Measurement of the Hypertriton Properties and Production with ALICE

The hypertriton (3 ΛH) is a bound state of a proton, a neutron, and a Λ baryon. Studying its internal structure is crucial to investigate the hyperon–nucleon (Y –N) strong interaction and offers insights into the inner core of neutron stars, where Λ production is favoured. Measuring precisely the 3 ΛH lifetime, τ3 ΛH, and Λ separation energy, BΛ, provide a powerful tool for constraining the parameters of the Y –N potential, as τ3 ΛH and BΛ directly reflect the strength of the Y –N interaction. The most precise measurements to date of τ3 ΛH and BΛ are obtained by the ALICE Collaboration, using the data sample of Pb–Pb collisions at a centre-of-mass energy per nucleon pair of √ sNN = 5.02 TeV. These measurements strongly support the loosely-bound nature of 3 ΛH and shed light on the Y –N interaction. Furthermore, the weakly bound nature of the 3 ΛH has important implications on our understanding of the nucleosynthesis mechanism in hadronic collisions. Indeed, the large size of the 3 ΛH wave function determines a large separation between the nuclei production models at low charged-particle multiplicity. For this reason, the first measurement of the production of 3 ΛH in p–Pb collisions at √ sNN = 5.02 TeV performed by ALICE represents an ideal probe for discriminating between the nuclei production mechanisms in high-energy hadron–hadron collisions

Investigating the hyperon-nucleon strong interaction with a precision measurement of the hypertriton lifetime in ALICE

The hypertriton is a bound state of a proton, a neutron and a Λ baryon. Studying its internalstructure is crucial to investigate the hyperon–nucleon strong interaction and offers insights intothe inner core of neutron stars, where Λ production is favoured. One powerful way to investigatethe hypertriton’s internal structure is to measure precisely its lifetime. The hypertriton is anextremely loosely bound object with a lambda separation energy E_Λ of only 130 keV. Thereforethe hypertriton lifetime is expected to be close to the one of the free Λ. Thanks to the very largeset of Pb–Pb collision data collected during LHC Run 2, the ALICE collaboration has performedsystematic studies on the hypertriton lifetime. The hypertriton 2-body mesonic decay channel hasbeen studied with the help of machine learning techniques for the signal extraction. The precisionof the new ALICE results on the hypertriton lifetime is comparable with the current world averageand the measured lifetime value confirms the weakly-bound nature of the hypertriton

Unveiling the (anti-)hypertriton properties with ALICE at the LHC

A Large Ion Collider Experiment (ALICE) is one of the four experiments installed at the CERN Large Hadron Collider (LHC). ALICE was designed and built to study a phase of the matter called Quark Gluon Plasma, which is formed in heavy-ion collisions at ultra-relativistic energies. The extreme energy densities reached in hadronic collisions at the LHC lead to a significant production of baryonic states. Among the thousands of particles produced, light (anti-)hypernuclei are of special interest. Indeed, the study of their internal structure represents a direct probe to investigate the strong interaction among hyperons and the ordinary matter. This thesis project is focused on the study of the properties of the lightest known hypernucleus, the hypertriton ($\mathrm{^{3}_{\Lambda}H}$) which is a bound state of a proton, a neutron and a $\Lambda$. The most precise measurements to date of the $\mathrm{^{3}_{\Lambda}H}$ lifetime and $\Lambda$ separation energy are performed by exploiting the large Pb--Pb data sample collected by ALICE during 2018. The $\mathrm{^{3}_{\Lambda}H}$ signal is extracted for the first time with a machine learning technique, allowing for a significant improvement in the discrimination between signal and background. The combined measurements confirm that the $\mathrm{^{3}_{\Lambda}H}$ is a loosely bound state with a large wave function radius extending up to $\sim$ 5 fm. In the second part of this thesis, the first measurement of the $\mathrm{^{3}_{\Lambda}H}$ production in p--Pb collisions is presented. Given the large spread of its wave function, the measured $\mathrm{^{3}_{\Lambda}H}$ yield in p--Pb collisions is a sensitive observable to test the nucleosynthesis in hadronic collisions and is a powerful tool for discriminating between different production models of nuclei. The $\mathrm{^{3}_{\Lambda}H}$ signal is extracted again with a machine learning approach, leading to a significance higher than 4 $\sigma$. The value of the yield favours a coalescence model to describe the nucleosynthesis, demonstrating that the $\mathrm{^{3}_{\Lambda}H}$ wave function directly influences its nuclear production mechanism in hadronic collisions. In the last part of this thesis a new algorithm for tracking the $\mathrm{^{3}_{\Lambda}H}$ and fully reconstruct its decay topology is presented: this method relies on the high granularity of the upgraded Inner Tracking System of ALICE, installed for the Run 3 of the LHC. Finally, the possibility to characterise the properties of $A\geq 4$ hypernuclei with the proposed NA60+ experiment is discussed, using the $^5_\Lambda\mathrm{He}$ as a use case

Probing the (anti-)hypertriton properties with ALICE at the LHC

The extreme energy densities reached in heavy-ion collisions at the LHC lead to an abundant production of nuclei and antinuclei. Of particular interest among these are the light (anti-)hypernuclei, as the study of their internal structure represents a direct probe to investigate the strong interaction between hyperons and nucleons. This talk is focused on the properties of the lightest known hypernucleus, the hypertriton (3ΛH), which is a bound state of a proton, a neutron and a Λ. The most precise measurements to date of the 3ΛH and anti-3ΛH lifetime τ and Λ separation energy BΛ are obtained using the data sample of Pb-Pb collisions at √sNN = 5.02  TeV collected by ALICE during the Run 2 of the LHC. The 3ΛH is reconstructed via its charged two-body mesonic decay channel (3ΛH→3He+π- + c.c.) &nbsp;and selected with machine learning techniques. The measured values τ = [ 253 ± 11 (stat) ± 6 (syst) ] ps and BΛ = [ 102 ± 63 (stat) ± 67 (syst) ] keV are compatible with predictions from effective field theories and confirm that the3ΛH structure is consistent with an extremely weak bound system.Refreshments will be served at 10:30</p

Clinical and hematologic parameters address the outcomes of non-small-cell lung cancer patients treated with nivolumab

Aim: This prospective study aimed to envisage the putative prognostic significance of clinical and hematologic parameters in advanced non-small-cell lung cancer patients treated with nivolumab. Materials & methods: Correlations of several parameters with disease control and survival outcomes were provided. Results: A total of 54 patients were included. An ECOG performance status 0-1, the lack of liver and bone metastases and a timeframe from the last systemic treatment ≥4 months correlated with better disease control. The same was observed for baseline low levels of white blood cells and neutrophils, for high levels of NK cells and a neutrophil/lymphocyte ratio <4. The mentioned parameters were also associated with longer overall survival. Conclusion: Nivolumab efficacy in non-small-cell lung cancer patients is influenced by clinicopathological parameters and specific leucocyte subsets

The circulating pool of functionally competent NK and CD8+ cells predicts the outcome of anti-PD1 treatment in advanced NSCLC

Introduction: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters. Methods: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes. Results: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg. Conclusion: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy

Role of Clock Genes and Circadian Rhythm in Renal Cell Carcinoma: Recent Evidence and Therapeutic Consequences

Circadian rhythm regulates cellular differentiation and physiology and shapes the immune response. Altered expression of clock genes might lead to the onset of common malignant cancers, including Renal Cell Carcinoma (RCC). Data from Cancer Genome Atlas (TCGA) indicate that clock genes PER1-3, CRY2, CLOCK, NR1D2 and RORα are overexpressed in RCC tissues and correlate with patients’ prognosis. The expression of clock genes could finely tune transcription factor activity in RCC and is associated with the extent of immune cell infiltration. The clock system interacts with hypoxia-induced factor-1α (HIF-1α) and regulates the circadian oscillation of mammalian target of rapamycin (mTOR) activity thereby conditioning the antitumor effect of mTOR inhibitors. The stimulation of natural killer (NK) cell activity exerted by the administration of interferon-α, a cornerstone of the first era of immunotherapy for RCC, relevantly varies according to circadian dosing time. Recent evidence demonstrated that time-of-day infusion directly affects the efficacy of immune checkpoint inhibitors in cancer patients. Compounds targeting the circadian clock have been identified and their role in the era of immunotherapy deserves to be further investigated. In this review, we aimed at addressing the impact of clock genes on the natural history of kidney cancer and their potential therapeutic implications

Drug-drug interactions (DDIs) in elderly patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib within the multicenter prospective trial ZEBRA/Meet-URO 9

Background: The oral tyrosine kinase inhibitor Cabozantinib (CABO) is frequently used to treat patients with metastatic RCC. Polypharmacy is common in elderly pts, thus several drug-drug interactions (DDIs) with cabozantinib may ensue. Methods: ZEBRA /MEET-URO 9 was a prospective, real world trial enrolling pts ≥ 70 years with mRRC treated with CABO at 13 Italian Oncology Centers. All concomitants drugs administered to pts were collected and categorized according to active principles and indication. DDIs were identified through a dedicated software (Lexicomp), scientific databases (Sider4.1) and published articles. Results: we enrolled 104 pts, median age 75.8 years (range 70.2-87.4 yrs). Overall, 91.4% of the cohort was treated at a reduced dose either upfront or due to side effects. Pts took a median of 6 concomitant drugs (IQR: 4-9), for a total of 131 active principles. Software analysis identified 4 DDIs (warfarin, apixaban, diltiazem and furosemide); whereas scientific reports allowed us to identify 15 additional DDIs involving metoprolol, nebivolol, olmesartan, amiloride, simvastatin, rosuvastatin, polyenoic omega-3 fatty acids, loperamide, metoclopramide, metformin, dutasteride, dexamethasone, prednisone, cetirizine and doxazosin. Seventy pts with potential DDIs experienced a trend for higher rate of grade 3-4 adverse events compared to other pts, although difference was not statistically significant (48.7% v 23.5 %, p=0.485). The table summarizes the main DDIs and suggestions to avoid or mitigate their effects Conclusions: the risk of DDIs was not negligible in our cohort of elderly mRCC pts treated with CABO, although the frequent dose reductions of CABO probably confounded their impact on toxicities. Unremitting attention to concomitant medications in the elderly is thus warranted

Evaluation of PBRM1, PD-L1, CD31, and CD4/CD8 ratio as a predictive signature of response to VEGFR-TKI–based therapy in patients with metastatic renal cell carcinoma (mRCC) with IMDC intermediate prognosis: Results from the APAChE-I Study

Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was &gt;0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p&lt;0.001) and OS (41.5 vs. 24.9, p=0.006) in pts receiving VEGFR-TKI-based therapies. The rate of AP+ tumors was 55.6% and 32.7% in pts with one or two IMDC risk factors, respectively (p=0.022). In the small cohort of pts treated with I/N, no differences were observed in PFS (p=0.64) and OS (p=0.75) between AP+ and AP-negative. Conclusions: The AP+ signature (loss of PBRM1, PD-L1 negative, and CD4/CD8 high ratio) was associated with improved clinical outcomes in mRCC pts at IMDC intermediate prognosis treated with VEGFR-TKI-based therapy; this correlation was significant regardless from the addition of IO to VEGFR-TKI monotherapy. Prospective validation of this signature is required for guiding the selection of the most appropriate 1L therapy