In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

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The aim of this study was to perform a national survey on occasionally discovered adrenal masses [adrenal incidentalomas (AI)] under the auspices of the Italian Society of Endocrinology. This multicentric and retrospective evaluation of patients with AI includes 1096 cases collected in 26 centers between 1980 and 1995. Relevant information was obtained by means of a specifically tailored questionnaire. Of the 1096 forms received, 1004 were retained for final analysis. Patients were 420 males and 584 females, aged between 15-86 yr (median, 58 yr). Mass size (computed tomography measurement) ranged from 0.5-25 cm (median, 3.0 cm). Hormonal work-up demonstrated that 85% of the masses were nonhypersecretory, 9.2% were defined as subclinical Cushing's syndrome, 4.2% were pheochromocytomas, and 1.6% were aldosteronomas. Adrenalectomy was performed in 380 patients with removal of 198 cortical adenomas (52%), 47 cortical carcinomas (12%), 42 pheochromocytomas (11%), and other less frequent tumor types. Patients with carcinoma were significantly younger than patients with adenoma (median, 46; range, 17-84; vs. 57, 16-83 yr; P = 0.05). Adenomas were significantly smaller than carcinomas (3.5, 1-15 vs. 7.5, 2.6-25 cm; P < 0.001), and a cut-off at 4.0 cm had the highest sensitivity (93%) in differentiating between benign and malignant tumors. Hormonal work-up of patients with subclinical Cushing's syndrome showed low baseline ACTH in 79%, cortisol unsuppressibility after 1 mg dexamethasone in 73%, above normal urinary free cortisol in 75%, disturbed cortisol rhythm in 43%, and blunted ACTH response to CRH in 55%. Only 43% of patients with pheochromocytoma were hypertensive, and 86% showed elevated urinary catecholamines. All patients with aldosteronoma were hypertensive and had suppressed upright PRA. These results indicate that mass size is the most reliable variable in separating benign from malignant AI. Adrenalectomy should be recommended for AI greater than 4.0 cm because of the increased risk of malignancy, especially in young patients. Endocrine evaluation should be performed in all patients to identify silent states of hormone excess.

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Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations O14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.

To investigate the activity of etoposide, doxorubicin, and cisplatin plus mitotane in the management of advanced adrenocortical carcinoma (ACC) patients, 72 patients with measurable disease not amenable to radical surgery were enrolled in a prospective, multicenter phase II trial. EDP schedule (etoposide 100 mg/m 2 on days 5-7, doxorubicin 20 mg/m 2 on days 1 and 8, and cisplatin 40 mg/m 2 on days 1 and 9) was administered intravenously every 4 weeks. Concomitantly, patients were given up to 4 g/day of oral mitotane. Five patients achieved a complete response and 30 a partial response, for an overall response rate of 48.6% (95% CI: 37

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