The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase. We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments. When expressed by transfection in COS-7 cells, the mutated receptors display a higher constitutive activation of adenylyl cyclase than wild type. This new disease entity is the germline counterpart of hyperfunctioning thyroid adenomas, in which different somatic mutations with similar functional characteristics have been demonstrated.

Since 1981, 20 patients with anaplastic giant cell carcinoma of the thyroid have been prospectively treated according to a combination regimen of chemotherapy and external beam radiation therapy. Two types of chemotherapy were used every 4 weeks, depending on the patient's age. For those younger than 65 years, a combination of doxorubicin (60 mg/m2) and cisplatin (90 mg/m2) was given, and for older patients mitoxantrone (14 mg/m2) was used. Radiotherapy was carried out between Day 10 and Day 20 of the first four cycles of chemotherapy. It delivered 17.5 Gy in 7 fractions to the neck and the superior mediastinum. Survival exceeding 20 months was observed in three patients. Complete neck tumor response was observed in five patients, among whom four had undergone previous operations. No response was seen in distant metastases, which were the cause of death in 14 patients. These treatment modalities are effective in some patients, both in terms of survival and of local control, avoiding death from local invasion. Gross tumor resection should be performed whenever possible but should not delay the commencement of this protocol. Toxicity was high and remains the main limiting factor.

Summary We studied 1771 patients treated for a thyroid cancer in two institutions. None of these patients had been treated with external radiotherapy and 1497 had received 1311. The average 1311 cumulative activity administered was 7.2 GBq, and the estimated average dose was 0.34 Sv to the bone marrow and 0.80. Sv to the whole body. After a mean follow-up of 10 years, no case of leukaemia was observed, compared with 2.5 expected according to the coefficients derived from Japanese atomic bomb survivors (P = 0.1). A total of 80 patients developed a solid second malignant neoplasm (SMN), among whom 13 developed a colorectal cancer. The risk of colorectal cancer was found to be related to the total activity of 1311 administered 5 years or more before its diagnosis (excess relative risk = 0.5 per GBq, P = 0,02).These findings were probably caused by the accumulation of 1311 in the colon lumen. Hence, in the absence of laxative treatment, the dose to the colon as a result of 1311 administered for the treatment of thyroid cancer could be higher than expected from calculation of the International Commission on Radiological Protection (ICRP). When digestive tract cancers were excluded, the overall excess relative risk of second cancer per estimated effective sievert received to the whole body was -0.2 (P = 0.6).Keywords: radiocarcinogenesis; carcinogenic effects of 1311; protracted exposure to radiation; thyroid cancer On account of the small population dose involved, published studies (IARC, 1994) of nuclear industry workers do not have sufficient power to make reliable comparisons with the risks estimated from the Japanese atomic bomb survivors (UNSCEAR, 1994). Hence, studies of adult populations undergoing protracted exposure to radiation for medical reasons are still necessary. For this purpose, '3'I is a suitable model, because its physical halflife is 8 days. The risks of solid tumours and leukaemia after administration of '3'I have been studied in several cohorts of adults (Hall et al 1991(Hall et al , 1992 Dottorini et al, 1995); nevertheless, the statistical power of these studies is still insufficient to derive precise coefficients.Another reason for studying the carcinogenic effects of '3'I is the fact that considerable amounts of various radioisotopes of iodine, including '3'I, were released in the atmosphere during the Chernobyl accident. A substantial increase in thyroid cancer incidence has been observed in children living in the most heavily contaminated areas at the time of the accident (Stsjazhko et al. 1995), but no increased incidence of other malignancies, including leukaemia, has been reported so far. More data are thus needed to predict future risks in populations that have been contaminated.We report the results of a study of 1771 patients treated for a thyroid cancer, of whom 651 had received 1311 for diagnosis, and 846 for therapy. Among the 2479 patients, 173 patients were excluded because they had died or were lost to follow-up during the first two years after the diagnosis of thyroid cancer; ...

Combinations of 5-fluorouracil (5-FU) and streptozocin and 5-FU and dacarbazine were given alternately to 20 patients with metastatic medullary thyroid carcinoma. Three partial responses and 11 long-term stabilizations were observed. No unexpected toxicity occurred.

The efficacy and safety of m-[131I]iodobenzylguanidine ([131I]MIBG) were assessed in 15 patients with malignant pheochromocytomas in a nonrandomized, single arm trial, in which patients were treated with [131I]MIBG (SA, 740 megabequerel/mg) every 3 months. Seven of these patients had bone and soft tissue metastases, 4 had only soft metastases, and 4 had only bone metastases. The follow-up period ranged from 6-54 months; the number of doses ranged from 2-11, with 2.9 (78.4 mCi) to 9.25 gigabequerel (GBq) (250 mCi)/administration and a cumulative activity from 11.1-85.90 GBq (300-2322 mCi). The absorbed cumulative dose in tumors ranged from 12-155 Gy. A beneficial effect of the treatment was observed in 9 patients (60%). No complete remission of the disease was observed. Seven patients died during the study, among whom 4 never responded to the treatment. Seven had hormonal responses (4 complete and 3 partial), with a duration ranging from 5-48 months. Among these patients, 4 relapsed, and 3 died within 3 months. Five patients had partial tumoral responses mainly located in soft tissues and for a duration ranging from 29-54 months. All patients with a hormonal response had objective improvement in clinical status and blood pressure. There was no clear-cut relationship between the cumulative dose and the responses. The main side-effect observed in 1 patient with widespread bone metastases after three doses (12.9 GBq) was a pancytopenia, which resolved after treatment was discontinued. This study suggests that repeated [131I]MIBG treatment could be effective in patients with advanced malignant pheochromocytoma.