Risk of cardiovascular toxicity with combination of immune-checkpoint inhibitors and angiogenesis inhibitors: a meta-analysis

IntroductionCombinations of immune checkpoint inhibitors (ICIs) and angiogenesis inhibitors (AIs) have been investigated for the treatment of several tumor types. Both ICIs and AIs may lead to cardiovascular adverse events, and their combination may potentially increase the risk for cardiovascular toxicity. In the present meta-analysis, we aim to assess the cardiovascular toxicity of ICIs plus AIs vs. AIs alone. Secondary objectives are non-cardiovascular adverse events and efficacy.MethodsSystematic review was performed according to PRISMA statement. Phase II and III randomized clinical trials were identified by searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts, from inception to June 2022. The pooled risks for overall response rate (ORR), 1-year progression-free survival (PFS), adverse events (AEs), immune-related AEs, (irAEs), hypertension, and vascular events defined as stroke, myocardial infarction and pulmonary embolisms, were calculated.ResultsIn terms of cardiovascular toxicity, we found higher risk for severe hypertension among patients treated with ICIs plus AIs as compared with those receiving AIs (OR 1.24, 95% CI: 1.01–1.53), but no significant difference was found for any-grade hypertension, and for vascular events. There was also no difference in terms of overall AEs, whereas the incidence of irAEs was increased in the ICIs plus AIs arm, as expected. In terms of efficacy, ICIs plus AIs achieved better ORR (OR 2.25, 95% CI: 1.70–2.97) and PFS (HR 0.49, 95% CI: 0.39–0.63) as compared to AIs alone.ConclusionThe addition of ICIs to AIs significantly increased the risk of high-grade hypertension, but not that of acute vascular events

Practical approach to vasculitides in adults: an overview of clinical conditions that can mimic vasculitides closely

Primary systemic vasculitides are rare diseases affecting blood vessel walls. The type and patterns of distribution of the organs affected usually reflect the size of the vessels predominantly involved, and the patterns of clinical manifestations are generally useful to reach a specific diagnosis. However, presenting symptoms may lack adequate specificity for a prompt diagnosis, leading to a diagnostic (and therapeutic) delay, often causing irreversible damage to the affected organs. Due to their rarity and variable clinical presentation, the diagnosis of primary vasculitides could be challenging for physicians. Vasculitis mimickers, i.e. the clinical conditions that could be likely mistaken for vasculitides, need to be carefully ruled out, especially before starting the immunosuppressive therapy. We present here a practical approach to the diagnosis of primary systemic vasculitides involving large, medium and small size vessels, and reviewed most of the conditions that could mimic primary systemic vasculitides

L’Oscillometria a impulsi nuovo test di funzionalità respiratoria per i bambini con asma

L’asma è una malattia infiammatoria cronica delle vie aeree che può interessare l’intero albero bronchiale. Recenti evidenze dimostrano che la disfunzione delle piccole vie aeree (o small airway dysfunction, SAD) è un fattore importante nella patogenesi e nell’espressione clinica della malattia. A causa delle difficoltà nella valutazione delle vie aeree periferiche con tecniche non invasive, risulta ancora poco chiaro il ruolo della SAD nell’asma pediatrico, che è invece assodato in età adulta. Secondo recenti lavori, le piccole vie aeree sono interessate già nelle prime fasi dell’asma, ma la spirometria, il test convenzionale per la valutazione della funzione polmonare, non esamina in modo sensibile la loro funzione, risultando alterata solo quando la disfunzione periferica diventa molto rilevante. L’infiammazione cronica e la SAD rappresentano fattori di rischio per la persistenza e la gravità dell’asma, lo scarso controllo della malattia e la progressiva riduzione della funzione polmonare con l’età. Identificare e quantificare il coinvolgimento sia delle vie aeree centrali che periferiche risulta pertanto clinicamente molto rilevante per una diagnosi precoce e per ottenere un buon controllo dell’asma, ridurre l’iperreattività bronchiale e monitorare la risposta al trattamento di fondo. Questo articolo descrive le evidenze recenti sul ruolo della SAD nello sviluppo e nel controllo dell’asma pediatrico e valuta il contributo di una nuova tecnica diagnostica disponibile in ambito ambulatoriale, l’oscillometria a impulsi, nella diagnosi precoce di SAD in età prescolare e scolare, nel monitoraggio dell’asma (in associazione alla spirometria) e nella gestione terapeutica

Outer Membrane Vesicles From The Gut Microbiome Contribute to Tumor Immunity by Eliciting Cross-Reactive T Cells

A growing body of evidence supports the notion that the gut microbiome plays an important role in cancer immunity. However, the underpinning mechanisms remain to be fully elucidated. One attractive hypothesis envisages that among the T cells elicited by the plethora of microbiome proteins a few exist that incidentally recognize neo-epitopes arising from cancer mutations ("molecular mimicry (MM)" hypothesis). To support MM, the human probiotic Escherichia coli Nissle was engineered with the SIINFEKL epitope (OVA-E.coli Nissle) and orally administered to C57BL/6 mice. The treatment with OVA-E.coli Nissle, but not with wild type E. coli Nissle, induced OVA-specific CD8(+) T cells and inhibited the growth of tumors in mice challenged with B16F10 melanoma cells expressing OVA. The microbiome shotgun sequencing and the sequencing of TCRs from T cells recovered from both lamina propria and tumors provide evidence that the main mechanism of tumor inhibition is mediated by the elicitation at the intestinal site of cross-reacting T cells, which subsequently reach the tumor environment. Importantly, the administration of Outer Membrane Vesicles (OMVs) from engineered E. coli Nissle, as well as from E. coli BL21(DE3)Delta ompA, carrying cancer-specific T cell epitopes also elicited epitope-specific T cells in the intestine and inhibited tumor growth. Overall, our data strengthen the important role of MM in tumor immunity and assign a novel function of OMVs in host-pathogen interaction. Moreover, our results pave the way to the exploitation of probiotics and OMVs engineered with tumor specific-antigens as personalized mucosal cancer vaccines

Circulating autoreactive proteinase 3(+) B cells and tolerance checkpoints in ANCA-associated vasculitis

BACKGROUND: Little is known about the autoreactive B cells in antineutrophil cytoplasmic antibody–associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3–reactive (PR3(+)) B cells. METHODS: Multicolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3(+) B cells (total and subsets). RESULTS: The frequency of PR3(+) B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%–6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%–5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%–2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3(+) B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3(+) memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3(+) B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3(+) B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001). CONCLUSION: This study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells. TRIAL REGISTRATION: ClinicalTrials.gov NCT00104299. FUNDING: The Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research

Unveiling the gravitational universe at mu-Hz frequencies

Funding Information: Open access funding provided by Università degli Studi di Milano - Bicocca within the CRUI-CARE Agreement. Publisher Copyright: © 2021, The Author(s).We propose a space-based interferometer surveying the gravitational wave (GW) sky in the milli-Hz to mu-Hz frequency range. By the 2040s, the mu-Hz frequency band, bracketed in between the Laser Interferometer Space Antenna (LISA) and pulsar timing arrays, will constitute the largest gap in the coverage of the astrophysically relevant GW spectrum. Yet many outstanding questions related to astrophysics and cosmology are best answered by GW observations in this band. We show that a mu-Hz GW detector will be a truly overarching observatory for the scientific community at large, greatly extending the potential of LISA. Conceived to detect massive black hole binaries from their early inspiral with high signal-to-noise ratio, and low-frequency stellar binaries in the Galaxy, this instrument will be a cornerstone for multimessenger astronomy from the solar neighbourhood to the high-redshift Universe.Peer reviewe

Validation of the Italian version of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire

Objectives The primary objective of this study was the translation and validation of the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire into Italian, denoted as AAV-PRO_ita. The secondary objective was to evaluate the impact of ANCA-associated vasculitis (AAV) on quality of life (QoL) and work impairment in a large cohort of Italian patients. Methods The study design took a prospective cohort study approach. First, the AAV-PRO was translated into Italian following the step guidelines for translations. The new AAV-PRO_ita questionnaire covered three disease domains: organ-specific and systemic symptoms and signs; physical function; and social and emotional impact. Second, Italian-speaking AAV patients were recruited from 17 Italian centres belonging to the Italian Vasculitis Study Group. Participants completed the AAV-PRO_ita questionnaire at three time points. Participants were also requested to complete the work productivity and activity impairment: general health questionnaire. Results A total of 276 AAV patients (56.5% women) completed the questionnaires. The AAV-PRO_ita questionnaire demonstrated a good internal consistency and test-retest reliability. Female AAV patients scored higher (i.e. worse) in all thee domains, especially in the social and emotional impact domain (P &lt; 0.001). Patients on glucocorticoid therapy (n = 199) had higher scores in all domains, especially in the physical function domain (P &lt; 0.001), compared with patients not on glucocorticoid therapy (n = 77). Furthermore, patients who had at least one relapse of disease (n = 114) had higher scores compared with those who had never had one (n = 161) in any domain (P &lt; 0.05). Finally, nearly 30% of the patients reported work impairment. Conclusion The AAV-PRO_ita questionnaire is a new 29-item, disease-specific patient-reported outcome measuring tool that can be used in AAV research in the Italian language. Sex, glucocorticoids and relapsing disease showed the greatest impact on QoL

New horizons for fundamental physics with LISA

The Laser Interferometer Space Antenna (LISA) has the potential to reveal wonders about the fundamental theory of nature at play in the extreme gravity regime, where the gravitational interaction is both strong and dynamical. In this white paper, the Fundamental Physics Working Group of the LISA Consortium summarizes the current topics in fundamental physics where LISA observations of gravitational waves can be expected to provide key input. We provide the briefest of reviews to then delineate avenues for future research directions and to discuss connections between this working group, other working groups and the consortium work package teams. These connections must be developed for LISA to live up to its science potential in these areas