Publications by authors named "Giovanna Mantovani"

140 Publications

Tolvaptan in the Management of Acute Euvolemic Hyponatremia After Transsphenoidal Surgery: A Retrospective Single-Center Analysis.

Front Endocrinol (Lausanne) 2021 24;12:689887. Epub 2021 May 24.

Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Introduction: Syndrome of inappropriate antidiuresis (SIAD) can be a complication of hypothalamus-pituitary surgery. The use of tolvaptan in this setting is not well established, hence the primary aim of this study was to assess the sodium correction rates attained with tolvaptan compared with standard treatments (fluid restriction and/or hypertonic saline). Furthermore, we compared the length of hospital stay in the two treatment groups and investigated the occurrence of overcorrection and side effects including osmotic demyelination syndrome.

Methods: We retrospectively reviewed 308 transsphenoidal surgical procedures performed between 2011 and 2019 at our hospital. We selected adult patients who developed post-operative SIAD and recorded sodium monitoring, treatment modalities and outcomes. Correction rates were adjusted based on pre-treatment sodium levels.

Results: Twenty-nine patients (9.4%) developed post-operative SIAD. Tolvaptan was administered to 14 patients (median dose 15 mg). Standard treatments were employed in 14 subjects (fluid restriction n=11, hypertonic saline n=1, fluid restriction and hypertonic saline n=2). Tolvaptan yielded higher adjusted sodium correction rates (12.0 mmolL/24h and 13.4 mmolL/48h) than standard treatments (1.8 mmolL/24h, p<0.001, and 4.5 mmolL/48h, p=0.004, tolvaptan). The correction rate exceeded 10 mmolL/24h or 18 mmolL/48h in 9/14 and 2/14 patients treated with tolvaptan, respectively, and in no patient who received standard treatments. No side effects including osmotic demyelination occurred. Tolvaptan was associated with a shorter hospital stay (1115 days, p=0.01).

Conclusions: Tolvaptan is more effective than fluid restriction (with or without hypertonic saline) and allows for a shortened hospital stay in patients with SIAD after transsphenoidal surgery. However, its dose and duration should be carefully tailored, and close monitoring is recommended to allow prompt detection of overcorrection.
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http://dx.doi.org/10.3389/fendo.2021.689887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181462PMC
May 2021

USP8 inhibitor RA-9 reduces ACTH release and cell growth in tumor corticotrophs.

Endocr Relat Cancer 2021 Jun 1. Epub 2021 Jun 1.

G Mantovani, Department of Clinical Sciences and Community Health, University of Milan, Milano, Italy.

Cushing's Disease (CD) is a rare endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. Pasireotide is the only pituitary-targeted drug approved for adult patients. Nevertheless, many side effects are encountered and a curative therapy is still challenging. Ubiquitin Specific Peptidase 8 (USP8) plays a crucial role in the modulation of corticotroph cells growth and ACTH secretion. Here, we explored the anticancer potential of the USP8 inhibitor RA-9 in USP8-wild type human tumor corticotroph cells and murine AtT-20 cells. Our results showed that RA-9 causes cell proliferation decrease (-24.3±5.2%, P<0.01) and cell apoptosis increase (207.4±75.3%, P<0.05) in AtT-20 cells, as observed with pasireotide. Moreover, RA-9 reduced ACTH secretion in AtT-20 cells (-34.1±19.5%,P<0.01), as well as in AtT-20 cells transfected with USP8 mutants, and in 1 out of 2 primary cultures in vitro responsive to pasireotide (-40.3±6%). A RA-9 mediated decrease of pERK1/2 levels was observed in AtT-20 cells (-52.3±13.4%, P<0.001), comparable to pasireotide, and in primary cultures, regardless of their in vitro responsiveness to pasireotide. Upregulation of p27 was detected upon RA-9 treatment only, both in AtT-20 cells (167.1±36.7%, P<0.05) and 1 primary culture tested (168.4%), whilst pCREB level was similarly halved in AtT-20 cells by both RA-9 and pasireotide. Altogether, our data demonstrate that RA-9 is efficient in exerting cytotoxic effects and inhibitory actions on cell proliferation and hormone secretion by modulating the expression of pERK1/2, pCREB and p27. Inhibition of USP8 might represent a novel strategy to target both USP8-wild type and USP8-mutated tumors in CD patients.
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http://dx.doi.org/10.1530/ERC-21-0093DOI Listing
June 2021

Clinical and hormonal findings in patients presenting with high IGF-1 and growth hormone suppression after oral glucose load - a retrospective cohort study.

Eur J Endocrinol 2021 Jun 1. Epub 2021 Jun 1.

G Mantovani, Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.

Objective: high IGF-1 and unsuppressed GH levels after glucose load confirm the diagnosis of acromegaly. Management of patients with conflicting results could be challenging. Our aim was to evaluate the clinical and hormonal evolution over a long follow-up in patients with high IGF-1 but normal GH nadir (GHn<0.4 μg/L according to the latest guidelines).

Design: retrospective cohort study.

Methods: we enrolled 53 patients presenting high IGF-1 and GHn<0.4 μg/L, assessed because of clinical suspicion of acromegaly or in other endocrinological contexts (e.g., pituitary incidentaloma). Clinical and hormonal data collected at the first and last visit were analyzed.

Results: at the first evaluation, the mean age was 54.1±15.4 years, 34/53 were females, median IGF-1 and GHn were +3.1 SDS and 0.06 μg/L, respectively. In the whole group, over a median time of 6 years, IGF-1 and GHn levels did not significantly change (IGF-1 mean of differences -0.58, p=0.15; GHn +0.03, p=0.29). In patients with clinical features of acromegaly, the prevalence of acromegalic comorbidities was higher than in the others (median of 3 vs 1 comorbidities per patient, p=0.005), especially malignancies (36% vs 6%, p=0.03), and the clinical worsening overtime was more pronounced (4 vs 1 comorbidities at the last visit).

Conclusions: in patients presenting high IGF-1 but GHn<0.4 μg/L, a hormonal progression is improbable, likely excluding classical acromegaly on its early stage. However, despite persistently low GH nadir values, patients with acromegalic features present more acromegalic comorbidities whose rate increases over time. Close clinical surveillance in this group is advised.
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http://dx.doi.org/10.1530/EJE-21-0024DOI Listing
June 2021

PTH resistance.

Mol Cell Endocrinol 2021 Jul 11;531:111311. Epub 2021 May 11.

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Via Lamarmora 5, 20122, Milan, Italy. Electronic address:

Parathyroid hormone (PTH), which is primarily regulated by extracellular calcium changes, controls calcium and phosphate homeostasis. Different diseases are derived from PTH deficiency (hypoparathyroidism), excess (hyperparathyroidism) and resistance (pseudohypoparathyroidism, PHP). Pseudohypoparathyroidism was historically classified into subtypes according to the presence or not of inherited PTH resistance associated or not with features of Albright's hereditary osteodystrophy and deep and progressive ectopic ossifications. The growing knowledge on the PTH/PTHrP signaling pathway showed that molecular defects affecting different members of this pathway determined distinct, yet clinically related disorders, leading to the proposal of a new nomenclature and classification encompassing all disorders, collectively termed inactivating PTH/PTHrP signaling disorders (iPPSD).
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http://dx.doi.org/10.1016/j.mce.2021.111311DOI Listing
July 2021

The "Parachute" Technique for the Endoscopic Repair of High-Flow Anterior Skull-Base CSF Leaks.

World Neurosurg 2021 May 8. Epub 2021 May 8.

Department of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; "Aldo Ravelli" Research Center, Milan, Italy; Department of Medical-Surgical Physiopathology and Transplantation, University of Milan, Milan, Italy.

Objective: This study aims to assess the feasibility and reliability of our endoscopic trans-nasal technique for the repair of cribriform and sellar high-flow cerebrospinal fluid (CSF) leaks.

Methods: A comparison between patients suffering from high-flow rhinorrhea and treated through a free grafting endoscopic technique or the "parachute" technique, our nasal packing proposal, was performed.

Results: Thirty-three patients were included. The mean age was 52 years (range: 36-68 years). The etiology of the CSF leaks was iatrogenic in 16 cases (48.5%), traumatic in 5 cases (15.2%), spontaneous in 11 cases (33.3%), and related to anterior skull base tumors in 1 case (3%). The bone defect affected the sphenoidal sinus in 20 cases (60.6%), the cribriform plate of the ethmoid in 10 cases (30.3%), and both the sphenoid and ethmoid in 3 cases (9.1%). The mean size of bone defects was 8.5 ± 3.9 mm. The median follow-up was 28 (64) months. A CSF leak recurrence occurred in no cases treated with the parachute technique and in 3 cases that underwent conventional endoscopic treatments. The CSF leak recurrences were associated with 2 iatrogenic and 1 post-traumatic fistula. All the CSF leak recurrences underwent the parachute technique, not showing second recurrences.

Conclusions: Our results suggest that the parachute technique is simple, safe, and effective. We recommend it as an alternative treatment to vascular flaps for the treatment of high-flow and recurrent fistulas.
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http://dx.doi.org/10.1016/j.wneu.2021.05.006DOI Listing
May 2021

Pseudohypoparathyroidism: focus on cerebral and renal calcifications.

J Clin Endocrinol Metab 2021 Mar 29. Epub 2021 Mar 29.

University Hospital of Pisa, Endocrine Unit 2, Pisa, Italy.

Context: Pseudohypoparathyroidism (PHP) is a group of disorders characterized by hypocalcemia, hyperphosphatemia and elevated PTH levels, as a result of end-organ resistance to PTH.

Objective: To describe a cohort of 26 patients with PHP, followed in a single tertiary center.

Design: Clinical, biochemical, radiological and genetic analysis of the GNAS gene were collected in 26 patients recruited since 2002.

Results: Ten patients harbored a GNAS mutation, 15 epigenetic abnormalities at the GNAS locus and one was negative. According to clinical, biochemical and genetic features, patients were classified as PHP1A, PHP1B and PPHP.

Patients: with PHP1A had an earlier diagnosis and more cases with family history, Albright hereditary osteodystrophy features (AHO), hormonal resistance and hypertension. Obesity was a common feature. No difference in biochemical values was present among PHP1A and PHP1B. Intracerebral calcification occurred in 72% of patients with no difference among PHP1A and PHP1B subgroups. No significant difference was observed between patients with and without intracerebral calcification for the time-weighted average values of total serum calcium, phosphate, calcium-phosphate product and PTH fold increase. A borderline association between cerebral calcification and age at the time of diagnosis (P =0.04) was found in the whole cohort of patients.No renal calcifications were found in the overall cohort.

Conclusions: Patients with PHP1A more frequently have AHO features as well as hypertension compared to PHP1B. PHP patients presented a high rate of intracerebral calcification with no significant difference between subgroups. No increased risk of renal calcifications was also found in the entire cohort.
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http://dx.doi.org/10.1210/clinem/dgab208DOI Listing
March 2021

A Novel Mechanism Regulating Dopamine Receptor Type 2 Signal Transduction in Pituitary Tumoral Cells: The Role of cAMP/PKA-Induced Filamin A Phosphorylation.

Front Endocrinol (Lausanne) 2020 16;11:611752. Epub 2021 Feb 16.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

The actin binding protein filamin A (FLNA) is required for somatostatin receptor 2 (SSTR2) and dopamine receptor 2 (DRD2) expression and signaling in GH- and PRL-secreting PitNETs, respectively, playing a role in tumor responsiveness to somatostatin receptors ligands and dopaminergic drugs. FLNA functions are regulated by several mechanisms, including phosphorylation. It has been shown that in GH-secreting PitNETs FLNA phosphorylation on Ser2152 (P-FLNA) switches FLNA function from a scaffold that allows SSTR2 signal transduction, to a signal termination protein that hampers SSTR2 antitumoral effects. Aims of the present study were to evaluate in PRL- and ACTH-secreting PitNETs cell lines MMQ and AtT-20 the effects of cAMP pathway activation and DRD2 agonist on P-FLNA and the impact of P-FLNA on DRD2 signal transduction. We found that forskolin increased (+2.2 ± 0.8-fold, p < 0.01 in MMQ; +1.9 ± 0.58-fold, p < 0.05 in AtT-20), and DRD2 agonist BIM53097 reduced (-49.4 ± 25%, p < 0.001 in MMQ; -45.8 ± 28%, p < 0.05 in AtT-20), P-FLNA on Ser2152. The overexpression of a phosphomimetic (S2152D) FLNA mutant in both cell lines prevented DRD2 antiproliferative effects, that were comparable in cells transfected with empty vector, wild-type FLNA as well as phosphodeficient FLNA mutant (S2152A) (-20.6 ± 5% cell proliferation, p < 0.001 in MMQ; -36.6 ± 12%, p < 0.01 in AtT-20). Accordingly, S2152D FLNA expression abolished the expected ability of BIM53097 to increase or decrease, in MMQ and in AtT20 respectively, ERK phosphorylation, an effect that was maintained in S2152A FLNA expressing cells (+1.8 ± 0.65-fold, p < 0.05 in MMQ; -55 ± 13%, p < 0.01 in AtT-20). In addition, the inhibitory effects of DRD2 on hormone secretion (-34.3 ± 6% PRL, p < 0.05 in MMQ; -42.8 ± 22% ACTH, p < 0.05 in AtT-20, in cells expressing S2152A FLNA) were completely lost in S2152D FLNA transfected cells. In conclusion, our data demonstrated that cAMP pathway and DRD2 agonist regulated FLNA activity by increasing or decreasing, respectively, its phosphorylation. Moreover, we found that P-FLNA prevented DRD2 signaling in PRL- and ACTH-secreting tumoral pituitary cell lines, suggesting that this FLNA modification might represent a new regulatory mechanism shared by different GPCRs. In PitNETs expressing DRD2, modulation of P-FLNA might suggest new pharmacological strategies to overcome drug resistance, and P-FLNA might represent a new biomarker for tumor responsiveness to dopaminergic agents.
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http://dx.doi.org/10.3389/fendo.2020.611752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921166PMC
May 2021

Corrigendum to 'Arterial Embolization and Second-Look in Spindle Cell Oncocytoma of the Pituitary Gland: Case Report and Review of Literature' [World Neurosurgery 142 (2020) 87-92].

World Neurosurg 2021 Apr 23;148:269. Epub 2021 Jan 23.

Unit of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; "Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

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http://dx.doi.org/10.1016/j.wneu.2020.12.156DOI Listing
April 2021

Pituitary tumors: genetic and molecular factors underlying pathogenesis and clinical behavior.

Neuroendocrinology 2021 Feb 1. Epub 2021 Feb 1.

Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.
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http://dx.doi.org/10.1159/000514862DOI Listing
February 2021

Case Report: Late-Onset Congenital Adrenal Hyperplasia and Acute Covid-19 Infection in a Pregnant Woman: Multidisciplinary Management.

Front Endocrinol (Lausanne) 2020 15;11:602535. Epub 2021 Jan 15.

Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: The impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH).

Case Description: A woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On second day, the mother was in good condition and was switched to oral steroid therapy. On third day she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition.

Conclusions: We report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.
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http://dx.doi.org/10.3389/fendo.2020.602535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845779PMC
February 2021

Filamin A is required for somatostatin receptor type 5 expression and pasireotide-mediated signaling in pituitary corticotroph tumor cells.

Mol Cell Endocrinol 2021 03 9;524:111159. Epub 2021 Jan 9.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy.

Somatostatin receptor type 5 (SST5) represents the main pharmacological target in the treatment of adrenocorticotroph hormone (ACTH)-secreting tumors. However, molecular predictors of responsiveness to pasireotide require further investigation. The cytoskeleton protein filamin A (FLNA) modulates the responsiveness to somatostatin analogs (SSA) treatment in other types of pituitary tumors by regulating somatostatin receptor type 2 (SST2)/dopamine receptor type 2 (DRD2) expression and activity. Here, we aimed to test the involvement of FLNA in the modulation of SST5 response to SSA in human and murine tumor corticotrophs. Western blot analysis of human corticotropinomas showed that FLNA and SST5 correlate. Both in human primary cultures and AtT-20 cells, FLNA genetic silencing caused a decrease of receptor expression level. Moreover, pasireotide-mediated SST5 downregulation observed in AtT-20 control cells was no further detected in FLNA silenced cells. In AtT-20 cells, in situ PLA experiments revealed an increased number of SST5-FLNA complexes following pasireotide incubation. Finally, FLNA knock down abolished pasireotide-induced SST5 actions on hormone secretion, cell proliferation and apoptosis. In conclusion, FLNA is implicated in SST5 expression modulation and signaling.
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http://dx.doi.org/10.1016/j.mce.2021.111159DOI Listing
March 2021

Hyperandrogenism by Liquid Chromatography Tandem Mass Spectrometry in PCOS: Focus on Testosterone and Androstenedione.

J Clin Med 2020 Dec 31;10(1). Epub 2020 Dec 31.

Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

The identification of hyperandrogenism in polycystic ovary syndrome (PCOS) is concerning because of the poor accuracy of the androgen immunoassays (IA) and controversies regarding which androgens should be measured. The aim of our study was to evaluate the impact of the assessment of testosterone (T) and androstenedione (A) by liquid chromatography in tandem with mass spectrometry (LC/MS-MS), in the diagnosis of PCOS. We evaluated 131 patients referred for suspected PCOS. Fourteen patients in total were excluded, some because of other diagnosis ( = 7) or incomplete diagnostic workup ( = 7). We measured T and A both by IA and LC-MS/MS in the 117 subjects included. We calculated free T (fT) by the Vermeulen formula and recorded clinical and metabolic data. 73 healthy females served as controls to derive immunoassays (IA) and LC-MS/MS reference intervals for T, fT and A. PCOS was confirmed in 90 subjects by IA and in 93 (+3.3%) by LC-MS/MS. The prevalence of biochemical hyperandrogenism in PCOS by LC-MS/MS increased from 81.7% to 89.2% if A was also considered. The most frequently elevated androgens were fT (73.1%) and A (64.5%) and they had similar levels of accuracy in differentiating PCOS and controls (0.34 ng/dL, Sn 91% Sp 89%; 1.16 ng/mL, Sn 91% Sp 88%, respectively). Free testosterone correlated with body mass index (BMI), homeostatic model assessment (HOMA)-index, glycated hemoglobin (HbA1c), and sex-binding globulin (SHBG). The results confirm that LC-MS/MS is slightly more sensitive than IA in the diagnosis of PCOS with LC-MS/MS detecting higher levels of fT and A. Moreover, assessment of fT and A by LC-MS/MS had a similar level of accuracy in discriminating between PCOs and control subjects. Lastly, fT by LC-MS/MS correlates with adverse metabolic parameters.
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http://dx.doi.org/10.3390/jcm10010119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795755PMC
December 2020

Procoagulant Imbalance in Klinefelter Syndrome Assessed by Thrombin Generation Assay and Whole-Blood Thromboelastometry.

J Clin Endocrinol Metab 2021 Mar;106(4):e1660-e1672

Fondazione IRCCS Ca' Granda Ospedale Maggiore, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.

Context: Klinefelter syndrome (KS) is a condition at increased risk of thrombosis compared to 46,XY men.

Objective: This work aimed to investigate the coagulation balance of KS patients by thrombin generation assay (TGA) and thromboelastometry.

Methods: An observational, cross-sectional study was conducted at 3 tertiary endocrinological centers in Milan, Italy. Fifty-eight KS patients and 58 age-matched healthy controls were included. Anticoagulant or antiplatelet therapy and known coagulation disorders were exclusion criteria. TGA was performed in platelet-poor plasma (PPP) and platelet-rich plasma (PRP). Whole-blood thromboelastometry and activities of coagulation factors were assessed. Endogenous thrombin potential (ETP), the area under the thrombin generation curve, assessed with and without thrombomodulin (ETP-TM+ and ETP-TM-), and their ratio (ETP ratio), were considered as indexes of procoagulant imbalance.

Results: Patients with KS displayed higher PPP-ETP-TM+ (mean 1528 vs 0.1315 nM × min; P < .001), PPP-ETP ratio (0.78 vs 0.0.70; P < .001), factor (F)VIII (135% vs 0.107%; P = .001), fibrinogen (283 vs 0.241 mg/dL; P < .001), and FVIII/protein C ratio (1.21 vs 0.1.06; P < .05) compared to controls. Protein C was comparable in the 2 groups. Similar results were observed in PRP. The ETP ratio was positively associated with FVIII (ρ = 0.538, P < .001) in KS. Thromboelastometry parameters confirmed evidence of hypercoagulability in KS.

Conclusion: Patients with KS display a procoagulant imbalance expressed by increased thrombin generation both in PPP and PRP, which is at least in part explained by increased FVIII levels. The procoagulant imbalance, which was confirmed by thromboelastometry, may be responsible for the thrombotic events observed in these patients. Further investigation on the benefit/risk ratio of antithrombotic prophylaxis is warranted.
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http://dx.doi.org/10.1210/clinem/dgaa936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993570PMC
March 2021

Inactivating PTH/PTHrP signaling disorders (iPPSDs): evaluation of the new classification in a multicenter large series of 544 molecularly characterized patients.

Eur J Endocrinol 2021 Feb;184(2):311-320

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy.

Objective: Pseudohypoparathyroidism and related disorders belong to a group of heterogeneous rare diseases that share an impaired signaling downstream of Gsα-protein-coupled receptors. Affected patients may present with various combination of symptoms including resistance to PTH and/or to other hormones, ectopic ossifications, brachydactyly type E, early onset obesity, short stature and cognitive difficulties. Several years ago we proposed a novel nomenclature under the term of inactivating PTH/PTHrP signaling disorders (iPPSD). It is now of utmost importance to validate these criteria and/or improve the basis of this new classification.

Design: Retrospective study of a large international series of 459 probands and 85 relatives molecularly characterized.

Methods: Information on major and minor criteria associated with iPPSD and genetic results were retrieved from patient files. We compared the presence of each criteria according to the iPPSD subtype, age and gender of the patients.

Results: More than 98% of the probands met the proposed criteria for iPPSD classification. Noteworthy, most patients (85%) presented a combination of symptoms rather than a single sign suggestive of iPPSD and the overlap among the different genetic forms of iPPSD was confirmed. The clinical and molecular characterization of relatives identified familial history as an additional important criterion predictive of the disease.

Conclusions: The phenotypic analysis of this large cohort confirmed the utility of the major and minor criteria and their combination to diagnose iPPSD. This report shows the importance of having simple and easily recognizable signs to diagnose with confidence these rare disorders and supports a better management of patients.
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http://dx.doi.org/10.1530/EJE-20-0625DOI Listing
February 2021

Pseudohypoparathyroidism, acrodysostosis, progressive osseous heteroplasia: different names for the same spectrum of diseases?

Endocrine 2021 Jun 11;72(3):611-618. Epub 2020 Nov 11.

Endocrinology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Pseudohypoparathyroidism (PHP), the first known post-receptorial hormone resistance, derives from a partial deficiency of the α subunit of the stimulatory G protein (Gsα), a key component of the PTH/PTHrP signaling pathway. Since its first description, different studies unveiled, beside the molecular basis for PHP, the existence of different subtypes and of diseases in differential diagnosis associated with genetic alterations in other genes of the PTH/PTHrP pathway. The clinical and molecular overlap among PHP subtypes and with different but related disorders make both differential diagnosis and genetic counseling challenging. Recently, a proposal to group all these conditions under the novel term "inactivating PTH/PTHrP signaling disorders (iPPSD)" was promoted and, soon afterwards, the first international consensus statement on the diagnosis and management of these disorders has been published. This review will focus on the major and minor features characterizing PHP/iPPSDs as a group and on the specificities as well as the overlap associated with the most frequent subtypes.
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http://dx.doi.org/10.1007/s12020-020-02533-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159830PMC
June 2021

Adrenal Insufficiency at the Time of COVID-19: A Retrospective Study in Patients Referring to a Tertiary Center.

J Clin Endocrinol Metab 2021 03;106(3):e1354-e1361

Endocrinology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.

Context: Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency (AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis.

Objective: Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients.

Design And Setting: We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas.

Patients: We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses.

Intervention: By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences.

Results: In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52).

Conclusions: AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls.
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http://dx.doi.org/10.1210/clinem/dgaa793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665569PMC
March 2021

VERTEBRAL FRACTURES ASSOCIATED WITH SPINAL SAGITTAL IMBALANCE AND QUALITY OF LIFE IN ACROMEGALY: A RADIOGRAPHIC STUDY WITH EOS 2D/3D TECHNOLOGY.

Neuroendocrinology 2020 Sep 25. Epub 2020 Sep 25.

Introduction: Acromegaly is commonly complicated by arthropathy and skeletal fragility with high risk of vertebral fractures (VFs).

Objective: This study aimed to assess whether VFs may be associated with sagittal spine deformities, arthropathy, impaired quality of life (QoL), pain and disability.

Methods: Thirty-eight patients with acromegaly (median age 55 years, 20 males) and 38 matched-control subjects were evaluated by a low dose sagittal and coronal planes, X-ray imaging system (EOS®-2D/3D) for morphometric VFs, radiological signs of spine arthropathy and spine deformities (Cobb thoracic index ≥ 40°, pelvic incidence minus lumbar lordosis ≥ 10°, pelvic tilt > 20°, sagittal vertical axis ≥ 4 cm) determining sagittal spine imbalance. Acromegalic patients were also evaluated by questionnaires for QoL (Acromegaly QoL Questionnaire [AcroQoL] and Short Form-36 [SF36]), pain and disability (Western Ontario and Mc Master University [WOMAC].

Results: Acromegalic patients showed higher prevalence of thoracic hyperkyphosis (i.e., Cobb thoracic index ≥ 40°; p=0.04), pelvic tilt > 20° (p=0.02) than control subjects. VFs were found in 34.2% of acromegalic patients (p=0.003 vs. control subjects), in relationship with higher prevalence of hyperkyphosis (p=0.03), pelvic tilt > 20° (p=0.04), sagittal vertical axis ≥ 4 cm (p=0.03) and moderate/severe subchondral degeneration (p=0.01). Moreover, patients with VFs had lower AcroQoL general health (p=0.007) and SF36 general health (p=0.002) scores and higher WOMAC pain (p=0.003) and global (p=0.009) scores than patients who did not fracture.

Conclusions: In acromegaly, VFs may be associated with spine deformities and sagittal imbalance, spine arthropathy, impaired QoL and disability.
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http://dx.doi.org/10.1159/000511811DOI Listing
September 2020

Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients.

Horm Res Paediatr 2020 5;93(3):182-196. Epub 2020 Aug 5.

Molecular (Epi)Genetics Laboratory, BioAraba Research Health Institute, Araba University Hospital-Txagorritxu, Vitoria-Gasteiz, Spain.

Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
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http://dx.doi.org/10.1159/000508985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140671PMC
August 2020

Metformin and Everolimus: A Promising Combination for Neuroendocrine Tumors Treatment.

Cancers (Basel) 2020 Aug 2;12(8). Epub 2020 Aug 2.

Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy.

Introduction: Treatment options for neuroendocrine tumors (NETs) are rarely curative, as NETs frequently show resistance to medical therapy. The use of everolimus, an mTOR inhibitor, is limited by the development of resistance, probably due to the activation of Akt signaling. In this context, the antidiabetic drug metformin is able to inhibit mTOR, providing a rationale for the use of metformin and everolimus in combination.

Methods: We investigated the effects of the metformin and everolimus combination on NET cell proliferation, apoptosis, colony formation, cell viability, NET spheroids growth and the involvement of the Akt and mTOR pathways, and also developed everolimus-resistant NET cells to further study this combination.

Results: Metformin and everolimus in combination are more effective than monotherapy in inhibiting pancreatic NET (PAN-NET) cell proliferation (-71% ± 13%, < 0.0001 vs. basal), whereas no additive effects were observed on pulmonary neuroendocrine tumor (PNT) cell proliferation. The combinatorial treatment is more effective than monotherapy in inhibiting colony formation, cell viability, NET spheroids growth rate and mTOR phosphorylation in both NET cell lines. In a PAN-NET cell line, metformin did not affect Akt phosphorylation; conversely, it significantly decreased Akt phosphorylation in a PNT cell line. Using everolimus-resistant NET cells, we confirmed that metformin maintained its effects, acting by two different pathways: Akt-dependent or independent, depending on the cell type, with both leading to mTOR suppression.

Conclusions: Considering the promising effects of the everolimus and metformin combination in NET cells, our results provide a rationale for its use in NET patients.
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http://dx.doi.org/10.3390/cancers12082143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464161PMC
August 2020

Growth hormone therapy at the time of Covid-19 pandemic: adherence and drug supply issues.

Eur J Endocrinol 2020 Oct;183(4):L13-L15

Endocrinology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1530/EJE-20-0481DOI Listing
October 2020

The suprasellar volume of nonfunctioning pituitary adenomas: a useful tool for predicting visual field deficits.

Pituitary 2020 Oct;23(5):552-557

Department of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Via Francesco Sforza, 20122, Milan, Italy.

Purpose: The aim of the present study is to assess the predictive value of the suprasellar volume (SSV) of nonfunctioning pituitary adenomas (NFPAs) for visual field (VF) impairment in order to guide clinical decision-making and improve neurosurgical management.

Methods: Two independent samples of patients with NFPAs (exploratory population N = 50, testing population N = 98) were included in the present study. In the first phase, we determined the optimal cut-off value of the SSV correlating with VF deficits in the exploratory population. In the second phase, we then studied the accuracy of identified cut-off in predicting a VF deficit in the testing population.

Results: In the exploratory population, the optimal cut-off value of the SSV to determine the presence of a VF deficit was 1.5 mL. Sensitivity and specificity of the cut-off were 81.3 and 100%, respectively. The positive predictive value (PPV) and the negative predictive value (NPV) were 100 and 75%, respectively. When we checked the identified cut-off score on the testing population, we found a sensitivity of 71% and a specificity of 100%. The PPV and NPV were 100 and 59.2%, respectively. In six cases with VF defects and SSV inferior to 1.5 mL, the displacement of optic chiasm was in superior position.

Conclusion: The SSV may represent an accurate method in routinely clinical practice for predicting VF deficit in patients affected by NFPA.
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http://dx.doi.org/10.1007/s11102-020-01060-0DOI Listing
October 2020

Prevalence and determinants of radiological vertebral fractures in patients with Klinefelter syndrome.

Andrology 2020 11 21;8(6):1699-1704. Epub 2020 Jul 21.

Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Italy.

Background: Klinefelter syndrome (KS) may induce skeletal fragility, but the studies so far published on this topic were mainly focused on the evaluation of bone mineral density (BMD) and bone microstructure, whereas data on fracture risk are still lacking.

Objective: To evaluate the prevalence and determinants of vertebral fractures (VFs), that is, the hallmark of osteoporosis, in subjects with KS.

Materials And Methods: Eighty-seven patients with KS (median age 41 years, range 18-64) were consecutively evaluated for radiological VFs (by quantitative morphometry) and lumbar spine and femoral neck BMD (by DXA). Fifty-five patients with KS were also evaluated by the fracture risk assessment (FRAX) tool.

Results: Low BMD was found in 22/87 (25.3%) patients [12 with osteopenia, three with osteoporosis and seven with "low BMD per age" (subject < 50 years with Z-score ≤-2.0 SD)] and VFs in 13/87 (14.9%) patients. In patients with VFs, the median spine deformity index was 2 (range 1-9). Prevalence of VFs was similar between healthy and low-BMD patients (15.9% vs 13.6%; P = .80). Noteworthy, patients with VFs had significantly higher age at diagnosis of KS as compared to patients who did not fracture (P = .039), without significant differences in age at the time of observation (P = .162), body mass index (P = .234), testosterone replacement therapy (P = .432), duration of testosterone therapy (P = .409), vitamin D therapy (P = 681), and serum testosterone levels (P = .338). Moreover, patients with VFs were more likely to complain back pain in comparison with those without VFs (33.3% vs 7.4%; P = .047). In 55 cases evaluated by the FRAX® tool, no significant differences in 10-year risk of major fracture (P = .270) and hip fracture (P = .860) were found between fractured and non-fractured patients.

Conclusions: This study provides first evidence that KS may be associated with risk of VFs in close relationship with delay in disease diagnosis but independently of BMD values and serum testosterone levels or testosterone therapy.
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http://dx.doi.org/10.1111/andr.12841DOI Listing
November 2020

Central hypogonadism in Klinefelter syndrome: report of two cases and review of the literature.

J Endocrinol Invest 2021 Mar 14;44(3):459-470. Epub 2020 Jun 14.

Laboratorio di Ricerche Endocrino-Metaboliche, Dipartimento di Medicina Endocrino-Metabolica, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149, Milan, Italy.

Purpose: Klinefelter syndrome (KS) is characterized by late adolescence/young adulthood onset of primary hypogonadism. Hypogonadotropic hypogonadism (HH), when congenital, is usually associated with absent/incomplete puberty and low/normal gonadotropins. We report the clinical and genetic features of two subjects with KS and an unexpected HH hormone profile.

Methods: Magnetic resonance imaging (MRI) of hypothalamus-pituitary region and next generation sequencing (NGS) of congenital HH-associated genes were obtained. A narrative review of the literature was conducted.

Results: Patients were diagnosed with Klinefelter syndrome following karyotype analysis. Nevertheless, they showed unusual features: both had incomplete puberty, low gonadotropins and testosterone levels, and the first one was anosmic. Sellar lesions were excluded by MRI, and NGS was negative in both subjects. Our data add to those of the only 14 similar cases reported so far. Unexplained HH rarely occurs in KS and is variably associated with anosmia, other pituitary hormones deficiencies and heterogeneous karyotypes. However, most cases show an early, pre-pubertal onset of hypogonadism. If the causes behind this gonadotropins defect are largely unknown, hereby we provide the first review of the literature on this topic and propose some pathogenetic hypotheses, including the coexistence of KS and congenital HH as suggested by overlapping clinical features in some of these patients.

Conclusion: HH is an exceptional occurrence in Klinefelter syndrome and is associated with heterogeneous phenotypes and, probably, aetiologies. Moreover, KS could underlie HH nonresponsive to gonadotropins. An exhaustive diagnostic workup and a tailored clinical management are advisable in these rare forms.
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http://dx.doi.org/10.1007/s40618-020-01324-3DOI Listing
March 2021

Arterial Embolization and Second-Look in Spindle Cell Oncocytoma of the Pituitary Gland: Case Report and Review of Literature.

World Neurosurg 2020 10 7;142:87-92. Epub 2020 Jun 7.

Unit of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; ‟Aldo Ravelli" Research Center for Neurotechnology and Experimental Brain Therapeutics, University of Milan, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Background: Spindle cell oncocytomas are extremely rare neoplasms of the sellar, parasellar, and suprasellar regions that can frequently mimic pituitary adenomas. Fewer than 50 cases have been ever reported in the literature, and there is no consensus on best treatments to be provided.

Case Description: We hereby present a challenging case of sellar and suprasellar spindle cell oncocytoma in a patient of 64 years. The patient, who presented with hydrocephalus, hypopituitarism, and visual deficit, underwent urgent transsphenoidal (TNS) resection of the mass, which was aborted for massive life-threatening bleeding. The patient received ventriculoperitoneal shunt with relief of symptoms. An endovascular embolization of tumor feeders from the distal portion of the right internal maxillary artery, in particular the sphenopalatine artery, was then performed and a second-look TNS surgery was feasible. The patient was discharged in optimal clinical condition, recovered both endocrinologic and visual deficits, and is now in follow-up.

Conclusions: We found that the oncocytoma was radiologically and clinically comparable with a pituitary adenoma, except for higher representation of vasculature. According to our recent experience and review of the literature, we believe that surgery (transsphenoidal or transcranial approach) is the recommended treatment in those who are symptomatic and preoperative embolization might be a suitable option to reduce intraoperative bleeding and increase radicality.
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http://dx.doi.org/10.1016/j.wneu.2020.05.255DOI Listing
October 2020

Beta-Arrestin 2 Is Required for Dopamine Receptor Type 2 Inhibitory Effects on AKT Phosphorylation and Cell Proliferation in Pituitary Tumors.

Neuroendocrinology 2021 8;111(6):568-579. Epub 2020 Jun 8.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.

Dopamine receptor type 2 (DRD2) agonists are the first-choice treatment for prolactin-secreting pituitary tumors but are poorly effective in nonfunctioning pituitary neuroendocrine tumors (NF-PitNETs). DRD2 reduces AKT phosphorylation in lactotrophs, but no data are available in NF-PitNETs. DRD2 effects on AKT are mediated by a β-arrestin 2-dependent mechanism in mouse striatum. The aim of this study was to investigate DRD2 effects on AKT phosphorylation and cell proliferation in human primary cultured NF-PitNET cells and in rat tumoral lactotroph cells MMQ, and to test β-arrestin 2 involvement. We found that the DRD2 agonist BIM53097 induced a reduction of the p-AKT/total-AKT ratio in MMQ (-32.8 ± 17.6%, p < 0.001 vs. basal) and in a subset (n = 15/41, 36.6%) of NF-PitNETs (subgroup 1). In the remaining NF-PitNETs (subgroup 2), BIM53097 induced an increase in p-AKT. The ability of BIM53097 to reduce p-AKT correlated with its antimitotic effect, since the majority of subgroup 1 NF-PitNETs was responsive to BIM53097, and nearly all subgroup 2 NF-PitNETs were resistant. β-Arrestin 2 was expressed in MMQ and in 80% of subgroup 1 NF-PitNETs, whereas it was undetectable in 77% of subgroup 2 NF-PitNETs. In MMQ, β-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, β-arrestin 2 transfection in subgroup 2 NF-PitNETs conferred to BIM53097 the ability to inhibit both p-AKT and cell growth. In conclusion, we demonstrated that β-arrestin 2 is required for DRD2 inhibitory effects on AKT phosphorylation and cell proliferation in MMQ and NF-PitNETs, paving the way for a potential role of β-arrestin 2 as a biomarker predicting NF-PitNETs' responsiveness to treatment with dopamine agonists.
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http://dx.doi.org/10.1159/000509219DOI Listing
June 2020

Treatment of Acromegalic Osteopathy in Real-life Clinical Practice: The BAAC (Bone Active Drugs in Acromegaly) Study.

J Clin Endocrinol Metab 2020 09;105(9)

Endocrinology, Diabetology and Medical Andrology Unit, Osteoporosis and Metabolic Bone Disease Section, Humanitas Clinical and Research Center, IRCCS, Rozzano-Milan, Italy.

Background: Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting.

Objective: To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly.

Study Design: Retrospective, longitudinal study including 9 tertiary care endocrine units.

Patients And Methods: Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ± 13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132).

Results: During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007).

Conclusions: Bone active drugs may prevent VFs in patients with active acromegaly.
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http://dx.doi.org/10.1210/clinem/dgaa363DOI Listing
September 2020

TNM 8th edition in thyroid cancer staging: is there an improvement in predicting recurrence?

Endocr Relat Cancer 2020 06;27(6):325-336

Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy.

TNM 8th edition introduces changes in the staging of patients with differentiated thyroid carcinoma (DTC). This study aims at assessing the value of TNM 8th edition in predicting response to therapy and structural recurrence of DTC. Four hundred and eighty DTC patients were retrospectively evaluated by 7th and 8th editions of TNM staging system in relationship with risk stratification, response to therapy and recurrence of disease as defined by 2015 ATA guidelines. As compared to the 7th edition, TNM 8th led to downstage 136 patients (28.3%), with 97.5% of patients falling into lower stages (I-II) and only 2.5% remaining in higher stages (III-IV) (P < 0.001). Patients who were downstaged in stages I-II by TNM 8th were classified more frequently at intermediate-high risk (P < 0.001), had more frequently structural incomplete response to therapy (P = 0.009) and had higher risk of structural recurrence (P = 0.002) as compared to patients who were in the same TNM stages but were not downstaged. Specifically, the risk of structural recurrence was significantly higher in patients in whom the downstaging was induced by changes in tumour classification (hazard ratio (HR) 6.18, 95% CI 2.20-17.40; P = 0.001) but not in those who were downstaged for the increase in age cut-off (HR 2.80, 95% CI 0.86-9.19; P = 0.09). In conclusion, TNM 8th edition did not show reliability in predicting aggressiveness of DTC. In fact, the downstaging of DTC patients especially when performed due to changes in tumour classification may overlook patients predisposed to structural recurrence, potentially causing uncertainty in the therapeutic decision-making at the time of disease's diagnosis.
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http://dx.doi.org/10.1530/ERC-19-0412DOI Listing
June 2020

Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology.

Cells 2020 01 25;9(2). Epub 2020 Jan 25.

Laboratory of Experimental Neurosurgery and Cell Therapy, Neurosurgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of "tumor education", characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network's complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.
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http://dx.doi.org/10.3390/cells9020294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072723PMC
January 2020

A severe inactivating PTH/PTHrP signaling disorder type 2 in a patient carrying a novel large deletion of the GNAS gene: a case report and review of the literature.

Endocrine 2020 02 14;67(2):466-472. Epub 2020 Jan 14.

Endocrine Unit 2, University Hospital of Pisa, Pisa, Italy.

Purpose: Pseudohypoparathyroidism (PHP), characterized by multihormone resistance and Albright's hereditary osteodystrophy (AHO), is caused by GNAS mutations. Whole or partial gene deletions are rare. All disorders due to inactivating mutations of the GNAS gene are now classified as "inactivating PTH/PTHrP signaling disorder type 2" (iPPSD2). This study reports a family harboring a large GNAS gene deletion in order to improve the knowledge of genotype-phenotype correlation of this disease.

Methods: An 18-year-old man with severe diffuse soft ossifications and multihormone resistance underwent to clinical, biochemical, radiological, and genetic studies. A review of the literature of other cases of iPPSD2 due to GNAS large deletions was performed focusing on clinical and biochemical features.

Results: The proband presented signs of hypocalcemia and marked AHO features. Laboratory tests revealed hypocalcemia, high levels of serum phosphate, PTH, TSH, and calcitonin despite therapy with calcium carbonate, calcitriol, and levothyroxine. Diffuse soft tissue ossifications and brain calcifications were shown by radiological exams. Family history was remarkable for hypocalcemia, neurocognitive impairment, and cerebral calcifications in his brother and AHO features in the maternal grandfather. The proband's mother showed short stature, whereas physical examination of the father was unremarkable. Genetic analysis of the GNAS gene revealed an unreported large deletion encompassing exons 1-7 in the proband, brother, and mother. By reviewing the literature, only six other cases were described.

Conclusions: We report a kindred harboring a large GNAS deletion. A genotype-phenotype correlation was observed in term of severity of tissue ossifications in the siblings but not in the mother.
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http://dx.doi.org/10.1007/s12020-020-02195-7DOI Listing
February 2020