Preoperative medical treatment in Cushing's syndrome : frequency of use and its impact on postoperative assessment : data from ERCUSYN

Background: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. Objective: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). Patients and methods: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). Results: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. Conclusions: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results

Decomposition of galactic X-ray emission with P

Context. X-ray observations of galaxies with high spatial resolution instruments such as Chandra have revealed that major contributions to their diffuse emission originate from X-ray-bright point sources in the galactic stellar field. It has been established that these point sources, called X-ray binaries, are accreting compact objects with stellar donors in a binary configuration. They are classified according to the predominant accretion process: wind-fed in the case of high-mass donors and Roche-lobe mass transfer in the case of low-mass donors. Observationally, it is challenging to reliably disentangle these two populations from each other because of their similar spectra. Aims. We provide a numerical framework with which spatially and spectrally accurate representations of X-ray binary populations can be studied from hydrodynamical cosmological simulations. We construct average spectra, accounting for a hot gas component, and verify the emergence of observed scaling relations between galaxy-wide X-ray luminosity (LX) and stellar mass (M*) and between LX and the star-formation rate (SFR). Methods. Using simulated galaxy halos extracted from the (48 h−1 cMpc)3 volume of the Magneticum Pathfinder cosmological simulations at z = 0.07, we generate mock spectra with the X-ray photon-simulator PHO

Clinical score system in the treatment of Cushing's disease: failure to identify discriminative variables from the German Cushing's Registry

PurposeTo develop a multidimensional and integrated clinical scoring instrument, that encompasses, summarizes and weights appropriately the desired clinical benefits of a treatment for Cushing's disease (CD).MethodsA panel of 42 variables potentially relevant to the clinical course ofCD was predefined by endocrinology experts taking into account relevant literature. Variables as well as biochemical disease activity assessed as urinary free cortisol (UFC) levels were evaluated at baseline and at least after 12months in patients treated between 2012 and 2016 in two Munich-based academic centres of the German Cushing's Registry. The primary endpoint was the identification of variables whose changes from baseline to follow-up visit(s) could characterize well biochemical cured from not cured patients after 12months.ResultsNinety nine patients with at least two consecutive visits were enrolled. Biochemical data were available for 138 visit-pairs among which UFC was not controlled in 48 (34.8%) and controlled in 90 (65.2%) first visits. In 41 (29.7%) consecutive visits (visit-pairs) changes in biochemical activity categories was observed between visits; concretely: in 17 (12.3%) consecutive visits changing from previously controlled to not controlled, and in 24 (17.4%) from uncontrolled to controlled biochemical activity. Multivariate statistical analyses (especially analyses of variance) based on data of the 138 visit-pairs were performed in order to proof possible effects of biochemical activity on clinical benefits. However, in none of the considered 42 variables corresponding to quality of life-dimensions, laboratory, anthropometric, musculo-skeletal or other clinical areas any statistically significant differences between different categories of biochemical activity were observed.ConclusionIt was not possible to provide clinical key parameters in our population of patients with CD discriminating biochemical cured from non-cured patients and to construct a clinical scoring system reflecting clinical treatment benefits

Long-Term Outcome of Primary Bilateral Macronodular Adrenocortical Hyperplasia after Unilateral Adrenalectomy

Unilateral adrenalectomy has been proposed in selected patients with primary bilateral macronodular adrenocortical hyperplasia (PBMAH), but its long-term outcome is unclear. Objective: The aim of this study was to analyze long-term clinical and biochemical outcomes of unilateral adrenalectomy vs bilateral adrenalectomy in patients with PBMAH in comparison with the outcome of cortisol-producing adenoma (CPA) treated with unilateral adrenalectomy. Design: Retrospective observational study in three German and one Italian academic tertiary care center. Patients and Methods: Twenty-five patients with PBMAH after unilateral adrenalectomy (unilat- ADX-PBMAH), nine patients with PBMAH and bilateral adrenalectomy (bilat-ADX-PBMAH), and 39 patients with CPA and unilateral adrenalectomy (unilat-ADX-CPA) were included. Results: Baseline clinical and biochemical parameters were comparable in patients with unilat-ADXPBMAH, bilat-ADX-PBMAH, and unilat-ADX-CPA. Directly after surgery, 84% of the patients with unilat-ADX-PBMAH experienced initial remission of Cushing syndrome (CS). In contrast, at last follow-up (median, 50 months), 32% of the patients with unilat-ADX-PBMAH were biochemically controlled compared with nearly all patients in the other two groups (P 5 0.000). Adrenalectomy of the contralateral side had to be performed in 12% of the initial patients with unilat-ADX-PBMAH. Three of 20 patients with unilat-ADX-PBMAH (15%) died during follow-up, presumably of CSrelated causes; no deaths occurred in the other two groups (P 5 0.008). Deaths occurred exclusively in patients who were not biochemically controlled after unilateral ADX

The USP8 mutational status may predict long-term remission in patients with Cushing's disease

ObjectiveAlmost half of the cases of Cushing's disease (CD) tumours carry recurrent activating somatic mutations in the ubiquitin-specific protease eight gene (USP8). The USP8 mutational status could predict remission in patients with CD, so our objective was to correlate the presence of somatic USP8 mutations with the rate of recurrence after transsphenoidal surgery (TSS) retrospectively. DesignBiochemical, radiological and clinical data were retrospectively assessed in 48 patients. USP8 mutational status was determined from corticotroph tumour samples. Association between USP8 mutational status, remission and recurrence was investigated. PatientsPatients with Cushing's disease from a single-centre cohort who underwent TSS between 1991 and 2012. MeasurementsLong-term remission and recurrence rate after TSS with at least 6months follow-up. Biochemical, radiological and clinical data, including sex, age at diagnosis, tumour size and pre-operative hormonal levels. USP8 mutational status. ResultsPatients with USP8 mutant corticotroph tumours (18 of 48; 37%) were diagnosed significantly earlier (meanSD 46 +/- 10years vs 53 +/- 11years; P=0.028) and presented with higher pre-operative 24-hour urinary-free cortisol levels (median IQR g/24hours 1174.0, 1184.5 vs 480.0, 405.3; P=0.045). The incidence of recurrence in a 10-year follow-up was significantly higher in patients with USP8 mutant tumours after the initial remission (58% vs 18% P=0.026). Recurrence appeared significantly earlier in these patients (months 70, 44-97 95% CI vs 102, 86-119 95% CI; P=0.019). ConclusionRecurrence appears to be more frequent and earlier after TSS in patients with USP8 mutant corticotroph tumours

Computer Vision Technology in the Differential Diagnosis of Cushing's Syndrome

Objective Cushing's syndrome is a rare disease characterized by clinical features that show morphological similarity with the metabolic syndrome. Distinguishing these diseases in clinical practice is challenging. We have previously shown that Computer vision technology can be a potentially useful diagnostic tool in Cushing's syndrome. In this follow-up study, we addressed the described problem by increasing the sample size and including controls matched by body mass index. Methods We enrolled 82 patients (22 male, 60 female) and 98 control subjects (32 male, 66 female) matched by age, gender and body-mass-index. The control group consisted of patients with initially suspected, but biochemically excluded Cushing's syndrome. Standardized frontal and profile facial digital photographs were acquired. The images were analyzed using specialized computer vision and classification software. A grid of nodes was semi-automatically placed on disease-relevant facial structures for analysis of texture and geometry. Classification accuracy was calculated using a leave-one-out cross-validation procedure with a maximum likelihood classifier. Results The overall correct classification rates were 10/22 (45.5 %)for male patients and 26/32 (81.3 %) for male controls, and 34/60 (56.7%) for female patients and 43/66 (65.2 %) for female controls. In subgroup analyses, correct classification rates were higherfor iatrogenic than for endogenous Cushing's syndrome. Conclusion Regarding the advanced problem of detecting Cushing's syndrome within a study sample matched by body mass index, we found moderate classification accuracy by facial image analysis. Classification accuracy is most likely higher in a larger sample with healthy control subjects. Further studies might pursue a more advanced analysis and classification algorithm

High mortality within 90 days of diagnosis in patients with Cushing's syndrome: results from the ERCUSYN registry.

OBJECTIVE: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. METHODS: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years. RESULTS: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. CONCLUSION: Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus