HEBE project: Healthy aging versus inflamm-aging: The role of physical exercise in modulating the biomarkers of age-associated and environmentally determined chronic diseases, study protocol.

Inflamm-aging refers to the chronic low-grade inflammation that occurs with aging and cellular senescence, and it is linked to various diseases. Understanding the markers involved in inflammation and aging, as well as their interaction with environmental factors and bodily control mechanisms, can provide crucial tools for assessing the resilience (i.e. the ability to adapt and improve) of the human body, particularly in the presence of chronic degenerative conditions or vulnerable life stages, that place the individual and the community to which he belongs in a state of potential fragility. HEBE focuses on physical exercise, along with nutritional and lifestyle recommendations, to reduce systemic inflammation and promote healthy aging. HEBE encompasses multiple research lines (LR). In the ongoing LR1 ("proof of concept"), healthy lifestyle recommendations were provided to University of Milan employees, and changes in quality of life and well-being were assessed using a specialized questionnaire. The first 100 eligible subjects, who expressed their willingness to participate, underwent a personalized physical exercise protocol based on clinical and objective assessments. Biomedical samples were collected at baseline (T0) and follow-up (T1) to establish a shared biobank and identify non-invasive biomarkers that monitor the impact of physical exercise on individual characteristics such as cardiovascular and metabolic health. Subsequently (LR2-LR10), the proof of concept findings will be expanded to include various conditions of vulnerability such as obesity, cancer, endocrine disorders, cardiovascular diseases, infertility, functional syndromes, respiratory disorders, neurodegenerative diseases, and autoimmune conditions. The research lines will leverage the expertise of the 94 participating investigators to form a collaborative network that maximizes the potential for investigation and knowledge exchange. This approach fosters a culture of health promotion and disease prevention. ClinicalTrials.gov Identifier: NCT05815732.

A case of early disease rebound after fingolimod discontinuation in a patient with multiple sclerosis and SARS-CoV-2 infection.

Fingolimod is approved in Italy as a second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Discontinuation of fingolimod may elevate the risk of relapses, typically manifesting after a relatively prolonged drug-free interval and often necessitating high doses of intravenous steroids for management. Similar to other viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can act as a trigger for MS relapses. In this context, we present a case of rebound following fingolimod discontinuation during a SARS-CoV-2 infection. Notably, the rebound occurred shortly after stopping the medication and responded effectively to low doses of oral steroids. Our case is discussed in light of existing literature, with speculation on potential mechanisms governing this unconventional disease course rebound. We also consider the possibility that SARS-CoV-2 infection might have contributed to or even triggered the MS relapse.

Activation of XBP1s attenuates disease severity in models of proteotoxic Charcot-Marie-Tooth type 1B.

Mutations in myelin protein zero (MPZ) are generally associated with Charcot-Marie-Tooth type 1B (CMT1B) disease, one of the most common forms of demyelinating neuropathy. Pathogenesis of some MPZ mutants, such as S63del and R98C, involves the misfolding and retention of MPZ in the endoplasmic reticulum (ER) of myelinating Schwann cells. To cope with proteotoxic ER-stress, Schwann cells mount an unfolded protein response (UPR) characterized by activation of the PERK, ATF6 and IRE1α/XBP1 pathways. Previous results showed that targeting the PERK UPR pathway mitigates neuropathy in mouse models of CMT1B; however, the contributions of other UPR pathways in disease pathogenesis remains poorly understood. Here, we probe the importance of the IRE1α/XBP1 signalling during normal myelination and in CMT1B. In response to ER stress, IRE1α is activated to stimulate the non-canonical splicing of Xbp1 mRNA to generate spliced Xbp1 (Xbp1s). This results in the increased expression of the adaptive transcription factor XBP1s, which regulates the expression of genes involved in diverse pathways including ER proteostasis. We generated mouse models where Xbp1 is deleted specifically in Schwann cells, preventing XBP1s activation in these cells. We observed that Xbp1 is dispensable for normal developmental myelination, myelin maintenance and remyelination after injury. However, Xbp1 deletion dramatically worsens the hypomyelination and the electrophysiological and locomotor parameters observed in young and adult CMT1B neuropathic animals. RNAseq analysis suggested that XBP1s exerts its adaptive function in CMT1B mouse models in large part via the induction of ER proteostasis genes. Accordingly, the exacerbation of the neuropathy in Xbp1 deficient mice was accompanied by upregulation of ER-stress pathways and of IRE1-mediated RIDD signaling in Schwann cells, suggesting that the activation of XBP1s via IRE1 plays a critical role in limiting mutant protein toxicity and that this toxicity cannot be compensated by other stress responses. Schwann cell specific overexpression of XBP1s partially re-established Schwann cell proteostasis and attenuated CMT1B severity in both the S63del and R98C mouse models. In addition, the selective, pharmacologic activation of IRE1α/XBP1 signaling ameliorated myelination in S63del dorsal root ganglia explants. Collectively, these data show that XBP1 has an essential adaptive role in different models of proteotoxic CMT1B neuropathy and suggest that activation of the IRE1α/XBP1 pathway may represent a therapeutic avenue in CMT1B and possibly for other neuropathies characterized by UPR activation.

SAA1-dependent reprogramming of adipocytes by tumor cells is associated with triple negative breast cancer aggressiveness.

Triple negative breast cancers (TNBC) are characterized by a poor prognosis and a lack of targeted treatments. Their progression depends on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Although adipocytes, the primary stromal cells of the breast, have been determined to be plastic in physiology and cancer, the tumor-derived molecular mediators of tumor-adipocyte crosstalk have not been identified yet. In this study, we report that the crosstalk between TNBC cells and adipocytes in vitro beyond adipocyte dedifferentiation, induces a unique transcriptional profile that is characterized by inflammation and pathways that are related to interaction with the tumor microenvironment. Accordingly, increased cancer stem-like features and recruitment of pro-tumorigenic immune cells are induced by this crosstalk through CXCL5 and IL-8 production. We identified serum amyloid A1 (SAA1) as a regulator of the adipocyte reprogramming through CD36 and P2XR7 signaling. In human TNBC, SAA1 expression was associated with cancer-associated adipocyte infiltration, inflammation, stimulated lipolysis, stem-like properties, and a distinct tumor immune microenvironment. Our findings constitute evidence that the interaction between tumor cells and adipocytes through the release of SAA1 is relevant to the aggressiveness of TNBC.

Differentiation States of Phenotypic Transition of Melanoma Cells Are Revealed by 3D Cell Cultures.

Melanoma is characterized by high metastatic potential favored by the epithelial-to-mesenchymal transition (EMT), leading melanoma cells to exhibit a spectrum of typical EMT markers. This study aimed to analyze the expression of EMT markers in A375 and BLM melanoma cell lines cultured in 2D monolayers and 3D spheroids using morphological and molecular methods. The expression of EMT markers was strongly affected by 3D arrangement and revealed a hybrid phenotype for the two cell lines. Indeed, although E-cadherin was almost undetectable in both A375 and BLM cells, cortical actin was detected in A375 2D monolayers and 3D spheroids and was strongly expressed in BLM 3D spheroids. The mesenchymal marker N-cadherin was significantly up-regulated in A375 3D spheroids while undetectable in BLM cells, but vimentin was similarly expressed in both cell lines at the gene and protein levels. This pattern suggests that A375 cells exhibit a more undifferentiated/mesenchymal phenotype, while BLM cells have more melanocytic/differentiated characteristics. Accordingly, the Zeb1 and 2, Slug, Snail and Twist gene expression analyses showed that they were differentially expressed in 2D monolayers compared to 3D spheroids, supporting this view. Furthermore, A375 cells are characterized by a greater invasive potential, strongly influenced by 3D arrangement, compared to the BLM cell line, as evaluated by SDS-zymography and TIMPs gene expression analysis. Finally, TGF-ß1, a master controller of EMT, and lysyl oxidase (LOX), involved in melanoma progression, were strongly up-regulated by 3D arrangement in the metastatic BLM cells alone, likely playing a role in the metastatic phases of melanoma progression. Overall, these findings suggest that A375 and BLM cells possess a hybrid/intermediate phenotype in relation to the expression of EMT markers. The former is characterized by a more mesenchymal/undifferentiated phenotype, while the latter shows a more melanocytic/differentiated phenotype. Our results contribute to the characterization of the role of EMT in melanoma cells and confirm that a 3D cell culture model could provide deeper insight into our understanding of the biology of melanoma.

Structured wound angiogenesis instructs mesenchymal barrier compartments in the regenerating nerve.

Organ injury stimulates the formation of new capillaries to restore blood supply raising questions about the potential contribution of neoangiogenic vessel architecture to the healing process. Using single-cell mapping, we resolved the properties of endothelial cells that organize a polarized scaffold at the repair site of lesioned peripheral nerves. Transient reactivation of an embryonic guidance program is required to orient neovessels across the wound. Manipulation of this structured angiogenic response through genetic and pharmacological targeting of Plexin-D1/VEGF pathways within an early window of repair has long-term impact on configuration of the nerve stroma. Neovessels direct nerve-resident mesenchymal cells to mold a provisionary fibrotic scar by assembling an orderly system of stable barrier compartments that channel regenerating nerve fibers and shield them from the persistently leaky vasculature. Thus, guided and balanced repair angiogenesis enables the construction of a "bridge" microenvironment conducive for axon regrowth and homeostasis of the regenerated tissue.

Changes in hospital admissions for facial fractures during and after COVID 19 pandemic: national multicentric epidemiological analysis on 2938 patients.

PURPOSE: The objective of this multicenter study was to examine the differences in maxillo-facial fractures epidemiology across the various phases of the SARS-CoV-2 pandemic. METHODS: This is a retrospective study on patients who underwent surgery for facial bone fractures in 18 maxillo-facial surgery departments in Italy, spanning from June 23, 2019, to February 23, 2022. Based on the admission date, the data were classified into four chronological periods reflecting distinct periods of restrictions in Italy: pre-pandemic, first wave, partial restrictions, and post-pandemic. Epidemiological differences across the groups were analysed. RESULTS: The study included 2938 patients. A statistically significant difference in hospitalization causes was detected between the pre-pandemic and first wave groups (p = 0.005) and between the pre-pandemic and partial restriction groups (p = 0.002). The differences between the pre- and post-pandemic groups were instead not significant (p = 0.106). Compared to the pre-pandemic period, the number of patients of African origin was significantly higher during the first wave and the post-pandemic period. No statistically significant differences were found across the periods concerning gender, age, fracture type, treatment approach, and hospital stay duration CONCLUSIONS: The COVID-19 pandemic brought about significant changes in fracture epidemiology, influenced by the restrictive measures enforced by the government in Italy. Upon the pandemic's conclusion, the fracture epidemiology returned to the patterns observed in the pre-pandemic period.

Usefulness of second 131I treatment in biochemical persistent differentiated thyroid cancer patients.

Background: Second 131I treatment is commonly performed in clinical practice in patients with differentiated thyroid cancer and biochemical incomplete or indeterminate response (BiR/InR) after initial treatment. Objective: The objective of the is study is to evaluate the clinical impact of the second 131I treatment in BiR/InR patients and analyze the predictive factors for structural incomplete response (SiR). Patients and methods: One hundred fifty-three BiR/InR patients after initial treatment who received a second 131I treatment were included in the study. The clinical response in a short- and medium- long-term follow-up was evaluated. Results: After the second 131I treatment (median 8 months), 11.8% patients showed excellent response (ER), 17% SiR, while BiR/InR persisted in 71.2%. Less than half (38.5%) of SiR patients had radioiodine-avid metastases. Patients who, following the second 131I treatment, experienced SiR had larger tumor size and more frequently aggressive histology and vascular invasion than those experienced BiR/InR and ER. Also, the median values of thyroglobulin on levothyroxine therapy (LT4-Tg), Tg peak after recombinant human TSH stimulation (rhTSH-Tg) and thyroglobulin antibodies (TgAb) were significantly higher in patients who developed SiR. At last evaluation (median: 9.9 years), BiR/InR persisted in 57.5%, while 26.2% and 16.3% of the patients showed ER and SiR, respectively. About half of BiR/InR patients (71/153 (46.4%)) received further treatments after the second 131I treatment. Conclusions: Radioiodine-avid metastatic disease detected by the second 131I is an infrequent finding in patients with BiR/InR after initial treatment. However, specific pathologic and biochemical features allow to better identify those cases with higher probability of developing SiR, thus improving the clinical effectiveness of performing a second 131I treatment.

Asymptomatic Patients With Brugada ECG Pattern: Long-Term Prognosis From a Large Prospective Study.

BACKGROUND: Brugada syndrome poses significant challenges in terms of risk stratification and management, particularly for asymptomatic patients who comprise the majority of individuals exhibiting Brugada ECG pattern (BrECG). The aim of this study was to evaluate the long-term prognosis of a large cohort of asymptomatic patients with BrECG. METHODS: Asymptomatic patients with BrECG (1149) were consecutively collected from 2 Italian centers and followed-up at least annually for 2 to 22 years. For the 539 asymptomatic patients (men, 433 [80%]; mean age, 46±13 years) with spontaneous type 1 documented on baseline ECG (87%) or 12-lead 24-hour Holter monitoring (13%), an electrophysiologic study (EPS) was proposed; for the 610 patients with drug-induced-only type 1 (men, 420 [69%]; mean age, 44±14 years), multiple ECGs and 12-lead Holter were advised in order to detect the occurrence of a spontaneous type-1 BrECG. Arrhythmic events were defined as sudden death or documented ventricular fibrillation or tachycardia. RESULTS: Median follow-up was 6 (4-9) years. Seventeen (1.5%) arrhythmic events occurred in the overall asymptomatic population (corresponding to an event-rate of 0.2% per year), including 16 of 539 (0.4% per year) in patients with spontaneous type-1 BrECG and 1 of 610 in those with drug-induced type-1 BrECG (0.03% per year; P<0.001). EPS was performed in 339 (63%) patients with spontaneous type-1 BrECG. Patients with spontaneous type-1 BrECG and positive EPS had significantly higher event rates than patients with negative EPS (7 of 103 [0.7% per year] versus 4 of 236 [0.2% per year]; P=0.025). Among 200 patients who declined EPS, 5 events (0.4% per year) occurred. There was 1 device-related death. CONCLUSIONS: The entire population of asymptomatic patients with BrECG exhibits a relatively low event rate per year, which is important in view of the long life expectancy of these young patients. The presence of spontaneous type-1 BrECG associated with positive EPS identifies a subgroup at higher risk. Asymptomatic patients with drug-induced-only BrECG have a minimal arrhythmic risk, but ongoing follow-up with 12-lead Holter monitoring is recommended to detect the appearance of spontaneous type-1 BrECG pattern.

Molecular Tumour Board (MTB): From Standard Therapy to Precision Medicine.

Background: In the metastatic setting, cancer patients may not benefit from standard care regimes and their diseases undergo drug resistance due to tumour cell heterogeneity and genomic landscape complexity. In recent years, there have been several attempts to personalise the diagnostic-therapeutic path and to propose novel strategies based on not only histological test results but also on each patient's clinical history and molecular biology. Profiling molecular tests allows physicians to investigate the single tumour genomic landscape and to promote targeted approaches. The Molecular Tumour Board (MTB) is a multidisciplinary committee dedicated to selecting individualised and targeted therapeutic strategies appropriate for patients suffering from diseases that present resistance to standard care. Materials and Methods: Our MTB settled in "Azienda Ospedaliero Universitaria delle Marche", Ancona (AN), Italy, and includes oncologists, molecular biologists, geneticists, and other specialists. Clinical cases are referred by physicians to the MTB, through the Cancer and Research Centre of the Marche Region (CORM), through a telemedicine platform. Four possible molecular profiles are available: FoundationOne® CDx e FoundationOne®Liquid CDx and two local Next Generation Sequencing (NGS) panels, with 16 DNA genes and 10 RNA genes respectively. The resulting genetic mutations and their analyses are evaluated by all the members of the Board and a report for each patient is provided with medical recommendations. Results: from June 2021 to May 2023, we collected data from 97 referral patients (M: 49, F: 48). The mean age was 60.6 years (range 22-83 years). 90 cases were approved for testing. Only seven patients were not eligible for genomic profiling. In two patients who were eligible, molecular profiling was not performed because a tissue sample was not available. Off-label therapy was recommended for three patients. 5% of cases (5/88) showed addressable driver mutations associated with an existing targeted therapy and were immediately enrolled. Conclusions: MTB presents a powerful tool for offering precise medical goals. Our Department of Clinical Oncology also takes advantage of the important role of multidisciplinary teams, through the establishment of CORM and MTB meetings, within which there is the chance to perform NGS-based analyses. It will be important in the future to implement the use of genomic profiling to improve personalised care and to guide the choice of suitable therapies and more appropriate management of patients.

Combination of percutaneous left appendage epicardial ligation and endo-epicardial atrial fibrillation ablation.

Introduction: Atrial fibrillation (AF) is the main cause of cardioembolic stroke. In high-bleeding-risk patients, long-life anticoagulation therapy is not permitted, and left atrial appendage (LAA) closure may be considered. LAA is also a critical substrate for AF. Epicardial LAA occlusion has several advantages: LAA ligation results in a favorable electrical and structural atrial remodeling, which decreases AF recurrence. Endocardial ablation alone is not efficient for all patients, and new evidence shows better outcomes in patients affected by persistent AF after a combined hybrid endo-epicardial ablation. Considering the synergic potential of these techniques, in this case series, they were both combined in a single procedure. Methods and results: We describe the treatment of 5 patients referred for refractory AF ablation and LAA closure. All patients had high thrombotic and previous major hemorrhage, with relative contraindication to life-long therapy with anticoagulation. A combined procedure of LAA ligation and endo-epicardial ablation was scheduled with short-term anticoagulation. LAA closure was performed with an epicardial approach using the LARIAT system. Then, LA mapping and ablation were performed, endocardially and then epicardially.All procedures were concluded without complications.At follow-up, in all patients, transesophageal echocardiography showed the complete occlusion of the LAA; therefore, anticoagulation therapy was interrupted. All patients were asymptomatic, and in the sinus rhythm, no hemorrhage or ischemic events occurred. Conclusion: The combination of percutaneous LAA ligation and endo-epicardial ablation was revealed to be feasible and safe and might represent a new approach for the treatment of refractory AF in patients with indication of LAA occlusion.

Environmental and Lifestyle Cancer Risk Factors: Shaping Extracellular Vesicle OncomiRs and Paving the Path to Cancer Development.

Intercellular communication has been transformed by the discovery of extracellular vesicles (EVs) and their cargo, including microRNAs (miRNAs), which play crucial roles in intercellular signaling. These EVs were previously disregarded as cellular debris but are now recognized as vital mediators of biological information transfer between cells. Furthermore, they respond not only to internal stimuli but also to environmental and lifestyle factors. Identifying EV-borne oncomiRs, a subset of miRNAs implicated in cancer development, could revolutionize our understanding of how environmental and lifestyle exposures contribute to oncogenesis. To investigate this, we studied the plasma levels of EV-borne oncomiRs in a population of 673 women and 238 men with a body mass index > 25 kg/m2 (SPHERE population). The top fifty oncomiRs associated with the three most common cancers in women (breast, colorectal, and lung carcinomas) and men (lung, prostate, and colorectal carcinomas) were selected from the OncomiR database. Only oncomiRs expressed in more than 20% of the population were considered for statistical analysis. Using a Multivariate Adaptive Regression Splines (MARS) model, we explored the interactions between environmental/lifestyle exposures and EV oncomiRs to develop optimized predictor combinations for each EV oncomiR. This innovative approach allowed us to better understand miRNA regulation in response to multiple environmental and lifestyle influences. By uncovering non-linear relationships among variables, we gained valuable insights into the complexity of miRNA regulatory networks. Ultimately, this research paves the way for comprehensive exposome studies in the future.

Restless Legs Syndrome and fatigue in multiple sclerosis: A cross-sectional clinical study.

BACKGROUND: Restless Legs Syndrome is a sleep-related sensorimotor disorder with a higher prevalence in Multiple Sclerosis (MS) patients than in the general population. Our aim was to determine the prevalence of RLS in a group of relapsing-remittent multiple sclerosis (RRMS) patients, and to investigate whether RLS is associated with MS-related disability, sleep quality, mood disorders and fatigue. METHODS: In this retrospective, mono-centric, observational study, 92 RRMS patients were recruited (median age 46.5 years, 68.5% female patients). Data on MS clinical and radiological variables were collected. Patients underwent a subjective evaluation with standardized questionnaires on sleep fatigue and mood, which were evaluated by an expert neurologists specialized in sleep disorders about the occurrence of RLS. RESULTS: Prevalence of RLS in our sample was of 47.8%. Patients with RLS had a significantly higher rate of worse sleep quality and fatigue, compared to non RLS subjects (respectively 56.8% vs. 35.4%, p=0.04 and 54.4% vs 22.7%, p=0.002). Univariate analysis showed that RLS was significantly more frequent in fatigued patients (66.7% vs 38.5% RLS- patients, p=0.009). Multivariate analysis showed that fatigue correlated with MS-related disability (OR 1.556, p=0.011), poor sleep quality (OR 1.192, p 0.036), and mood disorders (OR 1.096, p 0.046). RLS appears to independently increase the risk of fatigue of 50%, without reaching clear statistical significance (OR 1.572, p 0,0079). CONCLUSION: Our study confirms the high prevalence of RLS in patients with multiple sclerosis and highlights the potential impact of RLS on fatigue and its strict interaction with sleep quality.

Digital health and Clinical Patient Management System (CPMS) platform utility for data sharing of neuromuscular patients: the Italian EURO-NMD experience.

BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.

Transcatheter ablation in patients with Brugada syndrome.

Since the first description of Brugada syndrome (BrS), several studies were carried out aimed at diagnosis, arrhythmic risk stratification, and available strategies for sudden death prevention. In high-risk patients, the use of an implantable cardiac defibrillator was an evident option since the first description of the syndrome. Nevertheless, this strategy, while proven, as expected, to be effective in sudden death prevention, does not prevent arrhythmias and may not be an adequate or accepted solution for all patients. The need of a non-pharmacological therapy as a potential solution based on the electrophysiological mechanisms underlying the syndrome, led to search for substrate as target for catheter ablation. Advances in the tools, technology, and technical approach enabled to launch studies aimed at mapping the epicardium of patients with BrS in order to identify and ablate the substrate. As described in previous work and in our experience, an anatomically identifiable electrical substrate, which correspond to the typical ECG, is the ablation target. Complete substrate is better identified in a larger area with sodium-channel-blockers. Ablation of all abnormal electrical potentials is able to normalize the ECG and prevent arrhythmias induction. Encouraging preliminary data, if confirmed by longer follow-up and by multicentre randomized study, could change the whole therapeutic management in BrS patients.

Reduction of Staphylococcus epidermidis in the mammary tumor microbiota induces antitumor immunity and decreases breast cancer aggressiveness.

The mammary gland hosts a microbiota, which differs between malignant versus normal tissue. We found that aerosolized antibiotics decrease murine mammary tumor growth and strongly limit lung metastasis. Oral absorbable antibiotics also reduced mammary tumors. In ampicillin-treated nodules, the immune microenvironment consisted of an M1 profile and improved T cell/macrophage infiltration. In these tumors, we noted an under-representation of microbial recognition and complement pathways, supported by TLR2/TLR7 protein and C3-fragment deposition reduction. By 16S rRNA gene profiling, we observed increased Staphylococcus levels in untreated tumors, among which we isolated Staphylococcus epidermidis, which had potent inflammatory activity and increased Tregs. Conversely, oral ampicillin lowered Staphylococcus epidermidis in mammary tumors and expanded bacteria promoting an M1 phenotype and reducing MDSCs and tumor growth. Ampicillin/paclitaxel combination improved the chemotherapeutic efficacy. Notably, an Amp-like signature, based on genes differentially expressed in murine tumors, identified breast cancer patients with better prognosis and high immune infiltration that correlated with a bacteria response signature. This study highlights the significant influence of mammary tumor microbiota on local immune status and the relevance of its treatment with antibiotics, in combination with breast cancer therapies.

Safety and efficacy of catheter ablation for ventricular tachycardia in elderly patients with structural heart disease: a systematic review and meta-analysis.

PURPOSE: Data regarding the age-specific outcomes of VT ablation in patients with structural heart disease (SHD) are scarce. We performed a systematic review and meta-analysis to evaluate the outcomes of VT ablation in elderly vs. younger patients with SHD. METHODS: MEDLINE/PubMed, Cochrane, and Google Scholar and references comparing VT ablation in elderly vs. younger patients were screened and studies included if matching inclusion and exclusion criteria. RESULTS: Five retrospective studies enrolling 2778 SHD patients (868 elderly vs. 1910 younger) were included. Compared to younger subjects, the elderly showed similar results in terms of acute ablation success (OR 0.78, 95% CI 0.54-1.13, p = 0.189) and minor complications (OR 1.74, 95% CI 0.74-4.09, p = 0.205), a trend toward a higher risk of major complications (OR 2.30, 95% CI 0.83-6.40, p = 0.110) and significantly higher rates of all complications (OR 2.67, 95% CI 1.51-4.71, p = 0.001) and periprocedural mortality (OR 1.93, 95% CI 1.24-3.01, p = 0.004). At a mean follow-up of 18 months, elderly patients showed similar long-term VT recurrence rate (OR 1.02, 95% CI 0.85-1.22, p = 0.861) and higher all-cause mortality (OR 2.00, 95% CI 1.40-2.86, p < 0.001). In elderly patients, urgent VT ablation is associated with higher risk of major complications (beta = 0.06, p < 0.001) and periprocedural mortality (beta = 0.03, p = 0.029), while advanced age is associated with higher risk of major complications (beta = 0.29 with p = 0.009) and all complications + periprocedural mortality (beta = 0.17 with p = 0.037). CONCLUSIONS: Compared to younger patients, VT ablation in elderly showed similar results in terms of acute ablation success and long-term VT recurrence rate with a significantly higher risk of all complications, periprocedural mortality, and long-term mortality, especially when the procedure is performed urgently and in the most aged patients. Large prospective multicenter randomized trials are required to confirm these findings.