Diagnosis of medullary carcinoma of the thyroid (MCT) by calcitonin assay using monoclonal antibodies: criteria for the pentagastrin stimulation test in hereditary MCT.

A new calcitonin (CT) immunoradiometric assay, using anti-11-7 and anti-24-32 CT fragment monoclonal antibodies was evaluated and compared to classical RIA. The sensitivity was 2.5 ng/L, the normal basal level (n = 83) was lower than 10 ng/L, the response to pentagastrin stimulation in control subjects was absent in nine and between 10-30 ng/L in nine others. (mean, 15.4). In patients with renal failure the basal level was increased between 10-52 ng/L. In patients with medullary thyroid carcinoma (MTC; n = 28), the basal level was between 189-28,900 ng/L. A pentagastrin test was performed as screening for familial MTC in eight patients with confirmed MTC at subsequent surgery; the calcitonin peak was equal or greater than 38 ng/L. Large differences exist between CT levels measured by RIA and immunoradiometric assay. The latter method provides a greater sensitivity to pentagastrin test and allows a better identification of microcarcinoma in hereditary cases of MTC.

99m Technetium labelled heparin: potential value as a tracer of heparin activity in pharmacokinetic and biodistribution studies.

Pharmacokinetics and biodistribution of 99m Technetium (99mTc) labelled heparin were studies to assess its value as a tracer of heparin kinetics in comparison with unlabelled heparin. In vitro, the stability and labelling efficiency (98%) of the labelled drug were excellent and elution was minimal. In vivo, after I.V. infusion of the drug, there was no difference in the same animal between anticoagulant activity measurements and radioactive countings, both displaying a plasmatic biexponential pattern (T1 = 2.9 minutes, T2 = 76 minutes). Biodistribution studies showed primarily liver, spleen and kidney accumulation, with no thyroid uptake. The advantages of this technetium labelling may therefore be used for the heparin drug in various experimental and pathological situations even in humans.

Liver-directed superparamagnetic iron oxide: quantitation of T2 relaxation effects.

A new liver-directed superparamagnetic iron oxide nanoparticle preparation, MDL, is described. MDL is derived from previously developed MD particles only by modification of the characteristics of the coating:chemical structure and charge. The biodistribution, pharmacokinetics, and intratissular localization of both 59Fe-labeled MD and MDL particles were analyzed. R2 relaxivities determined in aqueous solution are compared to measurements in liver tissue and to R2 of nanoparticles incorporated into synthetic microcapsules, which represent a simplified cell pattern. T2 relaxation effects of both preparations in liver tissue are discussed relative to physical parameters such as iron oxide core dimension, total particle size, and charge, and pharmacological properties such as biodistribution, pharmacokinetics, and extra/intracellular localization.

Iron oxide nanoparticles for use as an MRI contrast agent: pharmacokinetics and metabolism.

The pharmacokinetics and metabolism of a new preparation of superparamagnetic iron oxide nanoparticles were evaluated by 59Fe radiotracer studies and histologic examination of mice liver and spleen tissues (light and transmission electron microscopy). In the first 30 min following IV injection of the product half of the dose injected remains in the blood, the other part being sequestered mainly by the mononuclear phagocyte system (MPS). In the first five days following IV administration of the nanoparticles, early metabolization of the iron oxide cores occurs, revealed by modification of their aspect in the lysosomes of Kupffer cells and macrophages of the splenic red pulp. The incorporation of 59Fe is then observed in RBC of the mice. These results are discussed in relation with the physicochemical properties of this new preparation of nanoparticles, and compared with current pharmacokinetic data concerning injectable particle systems.

Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: contribution of microencapsulation to improved biodistribution.

We have developed a new method of synthetizing superparamagnetic iron oxide nanoparticles, consisting in the modifications of Molday's method, which ensures high relaxivity (2.4 10(5) s-1.M-1.L), good chemical stability, singular biodistribution and a considerable safety margin. The ED (Efficace Dose) to LD50 ratio is 1/2400 instead of 1/50 for Gd-DTPA. In order to develop a magnetite-delivery system to the liver we have incorporated the nanoparticles into biodegradable synthetic microcapsules. Encapsulated 59Fe oxide nanoparticles are injected into rats; in these conditions the sequestration is 9-fold greater in liver and 6 and 5 times lower in blood and carcase, respectively. This modification of the biodistribution enables the use of magnetite containing microcapsules at only 0.3 mg/kg iron to obtain an improved contrast in liver.

[Chronic autoimmune thyroiditis and C-cell hyperplasia. Study of calcitonin secretion in 24 patients]. / Thyroïdite chronique auto-immune et hyperplasie des cellules C. Etude de la sécrétion de calcitonine chez 24 patients.

Serum calcitonin (CT) was determined by radioimmunoassay, using two monoclonal antisera, in 22 women and two men, who had Hashimoto's thyroiditis as confirmed by echographic, immunological or cytological criteria; in 23 patients, serum CT levels were measured after intravenous infusion of pentagastrin (Pg). In 21 cases, basal and Pg stimulated serum CT concentrations were normal. A 61-year-old woman and a 63-year-old man, both euthyroid, had high serum basal CT: 12 pg/ml and 35 pg/ml; infusion of Pg resulted in abnormal increases in serum CT levels: respectively 64 pg/ml and 115 pg/ml. Another patient, a 65-year-old woman with primary hypothyroidism had high serum basal CT: 90 pg/ml (the Pg stimulation test was not done because of ischemic heart disease). Each of these 3 patients had a total thyroidectomy. Pathological examination of the thyroid showed typical features of Hashimoto's thyroiditis and extensive C-cell hyperplasia. After surgery, serum CT levels fell to normal. Therefore, a high serum CT can be observed as the consequence of C-cell hyperplasia in Hashimoto's thyroiditis.

[Low levels of TSH measured by a sensitive assay: do they reflect hyperthyroidism? A critical analysis of 580 cases]. / Les valeurs basses de la TSH mesurée par méthode ultra-sensible sont-elles le témoin d'une hyperthyroidie? Analyse critique de 580 observations.

Highly sensitive TSH assays make it easier to diagnose thyroid diseases. During one year, we performed 5,300 sensitive TSH assays (normal range: 0.15-4 mU/l) in various patients. The purpose of this work was to test the value of the low TSH plasma concentrations found in 580 patients. In 99.7 percent of the cases, low TSH levels were the consequence of a thyroid disorder or a treatment by thyroid hormones; non thyroidal illnesses were detected in only 0.3 percent. However, not all TSH values below 0.15 mU/l were associated with overt or occult thyrotoxicosis. When TSH was undetectable (less than 0.04 mU/l), and excluding thyroid hormone-treated patients, thyrotoxicosis was present in 97 percent of the cases. On the other hand, when TSH values were between 0.04 and 0.15 mU/l, 41 percent of the patients failed to show any sign or symptom of hyperthyroidism, although they had functioning thyroid nodules, multinodular goitre or iodine overload, or they received thyroid hormones.

Monoclonal immunoradiometric assay of calcitonin improves investigation of familial medullary thyroid carcinoma.

Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularly occult familial MTC. In previous radioimmunoassays of calcitonin, polyclonal antibodies were used. Here we evaluate a new two-site immunoradiometric assay (IRMA) of calcitonin based on use of monoclonal antibodies. We assayed samples from healthy subjects, patients with renal failure, and subjects from families affected by MTC. Basal values for healthy subjects were all less than 10 ng/L. Renal failure is associated with increased basal CT. The CT peak under pentagastrin stimulation in healthy patients was less than 30 ng/L. In familial screening, basal values greater than 10 ng/L or peak values greater than 30 ng/L correspond to subjects with histologically confirmed MCT or micro-MCT. Polyclonal RIA performed in the same subjects failed to detect the moderate increase of CT that IRMA demonstrated. Preliminary results indicate that this new method may allow earlier detection of CT increase and thus improved diagnosis of MCT, particularly in familial screening. Monitoring surgical patients could also be improved by this new assay.

Thyroid uptake of MIBG in Sipple's syndrome.

The use of the adrenomedullary tracer metaiodobenzylguanidine (MIBG) in the localization of medullary carcinoma of the thyroid (MCT) is based on the embryologic relationship of the APUD cell series. The authors report the results obtained in six patients with MCT: two had Sipple's syndrome and four sporadic forms of the disease. MIBG uptake by the CMT was observed in both cases of Sipple's syndrome and in only one of the other cases. Scintigraphic detection seems to depend on the clinical features, the size of the tumour and also on the part played by its secretory function. MCT would thus appear to be more frequently visualized by MIBG in cases of Sipple's syndrome than in sporadic cases. The procedure therefore seems useful in the diagnosis, follow up and even in the treatment of MCT.

Four nonisotopic immunoassays of free thyroxin evaluated.

We evaluated four new nonisotopic immunoassays of free thyroxin (FT4)--Amerlite FT4 (Amersham International), Magic Lite FT4 (Ciba Corning Diagnostics), Stratus FT4 (Dade--Baxter Travenol), and FT4 Enzelsa (Compagnie ORIS Industrie)--by comparison with two FT4 radioimmunoassays: Amerlex and Sclavo. Inter- and intra-assay coefficients of variation were less than 10% in the working range and there was no significant interaction between the tracer conjugate and albumin. All methods except Enzelsa gave results equivalent to those obtained with the Sclavo chromatographic technique. In a population consisting of 325 euthyroid subjects and 111 hyperthyroid and 61 hypothyroid patients without any treatment, we observed slight overlaps between the hyperthyroid and euthyroid populations and diagnostic sensitivities were approximately 0.95 and 0.80 for hyperthyroidism and hypothyroidism. In specific populations (69 patients with chronic renal failure, 20 patients in intensive-care, 17 patients treated with heparin, and 27 pregnant women), results were quantitatively similar to those obtained by the Sclavo assay. We conclude that these nonisotopic methods are a valid alternative to current radioisotopic commercial methods.

Radioiodinated meta-iodobenzylguanidine uptake in medullary thyroid cancer. A French cooperative study.

Fifty meta-iodobenzylguanidine (MIBG) scintiscans were performed in three groups of medullary thyroid cancer (MTC) patients. Group 1 (n = 11) included treated patients with normal calcitonin levels; Group 2 (n = 24) included patients with elevated calcitonin levels due to sporadic and isolated MTC; Group 3 (n = 15) included patients with elevated calcitonin levels due to familial MTC or multiple endocrine neoplasia Type IIA syndrome (MEN). In Group 1 three pheochromocytoma were depicted by MIBG scintiscan. In Group 2 MTC was seen in a small number of patients (3 of 24). In Group 3, besides adrenal hyperplasia and pheochromocytoma four patients, MIBG scintigraphy showed where MTC had localized and spread in almost half of patients (7 of 15). MIBG uptake occurred in patients with relatively high calcitonin level (greater than 0.6 nmol/l). These data indicate that in patients with familial MTC or MEN syndrome, MIBG scintiscan can be useful not only in detecting associated pheochromocytoma, but also in showing MTC.