid cancer cells to survive in non-adherent conditions. We conclude that NFV inhibits proliferation and induces DNA damage in thyroid cancer cell lines. Our in vitro data suggest that NFV has a potential to become a new thyroid cancer therapeutic agent.


Subject(s)
Antineoplastic Agents/pharmacology , Nelfinavir/pharmacology , Thyroid Neoplasms/drug therapy , Apoptosis/drug effects , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , DNA Damage , Extracellular Signal-Regulated MAP Kinases/metabolism , HIV Protease Inhibitors/pharmacology , Humans , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism
15.
Am J Pathol ; 186(8): 2105-2116, 2016 08.
Article in English | MEDLINE | ID: mdl-27315778

ABSTRACT

The subfamily of ß2 integrins is implicated in macrophage fusion, a hallmark of chronic inflammation. Among ß2 family members, integrin Mac-1 (αMß2, CD11b/CD18) is abundantly expressed on monocyte/macrophages and mediates critical adhesive reactions of these cells. However, the role of Mac-1 in macrophage fusion leading to the formation of multinucleated giant cells remains unclear. Moreover, the role of integrin αDß2 (CD11d/CD18), a receptor with recognition specificity overlapping that of Mac-1, is unknown. We found that multinucleated giant cells are formed in the inflamed mouse peritoneum during the resolution phase of inflammation, and their numbers were approximately twofold higher in wild-type mice than in Mac-1(-/-) mice. Analyses of isolated inflammatory peritoneal macrophages showed that IL-4-induced fusion of Mac-1-deficient cells was strongly reduced compared with wild-type counterparts. The examination of adhesive reactions known to be required for fusion showed that spreading, but not adhesion and migration, was reduced in Mac-1-deficient macrophages. Fusion of αDß2-deficient macrophages was also significantly decreased, albeit to a smaller degree. Deficiency of intercellular adhesion molecule 1, a counter-receptor for Mac-1 and αDß2, did not alter the fusion rate. The results indicate that both Mac-1 and αDß2 support macrophage fusion with Mac-1 playing a dominant role and suggest that Mac-1 may mediate cell-cell interactions with a previously unrecognized counter-receptor(s).


Subject(s)
CD11 Antigens/metabolism , Inflammation/pathology , Integrin alpha Chains/metabolism , Macrophage-1 Antigen/metabolism , Macrophages/cytology , Animals , Cell Fusion , Disease Models, Animal , Flow Cytometry , Fluorescent Antibody Technique , Giant Cells/cytology , Giant Cells/metabolism , Inflammation/metabolism , Macrophages/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Peritonitis
16.
Thyroid ; 24(10): 1488-500, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24921429

ABSTRACT

BACKGROUND: Spinal metastases (SMs) due to thyroid cancer (TC) are associated with significantly reduced quality of life. The goal of this study is to analyze the clinical manifestations, presentation, and treatments of TC SMs, and to describe specific features of SMs associated with different TC types. PATIENTS AND METHODS: A retrospective analysis of 202 TC SM patients treated at Medstar Washington Hospital Center (37) and collected from the literature (165) was performed. RESULTS: The mean age of patients with SMs was 56.9±14.7 years, and the female-to-male ratio was 2.1:1. Of all patients, 29% (28% of follicular thyroid cancer [FTC] and 37% of papillary thyroid cancer [PTC]) had SMs only. Twenty-nine percent of all patients and 54% of patients with single-site SMs had neither bone non-SMs nor solid organ metastases at the time of presentation. Thirty-five percent of patients had SMs as an initial presentation of TC. TC patients presenting with SMs had a lower rate of other bone and visceral involvement compared with patients whose SMs were diagnosed at the time of thyroid surgery or during follow-up (p<0.05). SMs were more often the initial manifestation of FTC (41% vs. 24%), while PTC SMs were more commonly diagnosed after TC diagnosis (76% vs. 59%; p<0.05). PTC SMs were more frequently diagnosed as synchronous (63% vs. 36% in FTC) versus FTC SMs that developed as metachronous metastases (64% vs. 37% in PTC; p<0.01). All FTC SMs developed within 82 (0-372) months and all PTC SMs within 35 (0-144) months (p<0.01). In FTC SMs as TC manifestation, solid organ metastases involvement was less common than in FTC SMs that were found after TC diagnosis (34% vs. 67%; p<0.01); multisite FTC SMs compared to solitary FTC SMs were associated with the development of other bone nonspinal metastases (82% vs. 30%; p<0.01) and solitary organ metastases (65% vs. 41%; p<0.01). These correlations were not observed in PTC SMs. FTC patients often had neural structure compression (myelopathy/radiculopathy; 72% vs. 36% in PTC), while PTC patients frequently were asymptomatic (38% vs. 5% in FTC; p<0.01). FTC SMs more commonly were (131)I-avid (p<0.01). FTC patients required surgery more frequently (72% vs. 55% in PTC; p<0.05). CONCLUSIONS: Our study reveals that a significant part of TC SMs patients have solitary spinal involvement at the time of presentation and may be considered for aggressive treatment with the intention to improve quality of life and survival. FTC SMs and PTC SMs appear to have distinct presentations, behavior, and treatment modalities, and should be categorized separately for treatment and follow-up planning.


Subject(s)
Adenocarcinoma, Follicular/secondary , Carcinoma/secondary , Spinal Neoplasms/secondary , Thyroid Neoplasms/pathology , Adenocarcinoma, Follicular/mortality , Adenocarcinoma, Follicular/therapy , Adult , Aged , Carcinoma/mortality , Carcinoma/therapy , Carcinoma, Papillary , District of Columbia , Female , Humans , Male , Middle Aged , Patient Selection , Retrospective Studies , Risk Factors , Spinal Neoplasms/mortality , Spinal Neoplasms/therapy , Thyroid Cancer, Papillary , Thyroid Neoplasms/mortality , Time Factors , Treatment Outcome
17.
Thyroid ; 24(10): 1443-55, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24827757

ABSTRACT

BACKGROUND: The spine is the most common site of bone metastases due to thyroid cancer, which develop in more than 3% of patients with well-differentiated thyroid cancer. Nearly half of patients with bone metastases from thyroid cancer develop vertebral metastases. Spinal metastases are associated with significantly reduced quality of life due to pain, neurological deficit, and increased mortality. SUMMARY: Treatment options for patients with thyroid spinal metastases include radioiodine therapy, pharmacologic therapy, and surgical treatments, with recent advances in radiosurgery and minimally invasive spinal surgery as well. Therapeutic interventions require a multidisciplinary approach and aim to control pain, preserve or improve neurologic function, optimize local tumor control, and improve quality of life. We have proposed a three-tiered approach to the management and practical algorithms for patients with spinal metastases from thyroid carcinoma. CONCLUSIONS: The introduction of novel and improved techniques for the treatment of spinal metastases has created the opportunity to significantly improve control of metastatic tumor growth and the quality of life for the patients with spinal metastases from thyroid cancer. In order for these options to be effectively used, a multidisciplinary approach must be applied in the management of the patients with thyroid spinal metastases.


Subject(s)
Carcinoma/secondary , Carcinoma/therapy , Spinal Neoplasms/secondary , Spinal Neoplasms/therapy , Thyroid Neoplasms/pathology , Algorithms , Carcinoma/mortality , Critical Pathways , Humans , Patient Selection , Quality of Life , Spinal Neoplasms/mortality , Thyroid Neoplasms/mortality , Treatment Outcome
18.
J Clin Endocrinol Metab ; 99(5): E734-45, 2014 May.
Article in English | MEDLINE | ID: mdl-24483157

ABSTRACT

CONTEXT: Mutations of RET tyrosine kinase are associated with the development of medullary thyroid cancer (MTC). The heat shock protein (HSP) 90 chaperone is required for folding and stability of RET mutants. HSP90 is a molecular target for the HIV protease inhibitor nelfinavir (NFV). OBJECTIVE: We hypothesized that treatment with NFV may lead to the inhibition of RET signaling and induction of apoptosis in MTC cells. DESIGN: Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to clinically achievable concentrations of NFV. JC-1 staining and caspase-3 cleavage assays were performed to measure mitochondrial membrane potential and apoptosis. Activation of RET signaling was examined by Western blot. Autophagy was monitored by the detection of the light-chain 3BII. Expression of HSP90 and LC3B were examined in 36 human MTCs. RESULTS: At a therapeutic serum concentration (10 µM), NFV inhibited the viability of TT and MZ-CRC-1 cells by 55% and 10%, respectively. In a dose-dependent manner, NFV inhibited cyclin D1 and caused caspase-3 cleavage. NFV decreased the level of RET protein and blocked the activation of RET downstream targets (phosphorylated ERK, phosphorylated AKT, and p70S6K/pS6). NFV induced metabolic stress, activated AMP-activated protein kinase and increased autophagic flux. Pharmacological inhibition of autophagy (chloroquine) augmented NFV-inducible cytotoxicity, suggesting that autophagy was protective in NFV-treated cells. NFV led to mitochondrial membrane depolarization and induced both oxidative stress and DNA damage. An antioxidant (n-acetylcysteine) attenuated DNA damage and prevented NFV-inducible apoptosis. HSP90 overexpression was found in 17 of 36 human MTCs and correlated with metastases and RET mutations. LC3B was detected in 20 of 36 human MTCs. CONCLUSIONS: NFV has a wide spectrum of activity against MTC cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of NFV molecular targets in metastatic MTC suggests that NFV has a potential to become a thyroid cancer therapeutic agent.


Subject(s)
Apoptosis/drug effects , Carcinoma, Medullary/metabolism , Down-Regulation/drug effects , HIV Protease Inhibitors/pharmacology , Nelfinavir/pharmacology , Proto-Oncogene Proteins c-ret/metabolism , Signal Transduction/drug effects , Thyroid Neoplasms/metabolism , Adult , Aged , Autophagy/drug effects , Carcinoma, Medullary/genetics , Carcinoma, Medullary/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Endoplasmic Reticulum Stress/drug effects , Female , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Humans , Male , Middle Aged , Mutation , Oxidative Stress/drug effects , Proto-Oncogene Proteins c-ret/genetics , Thyroid Neoplasms/genetics , Thyroid Neoplasms/pathology
19.
Endocr Relat Cancer ; 21(3): R183-94, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24446492

ABSTRACT

Repositioning of established non-cancer pharmacotherapeutic agents with well-known activity and side-effect profiles is a promising avenue for the development of new treatment modalities for multiple cancer types. We have analyzed some of the medications with mechanism of action that may have relevance to thyroid cancer (TC). Experimental in vitro and in vivo evidences, as well as results of clinical studies, have indicated that molecular targets for medications currently available for the treatment of mood disorders, sexually transmitted diseases, metabolic disorders, and diabetes may be active and relevant in TC. For instance, the derivatives of cannabis and an anti-diabetic agent, metformin, both are able to inhibit ERK, which is commonly activated in TC cells. We present here several examples of well-known medications that have the potential to become new therapeutics for patients with TC. Repositioning of established medications for the treatment of TC could broaden the scope of current therapeutic strategies. These diverse treatment choices could allow physicians to provide an individualized approach to optimize treatment for patients with TC.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Repositioning , Thyroid Neoplasms/drug therapy , Humans
20.
World Neurosurg ; 82(6): 1171-86, 2014 Dec.
Article in English | MEDLINE | ID: mdl-23178919

ABSTRACT

OBJECTIVE: Monocyte-derived cells of the brain (MDCB) are a diverse group of functional immune cells that are also highly abundant in gliomas. There is growing evidence that MDCB play essential roles in the pathogenesis of gliomas. The aim of this review was to collate and systematize contemporary knowledge about these cells as they relate to glioma progression and antiglioblastoma therapeutic modalities with a view toward improved effectiveness of therapy. METHODS: We reviewed relevant studies to construct a summary of different MDCB subpopulations in steady state and in malignant gliomas and discuss their role in the development of malignant gliomas and potential future therapies. RESULTS: Current studies suggest that MDCB subsets display different phenotypes and differentiation potentials depending on their milieu in the brain and exposure to tumoral influences. MDCB possess specific and unique functions, including those that are protumoral and those that are antitumoral. CONCLUSIONS: Elucidating the role of mononuclear-derived cells associated with gliomas is crucial in designing novel immunotherapy strategies. Much progress is needed to characterize markers to identify cell subsets and their specific regulatory roles. Investigation of MDCB can be clinically relevant. Specific MDCB populations potentially can be used for glioma therapy as a target or as cell vehicles that might deliver cytotoxic substances or processes to the glioma microenvironment.


Subject(s)
Brain Neoplasms/pathology , Brain/cytology , Brain/pathology , Glioma/pathology , Monocytes/pathology , Dendritic Cells/pathology , Humans , Inflammation/pathology , Macrophages/pathology , Microglia/pathology , Myeloid Cells/pathology , Receptor, TIE-2/biosynthesis
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