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A simple and practical provocative test is needed for early asymptomatic pheochromocytoma, which is a major risk for patients with multiple endocrine neoplasia type 2 (MEN-2). We measured plasma catecholamines before and after submaximal exercise in 26 MEN-2 gene carriers, eight of whom with asymptomatic pheochromocytoma, nine with medullary thyroid carcinoma and 10 after uni- or bilateral adrenalectomy. Seventeen clinically healthy individuals and 11 patients with neurovegetative lability and symptoms mimicking pheochromocytoma served as controls. Plasma adrenaline, noradrenaline and dopamine increased after exercise except for adrenaline after bilateral adrenalectomy. The post-exercise levels of adrenaline and the adrenaline/dopamine ratio were significantly higher in the pheochromocytoma patients compared to the healthy controls and the patients with neurovegetative lability, while the patients with medullary thyroid carcinoma represented an intermediate group with a high probability of developing adrenal tumors. The present method is a physiological test with a high sensitivity and specificity. It is practical and well suited for repeated examinations and seems to be of value for the detection of early pheochromocytoma in MEN-2 patients. Furthermore, the test could be used in the differential diagnosis between pheochromocytoma and neurovegetative lability.

A case of glucagonoma syndrome with necrolytic migratory erythema, glossitis, anemia, hyperglucagonemia and a malignant, pancreatic A-cell tumour in a 68-year-old male is described. Gel filtration of the highly elevated circulating glucagon immunoreactivity (2200 pg/ml) demonstrated 60% pancreatic glucagon and 30% “proglucagon”. Metabolic studies before operation demonstrated suppression of the total plasma glucagon concentration on oral glucose tolerance test, unchanged total plasma glucagon concentration during intravenous glucose tolerance test and insulin-induced hypoglycemia. Administration of arginine was followed by a rise in both the pancreatic glucagon and the “proglucagon”, whereas alanine increased only the pancreatic glucagon. The plasma somatostatin level was immeasurable preoperatively. Somatostatin infusion completely suppressed the release of the pancreatic glucagon but did not significantly affect the “proglucagon”. After removal of the tumour the skin lesions disappeared and the total plasma glucagon values fell to normal levels (120 pg/ml). Also, other abnormal laboratory findings returned to normal, including the preoperatively observed renal glucosuria.

To compare unilateral and bilateral neck exploration for primary hyperparathyroidism in a prospective randomized controlled trial.Based on the assumption that unilateral neck exploration for a solitary parathyroid adenoma should reduce operating time and morbidity, a variety of minimally invasive procedures have challenged the idea that bilateral neck exploration is the gold standard for the surgical treatment of primary hyperparathyroidism. However, to date, no open prospective randomized trial has been published comparing unilateral and bilateral neck exploration.Ninety-one patients with the preoperative diagnosis of primary hyperparathyroidism were randomized to unilateral or bilateral neck exploration. Preoperative scintigraphy and intraoperative parathyroid hormone measurement guided the unilateral exploration. Gross morphology and frozen section determined the extent of parathyroid tissue resection in the bilateral group. The primary end-point was the use of postoperative medication for hypocalcemic symptoms.Eighty-eight patients (97%) were cured. Histology and cure rate did not differ between the two groups. Patients in the bilateral group consumed more oral calcium, had lower serum calcium values on postoperative days 1 to 4, and had a higher incidence of early severe symptomatic hypocalcemia compared with patients in the unilateral group. In addition, for patients undergoing surgery for a solitary parathyroid adenoma, unilateral exploration was associated with a shorter operative time. The cost for the two procedures did not differ.Patients undergoing a unilateral procedure had a lower incidence of biochemical and severe symptomatic hypocalcemia in the early postoperative period compared with patients undergoing bilateral exploration. Unilateral neck exploration with intraoperative parathyroid hormone assessment is a valid surgical strategy in patients with primary hyperparathyroidism with distinct advantages, especially for patients with solitary parathyroid adenoma.

Background The distinction between solitary parathyroid adenoma and hyperplasia can sometimes be difficult during surgery for primary hyperparathyroidism (pHPT), especially in patients who have undergone previous thyroid or parathyroid surgery. The use of intraoperative parathyroid hormone (PTH) monitoring as a possible diagnostic tool was therefore investigated. Methods Intraoperative levels of PTH were measured in 119 patients during 121 operations (including 14 reoperations) for pHPT. The mean(s.d.) preoperative serum calcium level was 2·79(0·21) mmol/l. Blood samples were drawn before, and at 5 and 15 min after, excision of the first enlarged parathyroid gland. PTH was analysed electively in 61 patients and on-line by a modified assay for intact PTH in 48 patients. Both procedures were used in ten patients. Results The mean(s.d.) decline in PTH concentration in 101 patients with primary exploration due to solitary adenoma was 63(17) per cent after 5 min (n = 84) and 83(10) per cent after 15 min. The patients with primary exploration because of multiglandular disease (n = 6) were correctly predicted not to have parathyroid adenoma. Conclusion Measurement of PTH levels during surgery for pHPT is a highly sensitive method for differentiating between single and multiple gland disease. The on-line monitoring of PTH is clinically useful in patients who have undergone previous neck surgery. Its role in pHPT surgery at primary exploration should be evaluated in prospective trials.

Background. Technetium 99m sestamibi was recently introduced for the preoperative localization of abnormal parathyroid glands in patients with primary hyperparathyroidism with promising results. However, the sensitivity of sestamibi and thallium to detect abnormal parathyroid glands is partly dependent on the gland size. In this study we compared the sensitivity of sestamibi subtraction scintigraphy with thallium subtraction scintigraphy in patients with predominantly mild increase in serum calcium level. Methods. Thirty-nine patients with primary hyperparathyroidism were included. The mean (± SD) serum level of calcium was 2.75 ± 0.17 mmol/L. In 28 (72%) of the patients the serum level of calcium was less than 2.85 mmol/L. These patients were classified as having mild abnormalities in serum calcium. All patients were investigated before operation with both sestamibi and thallium subtraction scintigraphy. Results. In two patients autonomous thyroid adenomas precluded subtraction scintigraphy. Sestamibi subtraction scintigraphy correctly localized 31 (86%) of 36 parathyroid adenomas compared with only 17 (47%) of 36 by thallium subtraction scintigraphy (p < 0.001). There was one false- positive result in the sestamibi group because of a thyroid adenoma, and two of the scans were negative. Both the sestamibi and the thallium subtraction scintigraphy localized one single enlarged gland in all three patients with multiple gland involvement. In no case was multiglandular disease predicted. Conclusions. Sestamibi subtraction scintigraphy is superior to thallium subtraction scintigraphy and has a high sensitivity to localize a solitary parathyroid adenoma in patients with mild increase in serum calcium level. The sensitivity decreases in patients with multiglandular parathyroid disease and concomitant thyroid nodular abnormalities.

Background. A significant number of patients with primary hyperparathyroidism (pHPT) who are surgically treated have increased serum levels of intact parathyroid hormone (PTH) during long-term follow-up despite normocalcemia. The cause and significance of this finding remain to be established. Methods. A total of 82 patients operated on for sporadic parathyroid adenoma were investigated before and at 8 weeks and 1 year after operation with serum levels of intact PTH, bone mineral content, and biochemical variables known to reflect PTH activity. Results. All patients had low or normal serum levels of calcium during follow-up. At 8 weeks after operation 20 (24%) patients had increased serum levels of PTH. These patients had severe parathyroid disease and low levels of 25(OH) vitamin D before operation. In contrast to patients with normal levels of PTH after operation, they did not have an elevated bone mineral content but had elevated levels of serum creatinin. At 1 year after operation 13 patients had elevated serum levels of PTH. Compared with patients with normal serum levels of PTH, they were older and had an increased frequency of cardiovascular disease and biochemical indications of compromised renal function. They did not have an elevated bone mineral content. Conclusions. Persistently increased serum levels of PTH indicate harmful effects of pHPT even after surgical cure, especially in elderly patients with severe disease before operation. The results in this investigation therefore favor early treatment of pHPT.

Neuroendocrine liver metastases are rare, yet they represent an entity that has attracted much attention lately. The protracted course of neuroendocrine tumors and the hormone origin of their typical incapacitating symptoms constitute a logical basis for well founded and bespoke treatment. Demonstration of the liver secondaries is best done by ultrasonography (US) and contrast-enhanced computed tomography (CT), which on the whole have replaced the invasive angiography techniques. By use of histochemical and molecular biologic methods the exact nature of the tumor can be typified in tissue samples obtained percutaneously, laparoscopically, or surgically. Localization of nonpalpable metastases of the liver is best done by intraoperative US. Surgical removal of liver metastases is curative in some cases and is usually effective in relieving the symptoms. Also, palliative debulking or cytoreductive surgery is often worthwhile as it offers a chance of prolonged survival and symptom relief. Similar benefits are achieved by ischemic therapy preferably by temporary dearterialization, which in our department is done on an outpatient basis using a specially designed (externally controlled) occluder applied during a single laparotomy that includes debulking when appropriate as well as cholecystectomy. Hormonal therapy with somatostatin analogs may be used as a single treatment or in combination with ischemic therapy. It has an ensured symptom-reducing effect, whereas its influence on tumor growth is unsettled. Lately similar effects have been ascribed to human leukocyte interferon. In conclusion the specific characteristics of neuroendocrine tumors and the available treatment arsenal favor an active treatment approach in patients who have developed liver metastases.

Background. Anaplastic carcinoma of the thyroid (ACT) rarely can be cured, but every effort should be made to improve prognosis and, above all, prevent death due to suffocation or large local tumor ulceration. Methods. From 1984 to 1992, 33 consecutive patients with ACT were treated prospectively according to a combined treatment program consisting of hyperfractionated radiotherapy, doxorubicin, and debulking surgery. Preoperative radiotherapy was administered to a target dose of 30 Gy and postoperatively to a total dose of 46 Gy. Radiotherapy was performed 5 days a week. The daily fraction was 1.0 Gy × 2 until 1988, after which it was 1.3 Gy × 2. Otherwise, the therapy remained unchanged. Twenty milligrams of doxorubicin were administered intravenously per week. Debulking surgery was possible in 23 patients (70%). Results. No patient failed to complete the protocol because of toxicity. There were no signs of local recurrence in 16 patients (48%). In only eight patients (24%) was death attributed to local failure. In four patients, survival with no evidence of disease exceeded 2 years. Improvement in local tumor control was marginally significant (P = 0.08) in the 17 patients treated in the latter part of the study, with no sign of local disease in 11 patients and deaths due to local failure in only 2 patients. The improved local control could not be attributed to any differences between the two series. Conclusion. Combination modality treatment of ACT is feasible and effective despite the patients' advanced age and locally advanced disease. There was a tendency for local control to be improved after accelerated radiotherapy.

Serum urate levels were studied in 18 patients with primary hyperparathyroidism (pHPT) and in 36 controls (group 2) matched for age, sex, nationality and blood pressure. These two groups were compared

Side localization of parathyroid adenomas was performed by venous sampling for intact parathyroid hormone (PTH) in 20 consecutive patients with primary hyperparathyroidism (pHPT) after induction of anesthesia. The results were thus available during surgery. Nineteen of the patients had solitary parathyroid adenoma, and one had hyperplasia. There was no complication to the procedure. A lateralizing PTH gradient for a parathyroid adenoma was obtained in 13 patients. At surgery 12 of them (92%) were proved correct; that is, the adenoma was localized on the same side. Thus the technique correctly lateralized the adenoma in 12 of 19 patients (63%). We therefore conclude that the method of intraoperative venous sampling for intact PTH is safe, and the predictive value of a lateralizing gradient is high. It could therefore be used as an adjunct to surgical skill and noninvasive localization procedures in selected cases, for instance in patients with prior neck surgery and hypercalcemic crisis.

Hypothesis A variety of clinical and biochemical variables may be associated with hypocalcemia after surgery for parathyroid adenoma. Design A prospective study of patients who underwent surgery for solitary parathyroid adenoma. Setting A university hospital department of surgery. Patients Eighty-six consecutive patients who underwent surgery for solitary parathyroid adenoma. Intervention Parathyroidectomy according to the principles of unilateral neck exploration. Main Outcome Measures Clinical and biochemical risk factors for early (≤4 days after surgery) and late (1 year after surgery) postoperative symptomatic and biochemical hypocalcemia. Results Twenty-two patients developed early symptomatic hypocalcemia. The difference in total serum calcium levels between patients, with and without early symptomatic hypocalcemia, was evident on the third and fourth postoperative days. Serum level of osteocalcin greater than 6.0 µg/L, bilateral neck exploration, and history of cardiovascular disease were risk factors for symptomatic hypocalcemia (odds ratios [95% confidence intervals]: 4.4 [1.4-14.1], 3.8 [1.3-11.6], and 0.1 [0.02-0.60], respectively). Patients with up to 1 risk factor had a possibility of only 7% to develop early symptomatic hypocalcemia. One year after surgery, 16 patients had low levels of total serum calcium (late biochemical hypocalcemia) and were asymptomatic. Preoperative intermittent hypercalcemia was associated with an increased risk for late biochemical hypocalcemia (odds ratio, 3.9; 95% confidence interval, 1.0-16.3). Conclusions Clinical and biochemical risk factors for early and late postoperative hypocalcemia in patients who underwent surgery for solitary parathyroid adenoma were found. A clinically useful prognostic index for early symptomatic hypocalcemia was constructed using these risk factors.

Valdemarsson S, Lindergard B, Tibblin S, Bergenfelz A (Lund University Hospital, Sweden). Increased biochemical markers of bone formation and resorption in primary hyperparathyroidism with special reference to patients with mild disease. J Intern Med 1998; 243: 115–22. Objectives .To evaluate the impact on bone turnover of primary hyperparathyroidism (pHPT) with special reference to patients with mild pHPT, using biochemical markers of bone formation and resorption. Design .A longitudinal study of patients with pHPT before and one year after surgical treatment. Setting .The Departments of Internal Medicine and Surgery, Lund University Hospital. Subjects .Forty consecutive patients with pHPT. Thirty of these patients had mild pHPT and are reported separately. Data on bone mineral was also compared to a reference population. Intervention All patients were operated upon and restudied one year later. Main outcome measures .Bone resorption and formation was studied by means of the serum concentrations of the telopeptide of the carboxyterminal region of type 1 collagen (ICTP) and of alkaline phosphatase (ALP), osteocalcin and the carboxyterminal propeptide of type 1 procollagen (PICP), respectively. Bone density was measured at the distal radius by single photon absorptiometry (SPA). Results .Bone formation markers consistenly decreased after parathyroid surgery: ALP from 3.51 ± 0.23 to 2.94 ± 0.21 µkat L−1 (P < 0.05), osteocalcin from 6.15 ± 0.53 to 2.89 ± 0.23 µg L−1 (P < 0.001) and PICP from 126.4 ± 10.9 to 96.0 ± 6.5 µg L−1 (P < 0.001). In parallel, the ICTP concentration, reflecting bone resorption, decreased from 5.10 ± 0.54 to 3.94 ± 0.34 µg L−1 (P < 0.001). There was not any significant change in distal radius bone mineral 1 one year after surgery. In the subgroup of patients classified as mild pHPT, a significant decrease was noted for osteocalcin, PICP and for ICTP but not for ALP, without significant changes in variables reflecting distal radius bone mineral content. Glomerular filtration rate was inversely correlated to serum levels of intact PTH, ionized calcium, alkaline phosphatase, osteocalcin and ICTP and directly correlated to the 1.25-dihydroxy-vitamin D concentrations. Conclusions .pHPT is associated with substantial changes in circulating levels of biochemical markers of bone formation and resorption. These findings are also present in patients with mild pHPT. Renal function should be considered in the evaluation of the impact of pHPT on bone turnover.

As a general principle in the treatment of primary hyperparathyroidism due to single adenoma, unilateral parathyroidectomy was applied to 50 patients and compared with another group of 50 conventionally explored patients. Twenty-five patients were explored only on the "adenoma" side. The other 25 patients were explored on both sides, avoiding biopsies at the first. In the conventionally explored patients, the adenoma was removed and one to three normal glands were biopsied. Oil-red-O technique was used in the intraoperative microscopical examination. The patients in whom the operation could be limited to the "adenoma" side had a statistically more favorable situation concerning early postoperative hypocalcemia, length of operation time, and need for calcium and vitamin D substitution. The principle of unilateral parathyroidectomy in conjunction with intraoperative oil-red-O staining technique is advocated in hyperparathyroidism due to single adenoma because it offers more reliable peroperative distinction between uni- and multi-glandular involvement, reduced operation time, decreased risk for complication, reduced early hypocalcemia, and more favorable technical conditions for reoperation.

The annual incidence of clinically diagnosed TC in Malmö was, on an average, 2.4 per 100,000 population during the years 1960-1977. This was 1.2 per 100,000 population lower than the corresponding incidence in the whole of Sweden as reported by the National Cancer Registry. The main reason for the difference was suggested to be inclusion in the official figures of autopsy cases and of cases with a benign diagnosis, rather than a true difference in the prevalence of TC. During the later part of the study an increase in the incidence of differentiated TC of approximately 70% was noted. This was considered to be due to increased health awareness and the availability of medical care, because only the number of tumors with less advanced growth increased. The average annual mortality from TC in Malmö was 0.9 per 100,000, which was 0.4 per 100,000 lower than the corresponding official rate in all of Sweden. The difference was suggested to be mainly due to inclusion in the official figures of persons not dying of TC. The mortality did not change significantly during the period of investigation. The percentage distribution by histologic type of tumors clinically diagnosed (N = 104) was as follows: papillary cancer, 65%; follicular, 21%; medullary, 4%; and anaplastic, 12%. The prognosis as estimated by the life table method was worst for patients with anaplastic TC, followed by those with follicular, papillary, and medullary TC. The validity of using the relationship of the tumor to the thyroid capsule (i.e., intrathyroidal and extrathyroidal growth) as a basis for classification into tumor stages was supported in the present study: the mortality in patients with intrathyroidal tumors was lower than in those with extrathyroidal tumors. The definition of occult TC--TC not larger than 1.5 cm, without regard to the relation to the thyroid capsule--was considered inappropriate and a change in the conception of occult TC was proposed. The presence or absence of node metastases in TC did not seem to have major significance for the prognosis. The significance of age for survival was strongly supported in our study. Deaths from TC clinically diagnosed before the age of 60 were infrequent, whereas the disease after this age increasingly often was fatal. This was partly due to a late onset of anaplastic TC and partly to a higher mortality in older than in younger patients with papillary or follicular TC.(ABSTRACT TRUNCATED AT 400 WORDS)

Ninety patients from a demographically welldefined area of, on an average, 243,000 inhabitants were surgically treated for thyroid carcinoma during an 18 year period. Sixty-five of the patients had papillary carcinoma, 20 follicular carcinoma, 4 medullary carcinoma, and 1 anaplastic carcinoma. Seventy-eight patients were operated on for cure, and among them, 23 had total thyroidectomy and 55 partial thyroidectomy. Additional therapy with thyroxine was given to all patients postoperatively. None of the patients treated for cure died from thyroid carcinoma at follow-up 2 to 20 years after diagnosis. One of 42 patients (2.4 percent) primarily treated for cure with lobectomy for papillary carcinoma had local recurrence in the thyroid bed which was excised successfully. No patient treated for cure of follicular carcinoma had local recurrence. All verified recurrences except one were diagnosed within 5 years of primary operation. We conclude that local recurrence after procedures less than total thyroidectomy that are considered to be curative is unusual provided that thyroxine is given postoperatively. Thus it seems that the reported high rates of microscopic carcinoma in the contralateral lobe in patients with unilateral cancer have little clinical significance. A conservative approach in most patients with localized thyroid carcinoma is indicated because it reduces the risk of postoperative complications.

The study comprised 191 cases of surgically treated hyperparathyroidism, with all principal types of parathyroid disease represented. At least two complete glands stained with a modified isopropanol oil red O method for fat, in addition to sections stained with hematoxylin-eosin, were available in each case. On the basis of the morphologic evaluation and the clinical follow-up data, it is concluded that access to two complete glands and the use of fat staining allow highly reliable intraoperative distinction between adenoma and hyperplasia. Of 105 patients followed up for at least one year (mean, 20 months) in whom adenomas were diagnosed, a single possible error was identified. In each of 68 cases classified as hyperplasia on the basis of two abnormal glands, every additional complete gland available (total, 182 glands) was at least partially abnormal, with distinct signs of hyperactivity, irrespective of size. The rate of equivocal findings for cases in which two glands were available (probably adenoma but hyperplasia not excluded) was 8 per cent in 165 cases of primary hyperparathyroidism. These results justify limitation of surgery to one side of the neck in patients in whom adenoma is diagnosed on the basis of a complete, functionally normal (inactive) gland in addition to the presumed adenoma. Thus, the methods described provide a basis for optimal utilization of imaging techniques that allow preoperative localization of parathyroid adenomas.

The sympathetic innervation of the normal human thyroid was investigated by a combination of fluorescence histochemistry and electron microscopic autoradiography. Sympathetic, adrenergic nerve fibers were numerous in the human thyroid, and they were mainly found in two locations: in relation to vessels, and in interfollicular spaces. The terminals of the vascular nerves were located very close to smooth muscle cells in the vessel wall, and the interfollicular nerve terminals had a similarly close relation to follicle cells; only the respective basement membranes intervened. It is concluded that, in man, there is a morphological basis for an influence of the sympathetic nervous system not only on thyroid vessels but also directly on thyroid follicle cells.

Primary hyperparathyroidism was studied in a well-defined geriatric population of 1129 individuals during a three-month interval. Primary hyperparathyroidism was diagnosed in 1.5%. The diagnosis was based on a morphologic and biochemic basis. From clinical material consisting of 400 patients treated surgically for primary hyperparathyroidism during a ten-year period, 158 patients (38%) above the age of 64 were studied. At the preoperative evaluation, neuromuscular symptoms were present in 80%, renal insufficiency and kidney stones in each 16%, constipation and/or anorexia in 38%. Ten per cent were considered asymptomatic. In 80% the primary hyperparathyroidism was caused by a solitary adenoma. Ninety-four per cent became normocalcemic following the operation. Consistent hypocalcemia requiring vitamin-D treatment occurred in 3%, and 2% had a persisting hypercalcemia or later recurrence. The therapeutic effect on the neuromuscular symptoms, constipation, anorexia, and renal stone formation was considered good or fair in most of the cases. Primary hyperparathyroidism in the elderly occurs with a high prevalence. It can be treated successfully by surgical therapy with a low cost of morbidity, mortality, and medical care.

Various chemotherapeutic modalities have been tried in the treatment of patients with malignant glucagonomas. Promising results have been reported after drug treatment with dimethyl-triazenoimidazole carboxamide (DTIC). We present a patient with a metastasizing pancreatic glucagonoma, in whom treatment with neither DTIC nor with the combination of streptozotocin and 5-fluorouracil resulted in any noticeable improvement.

A case of malignant endocrine tumour of the jejunum, associated with severe duodenal ulcer is described. The tumour and a local metastasis were examined by immunohistochemistry and found to contain abundant somatostatin-immunoreactive cells together with less numerous cells displaying gastrin immunoreactivity. This is to our knowledge the first case of intestinal somatostatinoma. The presence of gastrin cells in the tumour may explain the ulcer diathesis.

In man, as well as in the mouse, there is morphologic and functional evidence for a direct, stimulatory influence of the sympathetic nervous system on the secretion of thyroid hormone by noradrenaline (NA), released from interfollicular adrenergic nerve terminals. In mice and rats, an age-related reduction of the sympathetic innervation of the thyoid has recently been observed. In the present study, possible age-related variations of the sympathetic innervation and the concentration of NA in human thyroid tissue were examined. Interfollicular adrenergic nerve terminals were studied by fluorescence histochemistry, and the tissue concentration of NA was measured by fluorometry. In apparently normal thyroid tissue, obtained from fetuses, young (20-45), and elderly (greater than 60) euthyroid people with thyroid cancer or hyperparathyroidism, the number of interfollicular adrenergic nerve terminals appeared to be reduced with increasing age, and the thyroid tissue concentration of NA was significantly lower in elderly than in young people. These findings may have functional importance.

One hundred four cases of clinically significant thyroid carcinoma (TC) occurred in a demographically well defined area with, on an average, 243,000 inhabitants, during an 18-year period, corresponding to a yearly incidence of 2.4 per 100,000. During the later years of the study there was an increase of the age-standardized incidence of differentiated TC. The reason for this is suggested to be a greater health awareness, because only the number of tumors with less advanced growth increased. Sixty-one patients had, as the only presenting sign, a solitary thyroid nodule, while 24 had obviously malignant disease. All cases were revised histologically. Sixty-six patients were found to have papillary carcinoma, whereas 22 cases were diagnosed as follicular, 4 as medullary, and 12 as anaplastic. The prognosis, as estimated by the life-table method, was worse for patients with anaplastic cancer followed by follicular, papillary, and medullary. Within the papillary group, patients with occult cancer, i.e., thyroid tumor not larger than 1.5 cm, and intrathyroidal cancer, i.e., thyroid tumor larger than 1.5 cm but not penetrating the thyroid capsule, had a cumulated survival rate not significantly different from the expected rate, and only 1 of the 46 patients belonging to these two subgroups, died from TC.

Twenty-five endocrine tumors of the rectum (rectal carcinoids) were examined immunohistochemically for various pancreatic and gut neurohormonal polypeptides. Twenty-one of the tumors were found to contain cells displaying pancreatic polypeptide (PP), glucagon, somatostatin, insulin, substance P, enkephalin or beta-endorphin immunoreactivity. At least 11 of the tumors contained more than one peptide hormone. In some of the tumors PP cells made up the major cell population, in others the glucagon cells constituted the majority. Only four of the tumors contained 5-hydroxytryptamine. Rectal endocrine tumors seem unique among gut endocrine tumors in that they may store immunoreactive enkephalin, beta-endorphin and even insulin. None of the patients displayed the carcinoid syndrome; symptoms were usually vague and uncharacteristic. In many cases the tumor was found at routine examination.

Based on the postulate that parathyroid adenoma is practically always a solitary lesion, unilateral parathyroidectomy including the homolateral normal parathyroid was applied as a principle in the treatment of this form of primary hyperparathyroidism. The exploration was confined to the adenoma side if this was the first to be explored. Intraoperative oil-red-O staining of frozen sections was used to exclude the possibility of a multiglandular involvement. This principle was applied in a consecutive series of 102 patients operated for hyperparathyroidism from 1977 to 1981 and diagnosed as parathyroid adenoma. In 43 patients where the abnormal gland was found on the side explored first, unilateral parathyroidectomy was performed on that side, avoiding exploration of the contralateral side. In 45 patients where normal glands were found on the side first explored, unilateral parathyroidectomy was performed on the contralateral side. In 14 patients other types of operations were performed as the above-mentioned principle could not be achieved. At follow-up 1 to 5 years after surgery, no cases of hypocalcemia were recorded. The results of the different operations were compared as to early and late hypocalcemia. Early hypercalcemia was more pronounced after a bilateral exploration. Two of the patients who had an atypical operation had a permanent need for vitamin D in order to maintain an adequate serum calcium level. Surgical principles for various possible exploratory findings are outlined. These are based upon the idea of performing a unilateral parathyroidectomy whenever intraoperative oil-red-O staining excludes multiglandular involvement as a cause for the hyperparathyroidism.

In search of new practical diagnostic methods for the early diagnosis of hereditary medullary carcinoma of the thyroid (MCT) calcitonin release has been studied following induction by pentagastrin, cholecystokinin-pancreozymin (the C-terminal octapeptide, C8-CCK, and the native swine extract), and ethanol in eighteen cases of MCT (all but one clinically occult), three 'borderline cases', seven first degree relatives of patients with hereditary MCT and thirty-five healthy controls. Pentagastrin, subcutaneous (s.c.) or intravenous (i.v.), induced a pronounced and rapid increase of serum calcitonin within 2-5 min. The elevation was roughly proportional to the tumour mass as estimated at operation. Seventeen out of eighteen MCT patients responded to s.c. pentagastrin with a significant increase in serum calcitonin and the response correlated well with that induced by calcium infusion test. Only two blood samples, at times 0 and 5 min, were necessary for diagnosis. In the MCT patients, i.v. pentagastrin produced more pronounced elevations of serum calcitonin than did s.c. pentagastrin, whereas no increase was seen in the control group. The subjective discomfort caused by i.v. pentagastrin was somewhat more intense but lasted shorter than that induced by s.c. administration. No serious complications were seen. All of nine MCT patients responded to C8-CCK with increments in serum calcitonin exceeding those of the control group and both of two responded similarly to the native cholecystokinin-pancreozymin extract. Generally the serum calcitonin response was lower and more variable after C8-CCK than after s.c. or i.v. pentagastrin, and the subjective discomfort was also more pronounced with abdominal cramps during the injection. Ethanol in the dose used was the least effective stimulator for serum calcitonin release. Clinically suspected MCT carriers with palpable tumours can be diagnosed by determination of the basal, i.e. non-stimulated serum calcitonin levels. Other possible Sipple genome carriers, who are at the time clinically healthy with normal basal serum calcitonin, should be subjected to a s.c. or i.v. pentagastrin stimulation test at each examination. These tests are much simpler to perform than a calcium infusion, test, but seem to have about the same sensitivity.

Histopathologic and clinical follow-up data on 42 patients observed 2-20 years after operations for oxyphil neoplasms of the thyroid are presented. In eight patients histologic signs of malignancy were found but only two patients showed a clinically malignant course with development of distant metastases. The results do not indicate that oxyphil thyroid neoplasms are especially prone to assume a malignant course with the mode of treatment applied. Our policy is to remove any differentiated epithelial thyroid neoplasm with at least lobectomy. Total thyroidectomy is reserved for cases with capsular penetration, blood vessel invasion and/or metastases.

The possible influence of cigarette smoking on goiter formation, thyroglobulin (Tg) secretion, and thyroid hormone production was assessed by estimations of the presence of palpable goiter and by RIAs of Tg, T3, rT3, T4, and TSH in sera from 441 women (48-53 yr old), representing a normal population included in a study on the prevalence of thyroid disease. Smoking habits were evaluated by a questionnaire, and the women were then classified as never smokers (n = 192), smokers (n = 169), and exsmokers (n = 80). Smokers were subdivided as moderate (1-19 cigarettes/day) and heavy (greater than or equal to 20 cigarettes/day). Palpable goiter was found in 15% of the smokers, in contrast to only 4% of the exsmokers and 9% of the never smokers. Among smokers, 37% had serum Tg values over 30 micrograms/liter (third quartile), while such values were found in only 16% of the exsmokers and 18% of the never smokers. In addition, smokers were found to have higher serum T3 and lower rT3 concentrations than never smokers; this difference was most pronounced in heavy smokers. Serum T4 was not different, while TSH was insignificantly lower in smokers than in nonsmokers. Exsmokers did not differ significantly from never smokers in any of these parameters. It seems possible that cigarette smoking may have two, calorigenically opposed, effects on thyroid hormone production; it may be goitrogenic (possibly due to inhaled thiocyanate), but it may also enhance the formation of T3 at the expense of rT3 formation.

Factors influencing the result of various forms of surgical treatment for pheochromocytoma were studied in patients with multiple endocrine neoplasia IIA (MEN IIA) syndrome. The material consisted of 18 patients belonging to 4 non-related families operated on during 1966–1981 with a mean follow-up time of 7.4 years. Twenty-seven adrenals were removed at 22 operations. In all adrenals, multiple pheochromocytomas and/or medullary hyperplasia were present. In 13 patients the first operation was a unilateral adrenalectomy. Four of these had to be reoperated on because of recurring or persisting symptoms. Five patients were operated on bilaterally at the first instance. In 4 of these, the reason was bilateral macroscopic tumor involvement. Various pre- and intraoperative findings were evaluated with respect to the surgical result. The maximum diameter of the largest tumor was the only factor relating positively to surgical success with unilateral operation. Of 9 patients who remained asymptomatic following unilateral adrenalectomy, 8 had tumors less than 5 cm in diameter. The 4 patients who had to be reoperated on with a contralateral adrenalectomy all had a maximum tumor diameter exceeding 5 cm. A pragmatic approach to the problem of timing and extent of adrenal surgery in MEN IIA is advocated. Clinical, biochemical, histopathological, genetic, and social dimensions of the disease should be taken into consideration when choosing the surgical procedure.

Glucagon, a substance originally thought exclusively to play a part in carbohydrate metabolism, has during recent years been found to possess several other important properties. Among them are influence on tubular reabsorption of electrolytes, 1 on adrenal medullary secretion, 2 on calcium metabolism, 3 on gastric secretion, 4 and on gastrointestinal motility. 5,6 During the last decade, cardiovascular effects have been added to the increasing list of glucagon characteristics. Shoemaker et al 7 reported an increase in liver blood flow after glucagon administration. They used the sulfobromophthalein (Bromosulphthalein [BSP]) sodium technique to study the hepatic blood flow. The flow increase paralleled the blood glucose rise. Merrill et al 8 demonstrated a vasodilatory effect of glucagon on the splanchnic vascular bed in perfusion experiments. Parmley et al 9 reported an inotropic and chronotropic effect on cardiac activity following glucagon injection in man. In a recent publication, Kock et al, 10 using

Glucagon, the polypeptide humoral substance produced mainly by the alpha cells of the pancreas, is generally considered as a metabolic hormone. Its influence on carbohydrate metabolism has been widely studied and is fairly well known. In addition to the glycogenolytic action, glucagon has also been found to have an inhibitory effect on gastrointestinal motility1-3and gastric acid secretion.4,5By which mechanisms these actions are produced by glucagon and if they are of any physiological significance is not known. The effect of glucagon on the cardiovascular system has been subject to much less study. In 1959, Shoemaker et al,6using sulfobromophthalein (Bromsulphalein [BSP]) methods, studied the effect of glucagon on hepatic blood flow in dogs. They found an increase of blood flow which coincided with the serum glucose increase. In 1962, Merrill et al7reported the effect of glucagon on the superior mesenteric vascular bed. In their

Glucagon has been suggested for treatment of hypoxic liver conditions because it is reported to increase the splanchnic flow and portal oxygenation. With use of hepatic dearterialization in the pig as an experimental model for hepatic ischemia, the effect of glucagon on the release of serum glutamic oxaloacetic transaminase, serum lactic dehydrogenase, and the acid hydrolases, beta-glucosidase and beta-galactosidase, was studied. In control experiments, glucagon gave no enzymatic release. Dearterialization by itself caused a typical pattern of enzyme increases, especially of the acid hydrolases. Dearterialization in combination with glucagon showed a significantly higher release of the investigated enzymes and the animals were more affected by the operation. Autopsy revealed patchy necroses in the liver parenchyma, reasonably more widespread after glucagon administration. This unexpected result might be due to other than circulatory effects of glucagon, eg, depletion of liver glycogen and instability of lysosomal membranes.

In recent years cardiovascular effects of glucagon have been demonstrated both in animals and man. Following a single injection of glucagon the hepatic blood flow increased approximately 100%.1,2This increase in hepatic blood flow is mainly due to a vasodilatory action of glucagon on the splanchnic vascular bed.3Glucagon exerts positive inotropic and chronotropic effects on the heart.4,5In dogs, a single injection of glucagon increased the cardiac output 36% and the coronary artery flow 54%.6The greatest flow increase produced by glucagon (190%) was recorded in the superior mesenteric artery.7 The mechanism by which glucagon exerts its cardiovascular effects is not known. Originally, Shoemaker et al1suggested that the increase in hepatic blood flow could be a consequence of increased metabolic activity of the liver incident to rapid glycogenolysis. However, the action of glucagon on cardiac performance was as effective on the isolated