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Background: Recurrence of acromegaly after successful surgery is a rare event, but no clear data are reported in the literature about its recurrence rates. This study aimed to evaluate the recurrence rate in a series of acromegalic patients treated by transsphenoidal surgery (TSS) with a long follow-up., Methods: We retrospectively analyzed data from 283 acromegalic patients who underwent TSS at two pituitary units in Milan (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and IRCCS Humanitas Research Hospital). The diagnosis and recurrence of acromegaly were defined by both elevated IGF-1 levels and a lack of GH suppression based on appropriate criteria for the assay used at the time of diagnosis., Results: After surgery, 143 patients (50%) were defined as not cured, 132 (47%) as cured and 8 (3%) as partially cured because of normalization of only one parameter, either IGF1 or GH. In the cured group, at the last follow-up (median time 86.8 months after surgery), only 1 patient (0.7%) showed full recurrence (IGF-1 + 5.61 SDS, GH nadir 1.27 µg/l), while 4 patients (3%) showed only increased IGF1. In the partially cured group at the last follow-up, 2/8 (25%) patients showed active acromegaly (IGF-1 SDS + 2.75 and + 3.62; GH nadir 0.6 and 0.5 µg/l, respectively)., Conclusions: In the literature, recurrence rates range widely, from 0 to 18%. In our series, recurrence occurred in 3.7% of patients, and in fewer than 1%, recurrence occurred with elevation of both IGF-1 and the GH nadir. More frequently (25%), recurrence came in the form of incomplete normalization of either IGF-1 or GH after surgery., (© 2024. The Author(s).)

Purpose: The bone strain index (BSI) is a marker of bone deformation based on a finite element analysis inferred from dual X-ray absorptiometry (DXA) scans, that has been proposed as a predictor of fractures in osteoporosis (i.e., higher BSI indicates a lower bone's resistance to loads with consequent higher risk of fractures). We aimed to investigate the association between lumbar BSI and vertebral fractures (VFs) in acromegaly., Methods: Twenty-three patients with acromegaly (13 males, mean age 58 years; three with active disease) were evaluated for morphometric VFs, trabecular bone score (TBS), bone mineral density (BMD) and BSI at lumbar spine, the latter being corrected for the kyphosis as measured by low-dose X-ray imaging system (EOS®-2D/3D)., Results: Lumbar BSI was significantly higher in patients with VFs as compared to those without fractures (2.90 ± 1.46 vs. 1.78 ± 0.33, p = 0.041). BSI was inversely associated with TBS (rho -0.44; p = 0.034), without significant associations with BMD (p = 0.151), age (p = 0.500), BMI (p = 0.957), serum IGF-I (p = 0.889), duration of active disease (p = 0.434) and sex (p = 0.563)., Conclusions: Lumbar BSI corrected for kyphosis could be proposed as integrated parameter of spine arthropathy and osteopathy in acromegaly helping the clinicians in identifying patients with skeletal fragility possibly predisposed to VFs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ileal (I) and pancreatic (Pan) neuroendocrine tumors (NETs) are among the most common digestive neuroendocrine neoplasms (NENs). Coexisting NETs at both sites are rare, and establishing the primary or metastatic nature of the two lesions may be crucial for the appropriate treatment. We reviewed all the clinical reports of patients with INETs or PanNETs, diagnosed and treated in our ENETS Center of Excellence between 2012 and 2022. We selected patients with a history of synchronous or metachronous neuroendocrine (NE) lesions at the ileum and pancreas. For those with available histological samples from both sites, an immunohistochemistry (IHC) analysis for CDX2, Islet1, and serotonin has been performed. We found seven patients with NET in both the ileum and pancreas. F to M ratio was 4:3, and the median age at first diagnosis was 54 years (42-79). Five cases had synchronous lesions; in 2 cases, PanNETs were diagnosed respectively 8 and 56 months, after INETs. In four patients, with available histological samples from both the sites, a pathologic review and the IHC analysis have been performed, identifying three different scenarios: (i) primary INET metastatic to the pancreas, (ii) primary PanNET metastatic to the ileum, and (iii) synchronous primary PanNET and INET. In our experience, coexisting ileal and pancreatic NENs are rare occurrences. A multidisciplinary evaluation case-by-case and, whenever feasible, a comprehensive histopathological examination are needed to distinguish between metastatic and primary disease, in order to properly treat the patient., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Identifying patients requiring glucocorticoid replacement therapy after pituitary surgery is challenging as the tests commonly used for the diagnosis of secondary adrenal insufficiency (SAI) are not recommended in the immediate postoperative period. There are controversial data on the role of postoperative days' morning cortisol, with no specific data for each cortisol assay. The aim of this study is to investigate the reliability of 8.00 a.m. cortisol of the first and second postoperative days in predicting SAI., Methods: Data of patients underwent pituitary surgery in Humanitas Research Hospital in Italy, from March 2017 to August 2022, were retrospectively analyzed. Definitive diagnosis of SAI was made through ACTH test 1 µg six weeks after surgery. Cortisol was measured through Beckman Access Cortisol and the diagnosis of SAI was made if cortisol peak was below 14.8 µg/dL (408 nmol/L) at 30 or 60 min after stimulus., Results: Of the sixty-four patients enrolled, seven developed SAI. The ROC curves demonstrated that both first- and second-day postoperative 8.00 a.m. cortisol predict SAI (AUC 0.94 and 0.95, respectively). The optimal thresholds were 15.6 µg/dL (430.3 nmol/L; accuracy 89%) for the first day and 11.5 µg/dL (317.2 nmol/L, accuracy 81%) for the second day. Patients who developed SAI had larger tumors (p = 0.004) and lower fT4 (p = 0.038) before surgery., Conclusions: Clinicians might rely on the first- and second- postoperative days 8.00 a.m. cortisol to identify patients to discharge with glucocorticoid replacement therapy waiting for the confirmation of SAI through the ACTH test., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The incidence of neuroendocrine neoplasm (NEN) and related carcinoid syndrome (CaS) has increased markedly in recent decades, and women appear to be more at risk than men. As per other tumors, gender may be relevant in influencing the clinical and prognostic characteristics of NEN-associated CS. However, specific data on carcinoid syndrome (CaS) are still lacking., Purpose: To evaluate gender differences in clinical presentation and outcome of CaS., Methods: Retrospective analysis of 144 CaS patients from 20 Italian high-volume centers was conducted. Clinical presentation, tumor characteristics, therapies, and outcomes (progression-free survival, PFS, overall survival, OS) were correlated to gender., Results: Ninety (62.5%) CaS patients were male. There was no gender difference in the site of primary tumor, tumor grade and clinical stage, as well as in treatments. Men were more frequently smokers (37.2%) and alcohol drinkers (17.8%) than women (9.5%, p = 0.002, and 3.7%, p = 0.004, respectively). Concerning clinical presentation, women showed higher median number of symptoms (p = 0.0007), more frequent abdominal pain, tachycardia, and psychiatric disorders than men (53.3% vs 70.4%, p = 0.044; 6.7% vs 31.5%, p = 0.001; 50.9% vs. 26.7%, p = 0.003, respectively). Lymph node metastases at diagnosis were more frequent in men than in women (80% vs 64.8%; p = 0.04), but no differences in terms of PFS (p = 0.51) and OS (p = 0.64) were found between gender., Conclusions: In this Italian cohort, CaS was slightly more frequent in males than females. Gender-related differences emerged in the clinical presentation of CaS, as well as gender-specific risk factors for CaS development. A gender-driven clinical management of these patients should be advisable., (© 2023. The Author(s).)

Purpose: Neuroendocrine neoplasms (NENs) are tumors that arise from cells of the endocrine system and are most common in the gastrointestinal tract, the pancreas, and the lungs. Their incidence is rapidly increasing and the therapeutic options available are limited., Methods: Since the immune system can interfere with tumor growth and response to therapy, using flow cytometry we investigated the immunophenotype in samples of peripheral blood leukocytes from patients with pancreatic (Pan-NENs) and pulmonary NENs (Lung-NENs). Moreover, we performed a multiplex analysis of 13 key cytokines and growth factors essential for the immune response in the plasma of NEN patients and controls., Results: Patients presented with a higher percentage of granulocytes, a lower percentage of lymphocytes, and an increase in the granulocytes to lymphocytes ratio compared to healthy donors. These alterations were more marked in patients with metastasis. Somatostatin analogs (SSAs) restored the immunophenotype of patients to that seen in healthy donors. Finally, Pan-NEN patients showed a higher plasma concentration of IP-10, MCP-1, and IL-8 compared to healthy donors, suggesting a potential role for these cytokines as diagnostic biomarkers., Conclusion: This study highlighted differences in the immunophenotype of patients with Pan- and Lung-NENs compared to healthy individuals; these alterations were partially restored by therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Carcinoid syndrome (CS), mostly associated with small intestinal neuroendocrine tumors (SI-NETs) or lung-related NETs, is characterized by symptoms related to hormonal secretion and long-term complications, including carcinoid heart disease (CHD), which is potentially life-threatening. In the early stages of the disease, symptoms are non-specific, which leads to delayed diagnoses. The availability of reliable tumor markers is crucial for a prompt diagnosis and proper management. This review summarizes available evidence on the role of 24 h urinary 5-hydroxyindolacetic acid (24u5HIAA), which is the urinary breakdown metabolite of serotonin, in the diagnosis/follow-up of NET-related CS, with a focus on its potential prognostic role, while eventually attempting to suggest a timeline for its measurement during the follow-up of NET patients. The use of 24u5HIAA is an established biomarker for the diagnosis of NETs with CS since it shows a sensibility and specificity of 100% and 85-90%, respectively. The downside of 24u5-HIAA is represented by the need for 24 h urine collection and the risk of confounding factors (foods and medication), which might lead to false positive/negative results. Moreover, 24u5HIAA is useful in the follow-up of NETs with CS since a shorter double time correlates to a higher risk of disease progression/disease-specific mortality. Furthermore, an elevation in 24u5-HIAA is correlated with a dismal prognosis because it is associated with an increased likelihood of CHD development and disease progression/mortality. Other potentially interesting biochemical markers have been proposed, including plasmatic 5HIAA, although further standardization and prospective studies are required to define their role in the management of NETs. Meanwhile, 24u5HIAA remains the most accurate CS biomarker.

Background: While low testosterone (T) was described as a predictor of unfavorable coronavirus-disease 19 (COVID-19) outcome in men, data concerning the role of T in women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are scant and limited to small cohorts. This study investigated the relationship between serum T values and outcomes of COVID-19 in a large female hospitalized cohort., Methods: One-hundred-sixty-eight adult women (median age 77, range 18-100 years; 154 in post-menopause) hospitalized for COVID-19 were assessed for PaO2/Fio2 ratio, serum T and inflammatory parameters., Results: Median duration for hospital stay was 14.2 days (range 1-115) with overall mortality of 26% (n = 44). Subjects who died were significantly older (p < 0.001), had significantly more comorbidities (p = 0.015) and higher serum T (p = 0.040), white blood cells (p = 0.007), c-reactive protein (CRP; p < 0.001), interleukin-6 (IL-6; p < 0.001), procalcitonin (PCT; p < 0.001), lactate dehydrogenase (LDH; p = 0.001), D-dimer (p = 0.035), fibrinogen (p = 0.038) and lower serum free-triiodothyronine (FT3; p < 0.001) and luteinizing hormone (LH; p = 0.024) values. In post-menopausal women, significant associations were observed between T levels and serum CRP (rho: 0.23; p = 0.002), IL-6 (rho: 0.41; p < 0.001), LDH (rho: 0.34; p < 0.001), D-Dimer (rho: 0.21; p = 0.008), PCT (rho: 0.26; p = 0.001) and HDL cholesterol (rho:  - 0,22, p = 0.008). In multivariate regression analyses, serum T maintained the significant association with mortality after correction for age, coexistent comorbidities and serum LH and FT3, whereas it was lost after correction for inflammatory parameters., Conclusion: In females, high serum T levels might be a mirror of inflammatory phenotype and worse COVID-19 course., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Secondary Adrenal Insufficiency (SAI) is a condition characterized by inappropriately low ACTH secretion due to a disease or injury to the hypothalamus or the pituitary. The evaluation when suspected is often challenging for the non-specific symptoms, the rarity of the disease, and the pitfalls associated with laboratory tests. A prompt and correct diagnosis of SAI is essential because although an adequate hormonal replacement therapy could be lifesaving, inappropriate life-long therapy with steroids can be harmful. The gold standard test for assessing the hypothalamus-pituitary-adrenal axis (HPA) is the insulin tolerance test (ITT), but due to safety issues is not widely used. Conversely, the ACTH stimulation test is a safer and well-tolerated tool for SAI diagnosis. However, data about its diagnostic accuracy show great variability due to both technical and interpretative aspects, such as dose, route of administration, the timing of the test, and assay used for cortisol measurements. Consequently, the clinical background of the patient and the pretest probability of HPA axis impairment become of paramount importance. We aimed to summarize the recent literature evidence in the conduction and interpretation of the ACTH stimulation test for the diagnosis of SAI to provide updated insights on its correct use in clinical practice.

Purpose: The main purpose of this study was to investigate the effects of 12 months of rhPTH (1-84) (Natpar ® ) treatment in a cohort of patients selected according to the indications of hypoparathyroidism guidelines. The use of recombinant human PTH (1-84) [rhPTH (1-84)] is approved as hormonal replacement therapy in patients with hypoparathyroidism not adequately controlled with conventional therapy., Methods: It is a multicenter, observational, retro-prospective, open label study. Eleven Italian Endocrinological centers, members of Hypoparathyroidism Working Group of the Italian Society of Endocrinology (HypoparaNET) were involved. Main outcome measures were serum and urinary calcium and phosphate concentration, calcium-phosphate product, renal function, oral calcium and vitamin D doses, and clinical manifestations., Results: Fourteen adult subjects, affected by chronic hypoparathyroidism, were treated with rhPTH (1-84) for 12 months. At 12 months of rhPTH (1-84) treatment, 61.5% of patients discontinued calcium supplement and 69.2% calcitriol. Mean albumin-adjusted total serum calcium levels quickly normalized after initiation of rhPTH (1-84) treatment compared to baseline (p = 0.009), remaining in the normal range until 12 months. Rare hypo-hypercalcemia episodes were reported. Renal function was maintained normal and no renal complications were reported. Serum and urinary phosphate and urinary calcium were maintained in the normal range. Mean phosphatemia levels linearly decreased from 3 months up to 12 months compared to baseline (p = 0.014). No severe adverse events were described., Conclusions: Biochemical and clinical results confirm the efficacy and safety of rhPTH (1-84) therapy, which represents an important option for hypoparathyroid patients unresponsive to conventional therapy., (© 2022. The Author(s).)

Purpose: Parasellar ectopic pituitary adenomas (pEPAs) are extremely rare tumors located out of the sella turcica. PEPAs are heterogeneous entities in terms of anatomical localization and secretion of anterior pituitary hormones., Methods: Multicenter retrospective study. Clinical charts' consultation of patients diagnosed with parasellar lesions, to identify all subjects fulfilling the diagnostic criteria of parasellar EPAs. Systematic review of the literature focused on the medical management of prolactin-secreting pEPAs and on the prevalence of radiological bone invasion in pEPAs., Results: We identified four cases of pEPAs: (1) 54-year-old female with a prolactin-secreting suprasellar EPA successfully treated with cabergoline; (2) 74-year-old male with a non-functioning EPA of the sphenoidal sinus treated with endoscopic transsphenoidal surgery; (3) 75-year-old female with a giant lesion of the skull base (maximum diameter 7.2 cm) diagnosed as a non-functioning EPA after biopsy; (4) 49-year-old male with a silent corticotroph EPA of the sphenoidal sinus and clivus. Three out of four cases had radiological evidence of invasion of the surrounding bone structures. A systematic review of the literature highlighted that medical therapy can be effective in prolactin-secreting pEPAs. Overall, we found mention of local invasiveness in 65/147 cases (44.2%), confirmed by radiological signs of bone invasion/erosion., Conclusion: Our experience confirms the heterogeneity of pEPAs in terms of clinical and radiological presentation, as well as hormone secretion. PEPAs show a high frequency of radiological bone invasion, though similar to that of sellar pituitary adenomas. Although extremely rare, pEPAs need to be considered in the differential diagnosis of parasellar lesions., (© 2022. Italian Society of Endocrinology (SIE).)

Objective: primary empty sella (PES) represents a frequent finding, but data on hormonal alterations are heterogeneous, and its natural history is still unclear. Our aim was to evaluate the pituitary function of patients with PES over a long follow-up., Design: multicenter retrospective cohort study enrolling patients referred between 1984-2020 to five Pituitary Units, with neuroradiological confirmed PES and a complete hormonal assessment., Methods: we analyzed hormonal (including basal and dynamic evaluations), clinical and neuroradiological data collected at diagnosis and at the last visit (at least 6 months of follow-up)., Results: we recruited 402 patients (females=63%, mean age=51.5 ± 16 years) with PES (partial, total, undefined in 66%, 13% and 21%, respectively). Hypopituitarism was present in 40.5% (hypogonadism=20.4%, hypoadrenalism=14.7%, growth hormone deficiency=14.7%, hypothyroidism=10.2%, diabetes insipidus=1.5%; multiple deficiencies=11.4%) and hypeprolactinemia in 6.5%. Interestingly, hormonal alterations were diagnosed in 29% of incidental PES. Hypopituitarism was associated with male sex ( p =0.02), suspected endocrinopathy ( p <0.001), traumatic brain injury ( p =0.003) and not with age, BMI, number of pregnancies and neuroradiological grade. A longitudinal assessment was possible in 166/402 (median follow-up=58 months). In 5/166 (3%), new deficiencies occurred, whereas 14/166 (8.4%) showed a hormonal recovery. A progression from partial to total PES, which was found in 6/98 patients assessed with a second imaging, was the only parameter significantly related to the hormonal deterioration ( p =0.006)., Conclusions: this is the largest cohort of patients with PES reported. Hypopituitarism is frequent (40%) but hormonal deterioration seems uncommon (3%). Patients need to be carefully evaluated at diagnosis, even if PES is incidentally discovered., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Carosi, Brunetti, Mangone, Baldelli, Tresoldi, Del Sindaco, Lavezzi, Sala, Mungari, Fatti, Galazzi, Ferrante, Indirli, Biamonte, Arosio, Cozzi, Lania, Mazziotti and Mantovani.)

Somatostatin receptor ligands (SRLs) represent a true milestone in the medical therapy for acromegaly. The first-generation SRLs (FG-SRLs), octreotide and lanreotide, have demonstrated good efficacy in disease control and tumor shrinkage, and are still considered first-line medical therapies. The development of long-acting release (LAR) formulations has certainly improved the therapeutic tolerability of these drugs, although many patients still experience therapy-related burden. As such, new formulations have recently been developed to improve adherence and therapeutic efficacy and more solutions are on the way. In the case of FG-SRL-resistant disease, pasireotide, the only second generation SRL currently available, demonstrated superiority in disease control and tumor shrinkage compared to FG-SRLs. However, its use in clinical practice is still limited due to concern for impairment in glucose homeostasis. In this review, we discuss the news about the present and future role of SRLs in acromegaly, exploring the therapeutical frontiers of this drug class. Moreover, we provide practical guidance on the use of pasireotide, based on the data in the literature and our clinical experience.

Purpose: Hypogonadism was described in high number of male subjects with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated whether low testosterone (T) values may influence the clinical presentation and outcome of SARS-CoV-2-related pneumonia in a large population of adult males with coronavirus disease 19 (COVID-19)., Methods: Two hundred twenty one adult males hospitalized for COVID-19 at the IRCCS Humanitas Research Hospital, Rozzano-Milan (Italy) were consecutively evaluated for arterial partial pressure oxygen (PaO 2 )/fraction of inspired oxygen (FiO 2 ) ratio, serum T and inflammatory parameters at study entry, need of ventilation during hospital stay and in-hospital mortality., Results: Subjects low T values (< 8 nmol/L; 176 cases) were significantly older (P = 0.001) and had higher serum interleukin-6 (P = 0.001), C-reactive protein (P < 0.001), lactate dehydrogenase (P < 0.001), ferritin (P = 0.012), lower P/F ratio (P = 0.001), increased prevalence of low T3 syndrome (P = 0.041), acute respiratory insufficiency (P < 0.001), more frequently need of ventilation (P < 0.001) and higher mortality rate (P = 0.009) compared to subjects with higher T values. In the multivariable regression analyses, T values maintained significant associations with acute respiratory insufficiency (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.79-0.94; P < 0.001 and in-hospital mortality (OR 0.80, 95% CI 0.69-0.95; P = 0.009), independently of age, comorbidities, thyroid function and inflammation., Conclusion: Low T levels values are associated with unfavorable outcome of COVID-19. Prospective studies are needed to evaluate the long-term outcomes of hypogonadism related to COVID-19 and the clinical impact of T replacement during and after acute illness., (© 2021. Italian Society of Endocrinology (SIE).)

Background: The fourth type of multiple endocrine neoplasia (MEN) is known as a rare variant of MEN presenting a MEN1-like phenotype and originating from a germline mutation in CDKN1B. However, due to the small number of cases documented in the literature, the peculiar clinical features of MEN4 are still largely unknown, and clear indications about the clinical management of these patients are currently lacking. In order to widen our knowledge on MEN4 and to better typify the clinical features of this syndrome, we present two more cases of subjects with MEN4, and through a review of the current literature, we provide some possible indications on these patients' management., Case Presentation: The first report is about a man who was diagnosed with a metastatic ileal G2-NET at the age of 34. Genetic analysis revealed the mutation p.I119T (c.356T>C) of exon 1 of CDKN1B, a mutation already reported in the literature in association with early-onset pituitary adenomas. The second report is about a 76-year-old woman with a multifocal pancreatic G1-NET. Genetic analysis identified the CDKN1B mutation c.482C>G (p.S161C), described here for the first time in association with MEN4 and currently classified as a variant of uncertain significance. Both patients underwent biochemical and imaging screening for MEN1-related diseases without any pathological findings., Conclusions: According to the cases reported in the literature, hyperparathyroidism is the most common clinical feature of MEN4, followed by pituitary adenoma and neuroendocrine tumors. However, MEN4 appears to be a variant of MEN with milder clinical features and later onset. Therefore, these patients might need a different and personalized approach in clinical management and a peculiar screening and follow-up strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lavezzi, Brunetti, Smiroldo, Nappo, Pedicini, Vitali, Trivellin, Mazziotti and Lania.)

Purpose: Hypovitaminosis D has emerged as potential risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the general population with variable effects on the outcome of the coronavirus disease-19 (COVID-19). The aim of this retrospective single-center study was to investigate the impact of hypovitaminosis D and secondary hyperparathyroidism on respiratory outcomes of COVID-19., Methods: Three-hundred-forty-eight consecutive patients hospitalized for COVID-19 at the IRCCS Humanitas Research Hospital, Rozzano, Milan (Italy) were evaluated for arterial partial pressure oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio, serum 25hydroxy-vitamin D [25(OH)D], parathyroid hormone (PTH) and inflammatory parameters at study entry and need of ventilation during the hospital stay., Results: In the entire population, vitamin D deficiency (i.e., 25(OH)D values < 12 ng/mL) was significantly associated with acute hypoxemic respiratory failure at the study entry [adjusted odds ratio (OR) 2.48, 95% confidence interval 1.29-4.74; P = 0.006], independently of age and sex of subjects, serum calcium and inflammatory parameters. In patients evaluated for serum PTH (97 cases), secondary hyperparathyroidism combined with vitamin D deficiency was significantly associated with acute hypoxemic respiratory failure at study entry (P = 0.001) and need of ventilation during the hospital stay (P = 0.031)., Conclusion: This study provides evidence that vitamin D deficiency, when associated with secondary hyperparathyroidism, may negatively impact the clinical outcome of SARS-CoV-2-related pneumonia., (© 2021. Italian Society of Endocrinology (SIE).)

Purpose: To evaluate the post- coronavirus disease-19 (COVID-19) outcome of thyroid function in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyrotoxicosis., Methods: This was a single-center prospective study involving 29 patients (11 females, 18 males; median age 64 years, range: 43-85) with thyrotoxicosis diagnosed after hospitalization for COVID-19 and then followed-up for a median period of 90 days (range: 30-120) after hospital discharge. At follow-up, patients were evaluated for serum thyrotropin (TSH), free-thyroxine (FT4), free-triiodiothyronine (FT3), TSH receptor antibodies (TRAb), thyroglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb) and ultrasonographic thyroid structure., Results: After recovery of COVID-19, serum TSH values significantly increased (P < 0.001) and FT4 values significantly decreased (P = 0.001), without significant change in serum FT3 (P = 0.572). At follow-up, 28 subjects (96.6%) became euthyroid whereas overt hypothyroidism developed in one case. At the ultrasound evaluation of thyroid gland, hypoecogenicity was found in 10 patients (34.5%) and in these cases serum TSH values tended to be higher than those without thyroid hypoecogenity (P = 0.066). All subjects resulted to be negative for TgAb, TPOAb and TRAb., Conclusion: In a short-term follow-up, thyroid function spontaneously normalized in most subjects with SARS-CoV-2-related thyrotoxicosis. However, thyroid hypoecogenicity was found in a remarkable number of them and future longer-term studies are needed to clarify whether this ultrasonographic alteration may predispose to develop late-onset thyroid dysfunction.

Purpose: The management of pituitary adenomas in the elderly has become a relevant clinical issue, in relationship with improved life expectancy and spreading use of imaging techniques. In this single-center and retrospective study, we investigated the impact of age on peri- and postsurgical outcomes in patients undergoing transnasal sphenoidal (TNS) surgery for pituitary adenomas., Methods: One-hundred-sixty-nine patients (62% males) undergoing endoscopic transphenoidal (TNS) surgery for nonfunctioning pituitary adenomas (NFPAs) were enrolled. Patients were subdivided into three groups according to age tertiles: ≤56 (group 1), 57-69 (group 2), and ≥70 (group 3) years. Postsurgical and endocrinological outcomes were evaluated and compared among the three age groups., Results: 37/169 patients (21.9%) developed at least one perisurgical complication, without significant association with the patients' age (P = 0.838), Charlson co-morbidity score (P = 0.326), and American Society of Anesthesiologist score (P = 0.616). In the multivariate regression analysis, the adenoma size resulted the only determinant of perisurgical complication (odds ratio [OR] 1.07, 95% confidence interval [C.I.] 1.00-1.13; P = 0.044). The development and the recovery of at least one pituitary hormone deficiency were observed in 12.2% and 14.2% of patients, respectively. The risk of developing new pituitary hormone deficiencies was correlated with cavernous sinus invasion as evaluated by magnetic resonance imaging (hazard ratio [HR] 4.19, 95% C.I. 1.39-12.66; P = 0.010), whereas the probability to normalize at least one pituitary hormone deficiency was significantly correlated with younger age of patients (HR 0.27, 95% CI 0.12-0.61; P = 0.002)., Conclusions: The results of this study reinforce the concept that endoscopic TNS surgery is a safe therapeutic option in the elderly patients with NFPA, even in presence of comorbidities and high anesthetic risk.

Pancreatic neuroendocrine tumors (Pan-NETs), are heterogeneous neoplasms, whose incidence and prevalence are increasing worldwide. Pan-NETs are characterized by the expression of somatostatin receptors (SSTs). In particular, SST2 is the most widely distributed SST in NETs, thus representing the main molecular target for somatostatin analogs (SSAs). SSAs are currently approved for the treatment of well-differentiated NETs, and radionuclide-labeled SSAs are used for diagnostic and treatment purposes. SSAs, by binding to SSTs, have been shown to inhibit hormone secretion and thus provide control of hypersecretion symptoms, when present, and inhibit tumor proliferation. After SSA binding to SST2, the fate of the receptor is determined by trafficking mechanisms, crucial for the response to endogenous or pharmacological ligands. Although SST2 acts mostly through G protein-dependent mechanism, receptor-ligand complex endocytosis and receptor trafficking further regulate its function. SST2 mediates the decrease of hormone secretion via a G protein-dependent mechanism, culminating with the inhibition of adenylyl cyclase and calcium channels; it also inhibits cell proliferation and increases apoptosis through the modulation of protein tyrosine phosphatases. Moreover, SST2 inhibits angiogenesis and cell migration. In this respect, the cross-talk between SST2 and its interacting proteins, including Filamin A (FLNA) and aryl hydrocarbon receptor-interacting protein (AIP), plays a crucial role for SST2 signaling and responsiveness to SSAs. This review will focus on recent studies from our and other groups that have investigated the trafficking and signaling of SST2 in Pan-NETs, in order to provide insights into the mechanisms underlying tumor responsiveness to pharmacological treatments., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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°, and 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 [SF-36]) and pain and disability (Western Ontario and McMaster University [WOMAC])., Results: Acromegalic patients showed higher prevalence of thoracic hyperkyphosis (i.e., Cobb thoracic index ≥40°; p = 0.04) and 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 SF-36 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., (© 2020 S. Karger AG, Basel.)

Objective: This study assessed thyroid function in patients affected by the coronavirus disease-19 (COVID-19), based on the hypothesis that the cytokine storm associated with COVID-19 may influence thyroid function and/or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may directly act on thyroid cells, such as previously demonstrated for SARS-CoV-1 infection., Design and Methods: This single-center study was retrospective and consisted in evaluating thyroid function tests and serum interleukin-6 (IL-6) values in 287 consecutive patients (193 males, median age: 66 years, range: 27-92) hospitalized for COVID-19 in non-intensive care units., Results: Fifty-eight patients (20.2%) were found with thyrotoxicosis (overt in 31 cases), 15 (5.2%) with hypothyroidism (overt in only 2 cases), and 214 (74.6%) with normal thyroid function. Serum thyrotropin (TSH) values were inversely correlated with age of patients (rho -0.27; P < 0.001) and IL-6 (rho -0.41; P < 0.001). In the multivariate analysis, thyrotoxicosis resulted to be significantly associated with higher IL-6 (odds ratio: 3.25, 95% confidence interval: 1.97-5.36; P < 0.001), whereas the association with age of patients was lost (P = 0.09)., Conclusions: This study provides first evidence that COVID-19 may be associated with high risk of thyrotoxicosis in relationship with systemic immune activation induced by the SARS-CoV-2 infection.

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., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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%, p < 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.

The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (-31 ± 12%, p < 0.05 vs basal at 100 μM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (-62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

Purpose: Minimally invasive image-guided thermal ablation has been proposed as alternative to surgery for treatment of benign thyroid nodules and recurrent differentiated thyroid carcinoma. Here, we report for the first time the use of radiofrequency ablation (RFA) in a patient with non-metastatic medullary thyroid carcinoma (MTC) who did not undergo surgery due to high anesthesiological risk., Methods and Results: A 64-year-old woman was referred to our institution for a routine endocrinological visit. No thyroid-related symptoms were present. She had a history of metabolic, cardiovascular and neurological diseases. On clinical examination, a nodular lesion of about 10 mm was palpable in the right thyroid lobe; ultrasonography (US) confirmed the presence of a 13 mm thyroid nodule in the lower pole of the right lobe, that was hypoechoic and with regular margins. Serum calcitonin (Ctn) level was significantly high (647 pg/mL). Fine-needle aspiration (FNA) of the thyroid nodule was negative for malignant cells, but the marked increase of Ctn level in the FNA wash-out fluid confirmed the diagnostic suspicion of MTC. Since patient refused surgery due to high anesthesiological risk, percutaneous US-guided RFA in single session was performed. At 6-months follow-up the serum Ctn level decreased from the initial value of 647 pg/mL, reaching near-normal range (15 pg/mL), and neck ultrasound showed a complete necrosis of the tumour. Afterward, serum Ctn slowly increased to 49 pg/mL at 15-month follow-up. The US performed at 6 and 12 months of follow-up revealed fibrotic tissue in place of the thyroid nodule, without evidence of cervical lymph-node metastases., Conclusions: This clinical case suggests that RFA may be effective and safe for treatment of MTC when surgery cannot be performed.

Objective: Cardiovascular disease is a major contributor to the increased mortality of acromegalic patients. Prolongation of the QT interval is considered an established risk factor for potentially fatal cardiac arrhythmias, an event frequently observed in acromegaly. Changes in ventricular repolarization have been observed with the use of octreotide, one of the somatostatin analogues (SSA) currently used for the medical treatment of this disease. Furthermore, octreotide is listed among the drugs able to prolong the QT interval. Thus, we elected to study the effects of long-term SSA administration on QT duration and left ventricular mass (LVM) in a group of acromegalic patients., Design and Patients: In a retrospective study, 30 acromegalic patients (19 women and 11 men, aged 25-77 years) were studied under basal conditions; 24 of them (15 women and nine men, aged 25-77 years) were studied again after 3-63 months of treatment (median 18 months) with SSA. Twenty-four healthy volunteers served as controls., Measurements: Patients and controls underwent electrocardiographic (ECG) analysis, and QT interval duration corrected for heart rate (QTc) was established according to the Bazett formula. In 17 of the SSA-treated patients, M- and B-mode echocardiography for the assessment of LVM index (LVMi) was performed., Results: Baseline QTc was significantly longer in patients than in controls. SSA administration was followed by a significant decrease in QTc, which reached a mean value similar to that measured in the controls. In particular, treatment with SSA normalized QTc in three out of the six patients with abnormally elevated values at baseline. After treatment, a significant reduction in heart rate was recorded, while LVMi displayed a slight but not significant decrease., Conclusions: Acromegalic patients frequently display an abnormally prolonged QT interval, a known risk factor for potentially fatal arrhythmias. Treatment of these patients with SSA is able to improve and even normalize this alteration, probably contributing to the beneficial effects of these drugs on cardiac rhythm in this endocrine disorder. The inclusion of octreotide in the list of drugs that may increase QTc should be reconsidered as regards its indication in acromegaly.

Respiratory disorders are common and important complications in acromegaly. Patients suffering from acromegaly display a 1.6-3.3 fold increase in mortality rate, which is due to respiratory disorders in 25% of cases. In these patients, mortality for lung disease is 2-3 fold higher than in the general population. Every portion of the respiratory system may be involved. Deformities of facial bones, edema and hypertrophy of the mucosae and pharyngeal and laryngeal cartilages, enlargement of the tongue and inspiratory collapse of the hypopharinx, all may contribute to respiratory alterations. Nasal polyps, "hormonal rhinitis", changes of the voice and snoring are common occurrences. Though rarely, a laryngocele may ensue. Pneumomegaly is frequently observed and, as suggested by functional studies, might be due to an increased number rather than volume of the alveoli. An obstructive respiratory syndrome caused by mucosal thickening of the upper airways and bronchi is observed in 25% of female and 70% of male patients. The sleep apnea syndrome (SAS) affects 60-70% of acromegalic patients. SAS may be of obstructive, central or mixed type. Obstructive SAS is the prevailing form in acromegaly. It is due to intermittent obstruction of upper airways with preserved activity of the respiratory center, as testified by the remarkable thoracic and abdominal respiratory efforts. The pathogenesis of the central type of SAS is more complex. Narrowing of the upper airways may induce reflex inhibition of the respiratory center. Moreover, increased GH levels and, possibly, defects in the somatostatinergic pathways, may increase the ventilatory response of the respiratory center to carbon dioxide, thereby leading to respiratory arrest. In the mixed type of SAS, the phenomena underlying the other two forms coexist. Oxygen desaturation concomitant with the apneic episodes accounts for the frequent nocturnal wakening and diurnal drowsiness. Among the clinical correlates of SAS, arterial hypertension is of particular interest due to the close correlation existing between the two disorders. Sleep deprivation related to SAS seems per se to favor the appearance of hypertension. Moreover, short lasting hypoxemia may induce prolonged elevations of blood pressure, mediated by decreased endothelial generation of nitric oxide. Thus, since cardiovascular events are the main cause of mortality in patients with acromegaly, it is reasonable to hypothesize that SAS is involved in the reduced life span of these patients.

Mass gatherings are special situations for which mass medical care must be preplanned. Acute emergencies occur at public gatherings and medical coverage on site has proven benefit. Responsibility of general plan, management of specific problems, transport planning, communications system, guidelines and protocols, special situations management, ancillary supports, sources of extra help for unforeseen needs are the most important items to consider. In mass gatherings the whole emergency medical service (EMS) planning and management has to depend on the emergency department direction, with its authority on all aspects of patient care in the EMS system. This report concerns the planning of EMS and of medical care in a situation at risk for mass casualties at the Formula I Grand Prix-Championship Racing 'San Marino' of Imola.