Search

Background: Human subjects with generalized growth hormone (GH) insensitivity due to GH receptor deficiency (GHRD)/Laron syndrome display a very low incidence of insulin resistance, diabetes, and cancer, as well as delayed age-related cognitive decline. However, the risk of cardiovascular disease (CVD) in these subjects is poorly understood. Here, we have assessed cardiovascular function, damage, and risk factors in GHRD subjects and their relatives., Methods: We measured markers of CVD in two phases: one in a cohort of 30 individuals (GHRD = 16, control relatives = 14) brought to USC (in Los Angeles, CA) and one in a cohort including additional individuals examined in Ecuador (where the subjects live) for a total of 44 individuals (GHRD = 21, control relatives = 23). Data were collected on GHRD and control groups living in similar geographical locations and sharing comparable environmental and socio-economic circumstances., Results: Compared to controls, GHRD subjects displayed lower serum glucose, insulin, blood pressure, smaller cardiac dimensions, similar pulse wave velocity, lower carotid artery intima-media thickness, lower creatinine, and a non-significant but major reduction in the portion of subjects with carotid atherosclerotic plaques (7% GHRDs vs. 36%, Controls p = 0.1333) despite elevated low-density lipoprotein cholesterol levels., Conclusion: The current study indicates that individuals with GHRD have normal or improved levels of cardiovascular disease risk factors as compared to their relatives., Funding: This study was funded in part by NIH/NIA grant P01 AG034906 to V.D.L., Competing Interests: Declaration of interests V.D.L. has equity interest in L-Nutra, which develops and sells medical food for the prevention and treatment of diseases., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The last years have seen unprecedented improvement in breast cancer (BC) survival rates. However, this entirely apply to female BC patients, since gender minorities (male, transgender/gender-diverse) are neglected in BC phase III registration clinical trials., Methods: We conducted a scoping review of phase III clinical trials of agents with a current positioning within the therapeutic algorithms of BC., Results: We selected 51 phase III trials. Men enrollment was allowed in 35.3% of trials. In none of the trial inclusion/exclusion criteria referred to transgender/gender-diverse people. A numerical higher rate of enrolled men was observed in the contemporary as compared to historical group. We found a statistically significant association between the drug class and the possibility of including men: 100%, 80%, 50%, 33.3%, 25%, 10% and 9.1% of trials testing ICI/PARP-i, ADCs, PI3K/AKT/mTOR-i, anti-HER2 therapy, CDK4/6-i, ET alone, and CT alone. Overall, 77409 patients were enrolled, including 112 men (0.2%). None of the trial reported transgender/gender-diverse people proportion. Studies investigating PARP-i were significantly associated with the highest rate of enrolled men (1.42%), while the lowest rates were observed for trials of CT (0.13%), ET alone (0.10%), and CDK 4/6-I (0.08%), p < 0.001., Conclusions: We confirmed that gender minorities are severely underrepresented among BC registration trials. We observed a lower rate of men in trials envisaging endocrine manipulation or in less contemporary trials. This work sought to urge the scientific community to increase the awareness level towards the issue of gender minorities and to endorse more inclusive criteria in clinical trials., Competing Interests: Declaration of competing interest FM reports personal fees from Roche, Novartis, Pfizer, Seagen, Gilead, Astrazeneca, Lilly, Menarini all outside the submitted work (all the disclosed activities are outside the submitted work). CDA reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Daiichi-Sankyo, Gilead, and GSK and speaker honoraria from Roche, Lilly, Novartis, Pfizer, Seagen, GSK, GILEAD, and Daiichi-Sankyo; travel Grants from Gilead and research support (to the Institution) from Novartis, GILEAD, and Daiichi-Sankyo outside the submitted work (all the disclosed activities are outside the submitted work). RC reports fees for talk or consultation from Novartis, Lilly, MSD, Gilead, Roche, Pfizer, Veracyte, Seagen, Astra Zeneca, Daichii Sankyo, Menarini, Pierre-Fabre (all the disclosed activities are outside the submitted work). EB has received grants or contracts from Astra-Zeneca, Roche and honoraria for lectures from Merck-Sharp & Dome, Astra-Zeneca, Pfizer, Eli-Lilly, Bristol-Myers Squibb, Novartis, Takeda and Roche; he has been member of Data Safety Monitoring Board or Advisory Board of Merck-Sharp & Dome, Pfizer, Novartis, Bristol-Myers Squibb, Astra-Zeneca, and Roche (all the disclosed activities are outside the submitted work). AV reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: AndromedaE20, Oncotech; support for attending meetings and/or travel: Pierre Fabre, Lilly, Gilead, Seagen, Novartis, MSD, Menarini (all the disclosed activities are outside the submitted work). LDM reports institutional grants from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, Astrazeneca, Gilead, Pierre Fabre; consulting fees: Eli Lilly, Gilead, Daiichi Sankyio; payment or honoraria for lectures, presentations, speakers bureaus: Roche, Novartis, Pfizer, Eli Lilly, Astrazeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, Agendia, Stemline; support for attending meetings and/or travel: Roche, Pfizer, Eisai, Daiichi Sankyo, Astrazeneca, Gilead; Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, Astrazeneca, Agendia, GSK, Seagen, Olema, MSD, Stemline Menarini (all the disclosed activities are outside the submitted work). FM reports consultancy fees from Roche, Novartis, AstraZeneca, Daiichy Sankyo, SeaGen, MSD, Eli Lilly, Pfizer, and Pierre Fabre, and Travel Grants from Roche and Astra Zeneca; from May 15th, 2023, FM is Roche employee (all the disclosed activities are outside the submitted work). VG reports personal fees for advisory board membership for AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Merck Serono, MSD, Novartis, Pfizer, Olema Oncology, Pierre Fabre; personal fees as an invited speaker for AstraZeneca, Daiichi Sankyo, Eli Lilly, Exact Sciences, Gilead, GSK, Novartis, Roche and Zentiva; personal fees for expert testimony for Eli Lilly. All the remaining authors have no conflict of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The process of vascular calcification has severe clinical consequences in a number of diseases, including diabetes, atherosclerosis, and end-stage renal disease. In the present study, we investigated the effect of policosanol (Poli), genistein (Gen), and vitamin D (VitD) separately and in association to evaluate the possible synergistic action on inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs)., Methods: Primary human VSMCs were cultured with either growth medium or growth medium supplemented with calcium and phosphorus (calcification medium) in combination with Poli, Gen, and VitD. Alizarin Red staining, mineralization, and the protein expression of RUNX2 and superoxide dismutase-2 (SOD2) were investigated., Results: All three substances tested were effective at reducing osteogenic differentiation of VSMCs in a dose-dependent manner. Poli+Gen, Poli+VitD, Gen+VitD treatment induced a greater inhibition of calcification and RUNX2 expression compared to single compounds treatments. Moreover, the association of Poli+Gen+VitD (Reduplaxin®) was more effective at inhibiting VSMCs mineralization and preventing the increase in RUNX2 expression induced by calcification medium but not modified SOD2 expression., Conclusions: The association of Pol, Gen, and VitD (Reduplaxin®) has an additive inhibitory effect on the calcification process of VSMCs induced in vitro by a pro-calcifying medium., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Vascular access recirculation during hemodialysis is associated with reduced effectiveness and worse survival outcomes. To evaluate recirculation, an increase in pCO 2 in the blood of the arterial line during hemodialysis (threshold of 4.5 mmHg) was proposed. The blood returning from the dialyzer in the venous line has significantly higher pCO 2 , so in the presence of recirculation, pCO2 in the arterial blood line may increase (ΔpCO 2 ) during hemodialysis sessions. The aim of our study was to evaluate ΔpCO 2 as a diagnostic tool for vascular access recirculation in chronic hemodialysis patients., Methods: We evaluated vascular access recirculation with ΔpCO 2 and compared it with the results of a urea recirculation test, which is the gold standard. ΔpCO 2 was obtained from the difference in pCO 2 in the arterial line at baseline (pCO 2 T1) and after 5 min of hemodialysis (pCO 2 T2). ∆pCO 2  = pCO 2 T2-pCO 2 T1., Findings: In 70 hemodialysis patients (mean age: 70.52 ± 13.97 years; hemodialysis vintage of 41.36 ± 34.54, KT/V 1.4 ± 0.3), ∆pCO 2 was 4 ± 4 mmHg, and urea recirculation was 7% ± 9%. Vascular access recirculation was identified using both methods in 17 of 70 patients, who showed a ∆pCO 2 of 10 ± 5 mmHg and urea recirculation of 20% ± 9%; time in months of hemodialysis was the only difference between vascular access recirculation and non-vascular access recirculation patients (22 ± 19 vs. 46 ± 36, p: 0.05). In the non-vascular access recirculation group, the average ΔpCO 2 was 1.9 ± 2 (p: 0.001), and the urea recirculation % was 2.8 ± 3 (p: 0.001). The ΔpCO 2 correlated with the urea recirculation % (R: 0.728; p < 0.001)., Discussion: ΔpCO 2 in the arterial blood line during hemodialysis is an effective and reliable diagnostic tool for identifying recirculation of the vascular access but not its magnitude. The ΔpCO 2 test application is simple and economical and does not require special equipment., (© 2023 The Authors. Hemodialysis International published by Wiley Periodicals LLC on behalf of International Society for Hemodialysis.)

A 44-year-old woman with obstetric antiphospholipid syndrome (APS) presented to our institution with suspected non ST-elevation myocardial infarction (NSTEMI). Shortly after coronary angiography, she developed diplopia, hypotension and chest pain with inferior ST elevation in 12-lead ECG. According to multidisciplinary evaluation, she promptly underwent systemic thrombolysis, with clinical and haemodynamic improvement. Eventually, a diagnosis of catastrophic APS was made, with multiorgan ischemic involvement confirmed by blood examinations and multimodal imaging techniques. A pluridisciplinary approach was central to define optimal medical therapy and in-hospital management that lead to clinical condition improvement at discharge. In this case, catastrophic APS was triggered or worsened by catheters insertion and invasive manoeuvres within the arterial lumen during coronary angiography. Recognizing catastrophic APS and its potential triggers, can be helpful to deliver prompt and accurate medical assistance. Moreover, in APS patients undergoing coronary angiography, preventive strategies are important to prevent possible unfavourable evolution in catastrophic APS., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Sacubitril/valsartan has changed the treatment of heart failure with reduced ejection fraction (HFrEF), due to the positive effects on morbidity and mortality, partly mediated by left ventricular (LV) reverse remodelling (LVRR). The aim of this multicenter study was to identify echocardiographic predictors of LVRR after sacubitril/valsartan administration., Methods and Results: Patients with HFrEF requiring therapy with sacubitril/valsartan from 13 Italian centres were included. Echocardiographic parameters including LV global longitudinal strain (GLS) and global peak atrial longitudinal strain by speckle tracking echocardiography were measured to find the predictors of LVRR [= LV end-systolic volume reduction ≥10% and ejection fraction (LVEF) improvement ≥10% at follow-up] at 6 month follow-up as the primary endpoint. Changes in symptoms [New York Heart Association (NYHA) class] and neurohormonal activations [N-terminal pro-brain natriuretic peptide (NT-proBNP)] were also evaluated as secondary endpoints; 341 patients (excluding patients with poor acoustic windows and missing data) were analysed (mean age: 65 ± 10 years; 18% female, median LVEF 30% [inter-quartile range: 25-34]). At 6 month follow-up, 82 (24%) patients showed early complete response (LVRR and LVEF ≥ 35%), 55 (16%) early incomplete response (LVRR and LVEF < 35%), and 204 (60%) no response (no LVRR and LVEF < 35%). Non-ischaemic aetiology, a lower left atrial volume index, and a higher GLS were all independent predictors of LVRR at multivariable logistic analysis (all P < 0.01). A baseline GLS < -9.3% was significantly associated with early response (area under the curve 0.75, P < 0.0001). Left atrial strain was the best predictor of positive changes in NYHA class and NT-proBNP (all P < 0.05)., Conclusions: Speckle tracking echocardiography parameters at baseline could be useful to predict LVRR and clinical response to sacubitril-valsartan and could be used as a guide for treatment in patients with HFrEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

An Implantable Cardioverter-Defibrillator was implanted in an asymptomatic 56-year-old man, with type 2 Brugada pattern on ECG, inducible ventricular fibrillation at elective electrophysiological study, and a family history of sudden cardiac death. Seventeen years later, the patient was admitted to the hospital due to palpitations related to a typical atrial flutter. A transthoracic echocardiogram unexpectedly revealed a clinically manifest hypertrophic cardiomyopathy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cognitive impairment and malnutrition are prevalent in patients on hemodialysis (HD), and they negatively affect the outcomes of HD patients. Evidence suggests that cognitive impairment and malnutrition may be associated, but clinical studies to assess this association in HD patients are lacking. The aim of this study was to evaluate the association between cognitive impairment evaluated by the Montreal Cognitive Assessment (MoCA) score and nutritional status evaluated by the malnutrition inflammation score (MIS) in HD patients. We enrolled 84 HD patients (44 males and 40 females; age: 75.8 years (63.5-82.7); HD vintage: 46.0 months (22.1-66.9)). The MISs identified 34 patients (40%) as malnourished; the MoCa scores identified 67 patients (80%) with mild cognitive impairment (MCI). Malnourished patients had a higher prevalence of MCI compared to well-nourished patients (85% vs. 70%; p = 0.014). MoCa score and MIS were negatively correlated (rho:-0.317; p < 0.01). Our data showed a high prevalence of MCI and malnutrition in HD patients. Low MoCA scores characterized patients with high MISs, and malnutrition was a risk factor for MCI. In conclusion, it is plausible that MCI and malnutrition are linked by common sociodemographic, clinical, and biochemical risk factors rather than by a pathophysiological mechanism.

The superior diagnostic accuracy of [68Ga]Ga-prostate-specific membrane antigen-11 (PSMA) ([68Ga]Ga-PSMA-11) compared to [18F]F-Fluorocholine Positron Emission Tomography/Computed Tomography (PET/CT) in Prostate Cancer (PCa) is established. However, it is currently unclear if the added diagnostic accuracy actually translates into improved clinical outcomes in oligometastatic PCa patients treated with [68Ga]Ga-PSMA-11 PET-guided metastasis-directed therapy (MDT). The present study aimed to assess the impact of these two imaging techniques on Progression-Free Survival (PFS) in a real-world sample of oligometastatic PCa patients submitted to PET-guided MDT. Thirty-seven oligometastatic PCa patients treated with PET-guided MDT were retrospectively enrolled. MDT was guided by [18F]F-Fluorocholine PET/CT in eleven patients and by [68Ga]Ga-PSMA-11 PET/CT in twenty-six. Progression was defined as biochemical recurrence (BR), radiological progression at subsequent PET/CT imaging, clinical progression, androgen deprivation therapy initiation, or death. Clinical and imaging parameters were assessed as predictors of PFS. [18F]F-Fluorocholine PET-guided MDT was associated with significantly lower PFS compared to the [68Ga]Ga-PSMA-11 group (median PFS, mPFS 15.47 months, 95% CI: 4.13−38.00 vs. 40.93 months, 95% CI: 40.93−40.93, respectively; p < 0.05). Coherently, the radiotracer used for PET-guided MDT resulted in predictive PFS at the univariate analysis, as well as the castration-resistant status at the time of MDT and the PSA nadir after MDT. However, in the multivariate analysis, castration resistance and PSA nadir after MDT remained the sole independent predictors of PFS. In conclusion, in the present proof-of-concept study, [68Ga]Ga-PSMA-11 provided higher PFS rates than [18F]F-Fluorocholine imaging in oligometastatic PCa patients receiving PET-guided MDT. Although preliminary, this finding suggests that enlarging the “tip of the iceberg”, by detecting a major proportion of the submerged disease thanks to next-generation imaging may favourably impact the oncological outcome of oligometastatic PCa treated with MDT.

Background: Approximately 5-10% of unselected breast cancer (BC) patients retain a hereditary predisposition related to a germline mutation in BRCA1/2 genes. The poly-ADP ribose polymerase (PARP)-inhibitors olaparib and talazoparib have been granted marketing authorization by both FDA and EMA for adults with BRCA1/2 germline mutations and HER2-negative (HER2-) advanced BC based on the results from the phase III OlympiAd and EMBRACA trials., Methods: The panel of the Italian Association of Medical Oncology (AIOM) Clinical Practice Guidelines on Breast Cancer addressed two critical clinical questions, adopting the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach and the Evidence to Decision framework (EtD), to develop recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related triple-negative (clinical question 1) and hormone receptor-positive (HR+)/HER2- (clinical question 2) advanced BC., Results: Two studies were eligible (OlympiAd and EMBRACA). For both clinical questions, the Panel judged the benefit/harm balance probably in favor of the intervention, given the favorable impact in terms of PFS, ORR, and QoL at an acceptable cost in terms of toxicity; the overall certainty of the evidence was low. The panel's final recommendations were conditional in favor of PARP-inhibitors over single-agent chemotherapy in both HR+/HER2-and triple-negative BC. Finally, the Panel identified and discussed areas of uncertainty calling for further exploration., Conclusions: The Panel of AIOM BC Clinical Practice Guideline provided clinical recommendations on the use of PARP-inhibitors, with respect to single-agent chemotherapy, in patients with BRCA-related HER2-advanced BC by adopting the GRADE methodology., Competing Interests: Declaration of competing interest FM personal fee from Roche, Novartis and Gilead outside the submitted work. MVD: personal fees from Eli Lilly, MSD, Exact Sciences, Novartis, Pfizer, Seagen, outside the submitted work; CC: consultan-cy/advisory role/speaker bureau: Pfizer, Novartis, Lilly, Roche, Gilead, MSD, Seagen, outside the submitted work; FM: Fees for advisory board participation; Novartis, Astra Zeneca, Daiichi Sankyo, SeaGen, MSD, Pfizer, Roche, PUMA, outside the submitted work; LDM: grants from Eli Lilly, personal fees from Eli Lilly, personal fees from Novartis, personal fees and non-financial support from Roche, personal fees from MSD, personal fees and non-financial support from Pfiz-er, personal fees from Genomic health, personal fees from Pierre Fabre, personal fees from Daiichi Sankyo, personal fees from Astrazeneca, personal fees from Seagen, personal fees and non-financial support from Eisai, personal fees from Ipsen, personal fees from Gilead, outside the submitted work; AZ: fees for advisory board; Lilly, Novartis, Astra Zeneca, Daiichi Sankyo, SeaGen, MSD, Pfizer, Roche, ExactSciences; LB: honoraria, consulting or advisory role Astra-Zeneca, Daiichi-Sankyo, Eisai, Exact Sciences, Gilead, Lilly, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Seattle Genetics; research Funding Celgene, Genomic Health, Novartis, all outside the submitted work; CM: personal consultancy fees from Bayer, Roche, Astrazeneca, Daiichi Sankyo, outside the submitted work., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate differences in coronavirus disease 2019 (COVID-19) mortality between patients with rheumatic musculoskeletal diseases (RMD) and the general population in Italy., Methods: We analysed the data from the national surveillance study promoted by the Italian Society for Rheumatology (CONTROL-19 database) including patients with RMD and COVID-19 between 26 March 2020 and 29 November 2020, compared with official data from the Italian population (within the same period) adjusted for age, sex and geographic location. The main outcome of the analyses was mortality. The relationship between RMD and mortality was analysed using adjusted logistic models and sensitivity analyses were conducted to support the robustness of our results., Results: We included 668 RMD patients (62.7% with inflammatory arthritis, 28.6% with systemic autoimmune diseases), who had a mean age of 58.4 years and of which 66% were female. Compared to the general population, the RMD population showed an increased risk of death (OR 3.10 (95% CI 2.29-4.12)), independently from the differences in age and sex distribution. Even after considering the potential influence of surveillance bias, the OR was 2.08 (95% CI: 1.55-2.73). Such excess of risk was more evident in the subgroup of younger patients, and more consistent in women. Subjects with systemic autoimmune diseases showed a higher risk of death than patients with any other RMDs., Conclusions: Patients with RMD and COVID-19 infection evidenced a significant increase in mortality during the first pandemic phases in Italy. These findings support the need for strong SARS-CoV-2 prevention in patients with rheumatic diseases.

MIS-C is a multisystem inflammatory syndrome that is characterized by multi-organ failure and cardiac involvement. The aim of this study was to describe the long-term cardiovascular outcome in a cohort of MIS-C pediatric patients, who were admitted to two Italian Pediatric Referral Centers. Sixty-seven patients (mean age 8.7 ± 4.7 years, male 60%) were included; 65 (97%) of them showed cardiac involvement. All of the patients completed one month of the follow-up, and 47% completed 1 year of it. ECG abnormalities were present in 65% of them, arrhythmias were present in 9% of them during an acute phase and it disappeared at the point of discharge or later. Pericarditis were detected in 66% of them and disappeared after 6 months. Coronaritis was observed in 35% of the children during an acute phase, and there were no more instances at the 1-year point. An LV dysfunction was present in 65% of the patients at the beginning of the study, with them having a full recovery at the point of discharge and thereafter. Elevated values of the NTproBNP and hsTp were initially detected, which progressively decreased and normalized at the points of discharge and FU. The CMR at the point of FU, there was a presence of long-term myocardial scars in 50% of the patients that were tested. No deaths that were caused by MIS-C during the FU were recorded. Cardiac involvement in MIS-C patients is almost the rule, but the patients' clinical course was satisfactory, and no additional events or sequelae were observed apart from there being long-term myocardial scars in 50% of the patients that underwent CMR.

Over the past decade, invasive techniques for diagnosing and monitoring cancers are slowly being replaced by non-invasive methods such as liquid biopsy. Liquid biopsies have drastically revolutionized the field of clinical oncology, offering ease in tumor sampling, continuous monitoring by repeated sampling, devising personalized therapeutic regimens, and screening for therapeutic resistance. Liquid biopsies consist of isolating tumor-derived entities like circulating tumor cells, circulating tumor DNA, tumor extracellular vesicles, etc., present in the body fluids of patients with cancer, followed by an analysis of genomic and proteomic data contained within them. Methods for isolation and analysis of liquid biopsies have rapidly evolved over the past few years as described in the review, thus providing greater details about tumor characteristics such as tumor progression, tumor staging, heterogeneity, gene mutations, and clonal evolution, etc. Liquid biopsies from cancer patients have opened up newer avenues in detection and continuous monitoring, treatment based on precision medicine, and screening of markers for therapeutic resistance. Though the technology of liquid biopsies is still evolving, its non-invasive nature promises to open new eras in clinical oncology. The purpose of this review is to provide an overview of the current methodologies involved in liquid biopsies and their application in isolating tumor markers for detection, prognosis, and monitoring cancer treatment outcomes., (© 2022. The Author(s).)

Aims: This sub-study deriving from a multicentre Italian register [Deformation Imaging by Strain in Chronic Heart Failure Over Sacubitril-Valsartan: A Multicenter Echocardiographic Registry (DISCOVER)-ARNI] investigated whether sacubitril/valsartan in addition to optimal medical therapy (OMT) could reduce the rate of implantable cardioverter-defibrillator (ICD) indications for primary prevention in heart failure with reduced ejection fraction (HFrEF) according to European guidelines indications, and its potential predictors., Methods and Results: In this observational study, consecutive patients with HFrEF eligible for sacubitril/valsartan from 13 Italian centres were included. Lack of follow-up or speckle tracking data represented exclusion criteria. Demographic, clinical, biochemical, and echocardiographic data were collected at baseline and after 6 months from sacubitril/valsartan initiation. Of 351 patients, 225 (64%) were ICD carriers and 126 (36%) were not ICD carriers (of whom 13 had no indication) at baseline. After 6 months of sacubitril/valsartan, among 113 non-ICD carriers despite having baseline left ventricular (LV) ejection fraction (EF) ≤ 35% and New York Heart Association (NYHA) class = II-III, 69 (60%) did not show ICD indications; 44 (40%) still fulfilled ICD criteria. Age, atrial fibrillation, mitral regurgitation > moderate, left atrial volume index (LAVi), and LV global longitudinal strain (GLS) significantly varied between the groups. With receiver operating characteristic curves, age ≥ 75 years, LAVi ≥ 42 mL/m 2 and LV GLS ≥-8.3% were associated with ICD indications persistence (area under the curve = 0.65, 0.68, 0.68, respectively). With univariate and multivariate analysis, only LV GLS emerged as significant predictor of ICD indications at follow-up in different predictive models., Conclusions: Sacubitril/valsartan may provide early improvement of NYHA class and LVEF, reducing the possible number of implanted ICD for primary prevention in HFrEF. Baseline reduced LV GLS was a strong marker of ICD indication despite OMT. Early therapy with sacubitril/valsartan may save infective/haemorrhagic risks and unnecessary costs deriving from ICDs., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

A cancer immune phenotype characterized by an active T-helper 1 (Th1)/cytotoxic response is associated with responsiveness to immunotherapy and favorable prognosis across different tumors. However, in some cancers, such an intratumoral immune activation does not confer protection from progression or relapse. Defining mechanisms associated with immune evasion is imperative to refine stratification algorithms, to guide treatment decisions and to identify candidates for immune-targeted therapy. Molecular alterations governing mechanisms for immune exclusion are still largely unknown. The availability of large genomic datasets offers an opportunity to ascertain key determinants of differential intratumoral immune response. We follow a network-based protocol to identify transcription regulators (TRs) associated with poor immunologic antitumor activity. We use a consensus of four different pipelines consisting of two state-of-the-art gene regulatory network inference techniques, regularized gradient boosting machines and ARACNE to determine TR regulons, and three separate enrichment techniques, including fast gene set enrichment analysis, gene set variation analysis and virtual inference of protein activity by enriched regulon analysis to identify the most important TRs affecting immunologic antitumor activity. These TRs, referred to as master regulators (MRs), are unique to immune-silent and immune-active tumors, respectively. We validated the MRs coherently associated with the immune-silent phenotype across cancers in The Cancer Genome Atlas and a series of additional datasets in the Prediction of Clinical Outcomes from Genomic Profiles repository. A downstream analysis of MRs specific to the immune-silent phenotype resulted in the identification of several enriched candidate pathways, including NOTCH1, TGF-$\beta $, Interleukin-1 and TNF-$\alpha $ signaling pathways. TGFB1I1 emerged as one of the main negative immune modulators preventing the favorable effects of a Th1/cytotoxic response., (© The Author(s) 2021. Published by Oxford University Press.)

Background: The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2-3 years of letrozole in postmenopausal patients with breast cancer who have already received 2-3 years of tamoxifen., Methods: This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I-III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2-3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635., Findings: Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2-3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5-13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57-66) in the control group and 67% (62-71) in the extended group (hazard ratio 0·78, 95% CI 0·65-0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed., Interpretation: In postmenopausal patients with breast cancer who received 2-3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2-3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2-3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer., Funding: Novartis and the Italian Ministry of Health., Translation: For the Italian translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests LDM receives honoraria and non-financial support from Roche, Novartis, Pfizer, MSD, Genomic Health, Takeda, Ipsen, Eisai, Eli Lilly, Celgene, Pierre Fabre, Seagen, Daiichi Sankyo, Exact Sciences, and Amgen. MM receives honoraria from Novartis, Pfizer, AstraZeneca, Roche, Eisai, Eli Lilly, and MSD. AF receives honoraria from Roche, Novartis, Eli Lilly, Daiichi Sankyo, Seagen, AstraZeneca, and Pfizer. SDP receives honoraria from Roche, Novartis, Pfizer, Celgene, Eli Lilly, AstraZeneca, Clovis, Seagen, Daichii Sankyo, and MSD. OG receives honoraria and non-financial support from Eisai, Novartis, MSD, Amgen, Eli Lilly, Pfizer, and Roche. CB receives honoraria from Novartis, Roche, and Eli Lilly. FPu receives honoraria from Eisai, Novartis, Astra Zeneca, Celgene, Roche, MSD, Daichii Sankyo, and Eli Lilly. GA receives honoraria from Roche, Amgen, AstraZeneca, Pfizer, Eli Lilly, Novartis, and MDS. FPo receives honoraria and non-financial support from MSD, Eli Lilly, and Novartis. ML acted as adviser for Roche, AstraZeneca, Eli Lilly, and Novartis; and receives honoraria from Takeda, Roche, AstraZeneca, Eli Lilly, Pfizer, Novartis, and Sandoz. FM receives honoraria from Roche, Novartis, Eli Lilly, Pierre Fabre, Novartis, Daichii Sankyo, Pfizer, AstraZeneca, Seagen, and Pierre Fabre. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neuroendocrine differentiation (NED) of prostate cancer represents an acknowledged predictor of resistant and more aggressive disease. NED can be functionally exploited in vivo using PET/CT imaging with somatostatin analogs radiolabeled with 68Ga. Many previous reports have shown that 18F-FDG PET/CT should also be used in cases such as guiding management, as NED is systematically associated with increased glycolysis. We hereby discuss the case of a metastatic prostate cancer patient in which 68Ga-Dotatoc PET/CT revealed the occurrence of NED with low FDG-avidity.

Aim: To evaluate, in Systemic sclerosis (SSc) patients, the body composition and the bone status according to the peripheral microcirculatory condition, assessed and scored by nailfold videocapillaroscopy (NVC, "Early", "Active", "Late" patterns)., Methods: Body composition and bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and dedicated software (GE Lunar USA) in 37 female SSc patients classified according to the 2013 EULAR/ACR criteria and 40 sex-matched healthy subjects. Clinical, laboratory, body composition and bone parameters were analyzed according to the different NVC patterns. Means were compared by the Student's t test or one-way analysis of variance; medians were compared by the Kruskal-Wallis test; and frequencies by the chi-square test., Results: Higher prevalence of vertebral (21% vs 7%) and femoral (35% vs 7%) osteoporosis (OP) was found in SSc. Particularly SSc patients with "Late" NVC pattern showed a significantly higher prevalence of vertebral (p = 0.018) and femoral OP (p = 0.016). Regional assessment of bone mass (BM) in seven different body areas showed a significantly lower BMD only at the total spine (p = 0.008) and femoral neck (p = 0.027) in advanced microvascular damage. Patients with "Late" NVC pattern showed a lower whole-body lean mass (LM) compared to "Early" and "Active" NVC patterns, particularly at upper limbs. To note, in all body sites, BMD correlates with LM and BMC according to NVC pattern severity., Conclusions: SSc patients with most severe microvascular damage show a significantly altered body composition and bone status suggesting a strong link between microvascular failure and associated muscle/bone sufferance.

Cardiovascular risk (CVR) is a broad term that includes traditional factors like hypertension, hyper lipidemia, abdominal obesity, hyperinsulinemia or overt type 2 diabetes mellitus (T2DM), and emerging ones such as hypothyroidism or inflammatory diseases. In epidemiologic studies, all of these factors are associated with atherogenesis and have complex interactions between them. They have in common an increased prevalence in the general population beginning in childhood, and are correlated with endothelial damage as demonstrated by echocardiographic modifications of the left ventricle or carotid intima-media thickness. Adolescence is a transition period where behavioural eating patterns develop and have a major impact on cardiovascular risk. To address these patterns, weight-loss programmes under medical supervision for overweight and obese adolescents are developed. It was observed that those who control the quality and quantity of their carbohydrates, by consuming more fruits and vegetables, associated with increased physical activity reduce their CVR. Some limited studies have shown that low carbohydrate diet (LCD) is safe and effective, but one should take into consideration the limited duration and the structure of the LCD. If there is a proper adherence to this type of nutritional intervention, it results in weight loss, improvement in insulin resistance, lipid profile and subclinical hypothyroidism reversal. We reviewed the literature starting from 2009 by searching all the observational, randomised clinical trials and meta-analyses on MEDLINE and SCOPUS databases regarding obesity and related metabolic diseases (dyslipidemia, type 2 diabetes, hypertension, hypothyroidism, LCD) in adolescents and synthesized the nutritional interventions for this population that could decrease CVR., (Copyright © 2020, Spandidos Publications.)

Purpose: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs., Methods: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis., Results: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis., Conclusions: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.

Objectives: Italy was one of the first countries significantly affected by the coronavirus disease 2019 (COVID-19) epidemic. The Italian Society for Rheumatology promptly launched a retrospective and anonymised data collection to monitor COVID-19 in patients with rheumatic and musculoskeletal diseases (RMDs), the CONTROL-19 surveillance database, which is part of the COVID-19 Global Rheumatology Alliance., Methods: CONTROL-19 includes patients with RMDs and proven severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) updated until May 3rd 2020. In this analysis, only molecular diagnoses were included. The data collection covered demographic data, medical history (general and RMD-related), treatments and COVID-19 related features, treatments, and outcome. In this paper, we report the first descriptive data from the CONTROL-19 registry., Results: The population of the first 232 patients (36% males) consisted mainly of elderly patients (mean age 62.2 years), who used corticosteroids (51.7%), and suffered from multi-morbidity (median comorbidities 2). Rheumatoid arthritis was the most frequent disease (34.1%), followed by spondyloarthritis (26.3%), connective tissue disease (21.1%) and vasculitis (11.2%). Most cases had an active disease (69.4%). Clinical presentation of COVID-19 was typical, with systemic symptoms (fever and asthenia) and respiratory symptoms. The overall outcome was severe, with high frequencies of hospitalisation (69.8%), respiratory support oxygen (55.7%), non-invasive ventilation (20.9%) or mechanical ventilation (7.5%), and 19% of deaths. Male patients typically manifested a worse prognosis. Immunomodulatory treatments were not significantly associated with an increased risk of intensive care unit admission/mechanical ventilation/death., Conclusions: Although the report mainly includes the most severe cases, its temporal and spatial trend supports the validity of the national surveillance system. More complete data are being acquired in order to both test the hypothesis that RMD patients may have a different outcome from that of the general population and determine the safety of immunomodulatory treatments.

Background: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc), associated with a progressive elevation in pulmonary vascular resistance and subsequent right heart failure and death. Due to unspecific symptoms, the diagnosis of PAH is often delayed. On this basis, it is of great value to improve current diagnostic methods and develop new strategies for evaluating patients with suspected PAH. Interleukin-32 (IL-32) is a proinflammatory cytokine expressed in damaged vascular cells, and the present study aimed to assess if this cytokine could be a new biomarker of PAH during SSc., Methods: The IL-32 expression was evaluated in the sera and skin samples of 18 SSc-PAH patients, 21 SSc patients without PAH, 15 patients with idiopathic PAH (iPAH) and 14 healthy controls (HCs), by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC). Receiver-operating characteristic (ROC) curves were performed to evaluate the cut-off of IL-32 in identifying patients with PAH. Furthermore, in SSc patients, correlation analyses were performed between IL-32 sera levels and mean pulmonary artery pressure (mPAP) evaluated by right heart catheterization (RHC) and systolic pulmonary artery pressure (sPAP), obtained by echocardiography. Additionally, the number of skin IL-32+ cells was correlated with modified Rodnan skin score (mRSS)., Results: In SSc-PAH patients, IL-32 sera levels were significantly higher when compared with SSc patients without PAH and patients affected by iPAH. The analysis of ROC curve showed that IL-32 sera levels above 11.12 pg/ml were able to predict patients with PAH (sensitivity = 90%, specificity = 100%). Furthermore, the IL-32 sera levels of patients with SSc correlated with both mPAP and sPAP. In the skin derived from SSc-PAH patients, the number of IL-32+ cells was significantly increased when compared with the skin derived from SSc patients without PAH, correlating with the mRSS., Conclusion: Our study suggested that sera determination of IL-32 may be a promising approach to evaluate the presence of PAH in SSc patients and together with longitudinal future studies could help to increase the understanding how these biomarkers mirror the vascular changes and the inflammatory process during SSc.

Echocardiography of right ventricular (RV)-arterial coupling obtained by the estimation of the ratio of the longitudinal annular systolic excursion of the tricuspid annular plane and pulmonary artery systolic pressure (TAPSE/PASP) has been found to be a remarkable prognostic indicator in patients with HF. Our aim was to evaluate the impact of TAPSE, PASP and their ratio in the prognostic stratification of outpatients with HF aged ≥70 years and reduced to mid-range ejection fraction (EF). A complete echocardiographic examination was performed in 400 outpatients with chronic HF and left ventricular (LV) EF ≤50% who averaged 77 years in age. During a median follow-up period of 25 months (interquartile range: 8-46), there were 135 cardiovascular deaths. Two different Cox regression models were evaluated, one including TAPSE and PASP, separately, and the other with TAPSE/PASP. In the first model, LV end-systolic volume index, age, no angiotensin converting enzyme (ACE) inhibitor use, TAPSE, PASP and gender were found to be independently associated with the outcome after adjustment for demographics, clinical, biochemical, echocardiographic data. In the second model, TAPSE/PASP resulted the most important independent predictor of outcome (hazard ratio [HR]:0.07, p<0.0001) followed by LV end-systolic volume index, no ACE inhibitor use, age and gender. The use of the variable TASPE/PASP improved the predictive value of the new multivariable model (area under the curve [AUC] of 0.74 vs AUC of 0.71; p<0.05). TASPE/PASP improved the net reclassification (NRI = 14.7%; p<0.01) and the integrated discrimination (IDI = 0.04; p<0.01). In conclusion, the study findings showed that assessment of RV-arterial coupling by TAPSE/PASP was of major importance to assess the prognosis of patients with chronic HF and LV EF ≤50% aged ≥70 years.

Optimal medical therapy (OMT) at discharge is recommended after acute coronary syndrome (ACS). Few studies report the impact of OMT on long-term clinical outcome in a real-world scenario. We evaluated the impact of discharge OMT on top of dual-antiplatelet therapy (DAPT) on clinical outcome in the real-world ACS population of the Survey on anTicoagulated pAtients RegisTer ANTIPLATELET registry. The primary end point was major adverse cardiac and cerebrovascular event (MACCE), a composite of death, myocardial infarction, stroke, or target vessel revascularization. The co-primary end point was net adverse cardiac and cerebrovascular event (NACE), based on MACCE plus major bleeding. Consecutive patients with ACS with 1-year follow-up were enrolled. They were evaluated at discharge for the use of a β-blocker, angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and statins. Optimal medical therapy was defined as the use of ≥2 of 3 medications. At multivariate analysis, both MACCE and NACE were significantly higher in non-OMT patients than in OMT patients (MACCE 18 [19] vs 59 [9], hazard ratio [HR] = 0.44 [0.26-0.75], P = .002, NACE 19 [20] vs 67 [10], HR = 0.47 [0.28-0.79], P = .004). In this real-world scenario, OMT at discharge on top of DAPT seems associated with a better clinical outcome compared with patients discharged on non-OMT.

Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous opioid system is close to the immune one because of the expression of opioid receptors on lymphocytes membrane. Here we analyzed the role of the Mu opioid receptor on B lymphocytes as a specific biomarker for FM and osteoarthritis (OA) patients. We enrolled three groups of females: FM patients, OA patients (chronic pain control group) and healthy subjects (pain-free negative control group). We collected blood samples to apply immunophenotyping analysis. Written tests were administrated for psychological analysis. Data were statistically analyzed. Final results showed that the percentage of Mu-positive B cells were statistically lower in FM and OA patients than in pain-free subjects. A low expression of Mu-positive B cell was not associated with the psychological characteristics investigated. In conclusion, here we propose the percentage of Mu-positive B cells as a biological marker for an objective diagnosis of chronic pain suffering patients, also contributing to the legitimacy of FM as a truly painful disease.

Introduction : Clinicians involved in pain management can finally include cannabis or cannabis-related products in their therapeutic armamentarium as a growing number of countries have approved them for pain relief. Despite the several benefits attributed to analgesic, anti-inflammatory and immunomodulatory properties of cannabinoids, there are still significant areas of uncertainty concerning their use in many fields of medicine. The biosynthesis and inactivation of cannabinoids are regulated by a complex signaling system of cannabinoid receptors, endocannabinoids (the endogenous ligands of cannabinoid receptors) and enzymes, with a variety of interactions with neuroendocrinological and immunological systems. Areas covered : A review of studies carried out during clinical development of cannabis and cannabis medical products in systemic rheumatic diseases was performed, highlighting the aspects that we believe to be relevant to clinical practice. Expert opinion : The growing public opinion, pushing toward the legalization of the use of cannabis in chronic pain and various rheumatological conditions, makes it necessary to have educational programs that modify the concerns and widespread preconceptions related to this topic in the medical community by increasing confidence. More extensive basic and clinical research on the mechanisms and clinical utility of cannabis and derivatives in various diseases and their long-term side effects is necessary.

Purpose:  To evaluate the diagnostic performance of strain ratio elastography (SRE) and shear wave elastography (SWE) alone and in combination with Thyroid Imaging Reporting and Data System (TIRADS) classification parameters to improve differentiation between benign and malignant thyroid nodules., Materials and Methods:  In this prospective study benign (n = 191) and malignant (n = 52) thyroid nodules were examined with high-resolution ultrasound (US) features using the TIRADS lexicon and SRE semiquantitative and SWE quantitative findings using histology or cytology as the gold standard with a 12-month follow-up. Sensitivity (Se), specificity (Sp) and the area under the ROC curve (AUROC) were used to evaluate the diagnostic performance of each feature and combinations of the methods., Results:  TIRADS score showed a sensitivity of 59.6 %, a specificity of 83.8 % with an AUROC of 0.717, a PPV of 50.0 % and an NPV of 88.4 %. SRE yielded the highest performance with a sensitivity of 82.7 %, a specificity of 92.7 % with AUROC of 0.877, a PPV 75.4 % and an NPV of 95.2 %. SWE (kPa) had a sensitivity and specificity of 67.3 % and 82.7 %, respectively, with an AUROC of 0.750, a PPV of 51.5 % and an NPV of 90.3 %. Differences were significant for SRE only but not for SWE., Conclusion:  Ultrasound elastography may improve thyroid nodule discrimination. In particular, SRE has a better performance than TIRADS classification, while their combination improves sensitivity., Competing Interests: Cantisani received honoraria for lectures from Bracco, Samsung and Canon.Dietrich CFD received honoraria: Hitachi, Siemens, Supersonic, Mindray, GE, Bracco.Radzina received honoraria for lectures from Canon and Bracco., (© Georg Thieme Verlag KG Stuttgart · New York.)

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA-namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa-environment interaction.

The role of oxidative stress, an imbalance between reactive oxygen species production (ROS) and antioxidants, has been described in several patho-physiological conditions, including cardiovascular, neurological diseases and cancer, thus impacting on individuals' lifelong health. Diet, environmental pollution, and physical activity can play a significant role in the oxidative balance of an organism. Even if physical training has proved to be able to counteract the negative effects caused by free radicals and to provide many health benefits, it is also known that intensive physical activity induces oxidative stress, inflammation, and free radical-mediated muscle damage. Indeed, variations in type, intensity, and duration of exercise training can activate different patterns of oxidant-antioxidant balance leading to different responses in terms of molecular and cellular damage. The aim of the present review is to discuss (1) the role of oxidative status in athletes in relation to exercise training practice, (2) the implications for muscle damage, (3) the long-term effect for neurodegenerative disease manifestations, (4) the role of antioxidant supplementations in preventing oxidative damages.

Introduction: Vernal keratoconjunctivitis (VKC) is a severe disease with a prevalence of < 1 case out of 10,000 in Europe, which occurs mainly in pediatric age and is characterized by a severe and often bilateral chronic inflammation of the ocular surface. The diagnosis is generally confirmed by the finding at the ocular examination of conjunctival hyperemia, papillary hypertrophy in the tarsal conjunctiva, giant papillae, papillae in the limbus region., Objective: Aim of this review is to provide an updated overview on the disease focused on clinical grading system, searching papers published in the last decade on VKC in scientific databases., Results: Currently there are no standardized criteria for diagnosis of VKC and there is no uniformity to define disease severity, which makes difficult to diagnose and treat the disease., Conclusions: Given the wide overlap of the symptoms of VKC with the allergic conjunctivitis, criteria of probable, possible or improbable diagnosis are needed, providing pediatricians with parameters useful for deciding whether to drive the patient to the ophthalmologist for diagnostic confirmation.

We investigated whether gender influences antiplatelet treatment in patients with acute coronary syndrome (ACS). The primary end point was major adverse cardiac and cerebrovascular events (MACCEs), a composite of death, myocardial infarction (MI), stroke, or target vessel revascularization. The coprimary end point was net adverse cardiac and cerebrovascular events (NACEs), based on MACCE plus major bleeding. From January 2014 to December 2016, 840 consecutive patients with ACS who completed 1-year follow-up were enrolled, 625 (74%) males and 215 (26%) females. Percutaneous coronary interventions (PCI) and drug-eluting stents (DES) were more often used in males (PCI: 532 [87%] vs 168 [80%], P = .02 and DES 474 [76%] vs 143 [66%], P = .01). Males were more often treated with dual antiplatelet therapy (DAPT; 94% vs 88%, P = .01). In DAPT, ticagrelor was the most prevalent strategy, regardless of gender (47% vs 49%, P = .68); clopidogrel was preferred in women (42% vs 33%, P = .04); and prasugrel was preferred in men (11% vs 17%, P = .04). At multivariate analysis, MACCE and NACE were similar between genders. Therefore, although P 2 Y 12 inhibitor choice in DAPT might be influenced by gender, a DAPT choice, tailored by balancing the ischemic/bleeding risk, has a similar clinical outcome irrespective of gender.

Fibromyalgia is characterised by chronic pain, fatigue and functional symptoms. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings related to the aetiopathogenesis, diagnosis, clinical aspects and treatment of FM published between January 2018 and January 2019.

Alzheimer's disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355 S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal hereditary disorder. Several authors have attempted to identify a kidney damage marker for predicting the prognosis and the effectiveness of therapy in ADPKD., Aim: To identify and quantify ADPKD, through a novel magnetic resonance imaging protocol with 3 Tesla (MRI 3Tesla), the presence of parenchymal fibrotic tissue at early stage of disease, able to correlate the glomerular filtrate and to predict the loss of the renal function., Methods: A total of 15 ADPKD patients had undergone renal testing on MRI 3Tesla at T0 and were revaluated after follow up (T1) of 5 years. We have evaluated renal function, plasma aldosterone concentration (PAC), insulin resistance and surrogate markers of atherosclerosis (carotid intima-media thickness, ankle/brachial index (ABI) and left ventricular mass index (LVMI)., Results: Our study showed a significant negative correlation between total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) during observation (P < 0.02). We showed a negative correlation between eGFR with total fibrotic volume (TFV) (P < 0.04) and total perfusion volume/TKV (P < 0.02). Moreover TFV was correlated positively with PAC (P < 0.05), insulin values (P < 0.05), ABI (P < 0.05) and LVMI (P < 0.01)., Conclusion: The MRI 3Tesla, despite the high costs, could be considered as a useful and non-invasive method in the evaluation of fibrotic tissue and progression of the disease in ADPKD patients. Further clinical trials on larger groups are due to confirm the results of this pilot study, suggesting that MRI 3Tesla can be useful to evaluate the effectiveness of new therapeutic strategies., (© 2018 Royal Australasian College of Physicians.)

Rheumatoid arthritis (RA) is a chronic inflammatory disease with increased risk of cardiovascular events and mortality that can be attributed to accelerated atherosclerosis. This pilot study aimed to investigate if changes in blood parameters were compatible with atherosclerotic events in RA patients. To this aim, 45 RA women (aged more than 18 years), and 25 age and gender-matched healthy donors (HD) were included. Biomarkers of oxidative stress, platelet activation and platelet aggregation were analysed in RA patients at baseline and after six months of treatment with disease modifying anti-rheumatic drugs (DMARDs). Flow cytometry analysis revealed that ca. 4% of platelets was in activated state (evaluated in term of Annexin V and PAC-1 positivity) in RA patients at baseline, and that the 76% of platelets displayed mitochondrial hyperpolarization. Moreover, platelets from RA patients at baseline aggregated more than those from HD after whole blood treatment with adenosine diphosphate. Interestingly, platelet aggregation in patients at baseline positively correlated with disease activity measured by DAS28 score. After six months of treatment with DMARDs, platelet activation and platelet aggregation reached values comparable to those of HD. Our preliminary data suggest that platelets might play an active role in the atherosclerosis occurring in RA patients.

Alport syndrome is due to mutations in one of the genes encoding (α3,4,5) type IV collagen resulting in defective type IV collagen, a key component of the glomerular basement membrane (GBM). The GBM is initially thin and, with ongoing remodeling, develops a thickened basket-woven appearance. We report a unique case of a 9-year-old boy who underwent biopsy for hematuria and proteinuria, diagnosed as IgA nephropathy, with normal GBM appearance and thickness. Because of a family history of hematuria and chronic kidney disease, he subsequently underwent genetic evaluation, and a mutation of α3 type IV collagen (COL4A3) was detected. Additional studies of the initial biopsy demonstrated abnormal type IV collagen immunostaining. A repeat biopsy 4 years later showed characteristic glomerular basement membrane morphology of Alport syndrome and scarring consistent with sequelae of IgA nephropathy. This is the first description of this unusual transition from an initial normal appearance of the glomerular basement membrane to the classic Alport phenotype., (Copyright © 2018. Published by Elsevier Inc.)

Background: Chronic kidney disease (CKD) is a highly prevalent condition. Urologic disorders are known causes of CKD, but often remain undiagnosed and underestimated also for their insidious onset and slow progression. We aimed to evaluate the prevalence of urological unrecognized diseases in CKD patients by uroflowmetry., Methods: We enrolled consecutive stable CKD outpatients. The patients carried out two questionnaires, the International Prostate Symptom Score and Incontinence Questionnaire-Short Form, and they also underwent uroflowmetry, evaluating max flow rate ( Q ), voiding time and voided volume values.max ), voiding time and voided volume values., Results: A total of 83 patients (43 males, mean age of 59.8 ± 13.3 years) were enrolled. Our study showed 28 males and 10 females with a significant reduction of Q (P < 0.001) while 21 females reported a significant increase of max (P < 0.001) with a prevalence of 49.5% of functional urological disease. Moreover, we showed a significant association between Q and creatinine (P = 0.013), estimated glomerular filtration rate (P = 0.029) and voiding volume (P = 0.05). We have not shown significant associations with age (P = 0.215), body mass index (P = 0.793), systolic blood pressure (P = 0.642) or diastolic blood pressure (P = 0.305). Moreover, Pearson's chi-squared test showed a significant association between max (P < 0.001) with a prevalence of 49.5% of functional urological disease. Moreover, we showed a significant association between Q  = 1.885, P = 0.170) and recurrent infection (χ max and creatinine (P = 0.013), estimated glomerular filtration rate (P = 0.029) and voiding volume (P = 0.05). We have not shown significant associations with age (P = 0.215), body mass index (P = 0.793), systolic blood pressure (P = 0.642) or diastolic blood pressure (P = 0.305). Moreover, Pearson's chi-squared test showed a significant association between Q max altered with CKD (χ 2  = 1.885, P = 0.170) and recurrent infection (χ 2  = 8.886, P = 0.012), while we have not shown an association with proteinuria (χ 2  = 0.484, P = 0.785), diabetes (χ 2  = 0.334, P = 0.563) or hypertension (χ 2  = 1.885, P = 0.170)., Conclusions: We showed an elevated prevalence of urological diseases in nephropathic patients; therefore, we suggest to include uroflowmetry in CKD patient assessment, considering the non-invasiveness, repeatability and low cost of examination. Uroflowmetry could be used to identify previously unrecognized urological diseases, which may prevent the onset of CKD or progression to end-stage renal disease and reduce the costs of management.

Objective: The relation between nasal flow and malocclusion represents a practical concern to pediatricians, otorhinolaryngologists, orthodontists, allergists and speech therapists. If naso-respiratory function may influence craniofacial growth is still debated. Chronic mouth-breathing is reported to be associated also with a characteristic pattern of dental occlusion. On the other hand, also malocclusion may reduce nasal air flows promoting nasal obstruction. Hereby, the aim of this review was to describe the relationship between rhinitis and malocclusion in children., Methods: An electronic search was conducted using online database including Pubmed, Web of Science, Google Scholar and Embase. All studies published through to January 30, 2017 investigating the prevalence of malocclusion in children and adolescents (aged 0-20 years) affected by rhinitis and the prevalence of rhinitis in children with malocclusion were included. The protocol was registered at PROSPERO - International prospective register of systematic reviews under CRD42016053619., Results: Ten studies with 2733 patients were included in the analysis. The prevalence of malocclusion in children with rhinitis was specified in four of the studies ranging from as high as 78.2% to as low as 3%. Two out of the studies reported the prevalence of rhinitis in children with malocclusion with a rate ranging from 59.2 to 76.4%., Conclusion: The results of this review underline the importance of the diagnosis and treatment of the nasal obstruction at an early age to prevent an altered facial growth, but the data currently available on this topic do not allow to establish a possible causal relationship between rhinitis and malocclusion.

Background: The aim of the present in vitro study was to investigate, in different genders, motor responses in surgical colonic specimens from patients with rectal cancer undergoing and not undergoing chemotherapy with capecitabine and radiotherapy., Methods: This in vitro study was conducted from October 2015 to August 2017 at the Experimental Pharmacology Laboratory at the National Institute "S. de Bellis" after collecting samples at the Department of Surgery. Segments of sigmoid colon were obtained from 15 patients (Male (M)/Female (F) = 8/7; control group, CG) operated on for elective colorectal resection for rectal cancer without obstruction and 14 patients (M/F = 7/7; study group, SG) operated on for elective colorectal resection for rectal cancer who also received chemotherapy, based on capecitabine twice daily, and radiotherapy. Isometric tension was measured on colonic circular muscle strips exposed to increasing carbachol or histamine concentrations to obtain concentration-response curves. The motor responses to electrically evoked stimulation were also investigated., Results: In males, carbachol and histamine caused concentration-dependent contractions in the CG and SG. An increased sensitivity and a higher response to carbachol and histamine were observed in SG than CG (P < 0.01). On the contrary, in females, the response to carbachol was not significantly different in CG from the SG and the maximal responses to carbachol were greater in CG than in SG (P < 0.001). The same applied to histamine for half-maximal effective concentrations and maximal response in that they were not significantly different in CG from the SG. Electrically evoked contractions were significantly more pronounced in males, especially in the SG (P < 0.05)., Conclusions: This preliminary in vitro study has shown gender differences in motor responses of colonic circular muscle strips in patients who had received chemotherapy with capecitabine and radiotherapy.

Background: Two risk scores have been developed to predict composite outcomes in atrial fibrillation (AF): the 2MACE and TIMI-AF scores. The aim of this study was to compare the predictive ability of these scores in 2 separate warfarin-treated cohorts (one 'real world', one clinical trial) of AF patients.Methods and Results:The 2MACE and TIMI-AF scores were calculated in the 'real-world' ATHERO-AF cohort (n=907), and in the randomized controlled AMADEUS trial (n=2,265). Endpoints were major adverse cardiovascular events (MACEs), net clinical outcomes (NCO) and a combination of them, namely "clinically relevant events" (CREs). ROC curves showed similar predictive ability for MACE for 2MACE and TIMI-AF, in both the ATHERO-AF (0.698 vs. 0.688, respectively P=0.783) and AMADEUS (0.657 vs. 0.569, respectively P=0.057) cohorts. Similarly, the TIMI-AF showed a comparable c-index with 2MACE for NCOs in the ATHERO-AF (0.676 vs. 0.667, P=0.737), and AMADEUS (0.666 vs. 0.663, P=0.859) cohorts. No differences were found between the 2 scores for the prediction of CREs (0.675 vs. 0.684, P=0.740 in ATHERO-AF and 0.669 vs. 0.667, P=0.889 in AMADEUS for 2MACE and TIMI-AF, respectively)., Conclusions: This study showed that the 2MACE and TIMI-AF scores had modest but significant predictive ability for composite outcomes in AF. The clinical usefulness of both scores was similar, but the 2MACE score may be simpler and easy to use.