The goal of this study was to explore the relationship of the BRAFV600E mutation with clinicopathologic factors and evaluate the effect of radioactive iodine (RAI) therapy in a large group of intermediate- and high-risk papillary thyroid cancer (PTC) patients with the BRAFV600E mutation and without distant metastases. We collected data for PTC patients who underwent total or near-total thyroidectomy and RAI treatment in our hospital from January 2014–December 2017. There were 1220 PTC patients who met the criteria, and the BRAFV600E mutation was observed in 979 of them (80.2%). Multivariate analysis identified that the BRAFV600E mutation remained independently associated with age at diagnosis, and bilaterality (OR = 1.023, 95% CI = 1.012–1.039, P < 0.001; OR = 1.685, 95% CI = 1.213–2.341, P = 0.002, respectively). In addition, the patients with bilateral PTCs had a higher prevalence of extrathyroid invasion, capsular invasion and fusion of metastatic lymph nodes than the unilateral PTC patients. The response to RAI therapy was evaluated in both the entire series and the patients with a high recurrence risk; no significant difference was discerned between the BRAFV600E mutation and the wild-type groups (P = 0.237 and P = 0.498, respectively). To summarize, our results confirmed that PTC patients with the BRAFV600E mutation exhibit more aggressive characteristics. In addition, the patients with bilateral PTC have a higher incidence of extrathyroid invasion. Moreover, BRAFV600E mutation PTC patients did not show a poorer clinical response after postsurgical RAI therapy, suggesting that RAI therapy may improve the general clinical outcome of these patients.
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Guoquan Zhu, Yuying Deng, Liqin Pan, Wei Ouyang, Huijuan Feng, Juqing Wu, Pan Chen, Jing Wang, Yanying Chen, and Jiaxin Luo
Joanna Klubo-Gwiezdzinska, John Costello Jr, Kirk Jensen, Aneeta Patel, Rok Tkavc, Douglas Van Nostrand, Kenneth D Burman, Leonard Wartofsky, and Vasyl Vasko
Amifostine is a potent scavenger of reactive oxygen species that is used for the salivary gland protection during therapy with radioactive iodine for thyroid cancer. There are no data on the potential effect of amifostine on thyroid cancer cells.
We investigated the effects of the active form of amifostine (WR-1065) on the response of thyroid cancer cells to treatment with DNA-damaging agents. WR-1065 was examined in human thyroid cancer cell lines (FTC133, TPC1, BCPAP and C643) and embryonic fibroblast cells NIH3T3. DNA damage was induced by exposure to H2O2 (0.1 mM), by treatment with the radiomimetic neocarzinostatin (NCS 250 ng/mL) and by γ-radiation (6 Gy). DNA damage, cell viability and apoptosis were examined.
We demonstrated the selective action of WR-1065 (0.1 mM), which prevented oxidative stress–induced DNA damage in fibroblasts, but did not protect thyroid cancer cells from DNA damage and apoptosis documented by caspase-3 and PARP cleavage after exposure to H2O2, NCS and γ-radiation. Prolonged exposure to WR-1065 (0.1 mM for 24 h) was toxic for thyroid cancer cells; this treatment decreased the number of viable cells by 8% in C643 cells, 47% in TPC cells, 92% in BCPAP cells and 82% in FTC 133 cells. The cytotoxic effects of WR-1065 were not associated with induction of apoptosis.
Our data show that amifostine has no protective effect on thyroid cancer cells against DNA-damaging agents in vitro and suggest that amifostine will not attenuate the efficacy of radioiodine treatment in patients with thyroid cancer.
Keiko Ohkuwa, Kiminori Sugino, Mitsuji Nagahama, Wataru Kitagawa, Kenichi Matsuzu, Akifumi Suzuki, Chisato Tomoda, Kiyomi Hames, Junko Akaishi, Chie Masaki, and Koichi Ito
Radioactive iodine (RAI) therapy is effective for differentiated thyroid cancer (DTC) patients with lung metastasis. However, some patients have a poor prognosis despite the RAI accumulation. The utility of inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), has been reported as a prognostic factor for many carcinomas. This study aimed to investigate the risk factors related to DTC patient survival with RAI-avid lung metastasis and to attempt risk stratification.
Design and methods
This retrospective study included 123 patients with RAI-accumulating lung metastatic DTC. The cause-specific survival (CSS) rate from the time of detection of lung metastasis was tested using the Kaplan–Meier log-rank test, and the multivariate analysis was calculated using the Cox proportional hazards model. NLR was retrospectively calculated using the blood sample collected before initial RAI treatment. The NLR cutoff value was 2.6 on the ROC curve.
Age ≥ 55 years at the time of operative treatment, follicular carcinoma, lung metastasis tumor ≥ 10 mm in diameter, age ≥ 55 years at the time of detection of lung metastasis, age ≥ 55 years at the time of RAI treatment, and NLR ≥ 2.6 at the initial RAI treatment were predictive of decreased CSS. Multivariate analysis identified that the independent prognostic factors were lung metastatic tumor ≥ 10 mm in diameter and NLR ≥ 2.6. Patients in the high-risk group with both factors had significantly lower CSS rates than those in the low- and intermediate-risk groups with one or none of these factors.
The high-risk group patients had significantly poorer survival, and these patients could be considered as future candidates for tyrosine kinase inhibitor therapy.
M L Gild, M Bullock, C K Pon, B G Robinson, and R J Clifton-Bligh
Metastatic differentiated thyroid cancers (DTC) are resistant to traditional chemotherapy. Kinase inhibitors have shown promise in patients with progressive DTC, but dose-limiting toxicity is commonplace. HSP90 regulates protein degradation of several growth-mediating kinases such as RET, and we hypothesized that HSP90 inhibitor (AUY922) could inhibit RET-mediated medullary thyroid cancer (MTC) as well as papillary thyroid cancer (PTC) cell growth and also radioactive iodine uptake by PTC cells. Studies utilized MTC cell lines TT (C634W) and MZ-CRC-1 (M918T) and the PTC cell line TPC-1 (RET/PTC1). Cell viability was assessed with MTS assays and apoptosis by flow cytometry. Signaling target expression was determined by western blot and radioiodine uptake measured with a gamma counter. Prolonged treatment of both MTC cell lines with AUY922 simultaneously inhibited both MAPK and mTOR pathways and significantly induced apoptosis (58.7 and 78.7% reduction in MZ-CRC-1 and TT live cells respectively, following 1 μM AUY922; P<0.02). Similarly in the PTC cell line, growth and signaling targets were inhibited, and also a 2.84-fold increase in radioiodine uptake was observed following AUY922 administration (P=0.015). AUY922 demonstrates in vitro activity against MTC and PTC cell lines. We observed a potent dose-dependent increase in apoptosis in MTC cell lines following drug administration confirming its anti-tumorigenic effects. Western blots confirm inhibition of pro-survival proteins including AKT suggesting this as the mechanism of cell death. In a functional study, we observed an increase in radioiodine uptake in the PTC cell line following AUY922 treatment. We believe HSP90 inhibition could be a viable alternative for treatment of RET-driven chemo-resistant thyroid cancers.
Danuta Gąsior-Perczak, Iwona Pałyga, Monika Szymonek, Artur Kowalik, Agnieszka Walczyk, Janusz Kopczyński, Katarzyna Lizis-Kolus, Anna Słuszniak, Janusz Słuszniak, Tomasz Łopatyński, Ryszard Mężyk, Stanisław Góźdź, and Aldona Kowalska
Delayed risk stratification (DRS) system by Momesso and coworkers was accepted by the American Thyroid Association as a diagnostic tool for the risk stratification of unfavorable clinical outcomes and to monitor the clinical outcomes of differentiated thyroid cancer (DTC) patients treated without radioactive iodine (RAI). The aim of this study was to evaluate the DRS system in patients with pT1aN0/Nx stage.
The study included 304 low-risk patients after thyroidectomy (n = 202) or lobectomy (n = 102) without RAI and were treated at a single center. The median age was 50.5 years, 91.1% were women and the median follow-up was 4 years. DRS of the treatment response was performed based on medical records and according to the criteria of Momesso and coworkers. Disease course (recurrence, death) and status (remission, persistent disease) on December 31, 2016 were evaluated. The relationship between unfavorable outcomes and the DRS system was evaluated.
Response to initial therapy was excellent in 272 patients (89.5%), indeterminate in 31 (10.2%) and biochemical incomplete (increased TgAb levels) in one (0.3%). Two patients in the excellent response group experienced recurrence at 6 and 7 years of follow-up (after lobectomy). None of the patients with indeterminate and biochemical incomplete response developed structural disease, and none of the patients died during the follow-up.
The DRS system was not useful for predicting the risk of unfavorable clinical outcomes and cannot be used to personalize the monitoring method of the disease in patients at pT1aN0/Nx stage who are not treated with RAI.
Madalena von Hafe, João Sergio Neves, Catarina Vale, Marta Borges-Canha, and Adelino Leite-Moreira
Thyroid hormones have a central role in cardiovascular homeostasis. In myocardium, these hormones stimulate both diastolic myocardial relaxation and systolic myocardial contraction, have a pro-angiogenic effect and an important role in extracellular matrix maintenance. Thyroid hormones modulate cardiac mitochondrial function. Dysfunction of thyroid axis impairs myocardial bioenergetic status. Both overt and subclinical hypothyroidism are associated with a higher incidence of coronary events and an increased risk of heart failure progression. Endothelial function is also impaired in hypothyroid state, with decreased nitric oxide-mediated vascular relaxation. In heart disease, particularly in ischemic heart disease, abnormalities in thyroid hormone levels are common and are an important factor to be considered. In fact, low thyroid hormone levels should be interpreted as a cardiovascular risk factor. Regarding ischemic heart disease, during the late post-myocardial infarction period, thyroid hormones modulate left ventricular structure, function and geometry. Dysfunction of thyroid axis might even be more prevalent in the referred condition since there is an upregulation of type 3 deiodinase in myocardium, producing a state of local cardiac hypothyroidism. In this focused review, we summarize the central pathophysiological and clinical links between altered thyroid function and ischemic heart disease. Finally, we highlight the potential benefits of thyroid hormone supplementation as a therapeutic target in ischemic heart disease.
Kusum Lata, Pinaki Dutta, Subbiah Sridhar, Minakshi Rohilla, Anand Srinivasan, G R V Prashad, Viral N Shah, and Anil Bhansali
Thyroid antibody positivity during pregnancy has been associated with adverse outcomes including miscarriage and preterm delivery. The aim of the study is to evaluate the obstetric outcome in pregnant women with recurrent miscarriage and their response to levothyroxine (l-T4) therapy.
Study design and methods
All pregnant and non-pregnant women between 21 and 35 years of age with a history of two or more consecutive miscarriages were included in the study. A third group comprising 100 pregnant women without a history of miscarriage were taken as healthy controls. Thyroid autoimmunity, prevalence of subclinical hypothyroidism and maternal and foetal complications were analysed in all the groups with appropriate statistical methods.
The mean age of the patients included in the study was 27.0±3.1 years. Of 100 pregnant patients with previous recurrent miscarriage, thyroid autoimmunity (thyroid peroxidase antibody (TPOAb+) >34 U/ml) was found in 31% of the cases. The incidence of subclinical hypothyroidism was higher in TPOAb+ group than in TPOAb− group (52 vs 16%; P=0.0002). There was no difference in the prevalence of miscarriage or obstetric outcomes between recurrent miscarriage and healthy pregnant women group irrespective of TPO status.
The prevalence of thyroid autoimmunity was higher in pregnant women with a history of recurrent abortion compared with healthy pregnant control population. Following l-T4 treatment, there was no difference in prevalence of miscarriage between hypothyroid and euthyroid individuals in TPOAb+ women.
Weiwei He, Bin Wang, Kaida Mu, Jing Zhang, Yanping Yang, Wei Yao, Sheli Li, and Jin-an Zhang
Accumulating data have shown that interleukin-27 (IL27) polymorphisms are linked to the susceptibility of some autoimmune diseases. We assessed whether there was an association between three single-nucleotide polymorphisms (SNPs) of IL27 gene and autoimmune thyroid diseases (AITDs).
Three SNPs (rs153109, rs17855750 and rs181206) of IL27 gene were genotyped by Hi-SNP high-throughput genotyping in 843 patients with AITDs (516 Graves’ disease (GD) and 327 Hashimoto’s thyroiditis (HT)) and 677 healthy controls in Chinese Han population.
Compared with controls, rs153109 displayed significant associations with GD in allele and genotype frequencies (P = 0.002 and P = 0.008, respectively) and rs17855750 displayed significant associations with HT in allele frequencies (P = 0.02), whereas no differences in genotype or allele frequencies were found between AITD patients and controls at rs181206.
Our study, for the first time, showed the significant association of the IL27 gene SNPs with AITD.
Lauren Bell, Ann Louise Hunter, Angelos Kyriacou, Annice Mukherjee, and Akheel A Syed
TSH receptor antibody (TRAb) is considered the gold standard diagnostic test for the autoimmunity of Graves’ disease (GD), which is commonly diagnosed clinically.
To evaluate the true positive (sensitivity) and true negative (specificity) rates of clinical diagnosis of GD or non-GD hyperthyroidism compared to the TRAb test.
University teaching hospital in North West England.
Patients in the Endocrinology service who had a TRAb measurement between December 2009 and October 2015.
Electronic patient records were studied retrospectively for a pre-TRAb clinical diagnosis of GD or non-GD hyperthyroidism. We examined descriptive statistics and binary classification tests; Fisher exact test was used to analyse contingency tables.
We identified 316 patients with a mean age of 45 (range, 17–89) years; 247 (78%) were women. Compared to the TRAb result, clinical diagnosis had a sensitivity of 88%, specificity 66%, positive predictive value 72%, negative predictive value 84%, false negative rate 12%, false positive rate 34%, positive likelihood ratio 2.6 and negative likelihood ratio 0.2 (P < 0.0001).
Clinicians were liable to both over- and under-diagnose GD. The TRAb test can help reduce the number of incorrect or unknown diagnoses in the initial clinical assessment of patients presenting with hyperthyroidism.
Isabel M Abreu, Eva Lau, Bernardo de Sousa Pinto, and Davide Carvalho
Previous studies suggested that subclinical hypothyroidism has a detrimental effect on cardiovascular risk factors, and that its effective treatment may have a beneficial impact on overall health. The main purpose of this review and meta-analysis was to assess whether subclinical hypothyroidism treatment is of clinical relevance, based on cardiovascular risk parameters correction. A systemic research of the literature using MEDLINE tool was performed to identify the relevant studies. Only placebo-controlled randomized control trials were included. A quantitative analysis was also performed. This systematic review and meta-analysis of randomized placebo-controlled trials assess the different impact of levothyroxine vs placebo treatment. A significant decrease in serum thyroid-stimulating hormone and total and low-density lipoprotein cholesterol was obtained with levothyroxine therapy (66, 9 and 14%, respectively) and, although modest, this could be significant in terms of reduction of the incidence of coronary artery disease. Other significant results of lipid parameters were not obtained. This systematic review provides a strong evidence-based data in favour of specific changes and beneficial effects of levothyroxine treatment.