Many clinical studies have reported a relatively high incidence of osteoporosis and fragility fractures in patients with Cushing syndrome (CS). However, few papers have investigated osteoporosis and CS in terms of pathogenesis, so this study explores the association between the 2 and predicts upstream micro-ribonucleic acids (miRNAs) through bioinformatics, which provides potential targets for simultaneous pharmacological interventions in both diseases and also provides a basis for pathological screening.

We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS).

Cushing syndrome (CS) is a rare and serious disease with high mortality. Patients are often diagnosed late in the course of the disease.

Cushing syndrome is a severe endocrine disorder of cortisol excess associated with major metabolic and cardiovascular sequelae. We recently identified somatic mutations in PRKACA, the gene encoding the catalytic (C) α subunit of protein kinase A (PKA), as being responsible for cortisol-producing adrenocortical adenomas (CPAs), which are a major cause of Cushing syndrome. In spite of previous studies on the two initially identified mutations (L206R, 199_200insW), the mechanisms of action of the clinically highly relevant PRKACA mutations remain poorly understood. Here, by investigating a large panel of PRKACA mutations, including all those identified so far in Cushing syndrome, we unexpectedly found that not all mutations interfere with the binding of regulatory (R) subunits as previously hypothesized. Because several mutations lie in a region of PKA Cα involved in substrate recognition, we investigated their consequences on substrate specificity by quantitative phosphoproteomics. We found that all three mutations analyzed (L206R, 200_201insV, and d244-248+E249Q) cause major changes in the preference of PKA for its targets, leading to hyperphosphorylation of several PKA substrates, most notably including histone H1.4 at Ser36, which is required for and promotes mitosis. This is reflected by a ninefold hyperphosphorylation of H1.4 in CPAs carrying the L206R mutation. Thus, our findings suggest that in addition to hampering binding to R subunits, PRKACA mutations act by altering PKA substrate specificity. These findings shed light on the molecular events leading to Cushing syndrome and illustrate how mutations altering substrate specificity of a protein kinase may cause human disease.

Hypercortisolism accounts for relevant morbidity and mortality and is often a diagnostic challenge for clinicians. A prompt diagnosis is necessary to treat Cushing's syndrome as early as possible.

Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy. Tissues mainly targeted by CS are bone and fat, both derived from progenitor cells named mesenchymal stem cells (MSCs). In addition, the pathogenic role of MSCs in other diseases sharing common properties with CS, such as an altered inflammatory profile and increased oxidative stress, has been identified. In this light, MSCs isolated from skin of control healthy subjects (C-MSCs), patients affected by endogenous CS (ENDO-MSCs), patients affected by iatrogenic CS (IATRO-MSCs) and patients affected by exogenous CS receiving steroid-sparing drugs (SS-MSCs), respectively, have been isolated and analyzed. ENDO- and IATRO-MSCs showed a reduced differentiative potential toward osteogenic and adipogenic lineages compared to C-MSCs, whereas SS-MSCs re-acquired the ability to differentiate, with a trend similar to control cells. In addition, MSCs from CS groups, compared to control MSCs, displayed a reduction in the secretion of cytokines (immune-suppression), a decreased expression of genes related to wound healing and a dysregulation of the enzymes/genes related to antioxidant capacity. In conclusion, our results suggest that the hallmarks of CS, such as wound healing impairment and immunosuppression, are already detectable in undifferentiated cells, which could be considered a potential therapeutic early target for control of CS.

No abstract available

To evaluate the performance of FKBP5 as a cortisol activity biomarker in patients with ACTH-dependent Cushing syndrome (CS).

Independent Cushing's adrenocorticotropic hormone (ACTH) syndrome can have several causes, including adrenal carcinoma or simple adrenal hyperplasia. Although the distinction between malignant and benign can be effectively made through imaging investigations, in the situation where there are bilateral formations, their hormonal activity is impossible to appreciate via non-invasive techniques. The present study includes the presentation of a clinical case on the basis of which a literature review was made. The clinical case pertains to a 32-year-old patient with ACTH-independent Cushing's syndrome and bilateral adrenal tumor formations leading to the utility of adrenal venous sampling to avoid bilateral adrenalectomy. A literature review was subsequently conducted focusing on articles pertaining to the PICO criteria in order to describe: The diagnosis of adrenal tumor masses, the decision on the type of surgery and most importantly, the impact of adrenal venous sampling in avoiding surgical resection. These interventions severely limit the patients' quality of life.

Late-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically.

Cushing syndrome (CS) has been described as a killing disease due its cardiovascular complications. In fact, chronic cortisol excess leads to a constellation of complications, including hypertension, hyperglycemia, adiposity, and thromboembolism. The main vascular alteration associated with CS is atherosclerosis.

Renal neuroendocrine tumors (RenNETs) are rare malignancies with largely unknown biology, hormone expression, and genetic abnormalities. This study aims to improve our understanding of the RenNETs with emphasis of functional, hormonal, and genetic features. Surgically resected RenNETs (N = 13) were retrieved, and immunohistochemistry and next-generation sequencing (NGS) were performed in all cases. In addition, all published RenNETs were systematically reviewed. Our cohort (4 men and 9 women, mean age 42, mean tumor size 7.6 cm) included 2 patients with Cushing syndrome (CS). WHO grade (23% G1, 54% G2, and 23% G3) and tumor progression did not correlate. CS-associated RenNETs (CS-RenNETs) showed a solid and eosinophilic histology and stained for ACTH, while the remaining non-functioning tumors had a trabecular pattern and expressed variably hormones somatostatin (91%), pancreatic polypeptide (63%), glucagon (54%), and serotonin (18%). The transcription factors ISL1 and SATB2 were expressed in all non-functioning, but not in CS-RenNETs. NGS revealed no pathogenic alterations or gene fusions. In the literature review (N = 194), 15 (8%) of the patients had hormonal syndromes, in which CS being the most frequent (7/15). Large tumor size and presence of metastasis were associated with shorter patients' survival (p < 0.01). RenNETs present as large tumors with metastases. CS-RenNETs differ through ACTH production and solid-eosinophilic histology from the non-functioning trabecular RenNETs that produce pancreas-related hormones and express ISL1 and SATB2. MEN1 or DAXX/ARTX abnormalities and fusion genes are not detected in RenNETs, indicating a distinct yet unknown molecular pathogenesis.

Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of periadrenal adipose tissue in response to cortisol excess impact systemic blood pressure levels in patients with CS.

Cushing syndrome is characterized by glucose intolerance, cardiovascular disease, and an enhanced systemic inflammatory response caused by chronic exposure to excess cortisol. Eosinopenia is frequently observed in patients with adrenal Cushing syndrome, but the relationship between the eosinophil count in peripheral blood and indicators of glucose level in patients with adrenal Cushing syndrome has not been determined.

Protein kinase A (PKA) subunit defects (in PRKAR1A and PRKACA) are known to contribute to adrenal tumor pathogenesis. We studied the PRKAR1B gene for any genetic changes in bilateral adrenocortical hyperplasia (BAH) and cortisol-producing adrenal adenomas (CPA).

We evaluated the accuracy of the 10 μg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering ΔACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Δcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of ΔACTH > 35% and Δcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering ΔACTH, Δcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different.

Previous studies have shown inconsistent results about the usefulness of bilateral inferior petrosal sinus sampling (BIPSS) in differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. This meta-analysis evaluated the diagnostic value of BIPSS via the published literature.

Carney complex (CNC) is a syndrome characterized by hyperplasia of endocrine organs and may present with clinical features of Cushing syndrome and acromegaly due to functional adrenal and pituitary gland tumors. CNC has been linked to mutations in the regulatory subunit of protein kinase A type I-alpha (PRKAR1A) gene.

Aim. To present specific aspects of adrenalectomy for Cushing's syndrome (CS) by introducing well established aspects ("do's") and less known aspects ("don'ts"). Material and Method. This is a narrative review. Results. The "do's" for laparoscopic adrenalectomy (LA) are the following: it represents the "gold standard" for secretor and non-secretor adrenal tumors and the first line therapy for CS with an improvement of cardio-metabolic co-morbidities; the success rate depending on the adequate patients' selection and the surgeon's skills. The "don'ts" are large (>6-8 centimeters), locally invasive, malignant tumors requiring open adrenalectomy (OA). Robotic adrenalectomy is a new alternative for LA, with similar safety and conversion rate and lower pain drugs use. The "don'ts" are the following: lack of randomized controlled studies including oncologic outcome, different availability at surgical centers. Related to the sub-types of CS, the "do's" are the following: adrenal adenomas which are cured by LA, while adrenocortical carcinoma (ACC) requires adrenalectomy as first line therapy and adjuvant mitotane therapy; synchronous bilateral adrenalectomy (SBA) is useful for Cushing's disease (only cases refractory to pituitary targeted therapy), for ectopic Cushing's syndrome (cases with unknown or inoperable primary site), and for bilateral cortisol producing adenomas. The less established aspects are the following: criteria of skilled surgeon to approach ACC; the timing of surgery in subclinical CS; the need for adrenal vein catheterization (which is not available in many centers) to avoid unnecessary SBA. Conclusion. Adrenalectomy for CS is a dynamic domain; LA overstepped the former OA area. The future will improve the knowledge related to RA while the cutting edge is represented by a specific frame of intervention in SCS, children and pregnant women. Abbreviations: ACC = adrenocortical carcinoma, ACTH = Adrenocorticotropic Hormone, CD = Cushing's disease, CS = Cushing's syndrome, ECS = Ectopic Cushing's syndrome, LA = laparoscopic adrenalectomy, OA = open adrenalectomy, PA = partial adrenalectomy, RA = robotic adrenalectomy, SCS = subclinical Cushing' syndrome.

To analyze and summarize the clinical characteristics, treatments, and prognosis of Cushing's syndrome (CS) with nocardiosis.