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Background: Pancreaticoduodenectomy is the only possible choice of treatment for peri-ampoullar neoplasms. Morbidity in pancreatic surgery is mainly related to the development of a postoperative pancreatic fistula (POPF). According to International Study Group on Pancreatic Fistula it is possible to grade POPF based on clinical variables. Three main different surgical strategies have been proposed to deal with the pancreatic stump following pancreaticoduodenectomy: pancreatojejunostomy, pancreatogastrostomy and pancreatic duct occlusion, but none of them has been clearly demonstrated to be superior to the others. The aim of our study is to evaluate the feasibility of duct occlusion and its correlations with postoperative pancreatic fistula, “brittle diabetes” and overall survival in a low volume centre. We decided to review our previous experience in the light of the recent Covid pandemic where, in our country, it has been forced in many regions to displace treatment of oncological patients in low volume hospitals with limited experienceMethods: We retrospectively reviewed 56 consecutive patients, from a prospective maintained database, who underwent Whipple’s procedure from January 2007 to December 2014 in a tertiary Hepatobiliary Surgery and Liver Transplant Unit with a low volume of pancreatic resections. The mean follow-up was 24.5 months. Results: The overall incidence of postoperative pancreatic fistula was 66.6%: 15 patients had a Grade A (31.25%), 13 a Grade B fistula (27.03%), and 4 (8.3%) suffered from a life-threatening Grade C fistula. At the last follow-up, 24 of the 28 patients who were alive (85.6%) habitually used substitutive pancreatic enzyme. Conclusion: Duct occlusion can be a safe alternative to pancreatic anastomosis especially in low volume centres and for those patients (age >75 years, obese, hard pancreatic texture, small pancreatic duct) at higher risk of clinically relevant POPF.Trial registration: 'retrospectively registered'

The topology of brain networks changes according to environmental demands and can be described within the framework of graph theory. We hypothesized that 24-hours long sleep deprivation (SD) causes functional rearrangements of the brain topology so as to impair optimal communication, and that such rearrangements relate to the performance in specific cognitive tasks, namely the ones specifically requiring attention. Thirty-two young men underwent resting-state MEG recording and assessments of attention and switching abilities before and after SD. We found loss of integration of brain network and a worsening of attention but not of switching abilities. These results show that brain network changes due to SD affect switching abilities, worsened attention and induce large-scale rearrangements in the functional networks.

Background Urinary tract infections (UTIs) are among the most common bacterial infection diagnosed in women. The standard therapy is represented by short course of anti-microbial treatment to eradicate causative pathogens. However, due to antibiotic treatment, normal microbiota of the gastrointestinal tract is at risk of depletion and prolonged use of antibiotics can lead to the development of resistant strains. The aim of this pilot study was to assess the efficacy of Acidif plus®, a novel preparation containing L-Methionine, Boswellia serrata and Hibiscus sabdariffa, in the treatment of UTIs in women, in comparison with standard antibiotic treatment with fosfomycin. Methods We performed a pilot clinical study with 88 patients with uncomplicated UTIs treated in ambulatory care clinics. The subjects recruited in the study were divided into two groups: the treatment group included 57 patients with both symptomatic and asymptomatic uncomplicated, bacteriuria-positive UTIs, who were treated by oral administration of Acidif plus® two tablets per day (1 tablet in the morning and 1 tablet in the evening) for 7 days. The control group included 31 patients with both symptomatic and asymptomatic bacteriuria-positive uncomplicated UTIs, treated with fosfomycin for two consecutive days. Clinical improvement of symptoms and urine bacteriuria were evaluated as treatment outcomes. Results More than 50% of Acidif plus® treated patients were free of symptoms of UTIs at the end of the treatment regime. In addition, Acidif plus® treatment was effective in eliminating the bacterial infection in the post-treatment urine cultures in more than 85% of the patients. Conclusions In this study Acidif plus® treatment in patients with uncomplicated UTIs was found to be non-inferior to the standard antibiotic therapy. In acute setting, Acidif plus® was shown to be even more effective in alleviating the symptoms than fosfomycin and in eliminating bacteria in urine cultures. It is therefore possible to propose Acidif plus® as a potential alternative option to reduce the problem of multi-drug resistance in urinary infections.

Background: Secondary prevention of atrial fibrillation (AF) could be carried out by means of antiarrhythmic drugs; however this strategy has not received any endorsement because these drugs are burdened by a high risk of proarrhythmic events (flecainide, sotalol) or extracardiac effects (amiodarone). Methods: In our retrospective cohort study we have compared amiodarone 200 mg per day with the strategy implying the renunciation of any specific drug as well as with the approach using oral anticoagulant (rivaroxaban) or a combined approach including amiodarone plus rivaroxaban. Results: A total of 255 patients with a history of AF (paroxysmal, persistent or long-lasting persistent) successfully treated with achievement of sinus rhythm have been gathered. Amiodarone has been the most effective option for AF secondary prevention, with regard to the recurrences of AF as well as rehospitalizations: P (Kruskal-Wallis test) < 0.05 for both, over a median follow-up of 24 months. Conclusions: Patients kept free from any specific drug therapy have been shown to experience more numerous AF relapses and related rehospitalizations. On the contrary, the amiodarone use has been associated with a decreased risk of AF recurrences and hospital admissions. Thus, amiodarone might be an efficacious tool for realizing a successful long-term AF secondary prevention. Cardiol Res. 2019;10(4):223-229 doi: https://doi.org/10.14740/cr909

e24056 Background: Anthracycline and trastuzumab are essential adjuvant therapies for a variety of cancers, particularly breast, and gastric and esophageal cancers. Whilst prolonging cancer-related survival, these agents can induce drug-related cardiotoxicity. Cardioprotective agents used to mitigate cardiotoxicity, such as angiotensin antagonists, angiotensin receptor blockers and beta‐blockers, are often poorly tolerated in these patients due to intravascular volume fluctuations, which are further escalated by the hemodynamic side effects of these agents. Spiruline, Reishi and Moringa are nutaceuticals with anti-inflammatory effects that are currently used in cancer patients to improve quality of life and fatigue. We hypothesize that the combination of Spirulina, Reishi and Moringa could reduce inflammation and cardiotoxicity of anthracyclines and trastuzumab. Methods: Human cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (200 nM) alone or in combination with a formulation composed by Spiruline, Reishi and Moringa (at 10, 25 and 50 µg/ml) for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α were also performed. Results: Spiruline, Reishi and Moringa in combination increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. The nutraceutical formulation reduces intracellular Ca2+ overload (-48,8% vs cells treated only to anticancer drugs; p < 0,001), lipid peroxidation (- 47,2 % compared to cells exposed only to anticancer drugs; p < 0,001). The expression of MyD88 and NLRP3 inflammasome were also reduced (-36,3 and -28,58 % vs cells exposed only to anticancer drugs, respectively; p < 0.001). Notably, Spiruline, Reishi and Moringa increased of 26,3% the production of IL-10 and IL-2. Cytokines involved in cardiotoxicity and chemoresistance were reduced, such as IL-1α and IL-1β (-18,3 and -27,4 % vs DOXO-TRA group), IL-6 (-31,2 % vs DOXO-TRA group) and IL17-α (-27,3 % vs DOXO-TRA group) (p < 0.01 for all). Conclusions: During exposure to doxorubicin and trastuzumab, the combination of Spiruline, Reishi and Moringa exerts cardioprotective and anti-inflammatory effects. Their properties are mediated by the reduction of iCa2+ content that consequently reduces lipid peroxidation and the expression of NLRP3- MyD88. These results indicating the potential use of this nutraceutical formulation in preclinical models of anthracycline and anti HER2 antibodies-mediated cardiotoxicity.

e24055 Background: Advanced glycosylation end-products (AGEs) are non-enzyme, protein glycosylation products caused by glucose-induced metabolic disorder, and play an important role in aging, cancer, metabolic syndrome and cardiovascular diseases. We aimed to assess whether AGEs and fructosilation products, such as methylglyoxal (MG) and N-carboxymethyllysine (N-CML) could increase susceptibility to cell damages induced by doxorubicin. Methods: Human cardiomyocytes were pre-exposed for 24h with low doses (50 mmol/L) of methylglyoxal (MG) or N-carboxymethyllysine (N-CML). After, cells were exposed to subclinical concentration of doxorubicin (at 100 and 200 nM) for 48 and 72h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Expression of p53 was also performed through western blot method. Results: Pre-exposure to methylglyoxal (MG) but especially to N-carboxymethyllysine (N-CML) increase cell mortality to doxorubicin of 48-53% compared to control. Pre-exposure to N-CML promotes premature death of cardiomyocytes to doxorubicin through NLRP3-driven pathways. Notably, MG and N-CML increased significantly the cardiotoxicity through NLRP3 inflammasome, Myd88 myddosome and cytochrome C-mediated apoptosis. Pre-exposure to N-CML and MG increase the secretion of interleukin-6 that increase cell apoptosis through a paracrine and autocrine mechanism. Induction of IL-6 reduces the expression of p53 resulting in the induction of the apoptotic process. Conclusions: These observations suggest that AGEs and fructosilation producs promotes premature cardiotoxicity of human cardiac cells exposed to doxorubicin by activation of NLRP3, Myd88-related pathways and downregulation of p53.

587 Background: The cumulative incidence of cardiac events in breast cancer patients treated with anthracycline and trastuzumab at 1 year after the diagnosis of cancer was 16.4%, at 2 years 23.8 %, and at 3 years 28.2%. Sodium glucose co-transporter 2 inhibitors, a new class of antidiabetic drugs, has shown measurable benefits in reduction of HF hospitalization and cardiovascular mortality. LCZ696 (neprilysin inhibitor + valsartan) as able to lower the risk of cardiovascular events in chronic heart failure. We hypothesize that dapagliflozin associated to LCZ696 could exerts cardioprotective effects in cellular models of doxorubicin and trastuzumab-induced cardiotoxicity. Methods: Human cardiomyocytes (HL-1 cells) were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin (50 nM) or LCZ696 (at 100 mM) or both in combination for 48h. Cell viability, apoptosis and necrosis were performed. Quantification of malondialdehyde, 4-hydroxynonenal and intracellular Ca2+ were performed through spectrophotometric methods. Anti-inflammatory studies were also performed (expression of NLRP3 inflammasome, TLR4/MyD88 pathways, nuclear expression of NF-kB). Intracellular concentration of IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF were also performed. Results: Dapagliflozin and LCZ696 increased synergistically the cell viability during exposure to doxorubicin and trastuzumab. Combination of dapagliflozin and LCZ696 reduces intracellular Ca2+ overload (-68,4% vs cells treated only to anticancer drugs; p

e24054 Background: Palmitoylethanolamide (PEA) is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. It is a new analgesic drug with anti-inflammatory effects through the induction of PPAR-related pathways. We aimed to assess whether palmitoylethanolamide co-incubated during doxorubicin and trastuzumab, reduces anticancer drugs-related cardiotoxicity in cellular models. Methods: Human vascular endothelial cells and cardiomyocytes were exposed to subclinical concentration of doxorubicin (at 100 and 200 nM) combined to trastuzumab (at 100 and 200 nM) alone or in combination with a formulation composed by palmitoylethanolamide 500 nM for 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of peroxisome proliferator-activated receptor-α; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Palmitoylethanolamide co-incubated with doxorubicin exerts vasculoprotective and cardioprotective effects, enhancing cell viability of 56.3-78.7 % compared to untreated cells (p < 0,001 for all). Notably, PEA reduced significantly the cardiotoxicity through peroxisome proliferator-activated receptor-α –related pathways and NLRP3 inflammasome but without the involvement of calcium homeostasis. Several cytokines and chemokines were also reduced confirming its anti-inflammatory effect. Conclusions: The present study demonstrates that palmitoylethanolamide protects against vasculotoxicity and cardiotoxicity of doxorubicin and trastuzumab by promoting an anti-inflammatory phenotype, representing a new therapeutic approach to resolve doxorubicin-induced vasculo-cardio toxicity and inflammation.

12063 Background: Doxorubicin-mediated adverse cardiovascular events are among the leading causes of morbidity and mortality in breast cancer patients. Sacubitril-valsartan (LCZ 696) is a combination drug, made up of neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan, used for the treatment of heart failure in patients with a reduced ejection fraction. We hypothesized that LCZ 696, administered during doxorubicin, could improve cardiac function and cardiac inflammation in preclinical models. Methods: Human fetal cardiomyocytes (HFC cell line) were exposed to subclinical concentration of doxorubicin (200 nM) alone or in combination with LCZ-696 (100 mM) for 72 h. After the incubation period, we performed the following tests: cell viability, apoptosis and necrosis; expression of malondialdehyde and 4-hydroxynonenal and concentration of intracellular Ca2+. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; NF-κB). C57Bl/6 mice were untreated (Sham, n = 6) or treated for 10 days with doxorubicin i.p at 2.17 mg/kg (DOXO, n = 6), LCZ-696 at 60 mg/kg (LCZ, n = 6) or doxorubicin combined to LCZ-696 (DOXO-LCZ, n = 6). Ejection fraction, radial and longitudinal strain were analyzed through transthoracic echocardiography (Vevo 2100). Cardiac tissue expression of NLRP3 inflammasome, Myd88, NF-kB and 13 chemokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IL-18, IFN-γ, TNF-α, G-CSF, and GM-CSF) were quantified. Results: LCZ-696 exerts cardioprotective effects, enhancing cell viability of 48-54.6% compared to only doxorubicin-treated cells (p < 0,001 for all); LCZ 696 decreased NLRP3, MyD88 and NF-kB expression in cardiac cells. In preclinical study, LCZ 696 improved significantly the EF and prevented the reduction of radial and longitudinal strain after 10 days of treatment with doxorubicin. A reduced expression of NLRP3, MyD88 and NF-kB in cardiac tissues was seen in DOXO-LCZ group compared to DOXO mice (p < 0.001). Cardiac expression of IL-1β, IL-6, TNF-α, G-CSF and GM-CSF were significantly reduced after treatment with LCZ-696 indicating anti-inflammatory properties. Conclusions: LCZ-696 exerts direct beneficial effects in cardiomyocytes exposed to doxorubicin. In preclinical models, LCZ-696 reduced inflammation and cytokine expression involved in doxorubicin-mediated cardiotoxicity.

Multipotent stem cells - such as mesenchymal stem/stromal cells and stem cells derived from different sources like vascular wall are intensely studied to try to rapidly translate their discovered features from bench to bedside. Vascular wall resident stem cells recruitment, differentiation, survival, proliferation, growth factor production, and signaling pathways transduced were analyzed. We studied biological properties of vascular resident stem cells and explored the relationship from several factors as Matrix Metalloproteinases (MMPs) and regulations of biological, translational and clinical features of these cells. In this review we described a translational and clinical approach to Adult Vascular Wall Resident Multipotent Vascular Stem Cells (VW-SCs) and reported their involvement in alternative clinical approach as cells based therapy in vascular disease like arterial aneurysms or peripheral arterial obstructive disease.

Resumo Baixas doses de edoxabana e enoxaparina sódica foram objeto de uma comparação retrospectiva implementada com a técnica do escore de propensão a fim de mitigar os efeitos das diferenças nas características clínicas basais de duas coortes e minimizar o risco de viés. Posteriormente, usando um modelo de riscos proporcionais de Cox, avaliou-se a associação de cada tipo de terapia com o risco do composto de morte por todas as causas, acidente vascular cerebral/ataque isquêmico transitório, hospitalizações e ocorrência de sangramentos maiores. Para essa análise, um valor de p < 0,05 foi considerado estatisticamente significante. A terapia com enoxaparina e cirrose hepática como causadora de trombocitopenia estiveram associadas ao aumento do risco do endpoint composto (enoxaparina: hazard ratio (HR): 3,31; IC 95%: 1,54 a 7,13; p = 0,0023; cirrose hepática, HR: 1,04; 95% CI: 1,002 a 1,089; p = 0,0410). Por outro lado, a terapia com edoxabana mostrou-se significativamente associada à diminuição do risco do endpoint composto (HR: 0,071; 95% CI: 0,013 a 0,373; p = 0,0019). Com base nessa análise retrospectiva, o edoxaban em doses baixas seria uma ferramenta farmacológica segura e eficaz para a profilaxia de eventos cardioembólicos em pacientes com FA e trombocitopenia. Abstract Low-dose edoxaban and enoxaparin sodium have been the subject of a retrospective comparison implemented with the propensity score technique in order to mitigate the effects of the differences in the basal clinical features of two cohorts and minimize the risk of bias. Subsequently, using a Cox proportional-hazards model, the association of each type of therapy with the risk of the composite of all-cause death, stroke/transient ischemic attack, hospitalizations and major bleeding events was assessed. For this analysis, a p-value < 0.05 was considered statistically significant. Therapy with enoxaparin and liver cirrhosis as causing thrombocytopenia were associated with increased risk of the composite endpoint (enoxaparin: hazard ratio (HR): 3.31; 95% CI: 1.54 to 7.13; p = 0.0023; liver cirrhosis, HR: 1.04; 95% CI: 1.002 to 1.089; p = 0.0410). Conversely, edoxaban therapy was significantly associated with decreased risk of the composite endpoint (HR: 0.071; 95% CI: 0.013 to 0.373; p = 0.0019). Based on this retrospective analysis, edoxaban at low doses would appear as an effective and safe pharmacological tool for the prophylaxis of cardioembolic events in patients with AF and thrombocytopenia.

The paper entitled "Health-related Quality of Life and Unscheduled Re-Hospitalizations After Coronary Revascularization: Significant Predictive Role of the MacNew Questionnaire" by Renato De Vecchis et al, which was published online on February 20, 2020, has been withdrawn by the Publisher due to self-plagiarism.

The paper entitled "Effects of a restricted water intake on various clinical and laboratory outcomes in patients with heart failure: a meta-analysis of randomized controlled trials" by Renato De Vecchis et al, which was published online on February 20, 2020, has been withdrawn by the Publisher due to self-plagiarism.

Background: The peak atrial longitudinal strain (PALS) is primarily an index of the reservoir function of atrial chambers. The conceptual basis exists to hypothesize that sacubitril/valsartan improves the expandability of atrial chambers in the reservoir phase of the atrial mechanical cycle, as a consequence of its effect of prolonging the half-life of natriuretic peptides. Therefore in this retrospective study we evaluated the repercussions of the administration of sacubitril/valsartan maintained for at least 12 months on the PALS. Methods: In our retrospective study a cohort of 40 patients treated with sacubitril/valsartan has been compared with a second cohort subjected to the conventional treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker. A general criterion to be satisfied was the presence of at least one episode of atrial fibrillation (AF) in the history of the enrolled patients. The study population was composed of New York Heart Association (NYHA) class II/III chronic heart failure (CHF) patients, due to the fact that the treating physicians of the patients whose clinical records were used as source of data, complied with the international guidelines that have so far validated sacubitril/valsartan exclusively for the CHF therapy. The aims were to verify whether the 1-year administration of sacubitril/valsartan is effective in improving the PALS, and also ascertain whether the drug is associated with a decreased risk of AF relapses over a mean retrospective observation period of 12 months. Results: Sacubitril/valsartan cohort was proven to benefit from a significant increase in average values of PALS (median: 26.5%; interquartile range (IQR): 22% - 30%), opposed to the much less pronounced increase in PALS found in the conventional therapy cohort (median: 22.5%; IQR: 18% - 25.5%). Additionally, the comparison made by means of one-way analysis of variance regarding the mean changes of PALS values, outlined clearly that the sacubitril/valsartan users had an increase in PALS after 1 year of therapy significantly greater (P < 0.001) compared to the patients taking the conventional drugs. Moreover, a risk significantly higher of AF recurrences (P = 0.001) was identified in the conventional therapy group compared to the sacubitril/valsartan group during a 12-month retrospective observation period. Conclusions: In the present retrospective cohort study a higher increase of PALS has been shown in the cohort treated with sacubitril/valsartan. Moreover, a reduced risk of AF recurrences has been shown in the sacubitril/valsartan users compared to the patients with CHF subjected to conventional treatment. J Clin Med Res. 2020;12(2):100-107 doi: https://doi.org/10.14740/jocmr4076

BACKGROUND Clinical efficacy of sacubitril/valsartan administered for the recommended indication of patients with reduced (

In the present retrospective cohort study, we have evaluated the missed or delayed atrial mechanical recovery in a population of patients with persistent or long-lasting persistent AF who achieved restoration of sinus rhythm on the ECG by electrical cardioversion (ECV). The endpoint of our study was the failure to recover the normal mechanics of the left atrium. Inclusion criterion was the persistent or long-lasting persistent atrial fibrillation successfully treated by means of ECV , provided that a pertinent documentation was made available, comprising ECG, conventional 2D echo-color-Doppler and speckle tracking echocardiography(STE) evaluation, with also a STE assessment of the atria at the days 1, 30 and 90 from the ECV freely available within the clinical record of the patient. Out of a total of 80 patients with persistent or long-standing persistent AF, retrospectively enrolled, as many as 22.5% of them did not achieve the normalization of their atrial STE profile, even though they had been converted to sinus rhythm on the ECG by means of ECV. The building of ROC curves allowed us to establish that early measurements of global atrial strain could serve to predict both the risk of failure to recover the atrial mechanical function and the one of AF relapses over a 12 month follow-up. The values of 18% and 17% were also calculated to serve as cut off values, respectively, for the risk of atrial mechanical dysfunction and for the risk of AF relapses over a 12 month follow-up. Failure to recover the atrial reservoir function can accompany a restoration of sinus rhythm on the ECG in patients with long-standing persistent AF. In this case, a serial STE evaluation could be useful to evaluate the atrial hypofunction over time.

e15039 Background: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel therapy to treat hypercholesterolaemia and related cardiovascular diseases. Evolocumab, a PCSK9 inhibitor, reduced the risk of cardiovascular events in patients with atherosclerotic cardiovascular diseases when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. Methods: Human fetal cardiomyocytes (HFC cell line), human HER2+ breast cancer cells were exposed to subclinical concentration of doxorubicin, trastuzumab, sequential treatment of both (all 100 nM), alone or in combination with evolocumab (50 nM) for 24 and 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Evolocumab co-incubated with doxorubicin alone or in sequence with trastuzumab exerts cardioprotective effects, enhancing cell viability of 35-43% compared to untreated cells (p < 0,05 for all); in cardiomyocytes Evolocumab reduced significantly the cardiotoxicity through MyD88/NF-KB/cytokines axis and mTORC1 Fox01/3α mediated mechanisms. In human HER2+ breast cancer cells, co-exposure of Evolocumab with doxorubicin and trastuzumab increased significantly cell apoptosis and necrosis through the involvement of key cytokines involved in chemoresistence. Conclusions: We demonstrated, for the first time, that the PCSK9 inhibitor evolocumab exerts direct effects in cardiomyocytes and human HER2+ breast cancer cells during doxorubicin and trastuzumab exposure turning on a new light on its possible use in the management of breast cancer therapies.

e15042 Background: Spirulina, a blue-green algae used in the daily diet of natives of Africa and America, has antioxidant, anticancer, antiviral, hepatoprotective, immune enhancing and lipid-lowering effects. Considering that doxorubicin-induced cardiotoxicity involves myocardial inflammation, ferroptosis and overexpression of several cytokines involved in cell dead and apoptosis, the use of spirulina during exposure to doxorubicin could be an intriguing method to reduces myocardial injuries in cancer patients undergoing treatment with anthracyclines. Methods: Human fetal cardiomyocytes (HFC cell line) were exposed to doxorubicin (from 10 to 500 nM), alone or in combination with spirulina extract (from 10 to 100 µg/ml) for 24 and 48h. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity, study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), intracellular Ca2+ homeostasis. Moreover, pro-inflammatory studied were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; mTORC1 Fox01/3a; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8, 6). Results: Spirulina extract, co-incubated with doxorubicin exerts cardioprotective effects, enhancing cell viability of 20-36.7 % compared to untreated cells (p

e15041 Background: The clinical trial “DECLARE-TIMI 58” (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a sodium glucose cotransporter 2 inhibitor (SGLT2i), reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. We aimed to study if dapagliflozin could exerts cardioprotective and anti-inflammatory effects in doxorubicin and trastuzumab-induced cardiotoxicity through the analysis of multiple biochemical mechanisms. Methods: HL-1 adult cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM. After the incubation period, we performed the following tests: determination of cell viability, through analysis of mitochondrial dehydrogenase activity (MTS assay), study of lipid peroxidation (quantifying cellular malondialdehyde and 4-hydroxynonenal), and of intracellular Ca2+ homeostasis. Moreover, anti-inflammatory studies were also performed (protein expression of NLRP3 inflammasome; p65/NF-κB and cytokines involved in cardiotoxicity (interleukins 1β, 8 and 6). Results: Dapagliflozin increases significantly the cardiomyocytes viability during exposure to doxorubicin and trastuzumab. Its cardioprotective properties are explainable by the reduction of intracellular Ca2+ overload (-47,6% vs cells treated only to anticancer drugs; p2+ homeostasis and inhibits the pro-inflammatory “NLRP3- NF-κB –cytokines” pathways. The overall picture obtained provides the proof of concept for translational studies designed to investigate the cardioprotective use of dapagliflozin in HER2+ breast cancer patients.

To evaluate the ability of oral supplements with immune-stimulating molecules (Sambucus nigra, Zinc, Tyndallized Lactobacillus acidophilus (HA122), Arabinogalactans, vitamin D, vitamin E and vitamin C) to reduce the inflammation of the upper airway tract and improve the outcome of otitis media with effusion (OME) in children.Randomized controlled trial. One-hundred ninety-eight children (CI 95%: 12-96 months) were divided into four groups. Group 1 (48 subjects) received 10 ml of oral supplements (OS) with immune-stimulating molecules for three months (20 days consecutively, then 10 days of suspension - the therapeutic scheme was repeated three times); Group 2 (54 children) underwent treatment with 10 ml of OS for 90 consecutive days; Group 3 (48 subjects) received 15 ml of OS for 45 consecutive days; a control group (48 children) underwent the standard treatment for rhinitis and OME. Outcome measures included otoscopy, tympanometry, fibroendoscopy, and the pure tone audiometry (PTA) at T0 (before treatment), T1 (45 days after treatment), and T2 (90 days after treatment).All children treated with OS showed a reduction of Upper Airway Infection (UAI) episodes and OME compared to the control group independent of the administration method and posology. The three groups treated with OS showed statistically significant differences between T0 and T2 for otoscopy, tympanometry, fibroendoscopy, and PTA. In Group 2, the otoscopy and the tympanometry scores improved at T1. Group 2 and 3 had better PTA results than Group 1.OS with immune-stimulating molecules should be considered as a supporting therapy in children affected by recurrent episodes of UAI associated with OME due to their capacity to improve the immune response and reduce the inflammatory phenomena. OS can improve the fibroendoscopic findings by restoring middle ear ventilation, in addition to their ability to reduce inflammation in the middle ear.