The Safety Profiles of Two First-Generation NTRK Inhibitors: Analysis of Individual Case Safety Reports from the FDA Adverse Event Reporting System (FAERS) Database

The first-generation tropomyosin receptor kinase (TRK) inhibitors, larotrectinib and entrectinib, represent exciting new developments in cancer treatment that offer relevant, rapid, and long-lasting clinical benefits. Larotrectinib and entrectinib are recommended as first-line treatments for locally advanced or metastatic non-small cell lung cancer (NSCLC) patients with positive TRK gene fusions. In this study, using the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database between 2019 and 2022, a retrospective analysis was conducted to evaluate the safety profiles of these drugs. During our study period, 807 individual case safety reports (ICSRs) related to larotrectinib or entrectinib were retrieved from the FAERS database, of which 48.7% referred to females and 24.7% referred to adult patients (18–64 years) with a median age of 61.0 years. A total of 1728 adverse drug reactions (ADRs) were identified. The most frequently reported ADRs were dizziness and pain, which belong to the System Organ Classes (SOCs) “nervous system disorders” and “general disorders and administration site conditions”. Regarding all ADRs, the median time to onset was 37.0 days for larotrectinib and 12.0 days for entrectinib. No evident safety concerns emerged in the long-term safety profiles (>365 days). Only 18 ICSRs were related to pediatric populations (≤16 years), of which 94.0% of the ICSRs were related to larotrectinib. The median age was 10.5 years, while most patients were female (44.4%). Our results show favorable risk-benefit profiles for larotrectinib and entrectinib. Considering the increased use of neurotrophic tyrosine receptor kinase (NTRK) inhibitors, continuous safety monitoring of larotrectinib and entrectinib is required for the detection of possible new adverse drug reactions

Late relapse after CAR-T cell therapy for adult patients with hematologic malignancies: A definite evidence from systematic review and meta-analysis on individual data

Chimeric Antigen Receptor (CAR)-modified T lymphocytes represent one of the most innovative and promising approaches to treating hematologic malignancies. CAR-T cell therapy is currently being used for the treatment of relapsed/refractory (r/r) B-cell malignancies including Acute Lymphoblastic Leukemia, Large B-Cell Lymphoma, Follicular Lymphoma, Multiple Myeloma and Mantle Cell Lymphoma. Despite the unprecedented clinical success, one of the major issues of the approved CAR-T cell therapy – tisagenlecleucel, axicabtagene, lisocabtagene, idecabtagene, ciltacabtagene and brexucabtagene – is the uncertainty about its persistence which in turn could lead to weak or no response to therapy with malignancy recurrence. Here we show that the prognosis of patients who do not respond to CAR-T cell therapy is still an unmet medical need. We performed a systematic review and meta-analysis collecting individual data on Duration of Response from at least 12-month follow-up studies. We found that the pooled prevalence of relapse within the first 12 months after CAR-T infusion was 61% (95% CI, 43%−78%); moreover, one year after the infusion, the analysis highlighted a pooled prevalence of relapse of 24% (95% CI, 11%−42%). Our results suggest that identifying potential predictive biomarkers of response to CAR-T therapy, especially for patients affected by the advanced stage of blood malignancies, could lead to stratification of the eligible population to that therapy, recognizing which patients will benefit and which will not, helping regulators to make decision in that way

Elliptic anisotropy measurement of the f0_0(980) hadron in proton-lead collisions and evidence for its quark-antiquark composition

International audienceDespite the f$_0$(980) hadron having been discovered half a century ago, the question about its quark content has not been settled: it might be an ordinary quark-antiquark ($\mathrm{q\bar{q}}$) meson, a tetraquark ($\mathrm{q\bar{q}q\bar{q}}$) exotic state, a kaon-antikaon ($\mathrm{K\bar{K}}$) molecule, or a quark-antiquark-gluon ($\mathrm{q\bar{q}g}$) hybrid. This paper reports strong evidence that the f$_0$(980) state is an ordinary $\mathrm{q\bar{q}}$ meson, inferred from the scaling of elliptic anisotropies ($v_2$) with the number of constituent quarks ($n_\mathrm{q}$), as empirically established using conventional hadrons in relativistic heavy ion collisions. The f$_0$(980) state is reconstructed via its dominant decay channel f$_0$(980) $\to$$\pi^+\pi^-$, in proton-lead collisions recorded by the CMS experiment at the LHC, and its $v_2$ is measured as a function of transverse momentum ($p_\mathrm{T}$). It is found that the $n_q$ = 2 ($\mathrm{q\bar{q}}$ state) hypothesis is favored over $n_q$ = 4 ($\mathrm{q\bar{q}q\bar{q}}$ or $\mathrm{K\bar{K}}$ states) by 7.7, 6.3, or 3.1 standard deviations in the $p_\mathrm{T}$$\lt$ 10, 8, or 6 GeV/$c$ ranges, respectively, and over $n_\mathrm{q}$ = 3 ($\mathrm{q\bar{q}g}$ hybrid state) by 3.5 standard deviations in the $p_\mathrm{T}$$\lt$ 8 GeV/$c$ range. This result represents the first determination of the quark content of the f$_0$(980) state, made possible by using a novel approach, and paves the way for similar studies of other exotic hadron candidates

Extracting the speed of sound in the strongly interacting matter created in ultrarelativistic lead-lead collisions at the LHC

International audienceUltrarelativistic nuclear collisions create a strongly interacting state of hot and dense quark-gluon matter that exhibits a remarkable collective flow behavior with minimal viscous dissipation. To gain deeper insights into its intrinsic nature and fundamental degrees of freedom, we extracted the speed of sound in this medium created using lead-lead (PbPb) collisions at a center-of-mass energy per nucleon pair of 5.02 TeV. The data were recorded by the CMS experiment at the CERN LHC and correspond to an integrated luminosity of 0.607 nb$^{-1}$. The measurement is performed by studying the multiplicity dependence of the average transverse momentum of charged particles emitted in head-on PbPb collisions. Our findings reveal that the speed of sound in this matter is nearly half the speed of light, with a squared value of 0.241 $\pm$ 0.002 (stat) $\pm$ 0.016 (syst) in natural units. The effective medium temperature, estimated using the mean transverse momentum, is 219 $\pm$ 8 (syst) MeV. The measured squared speed of sound at this temperature aligns precisely with predictions from lattice quantum chromodynamic (QCD) calculations. This result provides a stringent constraint on the equation of state of the created medium and direct evidence for a deconfined QCD phase being attained in relativistic nuclear collisions

Search for CPCP violation in D0^0→\to KS0^0_\mathrm{S}KS0^0_\mathrm{S} decays in proton-proton collisions at s\sqrt{s} = 13 TeV

International audienceA search is reported for charge-parity D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ violation in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ decays, using data collected in proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded by the CMS experiment in 2018. The analysis uses a dedicated data set that corresponds to an integrated luminosity of 41.6 fb$^{-1}$, which consists of about 10 billion events containing a pair of ẖadrons, nearly all of which decay to charm hadrons. The flavor of the neutral D meson is determined by the pion charge in the reconstructed decays D$^{*+}$$\to$ D$^0\pi^+$ and D$^{*-}$$\to$ D$^0\pi^-$. The D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$$CP$ asymmetry in D$^0$$\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ is measured to be $A_{CP}$( K$^0_\mathrm{S}$K$^0_\mathrm{S}$) = (6.2 $\pm$ 3.0 $\pm$ 0.2 $\pm$ 0.8)%, where the three uncertainties represent the statistical uncertainty, the systematic uncertainty, and the uncertainty in the measurement of the D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry in the D$^0$ $\to$ K$^0_\mathrm{S}\pi^+\pi^-$ decay. This is the first D$^0$ $\to$ K$^0_\mathrm{S}$K$^0_\mathrm{S}$ $CP$ asymmetry measurement by CMS in the charm sector as well as the first to utilize a fully hadronic final state

Test of lepton flavor universality in B± ⁣→ ⁣K±μ+μ− {\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-} and B± ⁣→ ⁣K±e+e− {\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mathrm{e}^+\mathrm{e}^- decays in proton-proton collisions at s= \sqrt{s} = 13 TeV

A test of lepton flavor universality in ${\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-}$ and ${\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mathrm{e}^+\mathrm{e}^-$ decays, as well as a measurement of differential and integrated branching fractions of a nonresonant ${\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-}$ decay are presented. The analysis is made possible by a dedicated data set of proton-proton collisions at $\sqrt{s} =$ 13 TeV recorded in 2018, by the CMS experiment at the LHC, using a special high-rate data stream designed for collecting about 10 billion unbiased b hadron decays. The ratio of the branching fractions $\mathcal{B}({\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-})$ to $\mathcal{B}({\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mathrm{e}^+\mathrm{e}^-)$ is determined from the measured double ratio $R(\mathrm{K})$ of these decays to the respective branching fractions of the ${\mathrm{B}^{\pm}} \!\to\! {\mathrm{J}/\psi} \mathrm{K^{\pm}}$ with ${\mathrm{J}/\psi} \!\to\!\mu^{+}\mu^{-}$ and $\mathrm{e}^+\mathrm{e}^-$ decays, which allow for significant cancellation of systematic uncertainties. The ratio $R(\mathrm{K})$ is measured in the range 1.1 $< q^2 <$ 6.0 GeV$^2$, where $q$ is the invariant mass of the lepton pair, and is found to be $R(\mathrm{K})=$ 0.78 $^{+0.47}_{-0.23}$, in agreement with the standard model expectation $R(\mathrm{K}) \approx$ 1. This measurement is limited by the statistical precision of the electron channel. The integrated branching fraction in the same $q^2$ range, $\mathcal{B}({\mathrm{B}^{\pm}} \!\to\! \mathrm{K^{\pm}}\mu^{+}\mu^{-}) =$ (12.42 $\pm$ 0.68) $\times$ 10$^{-8}$, is consistent with the present world-average value and has a comparable precision.A test of lepton flavor universality in B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$ and B$^{\pm}$$\to$ K$^{\pm}$e$^+$e$^-$ decays, as well as a measurement of differential and integrated branching fractions of a nonresonant B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$ decay are presented. The analysis is made possible by a dedicated data set of proton-proton collisions at $\sqrt{s}$ = 13 TeV recorded in 2018, by the CMS experiment at the LHC, using a special high-rate data stream designed for collecting about 10 billion unbiased b hadron decays. The ratio of the branching fractions $\mathcal{B}$(B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$) to $\mathcal{B}$(B$^{\pm}$$\to$ K$^{\pm}$e$^+$e$^-$) is determined from the measured double ratio $R$(K) of these decays to the respective branching fractions of the B$^\pm$$\to$ J/$\psi$K$^\pm$ with J/$\psi$$\to$$\mu^+\mu^-$ and e$^+$e$^-$ decays, which allow for significant cancellation of systematic uncertainties. The ratio $R$(K) is measured in the range 1.1 $\lt q^2 \lt$ 6.0 GeV$^2$, where $q$ is the invariant mass of the lepton pair, and is found to be $R$(K) = 0.78$^{+0.47}_{-0.23}$, in agreement with the standard model expectation $R$(K) $\approx$ 1. This measurement is limited by the statistical precision of the electron channel. The integrated branching fraction in the same $q^2$ range, $\mathcal{B}$(B$^{\pm}$$\to$ K$^{\pm}\mu^+\mu^-$) = (12.42 $\pm$ 0.68) $\times$ 10$^{-8}$, is consistent with the present world-average value and has a comparable precision

Development of the CMS detector for the CERN LHC Run 3

International audienceSince the initial data taking of the CERN LHC, the CMS experiment has undergone substantial upgrades and improvements. This paper discusses the CMS detector as it is configured for the third data-taking period of the CERN LHC, Run 3, which started in 2022. The entire silicon pixel tracking detector was replaced. A new powering system for the superconducting solenoid was installed. The electronics of the hadron calorimeter was upgraded. All the muon electronic systems were upgraded, and new muon detector stations were added, including a gas electron multiplier detector. The precision proton spectrometer was upgraded. The dedicated luminosity detectors and the beam loss monitor were refurbished. Substantial improvements to the trigger, data acquisition, software, and computing systems were also implemented, including a new hybrid CPU/GPU farm for the high-level trigger

The CMS Statistical Analysis and Combination Tool: COMBINE

International audienceThis paper describes the COMBINE software package used for statistical analyses by the CMS Collaboration. The package, originally designed to perform searches for a Higgs boson and the combined analysis of those searches, has evolved to become the statistical analysis tool presently used in the majority of measurements and searches performed by the CMS Collaboration. It is not specific to the CMS experiment, and this paper is intended to serve as a reference for users outside of the CMS Collaboration, providing an outline of the most salient features and capabilities. Readers are provided with the possibility to run COMBINE and reproduce examples provided in this paper using a publicly available container image. Since the package is constantly evolving to meet the demands of ever-increasing data sets and analysis sophistication, this paper cannot cover all details of COMBINE. However, the online documentation referenced within this paper provides an up-to-date and complete user guide

Searches for violation of Lorentz invariance in tt‾ \mathrm{t} \overline{\mathrm{t}} production using dilepton events in proton-proton collisions at s= \sqrt{s}= 13 TeV

A search for violation of Lorentz invariance in the production of top quark pairs ($\mathrm{t} \overline{\mathrm{t}}$) is presented. The measured normalized differential $\mathrm{t} \overline{\mathrm{t}}$ production cross section, as function of the sidereal time, is examined for potential modulations induced by Lorentz-invariance breaking operators in an effective field theory extension of the standard model (SM). The cross section is measured from collision events collected by the CMS detector at a center-of-mass-energy of 13 TeV, corresponding to an integrated luminosity of 77.8 fb$^{-1}$, and containing one electron and one muon. The results are found to be compatible with zero, in agreement with the SM, and are used to bound the Lorentz-violating couplings to be in ranges of 1-8 $\times$ 10$^{-3}$ at 68% confidence level. This is the first precision test of the isotropy in special relativity with top quarks at the LHC, restricting further the bounds on such couplings by up two orders of magnitude with respect to previous searches conducted at the Tevatron.A search for violation of Lorentz invariance in the production of top quark pairs ($\mathrm{t\bar{t}}$) is presented. The measured normalized differential $\mathrm{t\bar{t}}$ production cross section, as function of the sidereal time, is examined for potential modulations induced by Lorentz-invariance breaking operators in an effective field theory extension of the standard model (SM). The cross section is measured from collision events collected by the CMS detector at a center-of-mass-energy of 13 TeV, corresponding to an integrated luminosity of 77.8 fb$^{-1}$, and containing one electron and one muon. The results are found to be compatible with zero, in agreement with the SM, and are used to bound the Lorentz-violating couplings to be in ranges of 1 - 8 $\times$ 10$^{-3}$ at 68% confidence level. This is the first precision test of the isotropy in special relativity with top quarks at the LHC, restricting further the bounds on such couplings by up two orders of magnitude with respect to previous searches conducted at the Tevatron

Dark sector searches with the CMS experiment

Astrophysical observations provide compelling evidence for gravitationally interacting dark matter in the universe that cannot be explained by the standard model of particle physics. The extraordinary amount of data from the CERN LHC presents a unique opportunity to shed light on the nature of dark matter at unprecedented collision energies. This Report comprehensively reviews the most recent searches with the CMS experiment for particles and interactions belonging to a dark sector and for dark-sector mediators. Models with invisible massive particles are probed by searches for signatures of missing transverse momentum recoiling against visible standard model particles. Searches for mediators are also conducted via fully visible final states. The results of these searches are compared with those obtained from direct-detection experiments. Searches for alternative scenarios predicting more complex dark sectors with multiple new particles and new forces are also presented. Many of these models include long-lived particles, which could manifest themselves with striking unconventional signatures with relatively small amounts of background. Searches for such particles are discussed and their impact on dark-sector scenarios is evaluated. Many results and interpretations have been newly obtained for this Report.Astrophysical observations provide compelling evidence for gravitationally interacting dark matter in the universe that cannot be explained by the standard model of particle physics. The extraordinary amount of data from the CERN LHC presents a unique opportunity to shed light on the nature of dark matter at unprecedented collision energies. This Report comprehensively reviews the most recent searches with the CMS experiment for particles and interactions belonging to a dark sector and for dark-sector mediators. Models with invisible massive particles are probed by searches for signatures of missing transverse momentum recoiling against visible standard model particles. Searches for mediators are also conducted via fully visible final states. The results of these searches are compared with those obtained from direct-detection experiments. Searches for alternative scenarios predicting more complex dark sectors with multiple new particles and new forces are also presented. Many of these models include long-lived particles, which could manifest themselves with striking unconventional signatures with relatively small amounts of background. Searches for such particles are discussed and their impact on dark-sector scenarios is evaluated. Many results and interpretations have been newly obtained for this Report