A pharmacoeconomic analysis from Italian guidelines for the management of prolactinomas.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure's specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

Urinary 5-Hydroxyindolacetic Acid Measurements in Patients with Neuroendocrine Tumor-Related Carcinoid Syndrome: State of the Art.

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.

The complementary role of PSMA expression and [18F]FDG PET/CT in predicting thyroid cancer outcome: from black and white to shades of gray, in the era of precision oncology.

BACKGROUND: The value of Prostate Specific Membrane Antigen (PSMA) in thyroid carcinoma (TC) is still unknown. We aimed to test the potential complementary role of PSMA expression and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) uptake on PET/CT as biomarkers for TC outcome prediction. MATERIALS AND METHODS: From a retrospective cohort of TC patients we selected those fulfilling the following inclusion/exclusion criteria: thyroidectomy in our Institution, available primary tumor tissue PSMA immunostaining, [18F]FDG PET/CT and follow-up data. PSMA staining was visually assessed. PET/CT was considered positive in case of [18F]FDG uptake higher than the background at the site of TC confirmed by cyto-/histology, and/or follow-up. Disease recurrence, radioiodine refractoriness (RAI-R) and status at last follow-up (LFU) were used as outcome endpoints. RESULTS: We included 23 subjects. Disease recurrence occurred in 18 patients (median time 11 months, range 1-40); among these 12/18 developed RAI-R (median time 28 months, range 2-221), and 13/18 had evidence of disease at LFU. PSMA expression was negative in 6/23 cases. PET/CT was negative in 11/23 patients (7/11 experienced recurrence). PET/CT was positive in 9/12 patients showing RAI-R and 10/13 cases with evidence of disease at LFU. All patients with positive PET/CT had a positive PSMA immunostaining. Six out of 11 patients with negative PET/CT were positive at immunostaining, showing lower PSMA expression (median score of 30%, range 0-80%) than patients with positive PET/CT. The TC samples without PSMA expression belonged to patients who resulted negative also at PET/CT (3 experienced recurrence, 2 were RAI-R, and 1 had disease at LFU). Four out of 11 patients who resulted negative at PET/CT exhibited very high PSMA expression (≥ 70%) and although 3 of them experienced recurrence, none resulted RAI-R, and only 1 had persistent disease at LFU. CONCLUSIONS: Primary tumor PSMA expression and [18F]FDG uptake seem to play a complementary prognostic role in TC. The majority of patients who expressed PSMA recurred. In the intermediate ATA risk class, patients with negative PSMA immunostaining recurred less than patients expressing PSMA. Additionally, although patients with a negative [18F]FDG PET/CT had a favourable long-term outcome, PSMA assessment might be useful to timely identify subjects at higher risk of recurrence.

Gastric Neuroendocrine Tumors (g-NETs): A Systematic Review of the Management and Outcomes of Type 3 g-NETs.

PURPOSE: to collect data from real-life experiences of the management of type 3 g-NETs and identify possible prognostic factors that may impact the decision-making process. METHODS: We performed a systematic review of the literature on type 3 g-NET management using the PubMed, MEDLINE, and Embase databases. We included cohort studies, case series, and case reports written in the English language. RESULTS: We selected 31 out of 556 articles from between 2001 and 2022. In 2 out of the 31 studies, a 10 mm and 20 mm cut-off size were respectively associated with a higher risk of gastric wall infiltration and/or lymph node and distant metastasis at diagnosis. The selected studies reported a higher risk of lymph node or distant metastasis at diagnosis in the case of muscularis propria infiltration or beyond, irrespective of the dimensions or grading. From these findings, size, grading, and gastric wall infiltration seem to be the most relevant factors in management staff making choices and prognoses of type 3 g-NET patients. We produced a hypothetical flowchart for a standardized approach to these rare diseases. CONCLUSION: Further prospective analyses are needed to validate the prognostic impact of the use of size, grading, and gastric wall infiltration as prognostic factors in the management of type 3 g-NETs.

Italian Guidelines for the Management of Prolactinomas.

INTRODUCTION: This guideline (GL) is aimed at providing a reference for the management of prolactin (PRL)-secreting pituitary adenoma in adults. However, pregnancy is not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinologi (AME) has identified potentially relevant outcomes, which have then been rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" have been considered in the systematic review of evidence and only those classified as "critical" have been considered in the formulation of recommendations. RESULTS: The present GL provides recommendations regarding the role of pharmacological and neurosurgical treatment in the management of prolactinomas. We recommend cabergoline (Cab) vs. bromocriptine (Br) as the firstchoice pharmacological treatment to be employed at the minimal effective dose capable of achieving the regression of the clinical picture. We suggest that medication and surgery are offered as suitable alternative first-line treatments to patients with non-invasive PRL-secreting adenoma, regardless of size. We suggest Br as an alternative drug in patients who are intolerant to Cab and are not candidates for surgery. We recommend pituitary tumor resection in patients 1) without any significant neuro-ophthalmologic improvement within two weeks from the start of Cab, 2) who are resistant or do not tolerate Cab or other dopamine-agonist drugs (DA), 3) who escape from previous efficacy of DA, and 4) who are unwilling to undergo a chronic DA treatment. We recommend that patients with progressive disease notwithstanding previous tumor resection and ongoing DA should be managed by a multidisciplinary team with specific expertise in pituitary diseases using a multimodal approach that includes repeated surgery, radiotherapy, DA, and possibly, the use of temozolomide. CONCLUSION: The present GL is directed to endocrinologists, neurosurgeons, and gynecologists working in hospitals, in territorial services or private practice, and to general practitioners and patients.

Time-dependent effect of GLP-1 receptor agonists on cardiovascular benefits: a real-world study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown cardiovascular benefits in cardiovascular outcome trials in type 2 diabetes mellitus. However, the most convincing evidence was obtained in subjects with established cardiovascular (CV) disease. We analyzed the determinants of GLP-1 RA-mediated CV protection in a real-world population of persons with type 2 diabetes with and without a history of CV events with long-term follow-up. METHODS: Retrospective cohort study of 550 individuals with type 2 diabetes (395 in primary CV prevention, 155 in secondary CV prevention), followed at a single center after the first prescription of a GLP-1 RA between 2009 and 2019. CV and metabolic outcomes were assessed. RESULTS: Median duration of follow-up was 5.0 years (0.25-10.8) in primary prevention and 3.6 years (0-10.3) in secondary prevention, with a median duration of treatment of 3.2 years (0-10.8) and 2.5 years (0-10.3) respectively. In the multivariable Cox regression model considering GLP-1 RA treatment as a time-dependent covariate, in the primary prevention group, changes in BMI and glycated hemoglobin did not have an impact on MACE risk, while age at the time of GLP-1 initiation (HR 1.08, 95% CI 1.03-1.14, p = 0.001) and GLP-1 RA cessation by time (HR 3.40, 95% CI 1.82-6.32, p < 0.001) increased the risk of MACE. Regarding the secondary prevention group, only GLP-1 RA cessation by time (HR 2.71, 95% CI 1.46-5.01, p = 0.002) increased the risk of MACE. With respect to those who withdrew treatment, subjects who continued the GLP-1 RA had significantly greater weight loss and lower glycated hemoglobin levels during follow-up. CONCLUSIONS: In this real-world type 2 diabetes population, discontinuation of GLP-1 RA treatment was associated to a higher risk of major cardiovascular events, in both subjects with and without a history of CV events.

Contrast Enhanced EUS for Predicting Solid Pancreatic Neuroendocrine Tumor Grade and Aggressiveness.

Pancreatic neuroendocrine tumor (PNET) behavior assessment is a daily challenge for physicians. Modern PNET management varies from a watch-and-wait strategy to surgery depending on tumor aggressiveness. Therefore, the aggressiveness definition plays a pivotal role in the PNET work-up. The aggressiveness of PNETs is mainly based on the dimensions and histological grading, with sometimes a lack of specificity and sensibility. In the last twenty years, EUS has become a cornerstone in the diagnostic phase of PNET management for its high diagnostic yield and the possibility of obtaining a histological specimen. The number of EUS applications in the PNET work-up has been rapidly increasing with new and powerful possibilities. The application of contrast has led to an important step in PNET detection; in recent years, it has been gaining interesting applications in aggressiveness assessment. In this review, we underline the latest experiences and opportunities in the behavior assessment of PNETs using contact-enhanced EUS and contested enhanced harmonic EUS with a particular focus on the future application and possibility that these techniques could provide.

P720R USP8 Mutation Is Associated with a Better Responsiveness to Pasireotide in ACTH-Secreting PitNETs.

Somatic mutations in the ubiquitin specific peptidase 8 (USP8) gene have been associated with higher levels of somatostatin (SS) receptor subtype 5 (SSTR5) in adrenocorticotroph hormone (ACTH)-secreting pituitary neuroendocrine tumors (PitNETs). However, a correlation between the USP8 mutational status and favourable responses to pasireotide, the somatostatin multi-receptor ligand acting especially on SSTR5, has not been investigated yet. Here, we studied the impact of USP8 mutations on pasireotide responsiveness in human and murine corticotroph tumor cells. SSTR5 upregulation was observed in USP8 wild-type primary tumor cells transfected with S718del USP8 mutant. However, cell transfection with S718del USP8 and C40-USP8 mutants in in vitro sensitive cultures from USP8 wild-type tumors abolished their ability to respond to pasireotide and did not confer pasireotide responsiveness to the in vitro resistant culture. Pasireotide failed to reduce ACTH secretion in primary cells from one S718P USP8-mutated tumor but exerted a strong antisecretory effect in primary cells from one P720R USP8-mutated tumor. In agreement, AtT-20 cells transfection with USP8 mutants led to SSTR5 expression increase but pasireotide could reduce ACTH production and cyclin E expression in P720R USP8 overexpressing cells, only. In situ Proximity Ligation Assay and immunoflurescence experiments revealed that P720R USP8 mutant is still able to bind 14-3-3 proteins in AtT-20 cells, without affecting SSTR5 localization. In conclusion, P720R USP8 mutation might be considered as a molecular predictor of favourable response to pasireotide in corticotroph tumor cells.

Case Report: A Novel ARMC5 Germline Mutation in a Patient with Primary Bilateral Macronodular Adrenal Hyperplasia and Hypogammaglobulinemia.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) represents an uncommon cause of endogenous hypercortisolism. Since the first description in 2003 in a French cohort, many papers have been published describing families as well as isolated individuals affected with this condition, who were found to harbor a genetic variants in the armadillo-repeat containing 5 (ARMC5) gene, a tumor-suppressor gene with a still unknown role in the disease pathogenesis. Studies in rat models suggested a possible link between ARMC5 damaging variants and the impairment of the cell-mediated immune response, leading to a higher susceptibility to bacterial and viral infections. To our knowledge, we describe the first case of a patient affected by PBMAH with hypogammaglobulinemia and monthly relapsing human herpes simplex viral infections. After the detection of subclinical Cushing's syndrome, a unilateral laparoscopic adrenalectomy was performed. Subsequent genetic analysis of ARMC5 performed on genomic DNA extracted both from the adrenal tissue and lymphocytes revealed a novel somatic frameshift variant in exon 1 (c.231_265del:p.A77Afs*13) and a novel germline variant in exon 6 (c.2436del: p. C813Vfs*104). After adrenalectomy, we observed a significant improvement of clinical features concerning both hypercortisolism and relapsing viral infections, thus suggesting a possible adjuvant role of hypercortisolism on a genetic-based derangement of the immune system.

Genetic Profiling of a Cohort of Italian Patients with ACTH-Secreting Pituitary Tumors and Characterization of a Novel USP8 Gene Variant.

Cushing's Disease (CD) is a rare condition characterized by an overproduction of ACTH by an ACTH-secreting pituitary tumor, resulting in an excess of cortisol release by the adrenal glands. Somatic mutations in the deubiquitinases USP8 and USP48, and in BRAF genes, have been reported in a subset of patients affected by CD. The aim of this study was to characterize the genetic profile of a cohort of 60 patients with ACTH-secreting tumors, searching for somatic mutations in USP8, USP48, and BRAF hotspot regions. Seven patients were found to carry USP8 somatic mutations in the well-characterized 14-3-3 protein binding motif (n = 5 P720R, n = 1 P720Q, n = 1 S718del); 2 patients were mutated in USP48 (M415I); no mutation was identified in BRAF. In addition, a novel USP8 variant, G664R, located in exon 14, upstream of the 14-3-3 protein binding motif, was identified in 1 patient. Functional characterization of USP8 G664R variant was performed in murine corticotroph tumor AtT-20 cells. Transient transfection with the USP8 G664R variant resulted in a significant increase of ACTH release and cell proliferation (+114.5 ± 53.6% and +28.3 ± 2.6% vs. empty vector transfected cells, p < 0.05, respectively). Notably, USP8 proteolytic cleavage was enhanced in AtT-20 cells transfected with G664R USP8 (1.86 ± 0.58-fold increase of N-terminal USP8 fragment, vs. WT USP8, p < 0.05). Surprisingly, in situ Proximity Ligation Assay (PLA) experiments showed a significant reduction of PLA positive spots, indicating USP8/14-3-3 proteins colocalization, in G664R USP8 transfected cells with respect to WT USP8 transfected cells (-47.9 ± 6.6%, vs. WT USP8, p < 0.001). No significant difference in terms of ACTH secretion, cell proliferation and USP8 proteolytic cleavage, and 14-3-3 proteins interaction was observed between G664R USP8 and S718del USP8 transfected cells. Immunofluorescence experiments showed that, contrary to S718del USP8 but similarly to WT USP8 and other USP8 mutants, G664R USP8 displays an exclusive cytoplasmic localization. In conclusion, somatic mutations were found in USP8 (13.3% vs. 36.5% incidence of all published mutations) and USP48 (3.3% vs. 13.3% incidence) hotspot regions. A novel USP8 variant was identified in a CD patient, and in vitro functional studies in AtT-20 cells suggested that this somatic variant might be clinically relevant in ACTH-secreting tumor pathogenesis, expanding the characterization of USP8 functional domains.

Weight change and glycemic control in type 2 diabetes patients during COVID-19 pandemic: the lockdown effect.

PURPOSE: The aim of this study was to evaluate the impact of the COVID-19 lockdown occurred in Italy from March 9th to May 18th, 2020 on anthropometric parameters and glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS: One hundred twenty-eight consecutive patients with T2DM (median age 70 years, 74 males) were retrospectively evaluated at the end of the lockdown period. Data on metabolic control were collected at different time: within three months before the lockdown (visit 0) and within the first six weeks after it (visit 1). RESULTS: During the lockdown, a significant increase in body weight (from 79.7 ± 18.7 kg to 81.4 ± 19.4 kg, p < 0.001), body mass index (BMI, from 29.5 ± 6 kg/m2 to 30.1 ± 6.3 kg/m2, p < 0.001), waist circumference (from 103.8 ± 13 cm to 105 ± 13.6 cm, p < 0.001), fasting plasma glucose (FPG; from 138.1 ± 29.4 mg/dL to 146.6 ± 36.4 mg/dL) and glycated hemoglobin (HbA1c; from 7 ± 0.8 to 7.3 ± 0.9%, p < 0.001) was observed. Weight gain was directly associated with HbA1c increase (ß 0.085, C.I. 95% 0.05-0.121; p < 0.001) while insulin therapy resulted to be the only significant independent predictor of HbA1c worsening at the multivariate logistic regression analysis (OR 2.40, C.I. 1.06-5.45; p = 0.035). CONCLUSIONS: The lockdown due to COVID-19 pandemic had a negative impact on body weight and glucose control in T2DM patients, in particular in those on insulin treatment. This finding provides a further rationale to optimize the diabetes management during eventually new period of home confinement.

Evaluation of the ex vivo Effects of Tamoxifen on Adipose-Derived Stem Cells: A Pilot Study.

Autologous fat grafting (AFG) is a safe and minimally invasive procedure to correct soft tissue defects. The benefit of AFG is attributed to adipose-derived stem cells (ASCs) in fat tissue graft. This technique is useful also in patients undergoing reconstructive surgery following quadrantectomy for breast cancer. However, these patients are frequently treated with tamoxifen. We evaluated the ex vivo effects of tamoxifen on ASCs to understand if cellular functions of ASCs are affected. We selected 24 female patients; 10 of which were breast cancer patients treated with quadrantectomy and tamoxifen. As control group, we selected 14 healthy female subjects (9 premenopausal and 5 menopausal). We found that tamoxifen has no effect on cellular proliferation, VEGF secretion or apoptosis of ASCs. The gene expression assessment demonstrated no impairment in differentiation capacity of ASCs. Our results showed that tamoxifen has no effect on cellular functions of ASCs for the first time in an ex vivo single-center study.

Update on vertebral fractures in pituitary diseases: from research to clinical practice.

Derangement of pituitary hormone axes can induce changes in bone remodeling and metabolism with possible alterations in bone microarchitectural structure and increased susceptibility to fractures. Vertebral fractures (VFs), which are a hallmark of skeletal fragility, have been described in a very large number of patients with pituitary diseases. These fractures are clinically relevant, since they predispose to further fractures and may negatively impact on patients' quality of life. However, the management of skeletal fragility and VFs in the specific setting of pituitary diseases is a challenge, since the awareness for this disease is still low, prediction of VFs is uncertain, the diagnosis of VFs cannot be solely based on a clinical approach and also needs a radiological and morphometric approach, the risk of fractures may not be decreased via treatment of pituitary hormone disorders, and the effectiveness of bone-active drugs in this setting is not always evidence-based. This review is an update on skeletal fragility in patients with pituitary diseases, with a focus on clinical and therapeutic aspects concerning the management of VFs.

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

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 ß-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 ß-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. ß-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, ß-arrestin 2 silencing prevented DRD2 inhibitory effects on p-AKT and cell proliferation. Accordingly, ß-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 ß-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 ß-arrestin 2 as a biomarker predicting NF-PitNETs' responsiveness to treatment with dopamine agonists.

Impact of Comorbidities and Glycemia at Admission and Dipeptidyl Peptidase 4 Inhibitors in Patients With Type 2 Diabetes With COVID-19: A Case Series From an Academic Hospital in Lombardy, Italy.

OBJECTIVE: Diabetes may unfavorably influence the outcome of coronavirus disease 19 (COVID-19), but the determinants of this effect are still poorly understood. In this monocentric study, we aimed at evaluating the impact of type 2 diabetes, comorbidities, plasma glucose levels, and antidiabetes medications on the survival of COVID-19 patients. RESEARCH DESIGN AND METHODS: This was a case series involving 387 COVID-19 patients admitted to a single center in the region of Lombardy, the epicenter of the severe acute respiratory syndrome coronavirus 2 pandemic in Italy, between 20 February and 9 April 2020. Medical history, pharmacological treatments, laboratory findings, and clinical outcomes of patients without diabetes and patients with type 2 diabetes were compared. Cox proportional hazards analysis was applied to investigate risk factors associated with mortality. RESULTS: Our samples included 90 patients (23.3%) with type 2 diabetes, who displayed double the mortality rate of subjects without diabetes (42.3% vs. 21.7%, P < 0.001). In spite of this, after correction for age and sex, risk of mortality was significantly associated with a history of hypertension (adjusted hazard ratio [aHR] 1.84, 95% CI 1.15-2.95; P = 0.011), coronary artery disease (aHR 1.56, 95% CI 1.04-2.35; P = 0.031), chronic kidney disease (aHR 2.07, 95% CI 1.27-3.38; P = 0.003), stroke (aHR 2.09, 95% CI 1.23-3.55; P = 0.006), and cancer (aHR 1.57, 95% CI 1.08-2.42; P = 0.04) but not with type 2 diabetes (P = 0.170). In patients with diabetes, elevated plasma glucose (aHR 1.22, 95% CI 1.04-1.44, per mmol/L; P = 0.015) and IL-6 levels at admission (aHR 2.47, 95% CI 1.28-4.78, per 1-SD increase; P = 0.007) as well as treatment with insulin (aHR 3.05, 95% CI 1.57-5.95; P = 0.001) and ß-blockers (aHR 3.20, 95% CI 1.50-6.60; P = 0.001) were independently associated with increased mortality, whereas the use of dipeptidyl peptidase 4 inhibitors was significantly and independently associated with a lower risk of mortality (aHR 0.13, 95% CI 0.02-0.92; P = 0.042). CONCLUSIONS: Plasma glucose levels at admission and antidiabetes drugs may influence the survival of COVID-19 patients affected by type 2 diabetes.

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

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 ±â€…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.

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

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.

Clinically Nonfunctioning Pituitary Incidentalomas: Characteristics and Natural History.

INTRODUCTION: Available data on pituitary incidentalomas mostly derive from small-scale studies, with heterogeneous inclusion criteria and limited follow-up. No paper has focused specifically on clinically nonfunctioning pituitary in-cidentalomas (CNFPIs). OBJECTIVE: To describe the charac-teristics and the natural history of patients diagnosed with CNFPIs. METHODS: Retrospective multicenter cohort study evaluating hormonal, imaging, and visual field characteristics at diagnosis and during follow-up of CNFPIs investigated in 2 Pituitary Centers. RESULTS: Three hundred and seventy-one patients were included (50.9% microadenomas, 35.6% males). Men were older and more likely to have a macroadenoma (p < 0.01). Totally, 23.7% of patients presented secondary hormonal deficits (SHDs), related to tumor size (higher in macroadenomas; p < 0.001) and age (higher in older patients; p < 0.001). Hypogonadism was the most frequent SHD (15.6%). Two hundred and ninety-six patients had follow-up data, 29.1% required surgery after first evaluation, and 97 had at least 3 years of follow-up. In total, 15.3% adenomas grew (more macroadenomas), but only in microadenomas patients with longer follow-up showed a higher growth trend. Totally, 5.2% of patients developed new SHDs (micro- vs. macroadenomas p = 1.000), and in 60% of them this was not associated with an increase in tumor size. Thirteen additional patients required surgery during follow-up (1 microadenoma at diagnosis). CONCLUSIONS: Macroadenomas and age are risk factors for SHD in CNFPIs, which occur at diagnosis in a quarter of patients. During follow-up, macroadenomas tend to grow more often, but microadenomas display higher growth trend as follow-up increases. Deterioration of pituitary function is not always related to adenoma growth.

Cytoskeleton Protein Filamin A Is Required for Efficient Somatostatin Receptor Type 2 Internalization and Recycling through Rab5 and Rab4 Sorting Endosomes in Tumor Somatotroph Cells.

The high expression of somatostatin receptor 2 (SST2) in growth hormone (GH)-secreting tumors represents the rationale for the clinical use of somatostatin analogs (SSAs) in acromegaly. Recently, the cytoskeletal protein Filamin A (FLNA) has emerged as key modulator of the responsiveness of GH-secreting pituitary tumors to SSAs by regulating SST2 signaling and expression. The aim of this study was to explore FLNA involvement in SST2 intracellular trafficking in tumor somatotroph cells. By biotinylation assay, we found that FLNA silencing abolished octreotide-mediated SST2 internalization in rat GH3 cell line (28.0 ± 2.7 vs. 4 ± 4.3% SST2 internalization, control versus FLNA small interfering RNAs (siRNA) cells, respectively, p < 0.001) and human GH-secreting primary cultured cells (70.3 ± 21.1 vs. 24 ± 19.2% SST2 internalization, control versus FLNA siRNA cells, respectively, p < 0.05). In addition, confocal imaging revealed impaired SST2 recycling to the plasma membrane in FLNA silenced GH3 cells. Coimmunoprecipitation and immunofluorescence experiments showed that FLNA, as well as ß-arrestin2, is timely dependent recruited to octreotide-stimulated SST2 receptors both in rat and human tumor somatotroph cells. Although FLNA expression knock down did not prevent the formation of ß-arrestin2-SST2 complex in GH3 cells, it significantly impaired efficient SST2 loading into cytosolic vesicles positive for the early endocytic and recycling markers Rab5 and 4, respectively (33.7 ± 8.9% down to 25.9 ± 6.9%, p < 0.05, and 28.4 ± 7.4% down to 17.6 ± 5.7%, p < 0.01, for SST2-Rab5 and SST2-Rab4 colocalization, respectively, in control versus FLNA siRNA cells). Altogether these data support an important role for FLNA in the mediation of octreotide-induced SST2 trafficking in GH-secreting pituitary tumor cells through Rab5 and 4 sorting endosomes.

PSMA expression level predicts differentiated thyroid cancer aggressiveness and patient outcome.

BACKGROUND: Prostate-specific membrane antigen (PSMA) is overexpressed on the endothelial cells of tumor neo-vessels of several solid malignancies, including differentiated thyroid cancer (DTC). We aimed to test the potential role of PSMA as a biomarker for DTC aggressiveness and outcome prediction. We retrospectively screened all patients who underwent thyroidectomy between 1 January 2010 and 31 December 2017 in our institution. Applying the inclusion (histological diagnosis of thyroid cancer and tissue availability) and exclusion criteria (no clinical or follow-up data or diagnosis of medullary thyroid cancer), a cohort of 59 patients was selected. The monoclonal mouse anti-human PSMA antibody was used to stain tissue sections. A 3-point scale was used to score PSMA positivity: 0-5% expression was considered as negative (score 0), 6-50% as moderately positive (score 1), and 51-100% as highly positive (score 2). A cumulative score (0-10%, 11-79%, and 80-100%) was also explored. Univariate and multivariate logistic regression analyses were performed to predict the presence of distant metastases, chosen as endpoint of aggressiveness. The area under the curve (AUC) was calculated. Cox models were built to predict patient outcome in terms of recurrence, iodine refractoriness, and status at last follow-up, which were calculated using the Kaplan-Meier failure function. RESULTS: At immunostaining, 12, 25, and 22 patients had scores of 0, 1, and 2, respectively. According to the cumulative score, PSMA expression was ≤ 10% in 17 cases, 11-79% in 31 cases, and ≥ 80% in 11 cases. At multivariate analysis, age, sex, histotype, vascular invasion, T and N parameters, and PSMA positivity were significant predictors of distant metastases. The AUC was 0.92. Recurrence or progression occurred in 19/59 patients. Twelve patients developed radioiodine (RAI) refractoriness, after a median time of 17 months (range 2-32). One patient died of DTC; 46 of the 58 patients alive at last follow-up were disease free. Median DFS was 23 months (range 3-82). The final multivariate model to predict RAI refractoriness included as covariates the stage, high PSMA expression (≥ 80%), and the interaction between moderate PSMA expression (11-79%) and stage. CONCLUSIONS: PSMA, a marker of neovasculature formation expressed by DTC, contributes in the prediction of tumor aggressiveness and patient outcome.