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Xavier Bertagna

Publications and source records attributed to Xavier Bertagna.

At least 19 recordsLinked to original sources
PubMed2026

Genomic characterization of aggressiveness in pituitary neuroendocrine tumors.

BACKGROUND: Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS: PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS: Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION: This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Humans↗
PubMed2006

Prognostic parameters of metastatic adrenocortical carcinoma.

CONTEXT: Prognostic parameters of metastatic adrenocortical carcinoma (ACC) are poorly characterized. OBJECTIVE: The objective of the study was to describe the clinical presentation of metastatic ACC and determine prognostic factors for survival. DESIGN: This was a retrospective cohort study (1988-2004). SETTING: The study was conducted in an institutional practice. PATIENTS: Participants included 124 consecutive patients with metastatic ACC, 70 from Gustave-Roussy Institute (main cohort) and 54 patients from the Cochin Hospital (validation cohort). Clinical data concerning all patients, histopathologic slides of primary tumors (44 in the main cohort and 40 in the validation cohort), and molecular biology data on 15 primary tumors (main cohort) were analyzed. INTERVENTION: There was no intervention. MAIN OUTCOME: The main outcome was the specific survival after discovery of the first metastasis (Kaplan-Meier method). This included univariate analysis on the main cohort, confirmed on the validation cohort and then analyzed in a multivariate analysis. RESULTS: In the main cohort, overall median survival was 20 months. In univariate analysis, the presence of hepatic and bone metastases, the number of metastatic lesions and the number of tumoral organs at the time of the first metastasis, a high mitotic rate (>20 per 50 high-power field), and atypical mitoses in the primary tumor predicted survival (P = 0.05, 0.003, 0.046, 0.001, 0.01, and < 0.001, respectively). The number of tumoral organs and a high mitotic rate were confirmed on the validation cohort (P = 0.009 and 0.03, respectively). These two parameters were confirmed in multivariate analysis (P = 0.0058 and 0.049). CONCLUSION: Metastatic ACC is a heterogeneous disease with poor outcome. The combination of the number of tumoral organs at the time of the first metastasis and the mitotic rate can predict different outcomes.

Adolescent↗
PubMed2006

Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome.

CONTEXT: Adrenalectomy is a radical treatment for hypercortisolism in Cushing's disease. However, it may lead to Nelson's syndrome, originally defined by the association of a pituitary macroadenoma and high plasma ACTH concentrations, a much feared complication. OBJECTIVE: The objective of the study was to reconsider Nelson's syndrome by investigating corticotroph tumor progression based on pituitary magnetic resonance imaging scan and search for predictive factors. DESIGN: This was a retrospective cohort study. SETTING: The complete medical records of Cushing's disease patients at Cochin Hospital were studied. PATIENTS: Patients included 53 Cushing's disease patients treated by adrenalectomy between 1991 and 2002, without previous pituitary irradiation. MEASUREMENTS: Clinical data, pituitary magnetic resonance imaging data, and plasma ACTH concentrations for all patients and pituitary gland pathology data for 25 patients were recorded. Corticotroph tumor progression-free survival was studied by Kaplan-Meier, and the influence of recorded parameters was studied by Cox regression. INTERVENTION: There was no intervention. RESULTS: Corticotroph tumor progression ultimately occurred in half the patients, generally within 3 yr after adrenalectomy. A shorter duration of Cushing's disease (adjusted hazard ratio: 0.884/yr), and a high plasma ACTH concentration in the year after adrenalectomy [adjusted hazard ratio per 100 pg/ml (22 pmol/liter): 1.069] were predictive of corticotroph tumor progression. In one case, corticotroph tumor progression was complicated by transitory oculomotor nerve palsy. During follow-up, corticotroph tumor progression was associated with the increase of corresponding ACTH concentrations (odds ratio per 100 pg/ml of ACTH variation: 1.055). CONCLUSION: After adrenalectomy in Cushing's disease, one should no longer wait for the occurrence of Nelson's syndrome: modern imaging allows early detection and management of corticotroph tumor progression.

Adolescent↗
PubMed2006

Reversal of glucocorticoids-dependent proopiomelanocortin gene inhibition by leukemia inhibitory factor.

We previously have described molecular mechanisms converging at the Nur response element-signal transducer and activator of transcription (STAT) composite site responsible for synergistic activation of the proopiomelanocortin (POMC) gene promoter by leukemia inhibitory factor (LIF) and CRH. In this study, we asked how glucocorticoids (GC), the physiological negative regulators of POMC gene expression, modulate this synergism. In the corticotroph cell line AtT-20, the response of the wild-type promoter to LIF+CRH was barely inhibited by GC, whereas a distal promoter subregion (-414/-293) encompassing the Nur response element-STAT site and devoid of the negative GC-responsive element located in the proximal domain, displayed a cooperative response to LIF+dexamethasone (DEX) and LIF+CRH+DEX treatments. LIF+CRH-stimulated ACTH secretion was also inefficiently inhibited by DEX in the same cell line. This study was focused thereafter on LIF+DEX cooperativity, which may be responsible, on the wild-type promoter, for lack of negative regulation by DEX of the LIF+CRH synergy. The STAT1-3 low-affinity site, in the context of the (-414/-293) subregion of the POMC promoter, was found necessary and sufficient for transcriptional synergism between activated GC receptor (GR) and STAT1-3. Moreover the activities of reporters specific for STAT1-3 or GR were reciprocally enhanced by DEX or LIF. Single and sequential chromatin immunoprecipitations revealed 1) a STAT-dependent corecruitment of coactivators after LIF and LIF+DEX stimulation and 2) a more lasting recruitment of both STAT3 and GR in the same enhanceosome on the endogenous POMC promoter after LIF+DEX joint stimulation than after the single one. Such events may be responsible for a lack of repressive property of GR unmasked on the whole POMC promoter during LIF+CRH stimulation and may contribute to the tonicity of the hypothalamic-pituitary-adrenal axis during inflammatory-infectious diseases.

Adrenocorticotropic Hormone↗
PubMed2006

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2006

Cushing's syndrome.

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.

Adrenocorticotropic Hormone↗
PubMed2006

Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients.

CONTEXT: Adrenocortical carcinomas (ACC) are rare tumors with a poor prognosis. Few reports concerning large and homogeneous series are available. OBJECTIVE: We aimed to determine the clinical characteristics and outcome of ACC and to identify prognostic factors. DESIGN AND SETTING: This study is a descriptive and multivariate analysis of a cohort from a single endocrinology center. PATIENTS: A total of 202 consecutive patients with ACC were studied. RESULTS: The sex ratio (female to male) was 2.7. Mean age at diagnosis was 44 +/- 16 yr (range, 11-88 yr). We found that 154 patients (76%) had hypersecreting tumors [mostly cortisol and androgens (47%), cortisol alone (27%), or androgens alone (6%)] and 43 patients (21%) had metastases at diagnosis. At initial staging or during follow-up, 85 patients (42%) had liver metastases, 79 patients (39%) had lung metastases, and 20 patients had bone metastases (10%). The survival rate was 37% at 5 yr. Multivariate analysis identified the following independent prognostic factors associated with shorter survival: older age at diagnosis [hazard ratio (HR), 1.03; P < 0.0001], initial MacFarlane extension stages 3 (HR, 4.42; P = 0.005) and 4 (HR, 7.93; P < 0.0001), and cortisol hypersecretion (HR, 3.90; P < 0.0001). Treatment with 1,1-dichlorodiphenildichloroethane (o,p'DDD) in the 3 months after surgery increased the survival rate of patients with cortisol-secreting tumors (HR, 0.40; P = 0.04). CONCLUSION: This study highlights the better prognosis of ACC diagnosed at a noninvasive local stage, the particularly poor prognosis of patients with cortisol-secreting tumors, and the beneficial effect of o,p'DDD therapy in this subgroup of patients.

Adrenal Cortex Neoplasms↗
PubMed2006

A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome, can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas, and endocrine tumors or be isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC and iPPNAD, but with no apparent genotype-phenotype correlation. OBJECTIVE: The objectives of the study were a detailed phenotyping for CNC manifestations in 12 kindreds bearing the same PRKAR1A mutation and a study of the consequences of the mutation and a potential founder effect. DESIGN: The study consisted of descriptive case reports. SETTING: The study was conducted at two referral centers. PATIENTS: The patients described in this study were referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently iPPNAD. RESULTS: We describe a 6-bp polypyrimidine tract deletion [exon 7 IVS del (-7-->-2)] in 12 unrelated kindreds that were referred for Cushing syndrome due to PPNAD. Nine of the patients had no family history; in two, there was a family history of iPPNAD. Only one patient met the criteria for CNC. Relatives carrying the same mutation had no manifestations of CNC or PPNAD, suggesting a low penetrance of this PRKAR1A defect. A founder effect was excluded by extensive genotyping of chromosome 17 markers. CONCLUSIONS: In conclusion, a small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly iPPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.

Adolescent↗
PubMed2006

Reduced myocardial contractility assessed by tissue Doppler echocardiography is associated with increased risk during adrenal surgery of patients with pheochromocytoma: report of a preliminary study.

BACKGROUND: Depressed myocardial contractility, although rarely reported in pheochromocytoma, might be underestimated. It may be a determinant of perioperative risk during adrenal surgery. METHODS: We prospectively studied consecutive patients with pheochromocytoma; myocardial function examined by standard and tissue Doppler echocardiography was compared with matched control subjects. The incidence of hemodynamic collapse during adrenal surgery was measured. RESULTS: A total of 15 patients were included (8 men, 46 [17] years, hypertension in 10). All but one had a normal left ventricular ejection fraction. However, compared with control subjects, they had a depressed systolic strain rate (SR) (1.8 [2.1] vs 4.1 [2.2] s(-1), P = .007). Furthermore, 6 of 8 patients with systolic SR less than 2 s(-1) experienced intraoperative collapse, versus 1 of 7 with SR greater than 2 s(-1) (P = .041). No association was observed with other variables. CONCLUSIONS: Patients with pheochromocytoma may have depressed myocardial contractility detected by tissue Doppler echocardiography despite a normal standard echocardiogram. A systolic SR less than 2 s(-1) was associated with an increased risk of perioperative collapse.

Adrenal Gland Neoplasms↗
PubMed2006

Mechanisms of disease: adrenocortical tumors--molecular advances and clinical perspectives.

Most adrenocortical tumors are benign, unilateral, adrenocortical adenomas that are often discovered incidentally. Adrenocortical cancer is rare. Exceptionally, adrenocortical tumors can be bilateral. Although most adrenocortical tumors occur sporadically, they may also feature in congenital and/or familial disease. The identification of germline genetic defects in familial diseases associated with adrenocortical tumors helped to define the somatic alterations in sporadic disease: for example, overexpression of insulin-like growth factor 2 and alterations at the 11p15 locus (observed in Beckwith-Wiedemann syndrome) are also found in most adrenocortical cancers. Similarly, inactivating mutations of the TP53 gene, located at 17p13 (observed in Li-Fraumeni syndrome), can also be found at the somatic level in sporadic adrenocortical cancers, as can 17p13 allelic losses. Components of the cyclic AMP signaling pathway--for example, adrenocorticotropic hormone receptors and other membrane receptors, Gs proteins and protein kinase A--can be altered to various degrees in adrenocortical tumors. More recently, gene profiling and genetic studies have shown that the Wnt-beta-catenin signaling pathway is frequently activated in adrenocortical tumors. These research findings already have profound implications for clinical management of patients with adrenocortical tumors, for example in unraveling the genetic origin of the disease in some patients, and in the development of molecular markers for diagnosis and prognosis. The new findings should also help in the development of new therapeutic options.

Adrenal Cortex Neoplasms↗
PubMed2006

Continuation of amiodarone therapy despite type II amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone is a powerful antiarrhythmic drug; however, its use may be complicated by thyrotoxicosis. When this occurs, clinicians must balance the continuation of amiodarone for antiarrhythmic purposes, and the discontinuation of treatment in order to prevent aggravation of the thyrotoxicosis. We studied the consequences of continuation or cessation of amiodarone in patients with type II amiodarone-induced thyrotoxicosis. METHODS: Consecutive patients who developed type II amiodarone-induced thyrotoxicosis between September 1997 and September 2000 were studied. Amiodarone was continued in patients with previous ventricular arrhythmia or supraventricular arrhythmia associated with severe haemodynamic changes and was withdrawn in the other patients. In patients with persistent, severe symptomatic thyrotoxicosis, corticosteroids were added to therapy. RESULTS: Thirteen patients were studied (nine with previous atrial fibrillation/flutter and four with ventricular tachycardia). Amiodarone treatment was continued in ten patients, including eight patients who received corticosteroids, and was temporarily halted in three patients. All patients recovered, with no difference in the duration of thyrotoxicosis between the two groups. Corticosteroid treatment was well tolerated and seemed to hasten the return to a euthyroid state (mean of 3.7 +/- 0.7 months vs 6.3 +/- 1.7 months). No recurrence of hyperthyroidism occurred during long-term follow-up. CONCLUSION: In patients who require amiodarone, treatment may be safely continued despite the development of type II amiodarone-induced thyrotoxicosis.

Adolescent↗
PubMed2005

Genetic testing in pheochromocytoma or functional paraganglioma.

PURPOSE: To assess the yield and the clinical value of systematic screening of susceptibility genes for patients with pheochromocytoma (pheo) or functional paraganglioma (pgl). PATIENTS AND METHODS: We studied 314 patients with a pheo or a functional pgl, including 56 patients having a family history and/or a syndromic presentation and 258 patients having an apparently sporadic presentation. Clinical data and blood samples were collected, and all five major pheo-pgl susceptibility genes (RET, VHL, SDHB, SDHD, and SDHC) were screened. Neurofibromatosis type 1 was diagnosed from phenotypic criteria. RESULTS: We have identified 86 patients (27.4%) with a hereditary tumor. Among the 56 patients with a family/syndromic presentation, 13 have had neurofibromatosis type 1, and germline mutations on the VHL, RET, SDHD, and SDHB genes were present in 16, 15, nine, and three patients, respectively. Among the 258 patients with an apparently sporadic presentation, 30 (11.6%) had a germline mutation (18 patients on SDHB, nine patients on VHL, two patients on SDHD, and one patient on RET). Mutation carriers were younger and more frequently had bilateral or extra-adrenal tumors. In patients with an SDHB mutation, the tumors were larger, more frequently extra-adrenal, and malignant. CONCLUSION: Genetic testing oriented by family/sporadic presentation should be proposed to all patients with pheo or functional pgl. We suggest an algorithm that would allow the confirmation of suspected inherited disease as well as the diagnosis of unexpected inherited disease.

Adolescent↗
PubMed2005

Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors.

Adrenocortical cancer is a rare cancer with a very poor prognosis. The genetic alterations identified to date in adrenocortical tumors are limited. Activating mutations of the Wnt signaling pathway have been observed in more frequent cancers, particularly digestive tract tumors. We investigated whether Wnt pathway activation is involved in adrenocortical tumorigenesis. In a series of 39 adrenocortical tumors, immunohistochemistry revealed abnormal cytoplasmic and/or nuclear accumulation of beta-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the beta-catenin gene was shown in 7 of 26 adrenocortical adenomas and in 4 of 13 adrenocortical carcinomas; these mutations were observed only in adrenocortical tumors with abnormal beta-catenin accumulation and most were point mutations altering the Ser45 of exon 3 (in the consensus GSK3-beta/CK1 phosphorylation site). Functional studies showed that the activating Ser45 beta-catenin mutation found in the adrenocortical cancer H295R cell line leads to constitutive activation of T-cell factor-dependent transcription. This is the first molecular defect to be reported with the same prevalence in both benign (27%) and malignant (31%) adrenocortical tumors. beta-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, beta-catenin alterations are more frequent in nonfunctioning tumors, suggesting that beta-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of beta-catenin in adrenocortical carcinomas suggests that other alterations might also be involved. This finding may contribute to new therapeutic approaches targeting the Wnt pathway in malignant adrenocortical tumors, for which limited medical therapy is available.

Adrenal Cortex Neoplasms↗
PubMed2005

Collision/composite tumors of the adrenal gland: a pitfall of scintigraphy imaging and hormone assays in the detection of adrenal metastasis.

CONTEXT: In patients with a history of extraadrenal tumor, incidental discovery of an adrenal mass necessitates excluding the possibility of metastatic malignancy. Detection of the malignant tissue is a difficult challenge when metastasis occurs in an adrenal adenoma, forming a collision/composite tumor. OBJECTIVE, DESIGN, AND SETTING: We report two patients with adrenal collision/composite tumors referred to two French university hospitals. PATIENTS AND RESULTS: Two patients with histories of mammary and sigmoid carcinomas, respectively, presented with adrenal mass discovered 8 and 3 yr after surgical removal of the primary tumor. In the two cases, computerized tomographic scan showed that the adrenal tumor contained two components with low and high attenuation values, respectively. Uptake of iodocholesterol by the adrenal tumor in case 1 and elevated plasma ACTH-stimulated 17-hydroxyprogesterone values in case 2 strongly argued for the diagnosis of primary adrenocortical tumors. Enlargement of the adrenal mass during follow-up in case 1 and association of the adrenal lesion with a hepatic mass in case 2 led to adrenalectomy. In both cases, histological examination of the tumor demonstrated the presence of metastatic carcinoma tissue in an adrenocortical adenoma, allowing classification of the neoplasia as a collision/composite tumor. CONCLUSION: These observations show that collision/composite tumors of the adrenal gland formed by carcinoma metastasis in benign adenomas are a pitfall of iodocholesterol scintigraphy and/or plasma steroid assays to exclude the diagnosis of adrenal metastasis. Conversely, computerized tomographic scan is a useful tool for the distinction between the benign and malignant tissues in adrenal collision/composite tumors.

19-Iodocholesterol↗
PubMed2005

Expression of growth hormone-releasing hormone receptor splicing variants in human primary adrenocortical tumours.

OBJECTIVE: Several splice variants (SVs) of GHRH receptor (GHRH-R) have been identified in various human cancers through which GHRH antagonists may exert their IGF-II-mediated antiproliferative action. Because the overexpression of the IGF-II gene is a frequent feature of adrenal carcinoma, we searched for the presence of GHRH-R SVs in these tumours. METHODS AND RESULTS: The expression of GHRH-R SVs was assessed by nested PCR in 45 human adrenocortical tumours. We have amplified 720-, 566- and 335-bp PCR products only in carcinomas. Their sequence revealed three open reading frames, corresponding to SV1, SV2 and SV4 of GHRH-R. SV2 was detected in five of 24 cancers examined, whereas the incidence of SV1 and SV4 was lower. Their simultaneous expression was observed in one carcinoma. No PCR products for SV3 or wild-type GHRH-R were found in carcinomas; mRNA for wild-type GHRH-R or SVs of GHRH-R were not observed either in adenomas or in normal adrenal or in NCI-H295R cells. Interestingly, all carcinomas which expressed SVs were also positive for the presence of GHRH mRNA. CONCLUSION: This is the first time that the expression of splice variants of GHRH-R has been demonstrated in human adrenal carcinoma. This study raises the possibility that splice variants might play a role in adrenal carcinogenesis and might offer the possibility for new therapeutic strategies at least in a subgroup of adrenal carcinomas.

Adenoma↗
PubMed2004

Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy.

The aim of this study was to identify predictor sets of genes whose over- or underexpression in human sporadic adrenocortical tumors would help to identify malignant vs. benign tumors and to predict postsurgical metastatic recurrence. For this, we analyzed the expression of 230 candidate genes using cDNA microarrays in a series of 57 well-characterized human sporadic adrenocortical tumors (33 adenomas and 24 carcinomas). We identified two clusters of genes (the IGF-II cluster containing eight genes, including IGF-II, and the steroidogenesis cluster containing six genes encoding steroidogenic enzymes plus eight other genes) whose combined levels of expression appeared to be good predictors of malignancy. This predictive value was as strong as that of the pathological score of Weiss. The analysis of the population of carcinomas (13 tumors) for genes whose expression would be strongly different between recurring and nonrecurring tumors allowed identification of 14 genes meeting these criteria. Among these genes, there are probably new markers of tumor evolution that will deserve additional validation on a larger scale. Taken together, these results show that the parallel analysis of the expression levels of a selected group of genes on microgram quantities of tumor RNA (a quantity that can be obtained from fine needle aspirations) appears as a complementary method to histopathology for the diagnosis and prognosis of evolution of adrenocortical carcinomas.

Adolescent↗
PubMed2004

In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism.

In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1-H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing's syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.

Adrenal Glands↗