M Boscaro

Università Politecnica delle Marche, Ancona, The Marches, Italy

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Publications (306)1058.95 Total impact

  • [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. Methods: 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, tumour size, duration of follow-up, surgical experience, year of study publication, and adverse events related to surgery were performed. Results: Of the 44 articles selected, only one reported endoscopic TSS. Data from a total of 6,400 patients who received microscopic TSS were extracted and analysed. 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 (3.1-47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for micro- versus macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience. Conclusions: 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.
    European journal of endocrinology / European Federation of Endocrine Societies. 01/2015;
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    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.
    Journal of Neuro-Oncology 01/2015; · 2.79 Impact Factor
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    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.
    Pituitary 12/2014; · 2.22 Impact Factor
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    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.
    Cancer Gene Therapy 12/2014; · 2.55 Impact Factor
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    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.
    Endocrine 12/2014; · 3.53 Impact Factor
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    ABSTRACT: Osteoporosis is a major public health problem also in men and it recognizes hypogonadism as a major cause.
    Journal of endocrinological investigation 10/2014; · 1.65 Impact Factor
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    ABSTRACT: 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.
    Journal of endocrinological investigation 10/2014; · 1.65 Impact Factor
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    ABSTRACT: Cushing's disease (CD) is associated with an increased risk of thrombotic events, particularly after surgery. No guidelines are available on the management of patients with CD undergoing pituitary transsphenoidal surgery (TSS). We aimed to compare the effectiveness of different prophylactic procedures on the prevention of thrombotic events after surgery in CD.
    Pituitary 09/2014; · 2.22 Impact Factor
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    ABSTRACT: Fracture risk data following curative treatment of Cushing's syndrome (CS) are scarce and the role of bisphosphonates in bone recovery after remission is controversial. We evaluated the effects of hypercortisolism remission in bone recovery in CS. Then, we assessed if the FRAX(®) algorithm calculated before the cure can predict fracture risk after cure.
    Journal of endocrinological investigation 07/2014; · 1.55 Impact Factor
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    ABSTRACT: Pasireotide is a multi-receptor-targeted somatostatin analogue approved in the EU and in the US for the treatment of adults with Cushing's disease (CD). Pasireotide has a safety profile similar to other somatostatin analogues with the exception of hyperglycemia. In this report and literature review, the current understanding of predicting a positive treatment response to pasireotide in CD and the management of diabetes mellitus (DM) during pasireotide treatment are discussed and analyzed.
    Pituitary 06/2014; · 2.22 Impact Factor
  • Endocrine Abstracts. 04/2014;
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    ABSTRACT: The Endocrine Society Clinical Guidelines recommend measuring 24h urinary free cortisol (UFF) using a highly accurate method as one of the first-line screening tests for the diagnosis of Cushing's Syndrome (CS). We evaluated the performance of UFF, urinary free cortisone (UFE), and the UFF/UFE ratio, measured using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The LC-MS/MS was used to analyze UFF and UFE in 43 surgically confirmed CS patients: 26 with Cushing's disease (CD, 16 de novo and 10 recurrences), 11 with adrenal and 6 with ectopic-CS; 22 CD patients in remission; 14 eu-cortisolaemic CD patients receiving medical therapy; 60 non-CS patients, and 70 healthy controls. Sensitivity and specificity were determined in the combined groups of non-CS patients, healthy controls, and CD in remission. UFF >170 nmol/24h showed 98.7% specificity and 100% sensitivity for de novo CS, whilst sensitivity was 80% for recurrent CD patients, who were characterized by lower UFF levels. The UFF/UFE and UFF+UFE showed lower sensitivity and specificity than UFF. Ectopic-CS patients had the highest UFF and UFF/UFE levels, which were normal in the CD remission patients and in those receiving medical therapy. Our data suggests high diagnostic performance of UFF excretion, measured using LC-MS/MS, in detecting de novo CS. UFF/UFE and UFF+UFE assessments are not useful in the first step of CS diagnosis, although high levels were found to be indicative of ectopic-CS.
    European Journal of Endocrinology 04/2014; · 3.69 Impact Factor
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    ABSTRACT: Late night salivary cortisol (LNSC) is useful for diagnosing hypercortisolism and monitoring patients with Cushing's disease (CD) following pituitary surgery. It may also be a better index of cortisol secretion than serum cortisol or urinary free cortisol (UFC). No data regarding the role of LNSC in the early monitoring of patients with CD receiving drug therapy has been published. We investigated the value of LNSC in monitoring the short-term efficacy of pasireotide. Seven patients who were enrolled in a phase II study investigating the efficacy of pasireotide in CD (CSOM230B2208) were included in this analysis. Patients self-administered subcutaneous pasireotide 600 μg bid for 15 days. LNSC and UFC levels were assessed at baseline and day 15. At baseline, all patients had elevated LNSC which was correlated significantly with UFC levels (r = 0.97, P = .0002). At day 15, LNSC was reduced in six patients. LNSC decreases were observed from day 1 (-20 %) and persisted until day 15 (overall mean reduction from baseline -51 %), with the greatest decrease on day 5 (-58 %). At day 15, UFC levels were decreased in all patients and normalized in one that restored also salivary cortisol rhythm. In patients with CD, pasireotide rapidly reduced and normalized both UFC and LNSC levels. LNSC may be a simple, non-invasive biomarker to assess the early response to pasireotide, particularly in determining whether cortisol rhythm is normalized in patients with normalized UFC levels. Further studies are warranted.
    Pituitary 01/2014; · 2.22 Impact Factor
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    ABSTRACT: Obesity is a complex multifactorial disease, which also has an impact on quality of life. The aim of this paper is to identify the correlates of perceived health related quality of life in obese, overweight and normal weight Italians older adults. 205 subjects at the age >= 60 yrs. were recruited into the Division of Endocrinology of the Polytechnic University of Marche Region, Ancona (Italy). A protocol of questionnaires was constructed for data collection, and included domains such as physical activity, quality of life, socio-psychological aspects. The association of the latter variables with SF-36 Health Survey physical component (PCS-36) were evaluated in the whole sample. Multiple linear regression models were used to assess the effect of independent variables on PCS-36 and the physical subscales of SF-36. PCS-36 showed a lower score in the obese and overweight subjects than the normal weight group (post-hoc test, p < 0.001 and p < 0.05 respectively). Age, gender (male), Body Mass Index, years of education, Physical Activity Scale for the Elderly (PASE) total score, Hospital Anxiety and Depression Scale anxiety, Hospital Anxiety and Depression Scale depression, number of medications prescribed and number of diseases were included in the model. Negative and significant PCS-associated variables included depression (p = 0.009), BMI (p = 0.001), age in years (p = 0.007), whereas positive and significant PCS-associated independent variables were years of education (p = 0.022), physical activity (p = 0.026). BMI was negatively associated with all the physical subscales of SF-36 (p < 0.05). Research funding should be invested in the study of the benefits accruing from reducing obesity in the elderly.
    BMC Public Health 01/2014; 14(1):35. · 2.32 Impact Factor
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    ABSTRACT: Cushing's disease is a rare chronic disease caused by a pituitary adenoma, which leads to excess secretion of adrenocorticotropic hormone (ACTH). The over-production of ACTH leads to hyperstimulation of the adrenal glands and a chronic excess of cortisol, resulting in the signs and symptoms of a severe clinical state (Cushing's syndrome) that leads to significant morbidity, negative impacts on the patient's quality of life, and, if untreated, increased mortality. The management of patients with Cushing's disease is complicated by the heterogeneity of the condition, with signs and symptoms that overlap with those of other diseases, and high subclinical incidence rates. Controversies surrounding the tests used for screening and identifying patients with Cushing's disease add to the challenge of patient management. Surgical intervention to remove the adenoma is the first-line treatment for patients with Cushing's disease, but medical therapies are useful in patients who relapse or are unsuitable for surgery. The recent introduction of pasireotide, the first pituitary-directed medical therapy, expands the number of treatment options available for patients with Cushing's disease. This state-of-the-art review aims to provide an overview of the most recent scientific research and clinical information regarding Cushing's disease. Continuing research into improving the diagnosis and treatment of Cushing's disease will help to optimize patient management.
    Endocrine 01/2014; 47(1). · 3.53 Impact Factor
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    ABSTRACT: In a basic study at the Andrology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy, we evaluated the pattern of mRNA endothelial nitric oxide synthase (eNOS) expression in human blood leucocytes isolated from normozoospermic fertile and asthenozoospermic infertile men to elucidate any pathogenic involvement in sperm cell motility. Forty infertile men with idiopathic asthenozoospermia and 45 normozoospermic fertile donors, age-matched, were included. Semen parameters were evaluated, and expression analysis of mRNA was performed in human leucocytes using reverse transcription polymerase chain reaction. Sperm volume, count, motility and morphology were determined, and eNOS expression and Western blotting analyses were performed. A positive correlation was observed between the concentrations of NO and the percentage of immotile spermatozoa. The mRNA of eNOS was more expressed in peripheral blood leucocytes isolated from asthenozoospermic infertile men versus those of fertile normozoospermic men (7.46 ± 0.38 versus 7.06 ± 0.56, P = 0.0355). A significant up-regulation of eNOS gene in peripheral blood leucocytes was 1.52-fold higher than that of fertile donors. It is concluded that eNOS expression and activity are enhanced in blood leucocytes in men with idiopathic asthenozoospermia.
    Andrologia 01/2014; · 1.17 Impact Factor
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    ABSTRACT: Introduction: The clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome. Methods: Adult patients with moderate-to-severe Cushing's disease (UFC levels >1.5xULN) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/day in two equal doses; the dose was escalated every 14 days to 10, 20, 40 and 100 mg/day until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC≤ULN or a ≥50% decrease from baseline at day 70. Results: Twelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0xULN. All 12 patients achieved UFC≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12) and headache (3/12). No serious drug-related AEs were reported. Conclusion: LCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.
    The Journal of Clinical Endocrinology and Metabolism 12/2013; · 6.31 Impact Factor
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    ABSTRACT: Functional hypercortisolism (FH) is caused by conditions able to chronically activate hypothalamic-pituitary-adrenal axis and usually occurs in cases of major depression, anorexia nervosa, bulimia nervosa, alcoholism, diabetes mellitus, simple obesity, polycystic ovary syndrome, obstructive sleep apnea syndrome, panic disorder, generalized anxiety disorder, shift work, and end-stage renal disease. Most of these states belong to pseudo-Cushing disease, a condition which is difficult to distinguish from Cushing's syndrome and characterized not only by biochemical findings but also by objective ones that can be attributed to hypercortisolism (e.g., striae rubrae, central obesity, skin atrophy, easy bruising, etc.). This hormonal imbalance, although reversible and generally mild, could mediate some systemic complications, mainly but not only of a metabolic/cardiovascular nature, which are present in these states and are largely the same as those present in Cushing's syndrome. In this review we aim to discuss the evidence suggesting the emerging negative role for FH.
    Endocrine 11/2013; 46(3). · 3.53 Impact Factor
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    ABSTRACT: This is the first study examining the impact of both clinical, biochemical, and genetic determinants in the occurrence of bone complications in patients with overt Cushing's syndrome (CS). It demonstrates that the degree and duration of hypercortisolism seem to play a major role in bone loss and fractures development in these patients. Bone loss and fractures are a common complication of CS. We investigate the role of gender, disease etiology, duration, and degree of hypercortisolism as well as the impact of glucocorticoid receptor (GR) polymorphisms on the development of bone complications in CS. Fifty-two patients with active CS (38 Cushing's disease and 14 with cortisol-secreting adrenal adenoma) were genotyped for GR polymorphisms (BclI, N363S, ER22/23EK, and A3669G). In all patients, clinical, hormonal, and biochemical markers of bone turnover, densitometric parameters [lumbar spine and left femur bone mineral density (BMD), T-score, Z-score] as well as the prevalence of bone demineralization and both vertebral and peripheral fractures were assessed. No differences were found in bone complications according to gender, disease etiology, and genetic variants distribution. Fractured patients compared to non-fractured ones showed increased levels of urinary free cortisol (UFC) and a more compromised densitometric profile. UFC levels correlated with the occurrence of vertebral fractures (r = 0.43, p = 0.009) while midnight serum cortisol correlated with L1-L4 BMD values (r = -0.35, p = 0.04). Disease duration correlated with the presence of peripheral fractures (r = 0.36, p = 0.04). While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism.
    Osteoporosis International 10/2013; 25(3). · 4.04 Impact Factor
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    ABSTRACT: In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease.
    Pituitary 08/2013; 17(4). · 2.22 Impact Factor

Publication Stats

6k Citations
1,058.95 Total Impact Points

Institutions

  • 2003–2013
    • Università Politecnica delle Marche
      • • Department of Clinical and Molecular Sciences - DISCLIMO
      • • Chair of Endocrinology
      • • Chair of Internal Medicine
      Ancona, The Marches, Italy
    • Università degli Studi di Brescia
      Brescia, Lombardy, Italy
  • 2012
    • Università degli Studi di Modena e Reggio Emilia
      Modène, Emilia-Romagna, Italy
  • 2010–2012
    • Azienda Ospedaliero Universitaria Ancona
      Ancona, The Marches, Italy
    • University Children's Hospital Basel
      Bâle, Basel-City, Switzerland
    • Massachusetts General Hospital
      • Neuroendocrine Center
      Boston, MA, United States
  • 2008
    • William Harvey Research Institute
      Londinium, England, United Kingdom
  • 1982–2008
    • University of Padova
      • • Department of Medicine DIMED
      • • Department of Molecular Medicine
      • • Department of Biomedical Sciences - DSB
      Padova, Veneto, Italy
  • 1998–1999
    • Università degli Studi di Torino
      • • Dipartimento di Scienze Chirurgiche
      • • Dipartimento di Scienze Mediche
      Torino, Piedmont, Italy
  • 1989–1993
    • University of Bologna
      • Division of Endocrinology
      Bologna, Emilia-Romagna, Italy
  • 1991–1992
    • University of Catania
      Catania, Sicily, Italy
  • 1990
    • University-Hospital of Padova
      Padua, Veneto, Italy