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The New England Journal of Medicine Apr 1999The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma...
BACKGROUND
The occurrence of symptomatic central hypothyroidism (characterized by low serum thyrotropin and thyroxine concentrations) in a patient with cutaneous T-cell lymphoma during therapy with the retinoid X receptor-selective ligand bexarotene led us to hypothesize that such ligands could reversibly suppress thyrotropin production by a thyroid hormone-independent mechanism and thus cause central hypothyroidism.
METHODS
We evaluated thyroid function in 27 patients with cutaneous T-cell lymphoma who were enrolled in trials of high-dose oral bexarotene at one institution. In addition, we evaluated the in vitro effect of triiodothyronine, 9-cis-retinoic acid, and the retinoid X receptor-selective ligand LGD346 on the activity of the thyrotropin beta-subunit gene promoter.
RESULTS
The mean serum thyrotropin concentration declined from 2.2 mU per liter at base line to 0.05 mU per liter during treatment with bexarotene (P<0.001), and the mean serum free thyroxine concentration declined from 1.0 ng per deciliter (12.9 pmol per liter) at base line to 0.45 ng per deciliter (5.8 pmol per liter) (P<0.001) during treatment. The degree of suppression of thyrotropin secretion tended to be greater in patients treated with higher doses of bexarotene (>300 mg per square meter of body-surface area per day) and in those with a history of treatment with interferon alfa. Nineteen patients had symptoms or signs of hypothyroidism, particularly fatigue and cold intolerance. The symptoms improved after the initiation of thyroxine therapy, and all patients became euthyroid after treatment with bexarotene was stopped. In vitro, LGD346 suppressed the activity of the thyrotropin beta-subunit gene promoter in thyrotrophs by as much as 50 percent, an effect similar to that of triiodothyronine and 9-cis-retinoic acid.
CONCLUSIONS
Hypothyroidism may develop in patients with cutaneous T-cell lymphoma who are treated with high-dose bexarotene, most likely because the retinoid X receptor-selective ligand suppresses thyrotropin secretion.
Topics: Aged; Bexarotene; Cohort Studies; Humans; Hypothyroidism; Ligands; Lymphoma, T-Cell, Cutaneous; Male; Promoter Regions, Genetic; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Tetrahydronaphthalenes; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Transcription Factors
PubMed: 10194237
DOI: 10.1056/NEJM199904083401404 -
The New England Journal of Medicine Feb 2013Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective... (Clinical Trial)
Clinical Trial
BACKGROUND
Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known.
METHODS
We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.
RESULTS
Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.
CONCLUSIONS
Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
Topics: Adult; Aged; Benzimidazoles; Female; Humans; Iodine Radioisotopes; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Male; Middle Aged; Mitogen-Activated Protein Kinases; Multimodal Imaging; Mutation; Neoplasm Metastasis; Positron-Emission Tomography; Radiometry; Symporters; Thyroid Neoplasms; Thyrotropin Alfa; Tomography, X-Ray Computed
PubMed: 23406027
DOI: 10.1056/NEJMoa1209288 -
The Journal of Clinical Endocrinology... May 2019BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI).
CONTEXT
BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI).
OBJECTIVES
To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR).
DESIGN
This was a pilot trial that enrolled from June 2014 to January 2016.
SETTING
Academic cancer center.
PATIENTS
Patients with RAIR, BRAF mutant thyroid cancer.
INTERVENTION
Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation.
MAIN OUTCOME MEASURE
The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I.
RESULTS
Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048).
CONCLUSIONS
Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.
Topics: Adult; Aged; Cell Dedifferentiation; Cell Differentiation; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Pilot Projects; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Radiation Tolerance; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyrotropin Alfa; Vemurafenib
PubMed: 30256977
DOI: 10.1210/jc.2018-01478 -
Medicina 2012The incidence of thyroid cancer has increased exponentially around the world (mostly papillary thyroid carcinoma). This growth may reflect the combined effects of... (Review)
Review
The incidence of thyroid cancer has increased exponentially around the world (mostly papillary thyroid carcinoma). This growth may reflect the combined effects of increased screening practices, together with changes in risk factors for thyroid cancer. In spite of this, disease specific mortality remained stable in the last three decades. Due to the fact that patients with papillary thyroid carcinoma often have a very good prognosis, with high survival in the long term follow-up compared with other types of carcinomas, there has been no need to change the standard treatment. The mainstays of thyroid cancer treatment are surgery (total or near-total thyroidectomy) with or without the additional administration of radioiodine (131I). These approaches are now in the center of discussion in all global forums. The current trend is to ensure the most effective and less harmful treatment and the most important issue at this point is to individualize patients according to tumor stage and risk of recurrence, to define which patients will benefit of more aggressive therapy and who could be handled with a more conservative approach.
Topics: Ablation Techniques; Humans; Incidence; Neck Dissection; Precision Medicine; Prevalence; Risk Factors; Thyroid Gland; Thyroid Neoplasms; Thyrotropin Alfa; Treatment Outcome
PubMed: 23241295
DOI: No ID Found -
PloS One 2021Low-iodine diet (LID) is a crucial preparation for radioactive iodine (RAI) treatment or scan in thyroid cancer. The aim of this study is to analyze the influence of...
Low-iodine diet (LID) is a crucial preparation for radioactive iodine (RAI) treatment or scan in thyroid cancer. The aim of this study is to analyze the influence of thyroid stimulating hormone (TSH) stimulation protocols and other clinical factors on LID adequacy. Thyroid cancer patients who underwent LID for RAI scan or treatment were retrospectively analyzed. Patients were guided to have LID for 2 weeks before RAI administration and urine iodine/creatinine ratio (UICR, μg/g Cr) was measured. TSH stimulation was conducted using either thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) injection. Adequacy of LID was classified by UICR as 'excellent (< 50)', 'adequate (50-100)', 'inadequate (101-250)' and 'poor (> 250)'. A total of 1715 UICR measurements from 1054 patients were analyzed. UICR was significantly higher in case of rhTSH use than THW (72.4 ± 48.1 vs. 29.9 ± 45.8 μg/g Cr, P < 0.001). In patients who underwent LID twice using both TSH stimulation protocols alternately, UICR was higher in case of rhTSH than THW regardless of the order of method. Among clinical factors, female, old-age, and the first LID were significant factors to show higher UICR. Although the adequacy of LID was 'adequate' or 'excellent' in most patients, multivariate analysis demonstrated that THW method, male, young age, and prior LID-experience were significant determinants for achieving 'excellent' adequacy of LID. In conclusion, UICR was higher and the proportion of 'excellent' LID adequacy was lower with rhTSH than with THW. UICR was higher also in women, old-age, and LID-naïve patients. Further researches are required to suggest effective methods to reduce body iodine pool in case of rhTSH use and to validate the efficacy of such methods on outcomes of RAI treatment.
Topics: Adult; Aged; Diet; Female; Humans; Iodine Radioisotopes; Male; Middle Aged; Retrospective Studies; Thyroid Neoplasms; Thyrotropin; Thyrotropin Alfa; Urine
PubMed: 34492048
DOI: 10.1371/journal.pone.0256727 -
Cureus Apr 2020The term "collision tumor" is described as the coexistence of two or more histologically distinct neoplastic morphologies separated by normal tissue in the same organ....
The term "collision tumor" is described as the coexistence of two or more histologically distinct neoplastic morphologies separated by normal tissue in the same organ. Simultaneous papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) of the same thyroid lobe is a very rare pathology. Herein, we report a case of PTC and FTC of the same thyroid lobe. A 79-year-old man was evaluated at our hospital for the presence of left hip pain of two-month duration after sustaining a physical trauma to the left side of his body three days prior to admission. X-ray imaging of the left femur revealed a large lytic bony lesion at the proximal end of left femur. Biopsy of the bone lesion was suggestive of FTC. Computed tomography (CT) of the neck revealed an enlarged thyroid with a cystic lesion in the left lobe of the thyroid gland. Total thyroidectomy was performed. Histopathology revealed two separate primary malignancies of PTC and FTC. Genetic studies for RAS gene mutation were negative. He was initiated on suppressive doses of levothyroxine following thyroidectomy. Three months after surgery, thyrotropin alfa stimulated 204.5 mCi I-131 was administered. At seven months of follow-up, the thyroglobulin level was in the lower end of the normal range and anti-thyroglobulin antibody (anti Tg) remained negative (< 1.0 IU/mL). He was doing well and reported no symptoms. For each type of well-differentiated thyroid cancers, several genes have been identified. However, thus far, no specific gene mutation responsible for the pathogenesis of the different tumor types has been described. Management of thyroid collision tumor is usually complex due to the presence of different pathology in the tumor tissues and given the fact that literature on this condition is limited. Typically, the treatment needs to be individualized. Our report brings up a concept that the occurrence is a rare phenomenon of simultaneous mutation of different genes that could give rise to different thyroidal neoplasms.
PubMed: 32377487
DOI: 10.7759/cureus.7539 -
PloS One 2016The incidence of papillary thyroid carcinoma (PTC) has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted...
BACKGROUND
The incidence of papillary thyroid carcinoma (PTC) has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid) act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.
METHODS
Thyroid Stimulating Hormone Receptor (TSHR) was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin) were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm) was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.
RESULTS
TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.
CONCLUSION
A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with fewer side effects and improved quality of life.
Topics: Animals; Antibodies, Neoplasm; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Drug Delivery Systems; Humans; Low-Level Light Therapy; Nanotubes, Carbon; Neoplasm Proteins; Receptors, Thyrotropin; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyrotropin Alfa
PubMed: 26901566
DOI: 10.1371/journal.pone.0149723 -
Therapeutic Advances in Endocrinology... Jun 2018It is necessary to stimulate serum thyroid-stimulating hormone (TSH) levels either endogenously by thyroid hormone withdrawal (THW) or exogenously by administration of...
BACKGROUND
It is necessary to stimulate serum thyroid-stimulating hormone (TSH) levels either endogenously by thyroid hormone withdrawal (THW) or exogenously by administration of recombinant human TSH (rhTSH) for radioactive iodine (RAI) therapy. Thyrotropin alfa (Thyrogen) has many advantages over THW. Radiation dose to laboratory staff while drawing blood for tests on the day 5 is one of the disadvantages of preferring Thyrogen. Our aim was to compare day 3 and day 5 blood test results after Thyrogen injections.
MATERIAL AND METHOD
In our study, Thyrogen was preferred in 32 differentiated thyroid cancer patients with a mean age of 50.5 ± 12.3 years. Thyrogen was injected on day 1 and day 2 intramuscularly in all patients before I-131 was given on day 3. A total of 22 patients received 5 mCi RAI for ablation control scintigraphy and 10 patients received 100-250 mCi RAI for ablation or therapy (high-dose group). Blood tests were performed on day 3 and day 5 after Thyrogen injections.
RESULTS
Mean TSH level was 98.1 mg/dl for day 3 and 29.5 mg/dl for day 5. In the diagnostic group, thyroglobulin (Tg) and anti-Tg levels were nearly the same on day 3 and day 5. In the therapy group, day 5 Tg levels were higher than day 3.
CONCLUSION
After Thyrogen injection of two consecutive days, blood sampling might be enough on day 3. Day 5 blood sampling may not be necessary routinely for radiation protection of laboratory staff. For the diagnostic group, if Tg and anti-Tg is normal then 5 mCi imaging may not be necessary.
PubMed: 29854387
DOI: 10.1177/2042018818770108 -
Aging Sep 2021Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and...
CONTEXT
Offspring from long-lived families have a different thyroid status than controls, characterised by higher circulating levels of thyroid stimulating hormone (TSH) and similar levels of thyroid hormone. Expression of the TSH receptor has previously been observed on various extrathyroidal tissues, including bone. However, potential physiological consequences of differences in circulating TSH as observed in familial longevity on bone tissue remain unclear.
OBJECTIVE
Based on the hypothesis that TSH may inhibit bone resorption, we explored whether offspring of long-lived families have lower bone turnover than controls at baseline as well as following a challenge with recombinant human TSH (rhTSH).
METHODS
Bone turnover markers CTX and P1NP were measured in fasted morning samples from 14 offspring and 12 controls at baseline and at 24 hour intervals following 0.1 mg rhTSH i.m. administration for four consecutive days.
RESULTS
At baseline, mean (SEM) CTX was 0.32 (0.03) ng/ml in offspring and 0.50 (0.04) ng/ml in controls, < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, < 0.01. Following rhTSH administration, both CTX and P1NP levels transiently increased over time and normalized towards baseline after 72 h (general linear modelling: CTX time = 0.01, P1NP time < 0.01); the response was similar between offspring and controls.
CONCLUSIONS
Bone turnover markers were lower at baseline in offspring from long-lived families than in controls but increased similarly following an rhTSH challenge.
Topics: Aged; Aged, 80 and over; Biomarkers; Bone Remodeling; Bone Resorption; Bone and Bones; Collagen Type I; Family; Female; Humans; Longevity; Male; Middle Aged; Peptide Fragments; Peptides; Procollagen; Recombinant Proteins; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyrotropin Alfa
PubMed: 34491903
DOI: 10.18632/aging.203511 -
The Kaohsiung Journal of Medical... Feb 2023This retrospective study was designed to compare the treatment response of patients with differentiated thyroid cancer (DTC) prepared for radioiodine ablation (RIA) with... (Comparative Study)
Comparative Study
Recombinant human thyrotropin versus thyroid hormone withdrawal preparation for radioiodine ablation in differentiated thyroid cancer: Experience in a South Taiwanese medical center.
This retrospective study was designed to compare the treatment response of patients with differentiated thyroid cancer (DTC) prepared for radioiodine ablation (RIA) with thyroid hormone withdrawal (THW) or recombinant human thyrotropin (rhTSH) stimulation. Patients with DTC were followed-up retrospectively between 2013 and 2018 in Kaohsiung Chang Gung Memorial Hospital, Taiwan. We compared the excellent response ratios between THW (49.9%) and rhTSH (50.1%) stimulation. Patients were then divided into subgroups, on the basis of age, sex, extrathyroidal extension, lymph node metastasis, and tumor-node-metastasis stage, for analysis. In all, 647 patients were followed-up after RIA. The ratios of THW or rhTSH use in the different subgroups were not statistically significant. In all the patients, the excellent response rate with THW and rhTSH was 80% and 76.5%, respectively, which was not statistically significant. The subgroup analysis, including age, sex, extrathyroidal extension, lymph node metastasis, and tumor-node-metastasis stage (low and high risk), showed similar results. Furthermore, the logistic regression analysis revealed no statistically significant differences among the subgroups. The multivariate analysis showed extrathyroidal extension, lymph node metastasis, and high I dose were the prognostic factors affecting the excellent response rate. In conclusion, the THW and rhTSH preparations for RIA were similar in terms of the excellent response rates and subgroup clinical outcomes.
Topics: Humans; Adenocarcinoma; Iodine Radioisotopes; Lymphatic Metastasis; Recombinant Proteins; Retrospective Studies; Thyroid Hormones; Thyroid Neoplasms; Thyrotropin; Thyrotropin Alfa; Treatment Outcome; Withholding Treatment
PubMed: 36448726
DOI: 10.1002/kjm2.12621