To investigate long-term survival after operation for primary hyperparathyroidism, a follow-up study was performed on 896 consecutive patients in whom this diagnosis had been clinically and microscopically verified. These patients were operated on in the years 1953-1982. Their mean age at operation was 57.3 years [standard deviation (SD) 13.1], overall cure rate was 97.0%, and postoperative mortality was 0.89%. Follow-up was 99.8% complete by the end of 1986. Mean follow-up time was 12.9 years (SD: 6.1). Two-hundred ninety-four patients were deceased, which was 118 more than in a control group (p less than 0.001). The latter was based on Swedish population statistics, matched for age, sex, and calendar year. Each year, the control group was the same size as the hyperparathyroid population. The risk of premature death remained increased (p less than 0.001) even after exclusion of poor-risk patients having their hyperparathyroidism diagnosed when being treated or followed because of other serious diseases. The main causes of premature death for the hyperparathyroid patients were cardiovascular and malignant diseases. Both occurred more often than in the control group (p less than 0.001). The results demonstrate that primary hyperparathyroidism causes damage that is not reversed by surgery.

A total of 195 patients had surgery for papillary thyroid cancer. The mean age at operation was 50 years. A microdissection technique was used for total thyroidectomy and lymph node clearance. Postoperative radioiodine tests showed no uptake or an uptake close to the background activity in 77% of the examined patients. By counting the lymph nodes removed at surgery we were able to check on the quality of the lymph node dissection. Men had a higher incidence (70%) of lymph node metastases than women (45%). Only 4% of the patients had radioiodine ablation of the thyroid remnant. The median follow-up time was 13 years. None of the patients below 45 years of age at surgery died of thyroid cancer. In the older age group eight patients died of thyroid cancer at a mean age of 75 years. Five of those who died of a thyroid carcinoma had distant metastases at diagnosis. Among patients with resectable disease, three (1.6%) died of thyroid cancer, all of whom had lived for more than 17 years after surgery. Hence longer follow-up is needed before we know the final mortality in our series. The results suggest that surgical technique and strategy can positively influence the survival of patients with papillary thyroid cancer.

The incidence of superior laryngeal nerve (SLN) lesions and their consequences in terms of voice quality was studied in 20 patients undergoing thyroid surgery, performed by surgeons who were not specialists in endocrine surgery. The SLN function was examined by electromyography (EMG) of the cricothyroid muscles before and after surgery. Voice analysis was performed through the registration of the average pitch and range of the speaking voice and the upper pitch limit. The perceptual voice quality was judged by a panel of listeners. Voice problems were registered through a questionnaire. The larynx status was examined by indirect laryngoscopy before and after surgery. Three patients who had not previously been operated on in the neck had partial SLN lesions before surgery. According to the EMG, no SLN at risk developed a complete lesion, but 58% of the SLN's developed partial lesions which persisted 1 year after surgery in all but 1 of the examined patients. Seven of 10 patients with isolated SLN lesions had postoperative voice problems, which had disappeared after 1 year in 4 of them. Standard indirect laryngoscopy failed to diagnose an isolated partial SLN paresis. A significant correlation was found between SLN lesion and a reduction in the average pitch of the speaking voice (p < 0.05). Partial SLN lesions cannot be diagnosed exclusively on voice symptoms and standard indirect laryngoscopy. EMG registrations make a definite diagnosis possible. Measurements of the average pitch of the voice could be used as a noninvasive screening procedure.

The previous finding of an increased risk of premature death in a consecutive series of 896 patients operated on for primary hyperparathyroidism between 1953 and 1982 [1] raised the question of the role that surgery plays in relation to the risk of death. In the present study, undertaken to examine that issue, 3 factors--age, calendar year of surgery, and time passed after surgery--have been found to be significantly related to the risk of death (p less than 0.001), each factor contributing independently. A correlation was found between a late calendar year of surgery and a low degree of hyperparathyroidism as evaluated by serum calcium and creatinine levels. There was an increased risk of premature death in all age groups. The risk was less among patients operated on in later years. The observed normalization of the increased risk of death with time after surgery also took place sooner in patients operated on in later years. Our findings of improved survival following surgical intervention contrasts favorably with the findings of others in studies of subjects with untreated mild hyperparathyroidism. We have also found that preoperative serum calcium levels affect the risk of death, and that there is an additional factor related to the calendar year of surgery affecting the risk of death. Circumstantial evidence indicates that the duration of hyperparathyroidism contributes to this factor. Our results also show that early surgery decreases the risk of premature death in mild cases of the disease.

Sixty-four consecutive patients with disseminated midgut carcinoids were treated during an 8-year period according to a single clinical protocol aimed at aggressive tumor reduction by surgery alone or with subsequent hepatic artery embolization. All patients had markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels (581 +/- 79 micromol/24 h) and hormonal symptoms. Fourteen patients (22%) reached anatomic and biochemical cure by surgery alone. At follow-up, the mean 5-HIAA levels were still normal after 69.0 +/- 6. 2 months; two patients had died from unrelated causes. With the introduction of somatostatin receptor scintigraphy, subclinical disease was diagnosed in 7 of these 14 patients. Forty patients with bilobar hepatic disease underwent embolization in combination with octreotide. In this group, 5-HIAA levels were still reduced by 55% after 71 +/- 11 months of follow-up, and the 5-year survival was 56%, estimated from the total death hazard function. After embolization, two subgroups could be identified with marked differences in their long-term response to treatment. Ten patients were not embolized owing to complicating diseases. The 5-year survival for the entire series was 58%. A significantly increased risk of cardiovascular deaths was seen, which underlines the importance of total survival analysis in a disease with multiple hormonal effects. It is concluded that an active surgical approach must be recommended to patients with the midgut carcinoid syndrome. In patients with bilobar hepatic disease, embolization combined with octreotide treatment markedly reduced the 5-HIAA excretion and suggested a prolonged 5-year survival.

The syndrome of resistance to thyroid hormone is characterized by elevated serum free thyroid hormones, failure to suppress pituitary thyrotropin secretion, and variable peripheral refractoriness to hormone action. Here we describe a novel leucine to valine mutation in codon 454 (L454V) of the thyroid hormone ␤ receptor (TR␤) in this disorder, resulting in a mutant receptor with unusual functional properties. Although the mutant protein binds ligand comparably to wild-type receptor and forms homo-and heterodimers on direct repeat, everted repeat, or palindromic thyroid response elements, its ability to activate transcription via these elements is markedly impaired. The hydrophobic leucine residue lies within an amphipathic ␣-helix at the carboxyl terminus of TR␤ and the position of the homologous residue in the crystal structure of TR␣ indicates that its side chain is solvent-exposed and might interact with other proteins. We find that two putative transcriptional mediators (RIP140 and SRC-1) exhibit hormone-dependent association with wild-type TR. In comparison, the interaction of this natural mutant (L454V) and artificial mutants (L454A, E457A) with RIP140 and SRC-1 is markedly reduced. Furthermore, coexpression of SRC-1 is able to restore the transcriptional activity of the L454V mutant receptor, indicating that the interaction of this residue with accessory proteins is critical for transcriptional activation. Finally, the occurrence of the L454V mutation in resistance to thyroid hormone, together with impaired negative regulation of the thyroidstimulating hormone ␣ promoter by this mutant, suggests that the amphipathic ␣-helix also mediates hormone-dependent transcriptional inhibition, perhaps via interaction with these or other accessory factors.Resistance to thyroid hormone (RTH) is characterized by elevated serum-free thyroid hormones, failure to suppress pituitary thyroid-stimulating hormone (TSH) secretion, and variable refractoriness to hormone action in peripheral tissues. Following the observation that familial RTH was tightly linked to the thyroid hormone receptor ␤ (TR␤) gene locus (1), a growing number of ␤-receptor mutations have been identified in kindreds with this disorder (2, 3). In keeping with other members of the nuclear receptor superfamily, the TR is organized into distinct functional domains (4). The carboxylterminal (D͞E) region of TR mediates hormone binding and nuclear localization functions and also contains sequences that mediate homodimeric TR interactions and the formation of heterodimers with the retinoid X receptor (RXR) (5). All the RTH mutations described to date localize to the D͞E domains and the majority cluster within two hot spots (6, 7). Their properties have provided valuable insights into structurefunction relationships in the receptor. Most mutant receptors exhibit reduced hormone binding (6-8), whereas their ability to localize to the nucleus is not impaired (8). With a few exceptions (9-11), mutant receptors retain the ability to form homodimers and they al...

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