Use of a topoisomerase I inhibitor (irinotecan, CPT-11) in metastatic adrenocortical carcinoma.
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BACKGROUND: Complete responses are rare after medical treatment of adrenocortical tumors. We performed a single center prospective study of the antitumor effect of irinotecan (CPT-11) in patients with metastatic adrenocortical cancer. PATIENTS AND METHODS: Since 1999, all patients with advanced progressive adrenocortical carcinoma, referred to the Institut Gustave-Roussy, have been enrolled prospectively in this study. CPT-11 (250 mg/m(2)) was administered intravenously on day 1 in a 2-h infusion, every 14 days. World Health Organization (WHO) criteria were used to evaluate tumor response and toxicity. RESULTS: During treatment, no dose or schedule modifications were made. A median of three courses were given (range 1-8), and all but two patients received at least three complete chemotherapy courses. No objective or complete responses were observed. The best response achieved was stabilization in three patients, lasting from 1.5 to 4 months. Significant toxicity occurred in two patients. CONCLUSIONS: Our results do not support a major role of CPT-11 in adrenocortical carcinoma. (+info)
Protein phosphatase 2A and phosphoprotein SET regulate androgen production by P450c17.
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Cytochrome P450c17 catalyzes 17 alpha-hydroxylation needed for cortisol synthesis and 17,20 lyase activity needed to produce sex steroids. Serine phosphorylation of P450c17 specifically increases 17,20 lyase activity, but the physiological factors regulating this effect remain unknown. Treating human adrenal NCI-H295A cells with the phosphatase inhibitors okadaic acid, fostriecin, and cantharidin increased 17,20 lyase activity, suggesting involvement of protein phosphatase 2A (PP2A) or 4 (PP4). PP2A but not PP4 inhibited 17,20 lyase activity in microsomes from cultured cells, but neither affected 17 alpha-hydroxylation. Inhibition of 17,20 lyase activity by PP2A was concentration-dependent, could be inhibited by okadaic acid, and was restored by endogenous protein kinases. PP2A but not PP4 coimmunoprecipitated with P450c17, and suppression of PP2A by small interfering RNA increased 17,20 lyase activity. Phosphoprotein SET found in adrenals inhibited PP2A, but not PP4, and fostered 17,20 lyase activity. The identification of PP2A and SET as post-translational regulators of androgen biosynthesis suggests potential additional mechanisms contributing to adrenarche and hyperandrogenic disorders such as polycystic ovary syndrome. (+info)
Dietary sodium restriction restores nocturnal reduction of blood pressure in patients with primary aldosteronism.
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The purpose of this study was to elucidate the effects of dietary sodium restriction on diurnal blood pressure (BP) variation in primary aldosteronism. We studied the diurnal variation in the systemic hemodynamic indices and in baroreflex sensitivity (BRS). In 13 subjects with aldosterone-producing adenomas (2 males; mean age, 39+/-2 years), intra-arterial pressure was monitored telemetrically on a normal salt diet (NaCl 10-12 g/day). Non-dippers were defined as those with a nocturnal reduction in systolic BP (SBP) of less than 10% of daytime SBP. Ten subjects showed a non-dipper pattern. Six of these "non-dippers" underwent repetitive hemodynamic studies on the last day of a 1-week low salt diet regimen (NaCl 2-4 g/day). Stroke volume was determined using Wesseling's pulse contour method, calibrated with indocyanine green dilution. BRS was calculated every 30 min as delta pulse interval/delta SBP on spontaneous variations. Nocturnal reduction of SBP was 4.1% on the normal salt diet. With sodium restriction, urinary sodium excretion decreased from 187+/-8 to 46+/-8 mmol/day, and body weight decreased from 57.9+/-2.1 to 56.6+/-1.9 kg. Night-time BP significantly decreased with dietary modification from 154+/-7/88+/-4 to 140+/-6/78+/-4 mmHg, whereas daytime BP was unaltered. With sodium restriction, cardiac index and stroke index decreased throughout the day. No significant difference was seen in either daytime or nighttime BRS between the two diets. We conclude that the non-dipper pattern is common in patients with an aldosterone-producing adenoma on a normal salt intake, and under such conditions, volume expansion appears to play a major role in the impairment of nocturnal BP reduction. (+info)
Comparison of thyroid transcription factor-1 and hepatocyte antigen immunohistochemical analysis in the differential diagnosis of hepatocellular carcinoma, metastatic adenocarcinoma, renal cell carcinoma, and adrenal cortical carcinoma.
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We compared the effectiveness of thyroid transcription factor-1 (TTF-1, cytoplasmic reactivity) and hepatocyte antigen (HPA) as markers for characterization of hepatocellular carcinoma (HCC) and as discriminators to distinguish HCC from its histologic and cytologic mimics. Formalin-fixed, paraffin-embedded sections of 258 specimens, including 76 HCCs, 85 metastatic adenocarcinomas, 75 renal cell carcinomas (RCCs), and 22 adrenal cortical carcinomas (ACCs), were evaluated. Specimens included tissue sections and cytologic material (cell blocks). Following heat-induced epitope retrieval, immunohistochemical studies were performed using an indirect immunoperoxidase technique. Cytoplasmic reactivity for TTF-1 was noted for 54 (71%) of 76 HCCs, 3 (4%) of 85 adenocarcinomas, none of 72 RCCs, and none of 22 ACCs. Cytoplasmic reactivity for HPA was observedfor 50 (66%) of 76 HCCs, 1 (1%) of 83 adenocarcinomas, none of 74 RCCs, and none of 21 ACCs. Cytoplasmic reactivity for TTF-1 and HPA is highly specific for HCC, although a minority of HCCs, particularly poorly differentiated tumors, may be nonreactive. Thus, these markers are usefulfor the characterization of HCC in tissue sections and cell blocks and are highly effective for distinguishing these tumors from other neoplasms included in the differential diagnosis. (+info)
p53 as a prognostic factor in adrenocortical tumors of adults and children.
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Mutations of the tumor suppressor gene p53 have been considered to be important determinants in several kinds of human cancer. Accumulation of p53 protein has been reported to correlate with more aggressive clinical behavior in some neoplasms. The role of p53 expression in adrenal cortical tumors (ACT) has not been elucidated but some studies have suggested its correlation with malignant behavior. Our objective was to determine if there is a correlation between the expression of immunoreactive p53 and the biological behavior of ACT. Fifty-seven ACT (21 from children and 36 from adults) were evaluated for p53 expression by immunohistochemistry in formalin-fixed paraffin-embedded tissue and analyzed in terms of outcome. The p53 parameter was utilized semiquantitatively. Tumors were classified as p53 negative when no positivity was observed, or when only few cells showed weak positivity (0/1+) and scored as p53 positive when there was a diffuse and strong nuclear positivity (2+/3+). In children, p53 positivity was associated with clinically malignant ACT and p53 negativity was associated with clinically benign ACT (P = 0.026). In adults' ACT, p53 positivity had an effect on disease-free survival (P<0.001) and also correlated with Weiss score, with a cutoff = 4 (P = 0.04). p53 expression was related to the clinical behavior of ACT in both children and adults and these findings seem to support a role for p53 in ACT progression. (+info)
Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis.
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Comprehensive expression profiling of tumors using DNA microarrays has been used recently for molecular classification and biomarker discovery, as well as a tool to identify and investigate genes involved in tumorigenesis. Application of this approach to a cohort of benign and malignant adrenocortical tissues would be potentially informative in all of these aspects. In this study, we generated transcriptional profiles of 11 adrenocortical carcinomas (ACCs), 4 adrenocortical adenomas (ACAs), 3 normal adrenal cortices (NCs), and 1 macronodular hyperplasia (MNH) using Affymetrix HG_U95Av2 oligonucleotide arrays representing approximately 10,500 unique genes. The expression data set was used for unsupervised hierarchical cluster analysis as well as principal component analysis to visually represent the expression data. An analysis of variance on the three classes (NC, ACA plus MNH, and ACC) revealed 91 genes that displayed at least threefold differential expression between the ACC cohort and both the NC and ACA cohorts at a significance level of P < 0.01. Included in these 91 genes were those known to be up-regulated in adrenocortical tumors, such as insulin-like growth factor (IGF2), as well as novel differentially expressed genes such as osteopontin (SPP) and serine threonine kinase 15 (STK15). Increased expression of IGF2 was identified in 10 of 11 ACCs (90.9%) and was verified by quantitative reverse transcriptase-polymerase chain reaction. Select proliferation-related genes (TOP2A and Ki-67) were validated at the protein level using immunohistochemistry and adrenocortical tissue microarrays. Our results demonstrated significant and consistent gene expression changes in ACCs compared to benign adrenocortical lesions. Moreover, we identified several genes that represent potential diagnostic markers and may play a role in the pathogenesis of ACC. (+info)
Conn's syndrome associated with Behcet's disease.
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A 39-yr-old woman, who had been treated for Behcet's disease for 4 yr, was admitted for further investigation of recently identified hypokalemia and hypertension. Suppressed plasma renin activity with elevated plasma aldosterone concentration and an anomalous postural decrease in plasma aldosterone were observed. An abdominal CT scan revealed a right adrenal mass. The patient was diagnosed with Conn's syndrome. The association of Conn's syndrome with Behcet's disease was thought to be coincidental. To our knowledge, this is the first case of Conn's syndrome associated with Behcet's disease. (+info)
Anthropometric, haemodynamic, humoral and hormonal evaluation in patients with incidental adrenocortical adenomas before and after surgery.
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OBJECTIVE: To compare clinical and humoral parameters before and after surgery in patients with incidental adrenocortical adenomas. DESIGN: Six patients with subclinical Cushing's syndrome and nine with non-functioning adenomas were investigated before and 12 Months after removal of the mass. METHODS: Anthropometric (body weight, body mass index and waist to hip ratio), haemodynamic (blood pressure and heart rate), metabolic (lipids and oral glucose tolerance test (OGTT)), hormonal (cortisol, plasma renin activity, aldosterone, androgens and catecholamines) and bone metabolism (hydroxyproline, parathyroid hormone, osteocalcin and ostase) parameters were evaluated. RESULTS: In the whole group, a significant decrease in body weight (69.7+/-3.5 vs 70.8+/-3.5 kg, P<0.03), in systolic (135.3+/-5.1 vs 145.6+/-4.9 mmHg, P<0.009) and diastolic (83.7+/-1.9 vs 91.0+/-3.5 mmHg, P<0.03) blood pressure and in glucose levels in response to OGTT (106.4+/-9.6 vs 127.5+/-6.5 mg/dl, P<0.05) was observed after surgery. All other parameters examined did not change significantly. This trend was also found in both groups separately. Analytical data showed a high frequency of overweight/obesity (66.6%), hypertension (66.6%) and impaired glucose profile (26.6%) in our patients, with a greater prevalence of these cardiovascular risk factors in the subclinical Cushing's syndrome group. After surgery, values normalized or improved in eight out of ten hypertensive patients and in three out of four patients with impaired glucose profile. CONCLUSIONS: Solid adrenocortical incidentalomas are associated with some cardiovascular risk factors which may be corrected after removal of the mass. Therefore, surgery may be an appropriate choice in patients with subclinical Cushing's syndrome but also in those with solid non-functioning adenomas and coexistent cardiovascular risk factors. (+info)