Paul A. Fitzgerald

An Overnight High-Dose Dexamethasone Suppression Test for Rapid Differential Diagnosis of Cushing's Syndrome

We have developed a high-dose dexamethasone suppression test that can be administered overnight with a single 8-mg dose and used the new procedure in the differential diagnosis of 83 patients with Cushings syndrome. In 76 patients with surgically or pathologically proven cause--60 with Cushings disease, 7 with the ectopic adrenocorticotrophic hormone syndrome, and 9 with adrenal tumors--suppression of plasma cortisol levels to less than 50% of baseline indicated a diagnosis of Cushings disease. The test had a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%. These values equal or exceed those of the standard 2-day test whether based on suppression of urinary 17-hydroxycorticosteroids or plasma cortisol. We conclude that this overnight, high-dose dexamethasone suppression test is practical and reliable in the differential diagnosis of Cushings syndrome.

Selective Venous Sampling for ACTH in Cushing's Syndrome: Differentiation Between Cushing's Disease and the Ectopic ACTH Syndrome

We performed selective venous catheterization and sampling for ACTH in six patients with ACTH-secreting pituitary adenomas (Cushings disease) and four patients with occult ectopic ACTH-secreting neoplasms. In five patients with Cushings disease in whom the inferior petrosal sinus could be catheterized, ACTH levels were unequivocally higher than simultaneous peripheral values: The ratio was greater than 2.0, with a range of 2.2 to 16.7. In contrast, the inferior petrosal sinus-to-peripheral ACTH ratio in three patients with ectopic ACTH secretion was less than 1.5. In the fourth patient, an arteriovenous gradient of 6.8 was shown 2 years before a bronchial carcinoid tumor was clinically apparent. Central-to-peripheral ACTH ratios at the level of the jugular bulb and jugular vein were not diagnostic. We conclude that selective venous ACTH sampling from the inferior petrosal sinus is a reliable and useful aid in the differential diagnosis of Cushings syndrome when standard clinical and biochemical studies are inconclusive.

Phase II Study of High-Dose [131I]Metaiodobenzylguanidine Therapy for Patients With Metastatic Pheochromocytoma and Paraganglioma

PURPOSE To evaluate the safety and efficacy of high-dose [(131)I]metaiodobenzylguanidine ([(131)I]MIBG) in the treatment of malignant pheochromocytoma (PHEO) and paraganglioma (PGL). METHODS Fifty patients with metastatic PHEO or PGL, age 10 to 64 years, were treated with [(131)I]MIBG doses ranging from 492 to 1,160 mCi (median, 12 mCi/kg). Cumulative [(131)I]MIBG administered ranged from 492 to 3,191 mCi. Autologous hematopoietic stem cells were collected and cryopreserved before treatment with [(131)I]MIBG greater than 12 mCi/kg or with a total dose greater than 500 mCi. Sixty-nine [(131)I]MIBG infusions were given, which included infusions to 35 patients treated once and infusions to 15 patients who received two or three treatments. Response was evaluated by [(123)I]MIBG scans, computed tomography/magnetic resonance imaging, urinary catecholamines/metanephrines, and chromogranin A. RESULTS The overall complete response (CR) plus partial response (PR) rate in 49 evaluable patients was 22%. Additionally, 35% of patients achieved a CR or PR in at least one measure of response without progressive disease, and 8% of patients maintained stable disease for greater than 12 months. Thirty-five percent of patients experienced progressive disease within 1 year after therapy. The estimated 5-year overall survival rate was 64%. Toxicities included grades 3 to 4 neutropenia (87%) and thrombocytopenia (83%). Grades 3 to 4 nonhematologic toxicity included acute respiratory distress syndrome (n = 2), bronchiolitis obliterans organizing pneumonia (n = 2), pulmonary embolism (n = 1), fever with neutropenia (n = 7), acute hypertension (n = 10), infection (n = 2), myelodysplastic syndrome (n = 2), and hypogonadism (n = 4). CONCLUSION Although serious toxicity may occur, the survival and response rates achieved with high-dose [(131)I]MIBG suggest its utility in the management of selected patients with metastatic PHEO and PGL.

Cushing's syndrome: Problems in diagnosis

Cushings syndrome, an unusual group of disorders characterized by hypercortisolism, must be considered in the differential diagnosis of such common clinical problems as hirsutism, menstrual irregularity, hypertension, diabetes mellitus, and obesity. Its distinct forms--pituitary-dependent Cushings syndrome (Cushings disease), adrenal tumor and ectopic ACTH syndrome--must be identified correctly so that specific therapy can be administered. In the majority of cases, use of a relatively simple diagnostic sequence will provide accurate and rapid diagnosis. However, in our experience with more than 60 patients, diagnostic difficulties may arise from a variety of conditions (e.g., drug interference, alcohol ingestion, and depression). In addition, unusual circumstances, such as unexpected responses to dexamethasone, may complicate the diagnosis. Our approach to these problems is illustrated through a report of seven cases, and we emphasize that the proper management of Cushings syndrome mandates a thorough marshalling of all the available data.

Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG).

Abstract:  Thirty patients with malignant pheochromocytoma (PHEO) or paraganglioma (PGL) were treated with high‐dose 131I‐MIBG. Pa tients were 11–62 (mean 39) years old: 19 patients males and 11 females. Nineteen patients had PGL, three of which were multifocal. Six PGLs were nonsecretory. Eleven patients had PHEO. All 30 patients had prior surgery. Fourteen patients were refractory to prior radiation or chemotherapy before 131I‐MIBG. Peripheral blood stem cells (PBSCs) were collected and cryopreserved. 131I‐MIBG was synthesized on‐site, by exchange‐labeling 131I with 127I‐MIBG in a solid‐phase Cu2+‐catalyzed exchange reaction. 131I‐MIBG was infused over 2 h via a peripheral IV. Doses ranged from 557 mCi to 1185 mCi (7.4 mCi/kg to 18.75 mCi/kg). Median dose was 833 mCi (12.55 mCi/kg). Marrow hypoplasia commenced 3 weeks after 131I‐MIBG therapy. After the first 131I‐MIBG therapy, 19 patients required platelet transfusions; 19 received GCSF; 12 received epoeitin or RBCs. Four patients received a PBSC infusion. High‐dose 131I‐MIBG resulted in the following overall tumor responses in 30 patients: 4 sustained complete remissions (CRs); 15 sustained partial remissions (PRs); 1 sustained stable disease (SD); 5 progressive disease (PD); 5 initial PRs or SD but relapsed to PD. Twenty‐three of the 30 patients remain alive; deaths were from PD (5), myelodysplasia (1), and unrelated cause (1). Overall predicted survival at 5 years is 75% (Kaplan Meier estimate). For patients with metastatic PHEO or PGL, who have good *I‐MIBG uptake on diagnostic scanning, high‐dose 131I‐MIBG therapy was effective in producing a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.

Pituitary ACTH dependency of nodular adrenal hyperplasia in Cushing's syndrome: Report of two cases and review of the literature

Cushings syndrome due to nodular adrenal hyperplasia comprises a clinically and biochemically heterogeneous group of disorders whose pathogenesis is unclear. We describe two patients with atypical steroid dynamics and large unilateral adrenal nodules who had pituitary ACTH-dependent disease. In the differential diagnosis of Cushings syndrome, we recommend repeated ACTH measurement and selective venous sampling-particularly in those patients with impaired dexamethasone suppressibility and abnormal findings on computerized tomography.

Cushing’s Syndrome due to Bilateral Adrenal Macronodular Hyperplasia with Undetectable ACTH: Cell Culture of Adenoma Cells on Extracellular Matrix

A 59-year-old man developed Cushings syndrome with massive bilateral adrenal macronodular hyperplasia. Plasma ACTH levels were undetectable both peripherally and in the inferior petrosal sinus. Computed tomography scans of his pituitary were normal. Hypercortisolism was not suppressed by high doses of dexamethasone. His adrenal cells were successfully isolated and grown on bovine corneal extracellular matrix. The cultured cells displayed strikingly rapid growth and hypersecretion of cortisol during incubation with control serum. Addition of the patients serum to cultured fetal adrenal cells did not accelerate their growth. This was the first experience with our in vitro system in this rare clinical condition. The techniques described here may be used for future in vitro adrenal studies. These in vivo and in vitro data indicate that this patients bilateral adrenal hyperfunction and growth were independent of ACTH.

Thyroid and hepatic function after high-dose 131I-metaiodobenzylguanidine (131I-MIBG) therapy for neuroblastoma†

131I‐Metaiodobenzylguanidine (131I‐MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and 131I‐MIBG is concentrated in the liver after 131I‐MIBG therapy. The aim of our study was to analyze the effects of 131I‐MIBG therapy on thyroid and liver function.

Fungal Infections in Cushing's Syndrome

Excerpt To the editor: We read with interest the report by Anthony and Greco (1) and describe another, more frequent infectious complication of spontaneous Cushings syndrome. We have observed that...

Cushing's disease revisited.

Harvey Cushing [I] presented and subsequently published his extraordinary study of basophilic pituitary adenomas in 1932. Validation of these observations followed long after his death through the fortunate coincidence of two developments: first, conclusive biochemical definition of pituitary-based hypercortisolism, for the first time differentiating this distinct clinical entity from other causes of hypercortisolism [2,3], and second, the evolution of transsphenoidal microsurgery not only providing an effective means of treating the disease but also permitting unequivocal documentation of ACTH-secreting microadenomas as a distinct entity [4]. Because it is now possible, in one simultaneous maneuver, to detect and remove minute adenomas situated in a pituitary gland of normal dimensions, the management of Cushing’s disease has undergone a revolutionary change. Until a superior form of treatment evolves, microsurgical removal of these remarkably occult adenomas offers the highest probability of restoring normal pituitary function to patients affected with the disease. The endocrinologic data from our initial series of patients were reported earlier [5]. When presented with a patient with Cushing’s disease, the surgeon can assume that the pituitary gland contains an ACTH-secreting adenoma. In a series of 44 intrasellar explorations in patients with Cushing’s disease, an adenoma was removed in every case. Three tumors, the smallest in the series, were missed at exploration and identified subsequently in serial sections of the excised glands. Microadenomas (diameter less than 10 mm) constituted the majority of adenomas.