Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial in Cushing's disease.

PURPOSE: Cushing's disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during osilodrostat (potent oral 11ß-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC). METHODS: LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing's disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study. RESULTS: At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control. CONCLUSIONS: Improvements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing's disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).

[Chronic pheochromocytoma-induced myocardial injuries: What should we expect from modern and classical echocardiographic tools?] / Apport du 2D strain et des outils échocardiographiques classiques pour la recherche d'anomalies myocardiques induites par l'exposition chronique à un phéochromocytome.

INTRODUCTION: Pheochromocytoma is a rare disease, which may manifest as severe cardiac complications. Apart from these situations, the "chronic" cardiac impact is not clearly defined. A cardiac MRI study suggests that these patients are carrying areas of fibrosis and foci of left ventricular myocarditis. Since these abnormalities are usually associated with altered left ventricular longitudinal systolic strain, we hypothesize that this strain is altered in patients with a "chronic" pheochromocytoma. METHOD: This retrospective case-control study was performed using patients from the Bordeaux University Hospital database, included between 2008 and 2016. We compared the left ventricular global longitudinal strain (GLS), radial and circumferential systolic strain and classic echocardiographic parameters between patients with pheochromocytoma and controls matched for age, sex, body mass index and systolic blood pressure. RESULTS: The analysis included 47 patients and 47 correctly matched controls. There were no statistically significant differences between the 2 groups in terms of GLS (-20.7±2.4% vs. -20.2±2.7%, P=0.40), radial strain, left ventricular mass or diastolic function. Left ventricular ejection fraction and circumferential strain were significantly higher in patients than in controls, with a significantly lower telediastolic diameter. CONCLUSION: No significant changes in GLS were observed in our pheochromocytoma patients, compared with controls. Several hypotheses may explain these results. The presence of fibrosis foci and areas of left ventricular myocarditis being associated with a poor cardiological prognosis, a systematic cardiac MRI could be discussed in these patients, until further studies are performed.

Persistent cortisol response to desmopressin predicts recurrence of Cushing's disease in patients with post-operative corticotropic insufficiency.

OBJECTIVE: Cushing's disease (CD) may recur despite corticotropic insufficiency (COI) following pituitary surgery. The predictive value of the desmopressin test (DT) for recurrence in this setting remains controversial. We have evaluated whether the disappearance of the response to DT predicts a low probability recurrence in a large cohort of patients with post-operative COI. DESIGN: Multicentre retrospective study. METHODS: Ninety-five patients with CD (women 82%, age 41 ± 14 years), responding preoperatively to DT and with early post-operative COI (08 00 am cortisol: <138 nmol/L), underwent a DT within 3 months post-surgery. Association between DT findings and the prediction of recurrence was tested using regression and ROC analyses. RESULTS: Recurrence occurred in 17/95 patients within 29 to 91 months. The cortisol peak (327, 95% CI (237-417) vs 121 (79-164) nmol/L, P = 0.0001) and absolute increment during DT (208 (136-280) vs 56 (22-90) nmol/L, P = 0.005) were greater in the recurrence vs remission group. Cortisol peak (AUC: 0.786 (0.670-0.902)) and increment (0.793 (0.672-0.914)) yielded a higher prognostic performance for recurrence than did the early post-operative 08 00 am cortisol (0.655 (0.505-0.804)). In the context of COI, cortisol peak >100 nmol/L and increment >30 nmol/L had a high negative predictive value (94, 95% CI (88-100) and 94, (88-100), respectively). Patients with a cortisol peak ≤100 nmol/L (vs >100) or an increment ≤30 nmol/L (vs >30) were less likely to have CD recurrence (odds ratios: 0.12, 95% CI (0.03-0.41) and 0.11 (0.02-0.36), respectively). CONCLUSION: The disappearance of the response to the post-operative DT was independently associated with a lower odds of CD recurrence and offers an incremental prognostic value, which may help to stratify patients with COI and refine their follow-up according to the risk of recurrence.

Diagnostic accuracy of computed tomography to identify adenomas among adrenal incidentalomas in an endocrinological population.

CONTEXT: The recent recommendations of the European Endocrine Society states that the performance of computed tomography (CT) to characterize 'true' adrenal incidentalomas (AIs) remains debatable. OBJECTIVE: To determine relevant thresholds for usual CT parameters for the diagnosis of benign tumors using robust reference standard among a large series of 'true' AIs recruited in an endocrinological setting. DESIGN: Retrospective study of 253 AIs in 233 consecutive patients explored in a single university hospital: 183 adenomas, 33 pheochromocytomas, 23 adrenocortical carcinomas, 5 other malignant tumors and 9 other benign tumors. Reference standard was histopathology in 118 AIs, biological diagnosis of pheochromocytoma in 2 AIs and size stability after at least 1 year of follow-up in 133 AIs. METHODS: Sensitivity, specificity and positive and negative predictive values were estimated for various thresholds of size, unenhanced attenuation (UA), relative and absolute wash-out (RPW, APW) of contrast media. 197 scans were reviewed independently in a blinded fashion by two expert radiologists to assess inter-observer reproducibility of measurements. RESULTS: Criteria associated with a 100% positive predictive value for the diagnosis of benign AI were: a combination of size and UA: 30 mm and 20 HU or 40 mm and 15 HU, respectively; RPW >53%; and APW >78%. Non-adenomatous AIs with rapid contrast wash-out were exclusively benign pseudocysts and pheochromocytomas, suggesting that classical thresholds of 60% and 40% for APW and RPW, respectively, can be safely used for patients with normal metanephrine values. Inter-observer reproducibility of all parameters was excellent (intra-class correlation coefficients: 0.96-0.99). CONCLUSIONS: Our study, the largest conducted in AIs recruited in an endocrinological setting, suggests safe thresholds for quantitative CT parameters to avoid false diagnoses of benignity.

Histologically Proven Bronchial Neuroendocrine Tumors in MEN1: A GTE 51-Case Cohort Study.

OBJECTIVE: To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death. br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis. METHODS: The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 [35.5-59.6] years by the Groupe d'étude des Tumeurs Endocrines was analyzed using time-to-event techniques. RESULTS: br-NETs were found in 51 patients (4.8%, [95% CI 3.6-6.2%]) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years [28-66]. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, [95% CI 0.02-5.14]). AC tended to have a worse prognosis than TC (p = 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (p = 10-4) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths. CONCLUSIONS: Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.

La chirurgie d'épargne surrénalienne : du cortex à la médulla: Cortical sparing surgery: from cortex to medulla.

The 2017 Endocrine Society annual meeting included several communications and debates on the conservative adrenal surgery in bilateral hereditary pheochromocytomas (BHP), bilateral adrenal macronodular hyperplasia (BAMH) and primary hyperaldosteronism (PHA). The general principle is to preserve a part of the adrenal cortex to prevent the occurrence of a definitive adrenal insufficiency. In BHP, cortical sparing surgery allows more than 50% of patients to maintain normal corticotropic function at 10 years with a low recurrence rate (~ 10%). Since the adrenal medulla cannot be removed entirely, recurrence seems inevitable and long-term follow-up is essential. Individual risk of malignancy must be taken into account. In BAMH responsible for Cushing syndrome, unilateral adrenalectomy induces a normalization of urinary free cortisol in 92 to 100% of cases and even corticotropic insufficiency in 40 to 100% of cases. This is most often transient. Late recurrences of Cushing's syndrome may occur in 13 to 60% of cases. Prolonged patient monitoring is therefore essential. In PAH with lateralized aldosterone production, minimally invasive partial adrenal surgery, which consists of removing only the adrenal adenoma visualized at TDM, allows an improvement blood pressure in about 94% of patients. However, failure or recurrence may occur. Its place therefore remains marginal in the treatment of the lateralized PAHs.

Cabergoline for Cushing's disease: a large retrospective multicenter study.

OBJECTIVE: The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. DESIGN: We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. METHODS: Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. RESULTS: Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). CONCLUSIONS: About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors

By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.

Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study.

BACKGROUND: MEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1. METHODS: The study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software. RESULTS: Intrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs. CONCLUSION: The present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Treatment of cushing's syndrome: an Endocrine Society Clinical Practice Guideline

OBJECTIVE: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. PARTICIPANTS: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. EVIDENCE: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies. CONSENSUS PROCESS: The Task Force achieved consensus through one group meeting, several conference calls, and numerous e-mail communications. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. CONCLUSIONS: Treatment of Cushing's syndrome is essential to reduce mortality and associated comorbidities. Effective treatment includes the normalization of cortisol levels or action. It also includes the normalization of comorbidities via directly treating the cause of Cushing's syndrome and by adjunctive treatments (eg, antihypertensives). Surgical resection of the causal lesion(s) is generally the first-line approach. The choice of second-line treatments, including medication, bilateral adrenalectomy, and radiation therapy (for corticotrope tumors), must be individualized to each patient.(AU)

MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines.

CONTEXT: Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports. OBJECTIVE: To improve the knowledge of MEN1 natural history before 21 years old. METHODS: Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the "Groupe d'étude des Tumeurs Endocrines" MEN1 cohort. RESULTS: The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases. CONCLUSIONS: Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms.

OBJECTIVES: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. METHODS: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1(-/-)) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. RESULTS: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1(-/-) mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1(-/-) mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1(-/-) mice. CONCLUSIONS: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity.

Per-operative hemodynamic instability in normotensive patients with incidentally discovered pheochromocytomas.

CONTEXT: The per-operative hemodynamic behavior of normotensive incidentally discovered pheochromocytomas is poorly documented. OBJECTIVE: To compare the per-operative hemodynamic instability and early postoperative outcome of normotensive pheochromocytomas, hypertensive pheochromocytomas, and benign non-pheochromocytoma adrenal incidentalomas (AIs). DESIGN: Retrospective cohort treated in a single center. PATIENTS AND METHODS: Fifty patients (10 normotensive pheochromocytomas, 24 hypertensive pheochromocytomas, and 16 AIs) were anesthetized and operated on by the same team, using laparoscopy in 78% of cases. Before surgery, 60% of normotensive and 95.8% of hypertensive pheochromocytomas received pretreatment with α-receptor or calcium channel blockers. All of the patients received the same intraoperative hemodynamic monitoring, including continuous direct intra-arterial pressure recording. RESULTS: All the features of hemodynamic instability, with the exception of the diastolic pressure nadir and fluid volume requirements, differed between hypertensive pheochromocytomas and AIs. Conversely, all features of hemodynamic instability were similar in hypertensive and normotensive pheochromocytomas. More specifically, by comparison with AIs, normotensive pheochromocytomas displayed higher maximal systolic pressure; more hypertensive, severe hypertensive, and hypotensive episodes; and a higher minimal heart rate, and also required more interventions to treat undesirable blood pressure elevations. Postoperative complications, all of which were mild, were more frequent in hypertensive pheochromocytomas than in normotensive pheochromocytomas (P < .03). CONCLUSIONS: Normotensive pheochromocytomas have roughly comparable per-operative hemodynamic instability to hypertensive pheochromocytomas and differ markedly from non-pheochromocytoma AIs. It is therefore crucial to identify normotensive pheochromocytomas among AIs when surgery is scheduled and to apply the standard of care for pheochromocytoma anesthesia.

Patients lost to follow-up in acromegaly: results of the ACROSPECT study.

OBJECTIVE: The complex management of acromegaly has transformed this disease into a chronic condition, with the risk of patients being lost to follow-up. The objective of this study was to estimate the proportion of acromegalic patients lost to follow-up in France and to determine the impact that abandoning follow-up has on the disease and its management. DESIGN: ACROSPECT was a French national, multicentre, cross-sectional, observational study. METHODS: Acromegalic patients were considered lost to follow-up if no new information had been entered in their hospital records during the previous 2 years. They were traced where possible, and data were collected by means of a recall visit or questionnaire. RESULTS: In the study population, 21% of the 2392 acromegalic patients initially followed in 25 tertiary endocrinology centres were lost to follow-up. At their last follow-up visit, 30% were uncontrolled, 33% were receiving medical therapy and 53% had residual tumour. Of the 362 traced, 62 had died and 77% were receiving follow-up elsewhere; the leading reason for abandoning follow-up was that they had not been informed that it was necessary. Our analysis of the questionnaires suggests that they were not receiving optimal follow-up. CONCLUSIONS: This study underlines the need to better inform acromegalic patients of the need for long-term follow-up, the absence of which could be detrimental to patients' health, and to develop shared care for what must now be regarded as a chronic disease.

[New insights in adrenal Cushing syndrome]. / Actualités du syndrome de Cushing d'origine surrénalienne.

The development of molecular biology tools has allowed major advances in the genetic determinism and the pathophysiology of pheochromocytomas and Conn's adenomas. However, the molecular pathophysiology of ACTH-independent Cushing's Syndrome was mostly unknown until recently. In 2014, major new insights concerning the physiopathology of ACTH-independent macronodular adrenal hyperplasias (AIMAH) and the cortisol-secreting adenomas have been published. Elsewhere, the cardiovascular consequences of the subclinical hypercortisolism due to adrenal incidentalomas, was described only in some cross-sectional studies. The natural history of these lesions has been documented in two large follow-up studies. These new data presented during the Endocrine Congress are summarized herein.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

Management of hyperglycaemia in Cushing's disease: experts' proposals on the use of pasireotide.

Cushing's disease causes considerable morbidity and mortality, including cardiovascular, metabolic, respiratory and psychiatric complications, bone demineralization and increased susceptibility to infections. Metabolic complications include a high prevalence of impaired glucose tolerance, fasting hyperglycaemia and diabetes. Although pituitary surgery is the gold-standard treatment, other treatment strategies such as radiotherapy and medical therapy to reduce cortisol synthesis may be proposed in the event of recurrence or failure, or when surgery is not an option. Bilateral adrenalectomy can also be considered. One of the medical treatments used in Cushing's disease is the somatostatin analogue pasireotide, which acts on adrenocorticotropic hormone (ACTH) secretion by the pituitary. Its efficacy in reducing urinary free cortisol, plasma cortisol and ACTH, and in improving the clinical signs of the disease has been demonstrated. Its observed adverse effects are similar to the known effects of first-generation somatostatin analogues, although disturbances of carbohydrate metabolism are more frequent and more severe with pasireotide. The aim of the present review was to summarize the epidemiology and pathophysiology of the disturbances of glucose metabolism that arise in Cushing's disease, and to propose recommendations for detecting and monitoring glucose abnormalities and for managing pasireotide-induced hyperglycaemia.

Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'etude des Tumeurs Endocrines database.

OBJECTIVE: Limited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management. METHODS: Analysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas. RESULTS: Adrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC. CONCLUSIONS: Adrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.