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Introduction: A case of fibroelastoma of the aortic valve in a patient with acute coronary syndrome has been reported. Cardiac papillary fibroelastomas (PFE) are rare cardiac tumours that are generally benign. In most cases they are incidental findings, their first clinical manifestation is often associated with embolic events. Case presentation: We present the case of a 63-year-old man who experienced coronary embolization without any indications of underlying coronary artery disease. Further investigation led to the identification of the cause of embolization. The concomitant presence of Salmonella bacteraemia, associated with symptoms of gastrointestinal inflammation and elevated inflammation indices, led to the hypothesis of valvular endocarditis. Therefore, a transoesophageal echocardiogram was performed, which confirmed the presence of a mobile, well-demarcated, echo-dense mass identified on the left coronary cusp. Despite the diagnostic uncertainty between fibroelastoma and endocarditic formation, the occurrence of the embolic event and the marked hypermobility we decided that prompt intervention was required. Surgical cleavage of the valve formation was performed, revealing macroscopic morphological characteristics consistent with PFE which was confirmed by the histological finding. Conclusions: This case highlight the importance of a comprehensive diagnostic approach, including transoesophageal echocardiography, in patients with embolic events with no obvious evidence of an embolic causes.

Introduction. Platinum-based chemotherapy represents the standard of care (SoC) for the first-line treatment of advanced urothelial carcinoma (mUC). The benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy was recently investigated. We performed an individual patient data (IPD) meta-analysis of phase 3 clinical trials comparing ICI-based treatments. Methods. A systematic literature search was conducted on the MEDLINE and CENTRAL databases. The results were filtered by including only reports on clinical trials or randomized clinical trials from 2018 to 2023, including 3047 patients from four clinical trials (EV302, CHECKMATE-901, IMVIGOR130, KEYNOTE-361). An IPD meta-analysis was performed by reconstructing IPD from Kaplan–Meier curves. The primary endpoints were overall survival (OS) and progression-free survival (PFS) of Pembrolizumab + EV compared to experimental arms of the other trials of immunotherapy + chemotherapy. Results. The OS analysis showed an advantage of IPD from EV302 vs. all the other trials. For EV302 vs. KEYNOTE-361, the HR was 0.51; for EV302 vs. IMVIGOR130, the HR was 0.47; and for EV302 vs. CHECKMATE-901, the HR was 0.66 (CI 95% 0.51–0.85). In the PFS analysis, the EV302 arm showed a statistically significant advantage compared to CHECKMATE-901 (HR 0.66) and versus IMVIGOR130 (HR 0.51). Limitations: By using reconstructed IPD curves, it was not possible to adjust patient-level covariates, and the heterogeneity of the included population may have affected the pooled results. Conclusions: The EV302 experimental arm showed better OS and PFS when compared to the other immunochemotherapy combinations. An immunochemotherapy combination strategy at the beginning of treatment in mUC seems to be superior in terms of OS and PFS compared to platinum-based chemotherapy alone. EV–Pembrolizumab resulted to have better outcomes compared to avelumab, rather than other immunochemotherapy combinations. However, given the heterogeneity of these studies, a longer follow up and prospective trials are needed to confirm these data.

It has been shown that the pathogenic variants (PVs) of the DNA Damage Response (DDR) genes, whether of a germinal or somatic nature, represent a predictive biomarker of high sensitivity to treatment with inhibitors of the enzyme poly-ADP-ribose polymerase (PARP) in patients with hormone-resistant metastatic prostate cancer (HRPCa). Moreover, the detection of PVs of the Homologous Recombination Repair (HRR) genes in PCa patients can help to define the patient’s prognosis and the choice of the therapeutic procedure. Among men with metastatic PCa, the frequency of PVs in HRR genes ranges from 11% to 33%, which is a significantly higher rate compared to non-metastatic PCa, where the incidence is between 5% and 10%. Next-Generation Sequencing (NGS) results were more commonly obtained from newly acquired somatic samples compared to archived samples (prostate biopsy or prostatectomy). We developed an experimental multidisciplinary prospective study in patients with a new diagnosis of high-risk PCa at biopsy. The aim was to evaluate the presence of PVs of different HRR genes in patients with the first diagnosis of PCa in relation to a metastatic or non-metastatic stage, tumor aggressiveness, and early risk of progression. Among 43 initial tumor samples from 22 patients, 25 samples from 12 patients were selected for library preparation based on their DNA concentration and quality. After the NGS, 14 different DNA variants were prioritized. Oncogenetic and likely oncogenetic variants were found in the ATM, BRCA1, PTEN, KMT2D, and CDH1 genes. Moreover, variants of uncertain significance were found in ATM, DDR2, FANCA, FOXA1, PLCB4, PTCH1, and RB1.

Summary: Background: Glucocorticoids (GC) are potent entrainers of the circadian clock. However, their effects on biological rhythms in chronic human exposure have yet to be studied. Endogenous hypercortisolism (Cushing's Syndrome, CS) is a rare condition in which circadian disruption is sustained by a tumorous source of GC excess, offering the unique opportunity to investigate GC's chronic effects in vivo. Methods: In a 12-month prospective case–control multicentre trial, the daily fluctuations in the number of circulating peripheral blood mononuclear cells (PBMCs) and the time-specific expression of clock-related genes were analysed in a cohort of 68 subjects, 34 affected by CS and 34 matched controls. Cosinor mixed effects model, rhythmicity algorithms and machine learning techniques were applied to the multi-level dataset. Findings: Multiple, 5-point daily sampling revealed profound changes in the levels, amplitude, and rhythmicity of several PBMC populations during active CS, only partially restored after remission. Clock gene analyses in isolated PBMCs showed a significant flattening of circadian oscillation of CLOCK, PER1, PER2, PER3, and TIMELESS expression. In active CS, all methods confirmed a loss of rhythmicity of those genes which were circadian in the PBMCs of controls. Most, but not all, genes regained physiological oscillation after remission. Machine learning revealed that while combined time-course sets of clock genes were highly effective in separating patients from controls, immune profiling was efficient even as single time points. Interpretation: In conclusion, the oscillation of circulating immune cells is profoundly altered in patients with CS, representing a convergence point of circadian rhythm disruption and metabolic and steroid hormone imbalances. Machine learning techniques proved the superiority of immune profiling over parameters such as cortisol, anthropometric and metabolic variables, and circadian gene expression analysis to identify CS activity. Funding: The research leading to these results has received funding from the European Union in the context of the National Recovery and Resilience Plan, Investment PE8 – Project Age-It: “Ageing Well in an Ageing Society”. This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022], the PRecisiOn Medicine to Target Frailty of Endocrine-metabolic Origin (PROMETEO) project (NET-2018-12365454) by the Italian Ministry of Health, and through internal funding to Sapienza University of Rome.

Introduction The allostatic load (AL) is a framework for conceptualising the physiological multisystemic impact of prolonged exposure to stress and its related side effects on mental health.Stress due to AL can influence the development and outcomes of cardiovascular diseases. AL increases the risk of coronary and peripherical artery diseases. AL emerges from the detection of emotional dimensions related to the disease, low psychosocial functioning and high rates of psychopathological signs in patients with hypertension or coronary heart disease.Method and analysis The primary endpoint of the PLAY-UP protocol is the implementation of a multidimensional model underlying the clinical treatment of patients with cardiovascular disease through the integration of medical and psychological clinical variables.PLAY-UP is a cohort study that will last for 24 months. 200 participants will be recruited and divided into three groups: early disease, midterm disease and long disease. All patients will undergo a clinical evaluation based on the detection of biological, medical and psychological indicators and variables. The evaluation battery will comprise three types of measurements: medical, psychological and pharmacological treatments. Clinical and psychological measurements will be processed in an integrated manner through the combination of all variables examined, elaborating the Allostatic Load Index from a longitudinal time perspective. The Allostatic Load Index will be calculated by measuring the z-score.Ethics and dissemination Ethical Committee Approval was obtained from CEtRA Abruzzo Region (IT) (ID 0461499/23). The results of the present project will be published in peer-reviewed journals, disseminated electronically and in print, and presented as abstracts and/or personal communications during national and international conferences.

Objective: To analyze data available in the literature regarding a possible prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in prostate cancer (PCa) patients stratified in non-metastatic and metastatic diseases. Methods: A literature search process was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. In our meta-analysis, the pooled event rate estimated and the pooled hazard ratio were calculated using a random effect model. Results: Forty-two articles were selected for our analysis. The pooled risk difference for non-organ confined PCa between high and low NLR cases was 0.06 (95% confidence interval [CI]: −0.03–0.15) and between high and low PLR cases increased to 0.30 (95% CI: 0.16–0.43). In non-metastatic PCa cases, the pooled hazard ratio for overall mortality between high and low NLR was 1.33 (95% CI: 0.78–1.88) and between high and low PLR was 1.47 (95% CI: 0.91–2.03), whereas in metastatic PCa cases, between high and low NLR was 1.79 (95% CI: 1.44–2.13) and between high and low PLR was 1.05 (95% CI: 0.87–1.24). Conclusion: The prognostic values of NLR and PLR in terms of PCa characteristics and responses after treatment show a high level of heterogeneity of results among studies. These two ratios can represent the inflammatory and immunity status of the patient related to several conditions. A higher predictive value is related to a high NLR in terms of risk for overall mortality in metastatic PCa cases under systemic treatments.

Background: Cheiloscopy, a forensic technique based on the uniqueness of labial traces, has traditionally relied on analog methods. While simple, these methods present significant limitations in terms of precision and reproducibility. The introduction of 3D technology, specifically high-resolution optical scanners, represents a pivotal advancement in overcoming these challenges. Objective: This pilot study aimed to explore the feasibility and potential advantages of 3D cheiloscopy in forensic science by analyzing its precision and repeatability compared to traditional analog methods. Methods: Two participants were selected as a pilot sample, and their lip impressions were captured using both analog techniques and a high-resolution intraoral scanner (Medit i700). A total of 40 samples were collected, equally distributed among operators with varying levels of experience. Surface deviation analysis was performed to compare the methods. Results: The 3D models demonstrated greater uniformity and resolution compared to the analog impressions, which were more prone to errors caused by material quality or operator pressure. Surface deviation analysis showed an average similarity of 70%, with a standard deviation of 0.229 mm. The digital methods also significantly reduced operator-dependent variability. Conclusions: This pilot study highlights the potential of 3D cheiloscopy to improve precision and standardization in forensic applications. While the small sample size limits the generalizability of the findings, the results provide a foundation for further research with larger and more diverse datasets. Future studies should explore the capability of 3D cheiloscopy to accurately match individuals and further validate its applicability in forensic and clinical contexts.

Introduction: Inappropriate sinus tachycardia (IST) is a syndrome characterized by unexpectedly fast and prolonged sinus rates at rest or with minimal physical activity. Epidemiologic characteristics are uncertain, but most patients are young and female. When IST occurs in athletes, its management (controlling symptoms and reducing heart rate) can present additional challenges. We designed an observational pilot study to investigate whether a food supplement can be useful in the treatment of IST when standard therapy is refused. Methods: We enrolled 50 consecutive recreational athletes affected by frequent recurrences of IST. Twelve-lead ECG and Holter ECG parameters were recorded at enrollment (T0) and after a 6-month treatment (T1) with the food supplement. Symptoms and quality of life were also evaluated through specific questionnaires. The study population was compared to a historical control group of 25 patients receiving ivabradine as treatment for the same clinical condition. Results: The resting ECG heart rate was 88.7 ± 12.4 bpm (T0) and 73.6 ± 6.6 bpm (T1) (p < 0.00001); Holter average heart rate was 88.4 ± 3.3 bpm and 74.9 ± 4.8 bpm (p < 0.0001). Holter ECG maximum heart rate was 147.1 ± 16.7 bpm and 139.2 ± 16.8 bpm (p = 0.06); Holter minimum heart rate was 49.9 ± 6.5 bpm and 50.5 ± 6.9 bpm (p = 0.33). Finally, the number of sustained episodes decreased from 3.3 ± 1.7 to 0.8 ± 0.8 (p < 0.00001). The following variations in ASTA scores were observed: ASTA symptom scale (range: 0–27) decreased from 14.9 ± 2.1 to 5.8 ± 1.4 (p < 0.00001), while ASTA HR QoL (range: 0–39) decreased from 24.1 ± 2.1 to 10.8 ± 2.3 (p < 0.00001). Conclusions: The findings of our pilot study suggest that this food supplement could play a beneficial role in managing symptoms and improving quality of life in recreational athletes affected by IST who refuse standard medical therapy. These clinical effects appear to correlate with significant improvements in resting ECG parameters and some Holter ECG parameters.

Background/Objectives: Skin regeneration is a rapidly advancing field with significant implications for regenerative medicine, particularly in treating wounds and burns. This study explores the potential of hydrogels functionalized with fibroblast-derived extracellular vesicles (EVs) to enhance skin regeneration in vivo. Being immunoprivileged, EVs minimize immune rejection, offering an attractive alternative to whole-cell therapies by replicating fibroblasts’ key roles in tissue repair. Methods: To promote EVs’ versatility and effective application across different conditions, a lyophilization method with lyoprotectants was optimized. Then, EVs were used to functionalize a hydrogel to perform experiments on murine cutaneous wound models. Results: Gelatin methacrylate (GelMA) was selected as the polymeric hydrogel due to its biocompatibility, tunable mechanical properties, and ability to support wound healing. Mechanical tests confirmed GelMA’s strength and elasticity for this application. Fibroblast-derived EVs were characterized using Western blot, Transmission Electron Microscopy, and NanoSight analysis, proving their integrity, size distribution, and stability. miRNome profiling identified enriched biological pathways related to cell migration, differentiation, and angiogenesis, emphasizing the critical role of EV cargo in promoting wound repair. In a murine model, hydrogels loaded with fibroblast-derived EVs significantly accelerated wound healing compared to controls (mean wound area 0.62 mm2 and 4.4 mm2, respectively), with faster closure, enhanced epithelialization, increased vascularization, and reduced fibrosis. Notably, the lyoprotectants successfully preserved the EVs’ structure and bioactivity during freeze-drying, reducing EVs loss by 35% compared to the control group and underscoring the feasibility of this approach for long-term storage and clinical application. Conclusions: This study introduces a novel scalable and adaptable strategy for regenerative medicine by combining fibroblast-derived EVs with GelMA, optimizing EVs’ stability and functionality for enhanced wound healing in clinical settings, even in challenging contexts such as combat zones or large-scale natural disasters.

The National Cancer Institute (NCI) recognizes the potential of technologies based on the use of nanoparticles (NPs) in revolutionizing clinical approaches to the diagnosis and prognosis of cancer. Recent research suggests that once NPs come into contact with the biological fluid of cancer patients, they are covered by proteins, forming a “protein corona” composed of hundreds of plasma proteins. The concept of a personalized, disease-specific protein corona, demonstrating substantial differences in NP corona profiles between patients with and without cancer, has been introduced. We developed the design of an experimental prospective single-center study with patients allocated in a 1:1:1 ratio of one of three arms: untreated patients with benign prostatic hyperplasia (BPH), untreated patients with non-metastatic prostate cancer (PCa), and metastatic prostate cancer patients starting systemic therapies with new androgen-targeted agents or taxanes. The protocol aims to develop and implement sensitive nanotools with two distinct objectives: First, to design NPs capable of selectively binding and detecting biomarkers in order to build a predictive diagnostic model to effectively discriminate between patient sera affected by BPH and PCa. Secondly, within the population with PCa, in the case of initial advanced metastatic diagnosis, the objective is to find biomarkers capable of predicting the response to systemic treatments to improve the precision and efficiency of monitoring treatment outcomes. For protein and metabolite corona experiments, we developed a cross-reactive sensor array platform with cancer detection capacity made of three liposomal formulations with different surface charges. For proteomic-NP studies, proteins were identified and quantified using nano-high-performance LC (nanoHPLC) coupled with MS/MS (nanoHPLC−MS/MS). Metabolites were instead analyzed using an untargeted metabolomic approach. Compared with previous review articles, the novelty of this review is represented by the analysis of the possible clinical applications of protein corona NPs focused on PCa and the presentation of a new clinical protocol in the metastatic phase of PCa.