Germline and somatic mutations of the RET proto-oncogene in apparently sporadic medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) occur sporadically or as part of inherited multiple endocrine neoplasia (MEN) type 2 syndromes. To recognize misdiagnosed familial cases and to establish the frequency of somatic mutations, a series of 50 patients, clinically diagnosed with sporadic MTC, were analyzed for mutations in the RET proto-oncogene. The clinical management of the patient and of the family is different in the two cases. Germline mutations were detected in three independent cases, demonstrating that they were associated to familial MTC. The mutations affected exon 11 in two cases and exon 14 in one case. Somatic mutations were detected in eight patients (30%) and they were indicative of sporadic MTC. In seven cases the mutation affected codon 918 of exon 16 and in one case codon 634 in exon 11. No RET mutations were detected in the remaining patients. A different genetic and clinical management is proposed for individuals with a diagnosis of familial or sporadic MTC.

[New developments in the treatment of medullary thyroid carcinoma]. / Nuovi sviluppi nella terapia del carcinoma midollare della tiroide.

Medullary thyroid carcinoma arises from the C cells, which produce a characteristic hormone, calcitonin. At present, surgery is the main treatment modality. Medullary thyroid carcinoma is usually treated with total thyroidectomy and with removal of nodes in the central portion of the neck and upper mediastinum. Cervical nodes dissection may be required for cancers affecting lateral neck nodes. Substitutive therapy with levo-thyroxine is indicated after surgery. External beam radiation therapy is not effective against advanced medullary thyroid carcinoma, while chemotherapy has a marginal activity. Biological therapy induces its anti-tumour activity through the inhibition of tumour cell growth without cytolysis and stimulating the antitumour immune response, in the absence of relevant side effects. On these bases, it can be suggested that chemo-refractory tumours could be still responsive to biological agents. In the last years somatostatin analogues and interferon have been used in the therapy of advanced and symptomatic medullary thyroid carcinoma, demonstrating an efficacious effect on neuroendocrine symptoms and on the production of calcitonin and an improving in quality of life. Even if there are no consistent data on the effects of biological agents on the reduction of tumour mass, the combined use of chemotherapy and biological therapy needs to be experimented in medullary thyroid carcinoma.

[Risk factors and prevention of thyroid carcinoma]. / Fattori di rischio e prevenzione del carcinoma della tiroide.

Thyroid carcinoma represents the most frequent endocrine tumor. Recent reports have documented an increase in the incidence of thyroid cancer. Its incidence varies geographically around the world from 0.9/ 100,000 men and 2.4/100,000 women in Great Britain to 8.8/100,000 men and 18.2/ 100,000 women in Hawaii. Radiation exposure has been strongly implicated as an aetiological factor. The greatest risk occurs with acute exposure to X and/or gamma rays, with a linear dose response curve, while the risk is inversely related to age at exposure with a latent period of 5-20 years. Together with irradiation, other factors (iodine, alcohol and calcium diet intake, hyperthyroidism, Hashi-moto's thyroiditis, Gardner syndrome, Cowden syndrome, pharmaceutical agents, hormonal factors, occupational exposure, activation of cellular oncogenes) have been associated with the risk of thyroid cancer. In prevention a policy should include regulations and methods for avoiding radiation exposure of the thyroid and for preventing nutritional deficiency and excess of iodine. Besides, early and continuous suppressive therapy of all patients affected by non-toxic goiter or treated previously with thyroidectomy, and a screening of medullary thyroid carcinoma (MTC) using pentagastrin stimulation test and restriction fragment length polymorphism analysis, in subjects with a familial history of MTC, are of paramount importance to prevent thyroid cancer.

111In-pentetreotide scintigraphy in the post-thyroidectomy follow-up of patients with medullary thyroid carcinoma.

Local and lymphnodal recurrences of medullary thyroid carcinoma (MTC) in thyroidectomy patients with elevated plasma levels of calcitonin and/or CEA can be detected using 111In-pentetreotide (Octreoscan: OCT) scintigraphy, although the sensitivity of this technique in localizing an intrathyroid recurrence of tumor is affected by the low target/non-target uptake ratio. The survival rate of patients with MTC, who have undergone thyroidectomy and who show evidence of a rise in plasma levels of calcitonin and/or CEA is closely linked to the number and localization of the metastases. However the role of conventional imaging techniques (X-rays, US, CT, and MR) in the follow-up after thyroidectomy is controversial. Numerous radiocompounds are currently being used to detect local and distant recurrences of MTC. The present study evaluated OCT and pentavalent 99mTc-dimercapto-succinic-acid (99mTc-DMSA-V) scintigraphy performed in 13 patients with a histologic diagnosis of MTC and in one with MEN 2A, all of whom had undergone thyroidectomy between 3 months and 15 years before. The patients also underwent 123I (NaCI) scintigraphy to evaluate the sites and extension of thyroidal remnants. 111In-pentetreotide scintigraphy was positive in 9/14 patients (64%); the 99mTc-DMSA-V was positive in 5/14 patients (35%). 111In-pentetreotide scintigraphy recognized 18 sites of abnormal uptake (12 in the neck); 9mmTc-DMSA-V detected 9 MTC recurrences in the same patients. In conclusion, 111In-OCT scintigraphy represents, in the authors' experience, a useful method, more sensitive than 9mmTc-DMSA-V, to detect MTC recurrences in patient follow-up post-thyroidectomy.

Treatment of advanced medullary thyroid carcinoma with a combination of recombinant interferon alpha-2b and octreotide.

BACKGROUND: The medical treatment of advanced medullary thyroid carcinoma (MTC) is still questionable. Results of chemotherapy are disappointing with almost no curative responses, few partial responses, and many side-effects. A recent report has suggested the activity of combination recombinant interferon alpha-2b (rIFN-alpha-2b) and octreotide, a somatostatin analogue, in the treatment of a metastatic carcinoid tumor. This new therapeutic schedule may be used in other neuroendocrine tumors. In this study we evaluated the therapeutic effectiveness of octreotide and rIFN-alpha-2b in patients with advanced MTC. METHODS: Eight patients affected by advanced MTC received octreotide at a daily dose of 150 micrograms for 6 months and subsequently at a daily dose of 300 micrograms for another 6 months, subcutaneously, and rIFN-alpha-2b at a daily dose of 5.000.000 IU intramuscularly 3 times a week for 12 months. Plasma calcitonin, carcinoembryonic antigenic levels, and morphologic staging were evaluated at 0, 1, 3, 6, and 12 months. RESULTS: The therapy was stopped in two patients because of diarrhea and toxicity of drugs used. Pre-existing diarrhea in four patients and flushing in one significantly improved during treatment. A maximum decrease of calcitonin was reached after 1 month in 2 patients and after 3 months in 4. In all of the patients carcinoembryonic antigen levels decreased during treatment. No significant changes of size of metastases were observed. CONCLUSIONS: The combination of octreotide and interferon is well tolerated and can be recommended for the treatment of advanced MTC.

[Contribution of pelvic ultrasonography in the diagnosis and follow-up of Turner's syndrome]. / Apport de l'échographie pelvienne dans le diagnostic et dans le follow-up du syndrome de Turner.

Between 1983 and 1988, 40 patients with Turner's syndrome, aged 8 to 26 years, underwent serial pelvic ultrasonography, in order to evaluate the morphofunctional parameters of the internal genital apparatus and correlate them with the karyotype and gonadotropin levels. Correlation of uterine and gonadal sonograms (site, size and echogenic potential) with the karyotype and the gonadotropin assays, permits the definition of each case and a personalized therapeutic approach as well as a control of its efficacy and/or its side-effects.

Effects of alendronate on bone loss in pre- and postmenopausal hyperthyroid women treated with methimazole.

High levels of thyroid hormones accelerate bone turnover. The aim of the present study was to evaluate the effects of treatment with alendronate in patients affected by hyperthyroidism and osteoporosis. We studied 40 hyperthyroid patients with bone loss, divided into two groups according to menopausal state. Before treatment and after 6 and 12 months, serum thyroid hormones levels, serum osteocalcin level and bone mineral density were evaluated. In all patients we observed an increase in bone mineral density after treatment with alendronate, and a corresponding decrease in serum osteocalcin level.

Evaluation of goiter endemia by ultrasound in schoolchildren in Val Sarmento (Italy).

Ultrasonography is an excellent and objective method for assessing thyroid volume, especially in children where clinical evaluation is inaccurate. The aim of this study was to evaluate the presence of goiter by thyroid ultrasound and palpation in 244 schoolchildren, 6 to 14 years old, living in some rural villages of Val Sarmento, a mountain area of Basilicata, Italy. In 1996 we revealed the presence of endemic goiter in 25% of the schoolchildren evaluated by palpation, according to World Health Organization (WHO) criteria, and in 15.9% of the schoolchildren evaluated by ultrasonography (7.5 MHz linear probe). The median urinary iodine excretion, taken from an extemporaneous sample of the first urines in the morning, was 62.2 microg/l. This study includes Val Sarmento, an area with mild-moderate grade (Grade I) of iodine deficiency, suggesting the need for iodine prophylaxis. Furthermore, it proves that the measurement of thyroid volume by ultrasonography is an essential instrumental method for a correct epidemiological study of endemic goiter, particularly in areas where there is mild iodine deficiency.