An evaluation of pharmacological options for Cushing's disease: what are the state-of-the-art options?

INTRODUCTION: Untreated Cushing's syndrome (CS) is associated with significant morbidity and mortality. Cortisol normalization is a key goal to treatment. Pituitary surgery remains the first-line approach for Cushing's disease, but sometimes it is impracticable, unsuccessful, or complicated by recurrence. Medical therapy has been historically considered a palliative. However, in the latest years, interest on this topic has grown due to both the availability of new drugs and the reevaluation of the old, commonly used drugs in clinical practice. AREAS COVERED: In this article, we will discuss the current options and future directions of medical therapy for CS, aiming at fitting best patients' features. An extensive literature search regarding already approved and investigational principles was conducted (PubMed, ClinicalTrials.gov. Available drugs include inhibitors of ACTH secretion, steroidogenesis inhibitors, and glucocorticoid receptor antagonists; drugs acting at different levels can be also combined in uncontrolled patients. EXPERT OPINION: Since there is still no standardized pharmacological approach and the superiority of one drug over another has not been established yet in the absence of comparative studies, each time clinicians' choices should be patient-tailored. Age, gender, tumor features, severity of hypercortisolism, comorbidities/complications, rapidity of action, side effects, drug-drug interactions, contraindications, availability, patients' preferences, and costs should be all considered.

Using temperament and character dimensions (TCI) to analyze the personality profiles of adults and older adults with cancer managed in outpatient settings.

Introduction: This study aimed to investigate profiles of personality evaluated by temperament and character dimensions (TCI) in 638 adult and older adult patients (CP) who had recently been diagnosed with breast, colon, lung, and other kinds of cancer (female and male subjects were assessed). Tests: Temperament and Character Inventory (TCI). Statistical analysis: cluster K-means analysis for personality traits. Results: Two different personality profiles emerged: "Low self-determination and pessimism" (Profile 1) and "Self-determination and self-caring (medium)" (Profile 2). The following significant differences were observed in the TCI dimensions between the two profiles: Temperament-Novelty-Seeking (NS) (p < 0.001); Harm-Avoidance (HA) (p < 0.001); Reward-Dependence (RD) (p < 0.001); Persistence (PS) (p < 0.001); Character-Self-Directness (SD) (p < 0.001); Cooperativeness (C) (p > 0.001); Self-Transcendence (ST) (p < 0.001). No differences in the two profiles were found between adult and elderly patients. Profile 1 - "Low self-determination and pessimism": Patients with this profile present low resistance to frustration, poor search for novelty and solutions (NS), anxiety and pessimism (medium HA), high social attachment and dependence on the approval of others (medium-high RD), and low self-determination (PS) as temperament dimensions; and medium-low self-direction, low autonomy and ability to adapt (SD-medium-low), medium cooperativeness (C), and low self-transcendence (ST) as character dimensions. Profile 2 - "Self-determination and self-caring (medium)": Patients with this profile have resistance to frustration, ability to search for novelty and solutions (medium-NS), low anxiety and pessimism (HA), low social attachment and dependence on approval (medium-low-RD), and determination (medium-high PS) as dimensions of temperament; and autonomy and capacity for adaptation and self-direction (SD), capacity for cooperation (high-CO), and self-transcendence (medium-high-ST) as character dimensions. Conclusion: Personality screening allows a better understanding of the difficulties of the individual patient and the planning of targeted psychotherapeutic interventions that promote quality of life and good adaptation to the disease course.

Structural Analysis of Social Behavior: Using Cluster Analysis to Examine Intrapsychic Personality Traits Associated With Depression in Women With Breast Cancer.

BACKGROUND: This study aimed to investigate personality traits associated with depression in breast cancer women (BCW). METHODS: Sample: 236 BCW recently diagnosed (early stages). Tests: SASB-Structural-Analysis of Social-Behavior; IPAT-CDQ-Depression. Statistical analysis: cluster K-Means analysis to explore SASB personality-traits considering the 8 SASB clusters (Cl); CDQ scores dichotomized by 50th percentile cutoff (high/low); Pearson's chi square test to compare CDQ levels and SASB traits. RESULTS: Cluster analysis results supported two distinguishable SASB personality traits (for all SASB Cl-Scales P < .001) classified as "Love and Autonomy" (62.2%) and "Control and Hate" (37.8%). Patients with Love/Autonomy traits are spontaneous, accept their deepest feelings and desire to be close to other people (Cl1, Cl2, Cl3, Cl4). They show a medium value of self-control and a low tendency to self-abusive and self-critical behaviors (Cl5, Cl6). They pay attention to themselves and to their needs at emotional and physical levels also if may be occasionally engaged in self-destructive behaviors (Cl7, Cl8). Women with Control/Hate traits are not spontaneous and do not always express emotions (C1, Cl2, Cl3, Cl4) and flexibility in their relationship with others (Cl5, Cl6). In stressful situations, they may ignore the option of choices for self-growth and neglect their needs and those of others (Cl7, Cl8). BCWs with Control/Hate traits scored higher in depression (P <.001) than those with the Love/Autonomy profile. CONCLUSIONS: Healthcare professionals should be aware of these personality traits and their association with depression to identify the psychologically most vulnerable BCW and improve the care they provide them. The psychotherapeutic intervention should be planned to face on the personality problems.

Acromegaly and male sexual health.

Acromegaly is a rare pathology characterized by chronic hypersecretion of Growth Hormone (GH) and Insulin-like Growth Factor-1 (IGF-1) that causes somatic, metabolic, and systemic changes. The somatotropic axis acts physiologically favoring gonadal function, but when GH is produced in excess it has deleterious effects on many aspects of male sexuality. It is widely demonstrated, in fact, that acromegaly induces hypogonadism through different mechanisms, both through direct mass effect on gonadotropic cells and through increased plasma levels of prolactin. Moreover, hypogonadism is also one of the factors linking acromegaly to erectile dysfunction (ED), but also metabolic complications of acromegaly and, probably, GH itself contribute to the genesis of this disorder. There are few data in the literature on the impact of the disease on fertility and testicular volume. Finally, knowledge of the role of GH hypersecretion on the occurrence of prostatic diseases such as benign prostatic hypertrophy and prostatic cancer appears to be of fundamental clinical importance in the long-term management of these patients.

Mesenchymal Stem Cells Exposed to Persistently High Glucocorticoid Levels Develop Insulin-Resistance and Altered Lipolysis: A Promising In Vitro Model to Study Cushing's Syndrome.

Background: In Cushing's syndrome (CS), chronic glucocorticoid excess (GC) and disrupted circadian rhythm lead to insulin resistance (IR), diabetes mellitus, dyslipidaemia and cardiovascular comorbidities. As undifferentiated, self-renewing progenitors of adipocytes, mesenchymal stem cells (MSCs) may display the detrimental effects of excess GC, thus revealing a promising model to study the molecular mechanisms underlying the metabolic complications of CS. Methods: MSCs isolated from the abdominal skin of healthy subjects were treated thrice daily with GCs according to two different regimens: lower, circadian-decreasing (Lower, Decreasing Exposure, LDE) versus persistently higher doses (Higher, Constant Exposure, HCE), aimed at mimicking either the physiological condition or CS, respectively. Subsequently, MSCs were stimulated with insulin and glucose thrice daily, resembling food uptake and both glucose uptake/GLUT-4 translocation and the expression of LIPE, ATGL, IL-6 and TNF-α genes were analyzed at predefined timepoints over three days. Results: LDE to GCs did not impair glucose uptake by MSCs, whereas HCE significantly decreased glucose uptake by MSCs only when prolonged. Persistent signs of IR occurred after 30 hours of HCE to GCs. Compared to LDE, MSCs experiencing HCE to GCs showed a downregulation of lipolysis-related genes in the acute period, followed by overexpression once IR was established. Conclusions: Preserving circadian GC rhythmicity is crucial to prevent the occurrence of metabolic alterations. Similar to mature adipocytes, MSCs suffer from IR and impaired lipolysis due to chronic GC excess: MSCs could represent a reliable model to track the mechanisms involved in GC-induced IR throughout cellular differentiation.

Osilodrostat oral tablets for adults with Cushing's disease.

INTRODUCTION: Endogenous Cushing's syndrome (CS) is a rare, multi-systemic condition resulting from chronic glucocorticoid excess sustained by a pituitary adenoma (Cushing's disease, CD), an adrenal adenoma or, less frequently, a neuroendocrine tumor. The optimal first-line option is surgery, but when it is contraindicated/refused, or in case of severe, life-threatening disease, medical treatment is a first-line choice. Osilodrostat (LCI699, Isturisa®) is a new, orally active adrenal steroidogenesis inhibitor currently approved by the FDA and EMA for the treatment of endogenous CS. AREAS COVERED: We illustrate the pharmacologic profile of osilodrostat and summarize the efficacy and safety of osilodrostat from the first phase I studies to the most recent evidence. EXPERT OPINION: Osilodrostat acts as a potent, reversible inhibitor of 11ß-hydroxylase (CYP11B1) and 18-hydroxylase (or aldosterone synthase, CYP11B2), counteracting both gluco- and mineralocorticoid production. According to the results of the LINC1, LINC2, and LINC3 studies and the preliminary findings of LINC4, osilodrostat offers an excellent efficacy in controlling hypercortisolism with a good tolerability. The non-negligible risk of adrenal insufficiency/steroid withdrawal symptoms, hypokalemia, and hyperandrogenism disorders, and the possibility, albeit rare, of pituitary tumor enlargement, require further confirmation and careful monitoring.

Pachychoroid spectrum disease and choriocapillary flow analysis in patients with Cushing disease: an optical coherence tomography angiography study.

PURPOSE: To investigate the presence of pachychoroid spectrum disease (PSD) in patients with Cushing disease (CD) and to evaluate subfoveal choroidal thickness (SFCT) and choriocapillary flow using spectral domain OCT (SD-OCT) with the enhanced depth imaging (EDI) and optical coherence tomography angiography (OCT-A). METHODS: Thirty-two patients with CD and 32 age- and sex-matched healthy volunteers were enrolled in this observational study. All participants had a complete ophthalmic examination including SD-OCT with EDI and OCT-A, and were subjected to the Perceived Stress Scale test (PSS). All patients with CD had hormone test including 24-h urinary-free cortisol (UFC) and plasma adrenocorticotropic hormone (ACTH). We compared SFCT and choriocapillary vessel density (CVD) between the two groups and evaluated the presence of PSD. We investigated the association of hormone level, SFTC, CVD with the presence of CD; the association between the hormone level, SFTC, CVD, the CD disease activity, and duration with the presence of PSD in CD patients; and the association between SFTC and CVD with the hormone level, the CD disease activity, and duration in CD patients. RESULTS: Higher values of SFCT and CVD were associated with CD (ß: 0.028, 95% CI: 0.014; 0.041; ß: 0.912, 95%CI: 0.205; 1.62, respectively). Twelve patients with CD (37.5%) reported a PSD in at least one eye, whereas no subject was found in control group (p < 0.001); in particular, 11 CD patients (34%) presented pachychoroid pigment epitheliopathy (PPE) and 1 CD patient (3%) presented polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization (PCV/AT1). In patients with CD, a significant positive association between SFCT and PSD was found (ß: 0.010, 95% CI 0.001; 0.019). CONCLUSION: A chronic state of hypercortisolism may have direct implications on the choroid. Patients with CD had higher SFCT values and a significant change in the choriocapillary flow compared to healthy controls. Moreover, PSD was observed only in CD patients.

ENSAT registry-based randomized clinical trials for adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

RNA Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights.

CONTEXT: Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. OBJECTIVE: To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms. DESIGN: Cross-sectional study. SETTING: University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT). PATIENTS: We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs). INTERVENTION: Ribonucleic acid (RNA) sequencing. MAIN OUTCOME MEASURES: Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing. RESULTS: Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation. CONCLUSIONS: MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

Mitotane Concentrations Influence Outcome in Patients with Advanced Adrenocortical Carcinoma.

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

Mitotane Concentrations Influence the Risk of Recurrence in Adrenocortical Carcinoma Patients on Adjuvant Treatment.

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

Personality (at Intrapsychic and Interpersonal Level) Associated With Quality of Life in Patients With Cancer (Lung and Colon).

The objective of this study was to determine the association of quality of life (QoL) and intrapsychic and interpersonal behaviors (Structural Analysis of Social Behavior [SASB]) of patients with cancer (lung: n = 88; age 62.8 ± 10.1; colon: n = 56; age 60.1 ± 11.4). Personality described by SASB clusters (Cls): SASB-Questionnaire; QoL tests: FACT_G and QLQ-C30. Patients with lung cancer (n = 88; age 62.8 ± 10.1) and colon cancer (n = 56; age 60.1 ± 11.4; all stages of severity). Multiple regression analyses. Multiple linear regression: dependent variable: FACT_G; covariates: physical functioning, cognitive functioning, SASB-Cl3-50°, SASB-Cl6-50°. Analysis of variance and t test confirm validity of the model (P < .001). SASB-Cl3 with FACT_G (P = .034); SASB-Cl6 with FACT_G (P = .002); age with FACT_G (P = .018); physical functioning with FACT_G (P < .001); cognitive functioning with FACT_G (P < .001). Personality traits such as self-critical and oppressive behaviors, low capacity for self-esteem, physical and cognitive functioning, and age (a higher age determines a better QoL) strongly determine QoL in patients with lung and colon cancer. This may suggest areas of therapeutic intervention.

Androgens in Cushing's Syndrome.

Although polycystic ovary syndrome (PCOS) is the most common androgen excess disorder, screening for Cushing's Syndrome (CS) should be considered in women with PCOS phenotype, particularly if they are also affected by other disturbances that increase their pretest probability (e.g., osteoporosis/bone fractures). Approximately 70-80% of women with CS present menstrual abnormalities, and PCOS findings are found in 46% of these patients. Diagnostic efforts should strengthen if the clinical picture is severe or of rapid onset in order to ensure the earliest and most appropriate treatment. If the diagnosis of CS is challenging, its differentiation from PCOS is not outdone: isolated PCOS may be associated to hypothalamic-pituitary-adrenal axis disruption, leading to false-positive results in screening tests. Because of this overlap, the diagnosis of CS is initially missed or delayed. Diagnostic utility of serum androgen assessment is controversial, but the widespread use of high-performance liquid chromatography and gas chromatography-mass spectrometry for urinary steroid profiling is showing promising results. According to the role of adrenocorticotropic hormone (ACTH) in adrenal androgen secretion, it is not surprising that the levels of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and androstenedione (A4) are generally elevated or in the upper normal range in patients with ACTH-dependent CS. Conversely, adrenal androgens are generally low in patients with cortisol-secreting adrenocortical adenoma. However, androgen-secreting adrenal tumors (adenoma and carcinoma) can be also associated with severe hyperandrogenism. Regression of hypercortisolism after treatment causes disappearance of hyperandrogenism. However, signs of androgen excess may be detectable in well-controlled CS as a result of ACTH compensatory response to certain adrenal steroidogenesis inhibitors.

Somatic PRKACA Mutations: Association With Transition From Pituitary-Dependent to Adrenal-Dependent Cushing Syndrome.

CONTEXT: Prolonged adrenal stimulation by corticotropin, as in long-standing Cushing disease (CD), leads to diffuse to nodular hyperplasia. Adrenal functional autonomy has been described in a subset of patients with CD, leading to the hypothesis of transition from ACTH-dependent to ACTH-independent hypercortisolism. OBJECTIVE: With the consideration that the catalytic α subunit of protein kinase A (PKA; PRKACA) somatic mutations are the most common finding in adrenal adenomas associated with ACTH-independent Cushing syndrome, our aim was to analyze PRKACA mutations in adrenals of patients with persistent/long-standing CD. DESIGN: Cross-sectional. SETTING: University hospital. PATIENTS: Two patients with long-standing CD and suspicion of coexistence of autonomous adrenal hyperfunction, according to pre and postoperative evaluations, were selected for this study, following an intensive literature search and patient-chart reviewing. INTERVENTION: Clinical data were analyzed. DNA was extracted from adrenal tissue for PRKACA sequencing. PKA activity was assayed. MAIN OUTCOME MEASURE: PRKACA somatic mutations. RESULTS: Both patients showed mutations of PRKACA in the macronodule in the context of micronodular adrenal hyperplasia. One patient harbored the previously described p.Leu206Arg substitution, whereas a p.Ser213Arg missense variation was detected in the adrenal nodule of the second patient. No mutations were detected in the adjacent adrenal cortex of the second patient. In silico analysis predicts that p.Ser213Arg can interfere with the interaction between the regulatory and catalytic subunits of PKA. CONCLUSIONS: Our study shows that PRKACA somatic mutations can be found in adrenal nodules of patients with CD. These genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD.

The medical treatment with pasireotide in Cushing's disease: an Italian multicentre experience based on "real-world evidence".

A phase III study has demonstrated that 6-month pasireotide treatment induced disease control with good safety in 15-26% of patients with Cushing's disease (CD). The aim of the current study was to evaluate the 6-month efficacy and safety of pasireotide treatment according to the real-world evidence. Thirty-two CD patients started pasireotide at the dose of 600 µg twice a day (bid) and with the chance of up-titration to 900 µg bid, or down-titration to 450 or 300 µg bid, on the basis of urinary cortisol (UC) levels or safety. Hormonal, clinical and metabolic parameters were measured at baseline and at 3-month and 6-month follow-up, whereas tumour size was evaluated at baseline and at 6-month follow-up. At baseline, 31 patients had very mild to moderate disease and 1 patient had very severe disease. Five (15.6%) patients discontinued treatment for adverse events; the remaining 27 patients (26 with very mild to moderate disease and 1 with very severe disease), reached 6-month follow-up. Considering the group of patients with very mild to moderate disease, responsiveness, defined by the normalization (<1 the upper limit of normal range, ULN) or near normalization (>1 and ≤1.1 ULN) of UC levels, was registered in 21 patients (full control in 19 and near control in 2), corresponding to 67.7% and 80.8% according to an "intention-to-treat" or "per-protocol" methodological approach, respectively. Weight, body mass index, waist circumference, as well as total and LDL-cholesterol significantly decreased, whereas fasting plasma glucose and glycated haemoglobin significantly increased. Hyperglycaemia was documented in 81.2%, whereas gastrointestinal disturbances in 40.6% of patients. In conclusion, in the real-life clinical practice, pasireotide treatment normalizes or nearly normalizes UC in at least 68% of patients with very mild to moderate disease, with consequent improvement in weight, visceral adiposity and lipid profile, despite the occurrence or deterioration of diabetes in the majority of cases, confirming the usefulness of this treatment in patients with milder disease and without uncontrolled diabetes.

Pituitary Adenoma Apoplexy: Review of Personal Series.

BACKGROUND: Pituitary apoplexy is a life-threatening event with unspecific clinical background and no standardized treatment. MATERIALS AND METHODS: The authors retrospectively analyzed seventeen patients affected by pituitary adenoma apoplexy and treated in a 10-year period. Thirteen patients underwent surgery through transsphenoidal route while four patients have been treated conservatively. RESULTS: The endoscopic surgical procedure showed a better result in term of complete removal of the tumor while in the "conservative" group less frequent evidence of hormones' deficiency has been registered. Once a residual lesions was observed a strict radiological follow-up is mandatory. CONCLUSIONS: According to dedicated literature and pre- and post-operative evidence of personal series, the authors try to provide an algorithm that could help in the standardization of the diagnostic and therapeutic pathways in patients with pituitary adenoma apoplexy.

Diagnostic accuracy of increased urinary cortisol/cortisone ratio to differentiate ACTH-dependent Cushing's syndrome.

BACKGROUND AND AIM: Differential diagnosis between Cushing's Disease (CD) and Ectopic ACTH Syndrome (EAS) may be a pitfall for endocrinologists. The increasing use in clinical practice of chromatography and mass spectrometry improves the measurement of urinary free cortisol (UFF) and cortisone (UFE). We have recently observed that cortisol to cortisone ratio (FEr) was higher in a small series of EAS; in this study we collected a larger number of ACTH-dependent Cushing's Syndrome (CS) to study the role of FEr to characterize the source of corticotropin secretion. MATERIALS AND METHODS: High-pressure liquid chromatography with UV detection (HPLC-UV, n=35) or liquid chromatography-tandem mass spectrometry (LC-MS/MS, n=72) were used to measure UFF, UFE and FEr in 83 patients with CD and 24 with EAS. RESULTS: UFF, UFE and FEr levels were higher in EAS than in CD (UFF: 6671 vs 549 nmol/24 hours; UFE: 2069 vs 464 nmol/24 hours; FEr: 4.13 vs 0.97; all P<.001). FEr >1.15 (the best ROC-based threshold) was able to distinguish CD from EAS with 75% sensitivity (SE) and 75% specificity (SP), AUC 0.811; results were similar between HPLC-UV (SE 73%, SP 79%, AUC 0.708) and LC-MS/MS (SE 77%, SP 73%, AUC 0.834; P=.727). The diagnostic accuracy of FEr was similar to that of CRH test or high-dose dexamethasone suppression test (respectively P=.171 and P=.683), also combined. Finally, FEr was able to increase the number of correct diagnosis in patients with discordant dynamic tests. CONCLUSIONS: Urinary FEr >1.15 was able to suggest EAS, with a diagnostic accuracy similar to that of other dynamic tests proposed to study ACTH-dependent CS.

Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study.

OBJECTIVE: Evidence is limited regarding outcome of patients with ectopic Cushing's syndrome (ECS) due to neuroendocrine tumors (NETs). DESIGN: We assessed the prognostic factors affecting the survival of patients with NETs and ECS. METHODS: Retrospective analysis of clinicopathological features, severity of hormonal syndrome, treatments from a large cohort of patients with NETs and ECS collected from 17 Italian centers. RESULTS: Our series included 110 patients, 58.2% female, with mean (±s.d.) age at diagnosis of 49.5 ± 15.9 years. The main sources of ectopic ACTH were bronchial carcinoids (BC) (40.9%), occult tumors (22.7%) and pancreatic (p)NETs (15.5%). Curative surgery was performed in 56.7% (70.2% of BC, 11% of pNETs). Overall survival was significantly higher in BC compared with pNETs and occult tumors (P = 0.033) and in G1-NETs compared with G2 and G3 (P = 0.007). Negative predictive factors for survival were severity of hypercortisolism (P < 0.02), hypokalemia (P = 0.001), diabetes mellitus (P = 0.0146) and distant metastases (P < 0.001). Improved survival was observed in patients who underwent NET removal (P < 0.001). Adrenalectomy improved short-term survival. CONCLUSIONS: Multiple factors affect prognosis of ECS patients: type of NET, grading, distant metastases, severity of hypercortisolism, hypokalemia and diabetes mellitus. BCs have the highest curative surgical rate and better survival compared with occult tumors and pNETs. Hypercortisolism plays a primary role in affecting outcome and quality of life; therefore, prompt and vigorous treatment of hormonal excess by NET surgery and medical therapy should be a key therapeutic goal. In refractory cases, adrenalectomy should be considered as it affects outcome positively at least in the first 2 years.

Effects of somatostatin and its analogues on progenitor mesenchymal cells isolated from human pituitary adenomas.

PURPOSE: Progenitor mesenchymal cells (PMCs) have been found also in epithelial tumors and may derive from cancer stem cells (CSCs) by EMT mechanism. In this scenario, the effects of traditionally drugs on PMCs become of primary concern for therapeutic approaches. Previously, we isolated PMCs from acromegalic (GHomas) and not-functioning pituitary adenomas (NFPAs). Here we evaluate: (1) the role of EMT on their origin; (2) the presence of the somatostatin receptors (SSTR1-5); (3) the effects of somatostatin (SST) and its analogues (SSAs) on PMCs proliferation, apoptosis and SSTR1-5 expression. METHODS: PMCs were isolated from GHomas and NFPAs; the expression of E-CADHERIN and TGFßRII (referred to EMT), the expression of the SSTR1-5 as well as the proliferation and apoptosis were tested before and after drugs administration. RESULTS: Results show a decrease of E-CADHERIN and an increase of TGFßRII, confirming an EMT involvement; SSTR1-5 are more expressed by PMCs from GHomas than from NFPAs. SST and SSAs administration does not affect cell proliferation and SSTR1-5 expression on PMCs from NFPAs while in PMCs from GHomas, cell proliferation showed a marked decrease and a corresponding increase in the expression of SSTR1-2. Apoptosis rate and EMT were not affected by drugs administration. CONCLUSIONS: Results indicate as EMT may be related to the presence of PMCs on pituitary tumors; SSAs, currently used in the management of human GHomas, exert anti-proliferative effect also in PMCs that, because of their derivation from CSCs, may be a new meaningful target for drugs treatment.