Natural History and Management of Familial Paraganglioma Syndrome Type 1: Long-Term Data from a Large Family

Head and neck paragangliomas are the most common clinical features of familial paraganglioma syndrome type 1 caused by succinate dehydrogenase complex subunit D (SDHD) mutation. The clinical management of this syndrome is still unclear. In this study we propose a diagnostic algorithm for SDHD mutation carriers based on our family case series and literature review. After genetic diagnosis, first evaluation should include biochemical examination and whole-body imaging. In case of lesion detection, nuclear medicine examination is required for staging and tumor characterization. The study summarizes the diagnostic accuracy of different functional imaging techniques in SDHD mutation carriers. 18F-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)-computed tomography (CT) is considered the gold standard. If it is not available, 123I-Metaiodobenzylguanidine (MIBG) could be used also for predicting response to radiometabolic therapy. 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET-CT has a prognostic role since high uptake identifies more aggressive cases. Finally, 68Ga-peptides PET-CT is a promising diagnostic technique, demonstrating the best diagnostic accuracy in our and in other published case series, even if this finding still needs to be confirmed in larger studies. Periodic follow-up should consist of annual biochemical and ultrasonographic screening and biannual magnetic resonance examination to identify biochemical silent tumors early

The spectrum of cardiac abnormalities in patients with acromegaly: results from a case-control cardiac magnetic resonance study

Purpose: Cardiac abnormalities are common in patients with acromegaly, contributing to the increased morbidity and mortality. Cardiac magnetic resonance (CMR) is the gold standard for measuring cardiac morpho-functional changes. This study aims to detect cardiac alterations in acromegaly through CMR, even when the disease is adequately controlled. Methods: In this, multicentre, case-control study, we compared consecutive patients with acromegaly, cured after surgery or requiring medical treatment, with matched controls recruited among patients harbouring non-functioning adrenal incidentalomas. Results: We included 20 patients with acromegaly (7 females, mean age 50 years) and 17 controls. Indexed left ventricular-end-diastolic volume (LV-EDVi) and LV-end-systolic volume (LV-ESVi) were higher in patients than in controls (p < 0.001), as were left ventricular mass (LVMi) (p = 0.001) and LV-stroke volume (LV-SVi) (p = 0.028). Right ventricle (RV) EDVi and ESVi were higher, whereas RV-ejection fraction (RV-EF) was lower (p = 0.002) in patients than in controls (p < 0.001). No significant differences were observed in the prevalence of cardiometabolic comorbidities, including hypertension, glucose and lipid metabolism impairment, obstructive sleep apnoea syndrome, and obesity. IGF1 x upper limit of normal significantly predicted LVMi (b = 0.575; p = 0.008). Subgroup analysis showed higher LVMi (p = 0.025) and interventricular septum thickness (p = 0.003) in male than female patients, even after adjusting cardiac parameters for confounding factors. Conclusions: The CMR analysis reveals a cluster of biventricular structural and functional impairment in acromegaly, even when the biochemical control if achieved. These findings appear specifically triggered by the exposure to GH-IGF1 excess and show sex-related differences advocating a possible interaction with sex hormones in cardiac disease progression

Ruolo diagnostico, prognostico e predittivo di risposta del NETest nelle neoplasie neuroendocrine

Il NETest è una metodica di biologia molecolare e, in particolare, di biopsia liquida, applicata alle neoplasie neuroendocrine (NEN), che si propone come nuovo biomarcatore altamente sensibile e specifico. Il NETest consente una sorta di gene signature del tumore, definendone il profilo trascrizionale mRNA, estratto dal sangue periferico. L’applicazione pratica è nella diagnosi, dove il NETest sembra identificare anche piccoli tumori localizzati, nella definizione prognostica, con l’identificazione dei tumori con maggiore tendenza alla progressione e alla recidiva post-chirurgica, nella riposta ai trattamenti, con l’identificazione precoce di progressione nel corso di terapie anti-tumorali. A fronte di risultati iniziali estremamente promettenti, il NETest necessita di una conferma su larga scala, in ampie casistiche multicentriche

Cardiac magnetic resonance reveals biventricular impairment in Cushing’s syndrome: a multicentre case-control study

Purpose: Cushing’s syndrome (CS) is associated with severe cardiovascular (CV) morbidity and mortality. Cardiac magnetic resonance (CMR) is the non-invasive gold standard for assessing cardiac structure and function; however, few CMR studies explore cardiac remodeling in patients exposed to chronic glucocorticoid (GC) excess. We aimed to describe the CMR features directly attributable to previous GC exposure in patients with cured or treated endogenous CS. Methods: This was a prospective, multicentre, case-control study enrolling consecutive patients with cured or treated CS and patients harboring non-functioning adrenal incidentalomas (NFAI), comparable in terms of sex, age, CV risk factors, and BMI. All patients were in stable condition and had a minimum 24-month follow-up. Results: Sixteen patients with CS and 15 NFAI were enrolled. Indexed left ventricle (LV) end-systolic volume and LV mass were higher in patients with CS (p = 0.027; p = 0.013); similarly, indexed right ventricle (RV) end-diastolic and end-systolic volumes were higher in patients with CS compared to NFAI (p = 0.035; p = 0.006). Morphological alterations also affected cardiac function, as LV and RV ejection fractions decreased in patients with CS (p = 0.056; p = 0.044). CMR features were independent of metabolic status or other CV risk factors, with fasting glucose significantly lower in CS remission than NFAI (p < 0.001) and no differences in lipid levels or blood pressure. Conclusion: CS is associated with biventricular cardiac structural and functional impairment at CMR, likely attributable to chronic exposure to cortisol excess independently of known traditional risk factors

Pathology reporting in neuroendocrine neoplasms of the digestive system: everything you always wanted to know but were too afraid to ask

During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals

Commentary: Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management

In the issue of March 2021, Lenschow et al. reported the case of a 46-year-old woman with recurrent, programmed death-ligand-1 (PD-L1) negative, tumor mutational burden (TMB)-high parathyroid carcinoma (PC), who showed stable disease as her best response on imaging, and a three-fold drop in PTH after treatment with intravenous pembrolizumab. Given the remarkable results obtained by Lenschow et al. with the anti-PD-1 agent pembrolizumab in the above-mentioned case, we performed an extensive search for possible further relevant data sources, including a) full published articles in international online databases (PubMed, Web of Science, Scopus, and Embase); b) preliminary reports in selected international meeting abstract repositories (American Society of Clinical Oncology, ASCO; European Neuroendocrine Tumor Society, ENET; European Society for Medical Oncology, ESMO); c) registered clinical trials in the U.S. National Institutes of Health registry of clinical trials (http://clinicaltrials.gov) and in any primary register of the WHO International Clinical Trials Registry Platform (ICTRP)

Immune and metabolic profile in acromegalic patients and the impact of the current medical treatment. Results from the PROMISE study

Introduction: Acromegaly is associated with several comorbidities, mainly cardiovascular, respiratory and metabolic diseases, with an increase in the last years of cancer as main cause of mortality. Conversely, little is known about the immune function in acromegaly, even if GH/IGF1 axis has long been supposed to play a role in immune modulation, mainly by affecting lymphocytes and monocytes. We aimed to evaluate the peripheral blood mononuclear cells (PBMCs) subpopulations in acromegalic patients (ACRO) in comparison with controls (CTRLs) and to investigate the impact of disease control and different medical treatments on PBMCs, metabolism and body composition. Material and Methods: This is an observational, prospective, single site, pilot study (NCT05069324). Twenty-nine patients (16 M and 13 F, mean age 51.3 15.6 years) with an active disease and 25 sex and age-matched healthy volunteers entered the study according to inclusion criteria. Twenty-five acromegalic patients underwent neurosurgery, 15 were on SSA treatment, and 10 patients on PEG (monotherapy or combined with SSA). Six patients with uncontrolled disease (IGF1 1.2 x ULN) on SSA treatment changed therapy (add or switch to PEG) and were evaluated after 8 weeks from the treatment change together with another group of 8 patients with stable disease. Anthropometric, metabolic and hormonal parameters were recorded along with full quantification of PBMCs evaluated by flow cytometry. Data are expressed as means SD or median (IQR) and statistical analysis was performed with parametric and non-parametric tests, as appropriate. Results: Immune cell profiling revealed in ACRO compared to CTRLs decreased monocytes with a higher proportion of non-classical and a lower proportion of intermediate subset. Moreover, ACRO had lower NK cells and CD16high NK with an increased proportion of the more naturally cytotoxic subset (CD56dim) and a decreased proportion of the NK cells more responsible of cytokine production (CD56bright), without changes in T and B-lymphocytes. In ACRO group no differences were found according to disease control and medical treatment. Conversely, in treated acromegalic patients body composition parameters were similar to CTRLs, with a higher fat mass, particularly localized at trunk, in PEG treated patients compared to SSA treatment. The introduction of PEG, in comparison with the stable treatment, improved after 8 weeks glycaemia and influenced the immune cells redistribution by increasing the proportion of non-classical monocytes and CD56bright NK cells, without body composition changes. Discussion: To the best of our knowledge, this study demonstrated for the first time that acromegalic patients showed an immunological fingerprint, characterised by decreased monocytes and NK cells and by an imbalance of immune innate cells subset, supporting the role of GH/IGF1 axis in immune system modulation. These results could represent the background for further studies, particularly considering the relationship between immune function and cancer and the higher cancer risk reported in acromegaly. The treatment change (add or switch to PEG) may influence immune cells redistribution, without body composition effects, supporting a potential role of PEG in immune regulation. However, further studies are needed to confirm these data and to better clarify the underlying mechanisms and their potential clinical implications

Neuroendocrine Neoplasms with Peculiar Biology and Features. MEN1, MEN2A, MEN2B, MEN4, VHL, NF1

A relevant number of neuroendocrine neoplasms (NENs) show a hereditary background being associated with a genetic endocrine neoplastic syndrome. Multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), variants MEN2A and MEN2B, and multiple endocrine neoplasia type 4 (MEN4) present NENs as main and typical manifestations, while Von Hippel–Lindau disease (VHL) and neurofibromatosis type 1 (NF1) are mainly characterized by neoplasms of non-neuroendocrine origin. Among NENs, pancreatic and thyroid tumors are most frequently associated with hereditary syndromes, the former being found in MEN1, MEN4, VHL, NF1, and the latter in MEN2A and B. Rare NEN sites are lung, thymus, and stomach, while pituitary and parathyroid adenomas are common in MEN1 and MEN4, as well as pheochromocytoma and paragangliomas in MEN2, VHL, NF1. The diagnosis of hereditary NENs is anticipated of approximately two to three decades as compared to the sporadic counterpart. At histology the neuroendocrine tumors associated with genetic syndromes associated with hereditary syndromes are generally well differentiated, low proliferating, multiple, and multifocal. They are also frequently functioning, thus resulting in different types of endocrine syndromes, such as hyperinsulinemic hypoglycemia, Zollinger–Ellison, hyperprolactinemia, hyperparathyroidism, hypersecretion of catecholamines, and other rarer syndromes. Neuroendocrine carcinomas are extremely rare

The Woman's Heart: Insights into New Potential Targeted Therapy

Cardiovascular disease is an increasingly common cause of death in women. There is as yet no consensus on the analysis of cardiovascular risk factors with regard to the specific, personalised treatment of pre- and post-menopausal women. Clinically significant cardioprotective and antiremodelling effects have been observed in animal and human studies exploring chronic inhibition of phosphodiesterase type 5 (PDE5). The relationship between the heart, estrogens and PDE5 inhibitors (PDE5is) remains unclear. Experimental data suggest potential beneficial effects on cardiac geometry, function, endothelial function and microvascular coronary flow in women. It was recently postulated that the efficacy of PDE5is is estrogen-dependent in female heart disease. A registered randomised, placebo-controlled study, RECOGITO (NCT01803828), aimed at identifying the genderspecific efficacy of long-term PDE5 inhibition in diabetic cardiomyopathy, is currently recruiting patients. Estrogen receptor modulation could be a new promising approach to heart protection via PDE5is. PDE5is could be indicated as a gender-oriented strategy in modulated cardiac dysfunction and remodelling and in cardiac risk factors for selected cardiovascular diseases

Is chronic inhibition of phosphodiesterase type 5 cardioprotective and safe? A meta-analysis of randomized controlled trials.

Background: The myocardial effects of phosphodiesterase type 5 inhibitors (PDE5i) have recently received consideration in several preclinical studies. The risk/benefit ratio in humans remains unclear. Methods: We performed a meta-analysis of randomized, placebo-controlled trials (RCTs) to evaluate the efficacy and safety of PDE5i on cardiac morphology and function. From March 2012 to December 2013 (update: May 2014), we searched English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and SCOPUS-selecting RCTs of continuous PDE5i administration that reported cardiovascular outcomes: cardiac geometry and performance, afterload, endothelial function and safety. The pooled estimate of a weighted mean difference between treatment and placebo was obtained for all outcomes using a random effects model. A test for heterogeneity was performed and the I-2 statistic calculated. Results: Overall, 1,622 subjects were treated, with 954 randomized to PDE5i and 772 to placebo in 24 RCTs. According to our analysis, sustained PDE5 inhibition produced: (1) an anti-remodeling effect by reducing cardiac mass (-12.21 g/m(2), 95% confidence interval (CI): -18.85; -5.57) in subjects with left ventricular hypertrophy (LVH) and by increasing end-diastolic volume (5.00 mL/m(2); 95% CI: 3.29; 6.71) in non-LVH patients; (2) an improvement in cardiac performance by increasing cardiac index (0.30 L/min/m(2), 95% CI: 0.202; 0.406) and ejection fraction (3.56%, 95% CI: 1.79; 5.33). These effects are parallel to a decline of N-terminal-pro brain natriuretic peptide (NT-proBNP) in subjects with severe LVH (-486.7 pg/ml, 95% CI: -712; -261). PDE5i administration also produced: (3) no changes in afterload parameters and (4) an improvement in flow-mediated vasodilation (3.31%, 95% CI: 0.53; 6.08). Flushing, headache, epistaxis and gastric symptoms were the commonest side effects. Conclusions: This meta-analysis suggests for the first time that PDE5i have anti-remodeling properties and improve cardiac inotropism, independently of afterload changes, with a good safety profile. Given the reproducibility of the findings and tolerability across different populations, PDE5i could be reasonably offered to men with cardiac hypertrophy and early stage heart failure. Given the limited gender data, a larger trial on the sex-specific response to long-term PDE5i treatment is required