[Show abstract][Hide abstract] ABSTRACT: Mitogen-activated protein kinase (MAPK) pathway is often deregulated in adrenocortical tumors (ACT) but with no concrete data confirming alteration rate. The objective of this study was to evaluate genetic alterations in key components of MAPK pathway. We found one BRAF mutation (p.V600E) and four HRAS silent mutations. No alteration was found in NRAS, KRAS, EGFR genes. The patient carrying BRAF mutation was further characterized by investigating his biomolecular and clinico-pathological findings. Therefore, even if MAPK signaling is activated in ACT, our results suggest that genetic alterations do not seem to represent a frequent mechanism of ACT tumorigenesis.
Preview · Article · Nov 2015 · Cancer Investigation
[Show abstract][Hide abstract] ABSTRACT: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAFV600E may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Being obese or overweight is often associated with impaired quality of life and psychological well-being (PWB) in comparison with normal-weight people (Giuli
, 2014), both in developed and developing countries. PWB is considered a very important correlate of subjective well-being in people with excess weight. The concept of PWB is based on Ryff's multidimensional model (Ryff, 2014), which considers well-being as eudaemonic concept, and includes six dimensions: autonomy, environmental mastery, personal growth, positive relations with others, purpose in life, and self-acceptance. Few studies have analyzed the role of specific correlates of perceived well-being in the obese and overweight Italian older population. The purpose of this study was to evaluate the role of perceived well-being in obese and overweight older adults. Our study included 124 overweight and obese older participants, aged 60 years or more, selected from patients attending the Division of Endocrinology, Department of Clinical and Molecular Sciences of Polytechnic University of Marche (Italy). As previously described (Giuli
, 2014), the participants were recruited on the basis of specific inclusion/exclusion criteria, in a period of three years (January 2010–December 2012).
No preview · Article · Aug 2015 · International Psychogeriatrics
[Show abstract][Hide abstract] ABSTRACT: As initial screening for Cushing's syndrome (CS) the Endocrine Society guidelines recommend one of the following: the 1-mg dexamethasone suppression test (DST), or late-night salivary cortisol (LNSC), or urinary free cortisol (UFC) measurement. We examined the diagnostic performance of the above-mentioned tests in a series of patients.
We retrospectively analyzed 137 patients with clinical conditions suggestive of hypercortisolism: 38 with confirmed CS diagnosis and 99 without (termed non-CS). UFC was measured by LC-MS/MS, while LNSC by radio-immunometric method and serum cortisol by chemiluminescence immunoassay.
Comparing CS versus non-CS, a cutoff of 138 nmol/L after 1-mg DST revealed the best specificity (SP, 97%), while the 50 nmol/L cutoff confirmed the best sensitivity (SE, 100%); the SE and SP for LNSC >14.46 nmol/L were respectively 84% and 89%, while for UFC >170 nmol/24h they were 97% and 91%. Overall, UFC revealed both a combined higher positive and a lower negative likelihood ratio among first-line tests (respectively 10.7 and 0.03). Computing a ROC-contrast analysis to compare the power of each single test with that of the others, alone or combined (DST+LNSC, DST+UFC and LNSC+UFC), or with that of all the tests together (DST+LNSC+UFC), UFC assay was at least as good as all the other possible combinations.
Measuring UFC by LC-MS/MS achieves the best accuracy in diagnosing CS among patients presenting with suspected hypercortisolism.
No preview · Article · Aug 2015 · The Journal of Clinical Endocrinology and Metabolism
[Show abstract][Hide abstract] ABSTRACT: Measurement of cortisol levels in saliva is a marker of free hormone. How salivary cortisol rhythm is affected by age, gender, the metabolic syndrome and estrogen-progestin therapy was evaluated in a community sample of adults.
One hundred twenty volunteers recruited from the Hospital staff and family members of the Endocrinology Unit were instructed to collect 7 salivary samples: the first on awakening (F(0)) and 6 more (F(1.5), F(5), F(6), F(10), F(11.5) and F(14)) over the next 14 hours. Each volunteer also underwent a complete physical evaluation and a comprehensive medical history was taken. Salivary cortisol was measured using a radioimmunometric assay. Daily cortisol secretion was evaluated computing the Area Under the Curve (AUC(F0)(→)(F14)); the F(14)/F(0) ratio was calculated as a marker of cortisol rhythm.
Median F(14) levels were higher in the subjects in the third tertile of age than in those falling in the second or in the first age tertile (respectively, 2.09 vs 1.33 vs 1.25 ng/mL, p=0.023 and p=0.006), in the hypertensive volunteers (2.44 vs 1.44 ng/mL, p=0.030) and in those with the metabolic syndrome (2.95 vs 1.4 ng/mL, p=0.002), with an elevated median F(14)/F(0) ratio (0.48 vs 0.19, p=0.006). According to the Kruskal-Wallis analysis of variance, the most important factor affecting F(14) value was age (p=0.001). AUC(F0)(→)(F14) was not influenced by gender, age, metabolic syndrome or estrogen-progestin therapy.
While it did not affect the daily cortisol rate, late-night salivary cortisol levels were found to be increased in the subjects in the higher age tertile and in those with the metabolic syndrome.
[Show abstract][Hide abstract] ABSTRACT: Cushing's syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a 'CS-VTE score' from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis.
[Show abstract][Hide abstract] ABSTRACT: Bilateral macronodular adrenal hyperplasia (BMAH) is a rare form of Cushing's syndrome (CS). A variety of in vivo tests to identify aberrant receptor expression have been proposed to guide medical treatment. Unilateral adrenalectomy (UA) may be effective in selected patients but little is known about recurrence during follow-up.
To describe a series of patients with BMAH and CS treated by different approaches, with a particular focus on the benefit of UA.
We retrospectively assessed 16 patients with BMAH and CS (11 females, 5 males), analysing the in vivo cortisol response to different provocative tests. Twelve of the 16 patients underwent UA and were monitored over the long-term.
Based on in vivo test results, octreotide LAR or propranolol were administered in one case of food-dependent CS and two patients with a positive postural test. A significant improvement in biochemical values was seen in all patients but with limited clinical response. UA was performed in 12 patients, producing long-term remission in three (106 ± 28 months; range: 80-135), recurrence in eight (after 54 ± 56 months; range 12-180) and persistence in one other. Four patients subsequently underwent contralateral adrenalectomy for overt CS, one received ketoconazole and four other patients remain under observation for subclinical CS. Conclusions: Medical treatment based on cortisol response to provocative tests had a limited role in our patients, whereas UA was useful in some of them. Although recurrence is likely, the timing of onset is variable and close follow-up is mandatory in order to identify it. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
No preview · Article · Mar 2015 · Clinical Endocrinology
[Show abstract][Hide abstract] ABSTRACT: CUSHING’S DISEASE: Excessive corticotroph hormone levels sustained by an adrenocorticotropic hormone-secreting pituitary adenoma lead to a severe clinical condition caused by excess cortisol secretion, called Cushing's disease (CD). Neurosurgery and radiotherapy are used to treat the pituitary adenoma directly, but new medical treatments targeting the corticotroph cells have recently become available.
This is a novel multireceptor ligand somatostatin (SST) analog with a high binding affinity for SST receptor 5, the predominant receptor in human corticotroph adenomas that is not downregulated by high cortisol levels (as SST receptor 2 is). Pasireotide has been recently approved by the European Medical Agency and the US Food and Drug Administration for treating adults with CD with recurrent hypercortisolism after surgery, or for whom surgery is not an option. A dose of 600-1,200 μg twice a day can normalize urinary free cortisol levels after 3 months of treatment in up to 28% of patients, reducing their blood pressure and improving their weight, lipid profile, and quality of life. Combining pasireotide with cabergoline to achieve a greater hormone response can normalize cortisol secretion in 50% of patients, and adding ketoconazole induces biochemical control in most patients with CD.
The adverse effects of pasireotide are similar to those of other SST analogs, including diarrhea, nausea, and biliary sludge or gallstones. Hyperglycemia is common during pasireotide treatment, which affects the secretion of pancreatic insulin and intestinal glucagon-like peptide 1. Self-monitoring is essential to achieve good metabolic control, and endocrinologists should first administer metformin if insulin resistance is evident and then add dipeptidyl peptidase 4 inhibitors/glucagon-like peptide 1 receptor agonists or insulin.
In recent years, medical treatment with pasireotide has been proposed as monotherapy for adults with CD characterized by mild to moderate hypercortisolemia, as well as in combination with other available therapies. It is generally well-tolerated, but endocrinologists need to monitor glucose levels to ensure prompt treatment.
Full-text · Article · Mar 2015 · Therapeutics and Clinical Risk Management
[Show abstract][Hide abstract] ABSTRACT: Objective:
A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease - including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence.
We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed.
Data from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0-96.6%; median, 77.9%) and recurrence (0-47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience.
The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.
Full-text · Article · Jan 2015 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Aggressive pituitary adenomas (PAs) are clinically challenging for endocrinologists and neurosurgeons due to their locally invasive nature and resistance to standard treatment (surgery, medical or radiotherapy). Two pituitary-directed drugs have recently been proposed: temozolomide (TMZ) for aggressive PA, and pasireotide for ACTH-secreting PA. We describe the experience of our multidisciplinary team of endocrinologists, neurosurgeons, neuroradiologists, oncologists, otolaryngologists and pathologists with TMZ and pasireotide treatment for aggressive PAs in terms of their radiological shrinkage and genetic features. We considered five patients with aggressive PA, three of them non-secreting (two ACTH-silent and one becoming ACTH secreting), and two secreting (one GH and one ACTH). TMZ was administrated orally at 150–200 mg/m2 daily for 5 days every 28 days to all 5 patients, and 2 of them also received pasireotide 600–900 µg bid sc. We assessed the MRI at the baseline and during TMZ or pasireotide treatment. We also checked for MGMT promoter methylation and IDH, BRAF and kRAS mutations. Considering TMZ, two patients showed PA progression, one stable disease and two achieved radiological and clinical response. Pasireotide was effective in reducing hypercortisolism and mass volume, combined with TMZ in one case. Both treatments were generally well tolerated; one patient developed a grade 2 TMZ-induced thrombocytopenia. None of patients developed hypopituitarism while taking TMZ or pasireotide treatment. No genetic anomalies were identified in the adenoma tissue. TMZ and pasireotide may be important therapies for aggressive PA, alone or in combination.
No preview · Article · Jan 2015 · Journal of Neuro-Oncology
[Show abstract][Hide abstract] ABSTRACT: Report the efficacy and safety of pasireotide sc in patients with Cushing's disease during an open-ended, open-label extension to a randomized, double-blind, 12-month, Phase III study.
162 patients entered the core study. 58 patients who had mean UFC ≤ ULN at month 12 or were benefiting clinically from pasireotide entered the extension. Patients received the same dose of pasireotide as at the end of the core study (300-1,200 μg bid). Dose titration was permitted according to efficacy or drug-related adverse events.
40 patients completed 24 months' treatment. Of the patients who entered the extension, 50.0 % (29/58) and 34.5 % (20/58) had controlled UFC (UFC ≤ ULN) at months 12 and 24, respectively. The mean percentage decrease in UFC was 57.3 % (95 % CI 40.7-73.9; n = 52) and 62.1 % (50.8-73.5; n = 33) after 12 and 24 months' treatment, respectively. Improvements in clinical signs of Cushing's disease were sustained up to month 24. The most frequent drug-related adverse events in patients who received ≥1 dose of pasireotide (n = 162) from core baseline until the 24-month cut-off were diarrhea (55.6 %), nausea (48.1 %), hyperglycemia (38.9 %), and cholelithiasis (31.5 %). No new safety issues were identified during the extension.
Reductions in mean UFC and improvements in clinical signs of Cushing's disease were maintained over 24 months of pasireotide treatment. The safety profile of pasireotide is typical for a somatostatin analogue, except for the frequency and degree of hyperglycemia; patients should be monitored for changes in glucose homeostasis. Pasireotide represents the first approved pituitary-targeted treatment for patients with Cushing's disease.
[Show abstract][Hide abstract] ABSTRACT: The Cancer Stem Cells (CSCs) theory suggests that genetic alterations in stem cells are the direct cause for cancer. The evidence for a CSC population that results in pituitary tumors is poor. Some studies report the isolation of CSCs, but a deep characterization of the stemness of these cells is lacking. Here, we report the isolation and detailed characterization of progenitor mesenchymal cells (PMCs) from both growth hormone-secreting (GH(+)) and non-secreting (NS) pituitary adenomas, determining the immunophenotype, the expression of genes related to stemness or to pituitary hormone cell types, and the differentiative potential towards osteo-, chondro- and adipogenic lineages. Finally, the expression of CD133, known as a marker for CSCs in other tumors, was analyzed. Isolated cells, both from GH(+) and NS tumors, satisfy all the criteria for the identification of PMCs and express known stem cell markers (OCT4, SOX2, KLF4, NANOG), but do not express markers of pituitary hormone cell types (PITX2, PROP1, PIT1). Finally, PMCs express CD133. We demonstrated that pituitary tumors contain a stem cell population that can generate cell types characteristic of mesenchymal stem cells, and express CD133, which is associated with CSCs in other tumors.Cancer Gene Therapy advance online publication, 19 December 2014; doi:10.1038/cgt.2014.63.
Full-text · Article · Dec 2014 · Cancer Gene Therapy
[Show abstract][Hide abstract] ABSTRACT: Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing's disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6 months; range 1-9 months) were available for sixteen patients. All patients received at 09:00 h a single subcutaneous (sc) injection of 600 μg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2 h for 8 h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600 μg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9 ± 24.3 and 48.1 ± 25.4 % compared to baseline. LNSC decreased in about 82 % of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68 % of patients. A fall >27 % of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91 %; specificity 100 %; positive predictive value 100 %; negative predictive value 75 %). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27 % as well as a LNSC normalization during PST is associated with a probability of 100 % of achieving a favorable response to pasireotide treatment in the medium/long term.
[Show abstract][Hide abstract] ABSTRACT: Background
Osteoporosis is a major public health problem also in men and it recognizes hypogonadism as a major cause.
To investigate the possible pathogenetic mechanisms on bone impairment in male hypogonadism and on its improvement in response to testosterone replacement treatment (TRT).
We retrospectively investigated the hormonal profile and bone mineral density (BMD), evaluated by DXA, in 17 middle-aged hypogonadal men treated for at least 5 years with TRT, compared with 21 recently diagnosed untreated hypogonadal males and 18 age- and BMI-matched healthy subjects.
No significant differences in clinical, biochemical and densitometric parameters were found among the three groups, with the exception of 25-OH vitamin D levels that were significantly higher in healthy subjects compared with hypogonadal patients. Untreated patients affected by central hypogonadism, despite similar hormonal levels, displayed significantly lower BMD and decreased LH and 25-OH vitamin D levels, compared with patients with primary hypogonadism. Among the treated patients, BMD parameters were similar regardless of the formulation of TRT.
A recent history of central hypogonadism, compared with primary hypogonadism, appears to adversely affect bone health independently of gonadal steroids levels. This could be due to lower LH levels and consequent reduction of vitamin D 25-hydroxylation in the testis.
No preview · Article · Oct 2014 · Journal of endocrinological investigation
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Several clinical studies testify the critical role played by estrogens in male bone metabolism. The aim of our study is to assess the effect of a single injection of testosterone enanthate in a group of hypogonadal men on 17β estradiol serum levels and some bone metabolic parameters.
Twenty-one hypogonadal males were given one testosterone enanthate injection (250 mg). Blood samples were drawn before the injection and after 1, 2 and 3 weeks. The following variables were measured: Total testosterone (TT), 17β estradiol (17β E2), Sex hormone binding globulin, total alkaline phosphatase, osteocalcin, and C-telopeptide of type I collagen (CTx).
After testosterone injection, both TT and 17β E2 increased, peaking 1 week after the injection. Individual observation of the response of 17β E2 to testosterone showed that a subgroup (n = 9) failed to respond with any increase in 17β E2 at any of the weekly tests (group E2-), while the remainder (n = 12) showed a significant increase in 17β E2, which reached a mean value three times higher than at baseline (group E2+). The E2- patients reached a TT peak lower than that observed in the E+ group. CTx serum levels declined progressively in the E2+ group, reaching the significance (p = 0.03) at the end of the study, while it did not change in E- group.
This study suggests that a single injection of testosterone might have different effects on the production of endogenous estrogens, and a significant reduction of bone resorption parameters takes place only in the patients who show a significant increase of 17ß estradiol in response to testosterone administration.
No preview · Article · Oct 2014 · Journal of endocrinological investigation