Familial longevity is associated with lower baseline bone turnover but not differences in bone turnover in response to rhTSH.

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, p < 0.01, whereas mean (SEM) P1NP was 39.6 (3.2) ng/ml in offspring and 61.8 (6.6) ng/ml in controls, p < 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 p = 0.01, P1NP time p < 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.

Effects of Thyrotropin on Peripheral Thyroid Hormone Metabolism and Serum Lipids.

BACKGROUND: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. OBJECTIVE: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. METHODS: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and 131I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. RESULTS: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. CONCLUSIONS: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.

Cytogenetic and dosimetric effects of (131)I in patients with differentiated thyroid carcinoma: comparison between stimulation with rhTSH and thyroid hormone withdrawal treatments.

A study directed to the cytogenetic and dosimetric aspects of radionuclides of medical interest is very valuable, both for an accurate evaluation of the dose received by the patients, and consequently of the genetic damage, and for the optimization of therapeutic strategies. Cytogenetic and dosimetric effects of (131)I in lymphocytes of thyroidectomized differentiated thyroid cancer (DTC) patients were evaluated through chromosome aberration (CA) technique: Euthyroid patients submitted to recombinant human thyroid-stimulating hormone (rhTSH) therapy (group A) were compared with hypothyroid patients left without levothyroxine treatment (group B). CA analysis was carried out prior to and 24 h, 1 week, 1 month and 1 year after radioiodine administration (4995-7030 MBq) in both groups. An activity-response curve of (131)I (0.074-0.740 MBq/mL) was elaborated, comparing dicentric chromosomes in vivo and in vitro in order to estimate the absorbed dose through Monte Carlo simulations. In general, radioiodine therapy induced a higher total CA rate in hypothyroid patients as compared to euthyroid patients. The frequencies of dicentrics obtained in DTC patients 24 h after treatment were equivalent to those induced in vitro (0.2903 ± 0.1005 MBq/mL in group A and 0.2391 ± 0.1019 MBq/mL in group B), corresponding to absorbed doses of 0.65 ± 0.23 Gy and 0.53 ± 0.23 Gy, respectively. The effect on lymphocytes of internal radiation induced by (131)I therapy is minimal when based on the frequencies of CA 1 year after the treatment, maintaining a higher quality of life for DTC patients receiving rhTSH-aided therapy.

Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

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.

Examining recombinant human TSH primed ¹³¹I therapy protocol in patients with metastatic differentiated thyroid carcinoma: comparison with the traditional thyroid hormone withdrawal protocol.

PURPOSE: Recombinant human thyroid-stimulating hormone (rhTSH)-based protocol is a promising recent development in the management of differentiated thyroid carcinoma (DTC). The objectives of this prospective study were: (1) to assess the feasibility and efficacy of the rhTSH primed (131)I therapy protocol in patients with DTC with distant metastatic disease, (2) to perform lesional dosimetry in this group of patients compared to the traditional protocol, (3) to document the practical advantages (patient symptoms and hospital stay) of the rhTSH protocol compared to the traditional thyroid hormone withdrawal protocol, (4) to document and record any adverse effect of this strategy, (5) to compare the renal function parameters, and (6) to compare the serum TSH values achieved in either of the protocols in this group of patients. METHODS: The study included 37 patients with metastatic DTC having lung or skeletal metastases or both. A comparison of lesional radiation absorbed dose, hospital stay, renal function tests, and symptom profile was undertaken between the traditional thyroid hormone withdrawal protocol and rhTSH-based therapy protocol. Dosimetric calculations of metastatic lesions were performed using lesion uptake and survey meter readings for calculation of effective half-life. Non-contrast-enhanced CT was used for assessment of tumor volume. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) QOL forms. A comparison of pretreatment withdrawal thyroglobulin (TG) was done with the withdrawal TG level 3 months after treatment. RESULTS: The mean effective half-life of (131)I in metastatic lesions was less during the rhTSH protocol (29.49 h) compared to the thyroid hormone withdrawal protocol (35.48 h), but the difference was not statistically significant (p = 0.056). The mean 24-h % uptake of the lesions during the traditional protocol (4.84 %) was slightly higher than the 24-h % uptake during the rhTSH protocol (3.56 %), but the difference was not found to be statistically significant (p = 0.301). The mean tumor radiation absorbed dose per mCi was less during the rhTSH protocol (6.04 rad/mCi) than during the thyroid hormone withdrawal protocol (8.68 rad/mCi), and the difference was statistically significant (p = 0.049), though visual analysis of the rhTSH posttherapy scans showed avid concentration of (131)I in the metastatic sites and revealed more lesions in 30 % of the patients compared to the traditional large dose scan and equal number of lesions in 65 % of the patients. Visual analysis of the traditional large dose scan, rhTSH pretreatment scan, and rhTSH posttherapy scans showed that the traditional large dose scan is better compared to the rhTSH 1 mCi scan as it showed more lesions in 19 of 37 patients (51.35 %). rhTSH posttherapy scans were better compared to the traditional large dose scans and rhTSH pretreatment scans. More lesions were seen on rhTSH posttherapy scans in 11 of 37 patients (29.7 %) compared to the traditional large dose scans and in 24 of 37 (64.86 %) patients compared to the rhTSH 1 mCi scans. Our findings demonstrate that the rhTSH primed pretreatment scan undertaken at 24 h after diagnostic dose is suboptimal to evaluate whether a metastatic lesion concentrates (131)I. The majority of these lesions demonstrated radioiodine accumulation in the posttreatment scan. Quality of life as assessed using EORTC QOL-3 forms clearly showed that rhTSH improved the quality of life of patients compared to the thyroid hormone withdrawal protocol. Functional scale and global health status were significantly better in the rhTSH protocol compared to the thyroid hormone withdrawal protocol (p < 0.001). The mean symptom scale score was significantly higher in the thyroid hormone withdrawal protocol (45.25) compared to the rhTSH protocol (13.59) (p < 0.001). Of the 20 patients, 4 (20 %) had more than 25 % increase in the TG value on follow-up. The median hospital stay of patients receiving (131)I therapy with the rhTSH protocol was shorter (2 days, range 2-8 days) compared to the thyroid hormone withdrawal protocol (3 days, range 1-8 days) and the difference was found to be statistically significant (p = 0.007). The mean serum creatinine level was significantly lower in the rhTSH protocol (0.826 mg/dl) than the thyroid hormone withdrawal protocol (0.95 mg/dl) (p = 0.013), though the mean blood urea level of patients during the rhTSH therapy protocol was slightly higher (22.81 mg/dl) than during the thyroid hormone withdrawal protocol (21.91 mg/dl) without statistical significance (p = 0.55). The mean serum TSH on day 2 of the rhTSH protocol was 140.99 µIU/ml (range 71-176 µIU/ml) compared to 72.62 µIU/ml (range 2.05-154 µIU/ml) in the traditional protocol after around 4-6 weeks of thyroid hormone withdrawal (p < 0.05). CONCLUSION: Overall, the rhTSH primed (131)I therapy protocol was found to be feasible and a good alternative to the thyroid hormone withdrawal protocol in patients with metastatic DTC. The lesional dosimetry findings need to be further examined in subsequent studies. The rhTSH primed pretreatment scan at 24 h after diagnostic dose is suboptimal to determine whether a metastatic lesion concentrates (131)I and the posttreatment scan is important for the correct impression.

Thyroid hormone concentrations in relation to age, sex, pregnancy, and perinatal loss in bottlenose dolphins (Tursiops truncatus).

This study evaluated circulating concentrations of thyroid hormones in relation to age, sex, pregnancy status, and perinatal loss in bottlenose dolphins (Tursiops truncatus) under human care. A total of 373 blood samples were collected from 60 individual dolphins housed at nine aquariums/oceanariums. Serum concentrations of total and free thyroxine (T4) and triiodothyronine (T3) were analyzed with commercial RIA kits validated for use with dolphins. While the effect of age was indicated by higher (P<0.0001) concentrations of total and free T4 and T3 in juveniles than adults, the effect of sex on thyroid hormones was inconclusive. The effect of pregnancy was indicated by higher (P<0.035) total and free T4 and T3 during early pregnancy compared to non-pregnancy. For both successful and unsuccessful pregnancy outcomes, maternal concentrations of thyroid hormones were highest during early, intermediate during mid, and lowest during late pregnancy (P<0.07 to P<0.0001). Compared to live and thriving births, concentrations of total and free T4 and total T3 were lower (P<0.08 to P<0.001) in dolphins with perinatal loss. Lower concentrations ranged from 10% to 14% during early, 11% to 18% during mid, and 23% to 37% during late pregnancy. In conclusion, the effects of age, reproductive status and stage of pregnancy on thyroid hormone concentrations are necessary factors to take into account when assessing thyroid gland function. Since perinatal loss may be associated with hypothyroidism in dolphins, analysis of serum T4 and T3 should be considered for those dolphins that have a history of pregnancy loss.

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.

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.).

Undetectable sensitive serum thyroglobulin (<0.1 ng/ml) in 163 patients with follicular cell-derived thyroid cancer: results of rhTSH stimulation and neck ultrasonography and long-term biochemical and clinical follow-up.

CONTEXT: Surveillance of patients with differentiated thyroid cancer (DTC) is achieved using serum thyroglobulin (Tg), neck ultrasonography (US), and recombinant human TSH (rhTSH)-stimulated Tg (Tg-stim). OBJECTIVE: Our primary aim was to assess the utility of rhTSH Tg-stim in patients with suppressed Tg (Tg-supp) below 0.1 ng/ml using a sensitive assay. Our secondary aims were to assess the utility of US and to summarize the profile of subsequent Tg-supp measures. DESIGN: This is a retrospective study conducted at two sites of an academic institution. PATIENTS: A total of 163 patients status after thyroidectomy and radioactive iodine treatment who had Tg-supp below 0.1 ng/ml and rhTSH Tg-stim within 60 d of each other were included. RESULTS: After rhTSH stimulation, Tg remained below 0.1 ng/ml in 94 (58%) and increased to 0.1-0.5 in 56 (34%), more than 0.5-2.0 in nine (6%), and above 2.0 ng/ml in four (2%) patients. Serial Tg-supp levels were obtained in 138 patients followed over a median of 3.6 yr. Neck US were performed on 153 patients; suspicious exams had fine-needle aspiration (FNA). All positive FNA were identified around the time of the initial rhTSH test. Six of seven recurrences were detected by US (Tg-stim >2.0 ng/ml in one, 0.8 in one and ≤ 0.5 in four). One stage IV patient had undetectable Tg-stim. CONCLUSION: In patients with DTC whose T(4)-suppressed serum Tg is below 0.1 ng/ml, long-term monitoring with annual Tg-supp and periodic neck US are adequate to detect recurrences. In our experience, rhTSH testing does not change management and is not needed in this group of patients.

Recombinant human TSH increases uptake and effective half-life of radioiodine in thyroid hormone secreting metastases of follicular thyroid cancer.

Follicular thyroid cancer with thyroid hormone secreting metastases is an extremely rare condition, with only a few cases reported world-wide. We here present the case of a 64-year-old female patient affected by follicular thyroid cancer with extensive thyroid hormone secreting metastases leading to TSH-suppression. We have also summarized the relevant diagnostic and therapeutic approaches and describe, for the first time, the effects of rhTSH-application in this rare tumor entity. In this patient, we found that rhTSH increased ¹³¹I-uptake into the thyroid hormone secreting metastases and prolonged the effective half-life of ¹³¹I. These effects of rhTSH should be considered when fixed activities of ¹³¹I are prescribed.

Acute effect of TSH on oxygenation state and volume of erythrocytes from subjects thyroidectomized for differentiated thyroid carcinoma.

We previously reported the presence in the membrane erythrocyte of a TSH receptor (TSHR), a G-protein coupled receptor, which responds to TSH with increased cAMP level. Since there is evidence for a role of G protein receptors as oxygen sensor(s) implicated in cell volume regulation, we hypothesized that erythrocyte TSHR, by TSH stimulation, could modify the erythrocyte volume and the oxygenation state of erythrocytes. We determined the effect of TSH on the gas analysis in 35 thyroidectomized patients for stage I differentiated thyroid cancer enrolled for recombinant human thyroid-stimulating hormone (rhTSH) test during chronic treatment with synthetic l-thyroxine. Moreover, we explored the influence of TSH on the shape of erythrocytes. Venous blood-gas analysis before and after TSH were determined with a pH/blood gas electrolyte and 682 CO-Oxymeter. In a subgroup of subjects (n=10), the isolated red blood cells (RBC) were analyzed by flow cytometry for morphological changes. After TSH stimulation, we found a significant decrease in PCO(2) (P<0.001), an increase in pH (P<0.01) and an increase of % O(2)-Hb (P<0.05) and pO(2) (P<0.05). By flow cytometry, the erythrocytes after TSH showed a significant enrichment on the mean number in the selected region R1 corresponding to bigger volumes (P<0.05, n=10). Finally, by contrast phase microscopy, when the cell area was measured, a mean increased volume was observed in erythrocytes after TSH compared to the basal before TSH (P<0.05). In conclusion, our results indicate that acute stimulation of TSH by rhTSH modifies the oxygenation state and volume of erythrocyte.

[Assessment of the efficacy, safety and pharmacokinetics of SKG-02 (recombinant human TSH) in postoperative diagnosis of well-differentiated thyroid cancer--a Japanese prospective, controlled, multicenter open-label study].

OBJECTIVE: This study sought to assess the safety, efficacy, impact on hypothyroid symptoms, and pharmacokinetics of SKG-02 (rhTSH, thyrotropin alfa) in the diagnostic follow-up of Japanese patients with well-differentiated thyroid carcinoma (WDTC). METHODS: Ten Japanese adults with WDTC were enrolled into a prospective, multicenter, open-label trial comparing diagnostic whole-body scintigraphy (dxWBS) and serum thyroglobulin (Tg) testing aided by SKG-02 versus these procedures aided by thyroid hormone withdrawal (THW). Patients were their own controls. Variables compared included scan set ability to detect radioiodine uptake by remnant or malignant thyroid tissue, scan set quality, diagnostic sensitivity of dxWBS and Tg testing alone or combined, frequency of hypothyroid signs/symptoms, and adverse events (AEs). SKG-02 pharmacokinetic variables including maximum concentration (Cmax), time to Cmax (Tmax) and the area under the time-concentration curve (AUC) were calculated. RESULTS: In a blinded evaluation by an independent committee of 3 nuclear medicine experts, 70% of SKG-02 dxWBS scan sets were rated "equivalent" (n = 7) or "superior" (n = 0) to their THW counterparts in ability to detect radioiodine uptake in healthy or malignant thyroid tissue. Therefore the study exceeded its primary endpoint of a 60% equivalence/superiority rate. SKG-02 Tg testing identified 3/3 cases of disease. Hypothyroid signs/symptoms were substantially more frequent during THW than during euthyroidism permitted by SKG-02 use. SKG-02 was well-tolerated, with no severe or serious drug-related AEs. Cmax was 240.8 +/- 65.9 microIU/ml, Tmax was 28.75 +/- 14.21 hr after the first SKG-02 injection, and AUC was 11,414 +/- 3,462 microIU hr/ml in 9 patients evaluable for pharmacokinetics. CONCLUSIONS: SKG-02 was safe and effective in the diagnostic follow-up of Japanese patients with WDTC, avoiding hypothyroid morbidity relative to THW. These and the pharmacokinetic findings were similar to those of overseas Phase III studies.