We propose a new fixed-target experiment for the study of electromagnetic and hard probes of the Quark-Gluon Plasma (QGP) in heavy-ion collisions at the CERN SPS. The experiment aims at performing ...measurements of the dimuon spectrum from threshold up to the charmonium region, and of hadronic decays of charm and strange hadrons. It is based on a muon spectrometer, which includes a toroidal magnet and six planes of tracking detectors, coupled to a vertex spectrometer, equipped with Si MAPS immersed in a dipole field. High luminosity is an essential requirement for the experiment, with the goal of taking data with 10\(^6\) incident ions/s, at collision energies ranging from \(\sqrt{s_{\rm NN}} = 6.3\) GeV (\(E_{\rm lab}= 20\) A GeV) to top SPS energy (\(\sqrt{s_{\rm NN}} = 17.3\) GeV, \(E_{\rm lab}= 158\) A GeV). This document presents the physics motivation, the foreseen experimental set-up including integration and radioprotection studies, the current detector choices together with the status of the corresponding R&D, and the outcome of physics performance studies. A preliminary cost evaluation is also carried out.
•Immune checkpoint inhibitors (ICIs) have shifted the therapeutic approach to NSCLC•Reproducible biomarkers of ICI benefit represent an unmet and urgent need•Circulating descriptors of cancer-host ...immune interaction were explored here•sPD-L1, CD8+PD-1+ and NK cells enclosed a highly prognostic immune effector score•Blood-based multiparametric models might non-invasively predict ICI response
Upfront criteria to foresee immune checkpoint inhibitors (ICIs) efficacy are far from being identified. Thus, we integrated blood descriptors of pro-inflammatory/immunosuppressive or effective anti-tumor response to non-invasively define predictive immune profiles in ICI-treated advanced non-small cell lung cancer (NSCLC).
Peripheral blood (PB) was prospectively collected at baseline from 109 consecutive NSCLC patients undergoing ICIs as first or more line treatment. Soluble PD-L1 (sPD-L1) (immunoassay), CD8+PD-1+ and NK (FACS) cells were assessed and interlaced to generate an Immune effector Score (IeffS). Lung Immune Prognostic Index (LIPI) was computed by LDH levels and derived Neutrophil-to-Lymphocyte Ratio (dNLR). All these parameters were correlated with survival outcome and treatment response.
High sPD-L1 and low CD8+PD-1+ and NK number had negative impact on PFS (P < 0.001), OS (P < 0.01) and ICI-response (P < 0.05). Thus, sPD-L1high, CD8+PD-1+low and NKlow were considered as risk factors encompassing IeffS, whose prognostic power outperformed that of individual features and slightly exceeded that of LIPI. Accordingly, the absence of these risk factors portrayed a favorable IeffS characterizing patients with significantly (P < 0.001) prolonged PFS (median NR vs 2.3 months) and OS (median NR vs 4.1) and greater benefit from ICIs (P < 0.01). We then combined each risk parameter composing IeffS and LIPI (LDHhigh, dNLRhigh), thus defining three distinct prognostic classes. A remarkable impact of IeffS-LIPI integration was documented on survival outcome (PFS, HR = 4.61; 95%CI = 2.32-9.18; P < 0.001; OS, HR=4.03; 95%CI=1.91-8.67; P < 0.001) and ICI-response (AUC=0.90, 95%CI=0.81-0.97, P < 0.001).
Composite risk models based on blood parameters featuring the tumor-host interaction might provide accurate prognostic scores able to predict ICI benefit in NSCLC patients.
Resistance to osimertinib in advanced EGFR-mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent ...therapeutic implications.
This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR-mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed.
Sixty-five advanced EGFR-mutated NSCLC patients treated with osimertinib in first- (n = 56) or in second-line (n = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification (n = 8), EGFR C797S (n = 3), and SCLC transformation (n = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively.
Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.
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