Survival following alpha particle pituitary irradiation for diabetic retinopathy.

The purpose of this study was to evaluate the mortality experience of persons with longstanding diabetes who had received pituitary irradiation for diabetic retinopathy compared to a matched group of persons with diabetes who had not had pituitary ablation. The irradiated cohort consisted of 167 patients treated at the Donner Pavilion (Lawrence Berkeley Laboratory, University of California, Berkeley), and the comparison cohort was the population evaluated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). Survival analyses were performed comparing the two cohorts using three different sets of matching criteria, each more restrictive than the previous analyses. The three different strategies were (1) matched only on severity of diabetic retinopathy; (2) matched on severity of retinopathy and age; and (3) matched on severity of retinopathy, age, gender, and hypertension status. Tests of comparison were the log-rank test, the Wilcoxon test, and the likelihood ratio test. For the model matching only on severity of retinopathy, mean survival was 8.3 years for the WESDR group and 9.4 years for the ablated group (p > 0.05 for all three statistical tests). For the model matched on retinopathy and age, mean survival was 8.9 years for the WESDR group and 9.2 years for the ablated group (p=0.05 log-rank test, 0.32 Wilcoxon test, and 0.06 likelihood ratio test). For the model matching on retinopathy, age, gender, and hypertension status, mean survival was 8.9 years for the WESDR group and 11.6 years for the ablated group (p=0.72 log-rank test, 0.08 Wilcoxon test, and 0.82 likelihood ratio test). These data are compatible with the notion that pituitary ablation, and therefore induced pituitary growth hormone deficiency, may not decrease survival in those with severe diabetic retinopathy.

Catastrophic antiphospholipid syndrome: response to repeated plasmapheresis over three years.

The catastrophic antiphospholipid syndrome (CAPS) is rare and usually fatal. In this report, we describe an unusual patient who, 31 years after experiencing an atypical preeclampsia-eclampsia presentation known today as the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), developed CAPS, which seemed to complicate a diagnosis of primary antiphospholipid syndrome. She responded to repeated plasmapheresis over 3 years. Anticoagulants, corticosteroids, intravenous gamma globulin, and intravenous cyclophosphamide had all failed to halt the progression of CAPS, but repeated plasmapheresis not only halted the condition, but it led to the reversal of a leukoencephalopathy. The relationship between HELLP syndrome and CAPS is discussed, and possible pathogenetic mechanisms that explain the efficacy of repeated plasmapheresis in this setting are suggested. It is postulated that perhaps plasmapheresis, through removal of cytokines or other mediators, disrupts the interaction between phospholipid-protein complexes and endothelial cells. Repeated plasmapheresis should be considered in the most refractory cases of CAPS when more conventional treatment regimens have failed.

Diabetic short-wavelength sensitivity: variations with induced changes in blood glucose level.

PURPOSE: To investigate variations in diabetic short-wavelength sensitivity with acute, induced changes in blood glucose level. METHODS: Increment threshold measures were obtained for short-wavelength-sensitive and middle/long-wavelength-sensitive cone pathways after an induced, acute change in blood glucose level in diabetic observers. RESULTS: Diabetic observers showed an increase in short-wavelength sensitivity, but no change in middle/long-wavelength sensitivity, with a rapid drop in blood glucose level. CONCLUSIONS: Experimentally induced changes in diabetic blood glucose levels can directly affect diabetic short-wavelength sensitivity.

A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth hormone-releasing factor.

We report the histological, ultrastructural, and immunocytochemical features of six hypothalamic gangliocytomas associated with pituitary GH cell adenomas and/or acromegaly. In four patients, the gangliocytoma was intrasellar, and no hypothalamic investigation was performed; in two patients, autopsy confirmed hypothalamic involvement. Four patients had a gangliocytoma associated with pituitary GH cell adenoma and acromegaly; electron microscopy demonstrated an intimate association between neurons and adenomatous GH cells. One patient had a gangliocytoma and a GH cell adenoma but no clinical evidence of acromegaly. In the sixth patient, clinical and biochemical acromegaly was manifest, but no pituitary adenoma was demonstrated. Using immunocytochemistry, human pancreatic tumor GRF (hptGRF-40) was localized in the majority of neurons of all six gangliocytomas. The pituitary adenomas and nontumorous adenohypophyses were negative for hptGRF-40. In addition, somatostatin, glucagon, and GnRH were demonstrated within some neurons of several tumors; insulin and gastrin stains were equivocal. These findings confirm previous proposals of production of a GRF by such gangliocytomas. While the significance of other peptides found in some of the tumors is uncertain, the presence of hptGRF-40 in neurons of these gangliocytomas supports the theory that GRF excess is the mechanism responsible for over-production of GH and provides evidence for a syndrome of hypothalamic acromegaly.

Hyperthyroidism and acromegaly due to a thyrotropin- and growth hormone-secreting pituitary tumor. Lack of hormonal response to bromocriptine.

A 47-year-old woman with acromegaly and hyperthyroidism was found to have an inappropriately normal serum thyrotropin level (1.5 to 2.5 microU/ml) that responded poorly to thyrotropin-releasing hormone but showed partial responsiveness to changes in circulating thyroid hormones. Serum alpha-subunit levels were high-normal and showed a normal response to thyrotropin-releasing hormone. Growth hormone and thyrotropin hypersecretion persisted despite radiotherapy and bromocriptine treatment. Selective trans-sphenoidal removal of a pituitary adenoma led to normalization of both growth hormone and thyrotropin levels. Both thyrotropes and somatotropes were demonstrated in the adenoma by the immunoperoxidase technique and electron microscopy.

Development of pseudotumor cerebri after the removal of an adrenocorticotropic hormone-secreting pituitary adenoma: case report.

A patient with Cushing's disease developed intracranial hypertension 1 month after the removal of an adrenocorticotropic hormone-secreting pituitary adenoma. A computed tomographic scan demonstrated normal ventricles and no intracranial mass, establishing the diagnosis of pseudotumor cerebri. The elevated intracranial pressure was apparently consequent to an abrupt reduction in circulating corticosteroids. The development of pseudotumor cerebri after the correction of endogenous hypercortisolism has not been reported previously. This potential complication of the surgical treatment of Cushing's disease can be managed with prompt recognition and appropriate treatment of the syndrome.

Treatment of acromegaly, Cushing disease and Nelson syndrome.

Since 1957 we have treated more than 429 patients who had pituitary neoplasms, most of which were hormone-secreting tumors. Long-term follow-up in the large group of patients treated for acromegaly shows a median survival of better than 16 years, with improvement over time. The short-term follow-up results in patients with Cushing* disease, Nelson syndrome and chromophobe adenoma are very encouraging. To compare these excellent results with those following surgical procedures, a large study of patients followed for a long period after the operations is needed.

Hypothalamic neuronal hamartoma associated with pituitary growth hormone cell adenoma and acromegaly.

A hypothalamic neuronal hamartoma associated with a sparsely granulated growth hormone cell adenoma of the pituitary and acromegaly is reported. It is suggested that the patient had a primary neuronal tumor, whose neurosecretory activity promoted the development of the growth hormone secreting pituitary adenoma causing acromegaly.

Specific radioimmunoassay of human beta-endorphin in unextracted plasma.

With an antiserum against human beta-endorphin (beta-EP) crossreacting less than 2% with human beta-lipotropin (beta-LPH) by weight we have developed a radioimmunoassay that can detect 1 pg beta-EP in diluted raw plasma. In a.m. fasting plasma of 14 normal subjects beta-EP ranged from less than 5 to 45 pg/ml. beta-EP was elevated in untreated, but normal in successfully treated Cushing's disease; undetectable in a patient with adrenal adenoma; extremely high in Nelson's syndrome; and elevated in a patient with bronchogenic carcinoma before, but undetectable after tumor resection. In subjects with intact hypothalamic-pituitary-adrenal axis, beta-EP was undetectable after dexamethasone and increased after metyrapone administration and insulin-induced hypoglycemia. beta-EP concentration was considerably lower in serum than in simultaneously collected plasma, but increased in serum left unfrozen for several hours after clot removal. Thus, beta-EP behaves like a hormone responding to the same stimuli as ACTH and beta-LPH and blood appears to contain enzymes both generating and destroying immunoreactive beta-EP.

Radioimmunoassay of human beta-lipotropin in unextracted plasma.

A sensitive and specific radioimmunoassay for human beta-lipotropin (betah-LPH) in unextracted plasma was developed using pur betah-LPH as tracer and standard and an antiserum not cross-reacting with human beta-MSH and hACTH. In healthy volunteers plasma betah-LPH ranged from less than 20 to 150 pg/ml at 8:00 a.m. and rose after metyrapone administration. betah-LPH was very low in panhypopituitarism, normal in most patients with untreated Cushing's disease, elevated in acromegaly and extremely high in Nelson's syndrome.

Heavy particle therapy: pituitary tumors.

Therapy with 910 MeV alpha particles provides a treatment with no mortality and an extremely low morbidity and has been highly successful in the control of pituitary hormone hypersecretion and tumor growth. It is possible to deliver radiation doses to the pituitary gland that are sufficiently high to inhibit or destroy the tumor cells that cause abnormal secretory activity without damaging the surrounding structures. The data demonstrate the effectiveness of this form of treatment in acromegaly, non-functioning pituitary tumors, prolactin secreting adenomas, Cushing's disease and Nelson's syndrome.

Rapid appearance of transient secondary adrenocortical insufficiency after alpha-particle radiation therapy for Cushing's disease.

A 17-year-old women received 12,000 rads of alpha-particle radiation for the treatment of Cushing's disease. One day after the completion of therapy, the patient developed nausea, vomiting, headache, and postural hypotension. Laboratory evaluation demonstrated a marked fall of the previously elevated urinary 17-hydroxycorticosteroids (17-OHCS) and undetectable plasma cortisols. The urinary 17-OHCS transiently returned to supranormal levels but over a 2 1/2-week period decreased and then remained low. The patient also demonstrated a subnormal urinary aldosterone excretion in relation to plasma renin activity (PRA) during 10 mEq/24 h sodium restriction. The remainder of the endocrine evaluation was normal, suggesting that pituitary function otherwise remained intact. One and one-half years after alpha-particle therapy, the patients's urinary 17-OHCS were normal and responded normally to metyrapone. The relationship between urinary aldosterone excretion and PRA also was normal. It is postulated that there was an infarction of an ACTH secreting pituitary tumor leaving the remainder of the pituitary intact. Achronically elevated circulating level of ACTH with sudden loss of ACTH secretion appeared to have been responsible for the initial low urinary aldosterone as well as the low urinary 17-OHCS. This is the first reported case of a presumed pituitary tumor infarction in association with alpha-particle pituitary radiation.

Heavy-particle therapy in acromegaly and Cushing disease.

A total of 349 patients with pituitary tumors, including acromegaly, Cushing disease, Nelson syndrome, prolactin-secreting adenoma, and chromophobe adenoma, have been treated with heavy-particle radiation during the past 17 years. The incidence of side effects has been low. Only 30 patients, 8.6%, have died, most of preexisting cardiovascular complications. Heavy particle therapy provides a form of treatment with no mortality and extremely low morbidity, and its use in treating pituitary disorders has resulted in dramatic improvement in the signs and symptoms of patients with acromegaly and Cushing disease.

Marked suppression of thyroid function in rats with gram-negative septicemia.

Gram-negative septicemia was induced in rats by two daily injections of fecal mixture into the thigh, after which the thyroid function was markedly suppressed for 2 days. Iodine metabolism was studied by organ radioassay and by imaging with a multiwire proportional chamber (MWPC) at various time intervals after intravenous injection of 125I. Plasma T3, T4, and TSH, measured by radioimmunoassays, were suppressed, as were the T3-resin uptakes. Fractional blood supply to the thyroid glands of the infected rats, studied by the 81Rb uptake method, was also found to be markedly reduced. Sections of the thyroid glands showed little structural change during the period of marked thyroid suppression. There was no biochemical evidence of renal failure in the septicemic rats.

Surgical experience with a microscopic transsphenoidal approach to pituitary tumors and non-neoplastic parasellar conditions.

Improved surgical microscopes and intraoperative radiofluoroscopic television have revived the transsphenoidal approach to pituitary tumors. The transsphenoidal approach offers an alternative to craniotomy, and in certain situations it has distinct advantages. The reported experience includes the common pituitary tumors, hypersecreting microadenomas, cerebrospinal rhinorrhea and parasellar aneurysms. The surgical technique, indications and contraindications, and results in 44 transsphenoidal operations are described.