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Purpose: Molecular diagnostics including next generation gene sequencing are increasingly used to determine options for individualized therapies in brain tumor patients. We aimed to evaluate the decision-making process of molecular targeted therapies and analyze data on tolerability as well as signals for efficacy.
Methods: Via retrospective analysis, we identified primary brain tumor patients who were treated off-label with a targeted therapy at the University Hospital Frankfurt, Goethe University. We analyzed which types of molecular alterations were utilized to guide molecular off-label therapies and the diagnostic procedures for their assessment during the period from 2008 to 2021. Data on tolerability and outcomes were collected.
Results: 413 off-label therapies were identified with an increasing annual number for the interval after 2016. 37 interventions (9%) were targeted therapies based on molecular markers. Glioma and meningioma were the most frequent entities treated with molecular matched targeted therapies. Rare entities comprised e.g. medulloblastoma and papillary craniopharyngeoma. Molecular targeted approaches included checkpoint inhibitors, inhibitors of mTOR, FGFR, ALK, MET, ROS1, PIK3CA, CDK4/6, BRAF/MEK and PARP. Responses in the first follow-up MRI were partial response (13.5%), stable disease (29.7%) and progressive disease (46.0%). There were no new safety signals. Adverse events with fatal outcome (CTCAE grade 5) were not observed. Only, two patients discontinued treatment due to side effects. Median progression-free and overall survival were 9.1/18 months in patients with at least stable disease, and 1.8/3.6 months in those with progressive disease at the first follow-up MRI.
Conclusion: A broad range of actionable alterations was targeted with available molecular therapeutics.
However, efficacy was largely observed in entities with paradigmatic oncogenic drivers, in particular with BRAF mutations. Further research on biomarker-informed molecular matched therapies is urgently necessary.
Long- and short-range correlations for pairs of charged particles are studied via two-particle angular correlations in pp collisions at s√=13 TeV and p−Pb collisions at sNN−−−√=5.02 TeV. The correlation functions are measured as a function of relative azimuthal angle Δφ and pseudorapidity separation Δη for pairs of primary charged particles within the pseudorapidity interval |η|<0.9 and the transverse-momentum interval 1<pT<4 GeV/c. Flow coefficients are extracted for the long-range correlations (1.6<|Δη|<1.8) in various high-multiplicity event classes using the low-multiplicity template fit method. The method is used to subtract the enhanced yield of away-side jet fragments in high-multiplicity events. These results show decreasing flow signals toward lower multiplicity events. Furthermore, the flow coefficients for events with hard probes, such as jets or leading particles, do not exhibit any significant changes compared to those obtained from high-multiplicity events without any specific event selection criteria. The results are compared with hydrodynamic-model calculations, and it is found that a better understanding of the initial conditions is necessary to describe the results, particularly for low-multiplicity events.
Modification of charged-particle jets in event-shape engineered Pb–Pb collisions at √sNN = 5.02 TeV
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Charged-particle jet yields have been measured in semicentral Pb−Pb collisions at center-of-mass energy per nucleon-nucleon collision sNN−−−√=5 TeV with the ALICE detector at the LHC. These yields are reported as a function of the jet transverse momentum, and further classified by their angle with respect to the event plane and the event shape, characterized by ellipticity, in an effort to study the path-length dependence of jet quenching. Jets were reconstructed at midrapidity from charged-particle tracks using the anti-kT algorithm with resolution parameters R= 0.2 and 0.4, with event-plane angle and event-shape values determined using information from forward scintillating detectors. The results presented in this letter show that, in semicentral Pb−Pb collisions, there is no significant difference between jet yields in predominantly isotropic and elliptical events. However, out-of-plane jets are observed to be more suppressed than in-plane jets. Further, this relative suppression is greater for low transverse momentum (< 50 GeV/c) R= 0.2 jets produced in elliptical events, with out-of-plane to in-plane jet-yield ratios varying up to 5.2σ between different event-shape classes. These results agree with previous studies indicating that jets experience azimuthally anisotropic suppression when traversing the QGP medium, and can provide additional constraints on the path-length dependence of jet energy loss.
The transverse-momentum (pT) spectra of K∗(892)0 and ϕ(1020) measured with the ALICE detector up to pT = 16 GeV/c in the rapidity range −1.2<y<0.3, in p-Pb collisions at the center-of-mass energy per nucleon-nucleon collision sNN−−−√ = 5.02 TeV are presented as a function of charged particle multiplicity and rapidity. The measured pT distributions show a dependence on both multiplicity and rapidity at low pT whereas no significant dependence is observed at high pT. A rapidity dependence is observed in the pT-integrated yield (dN/dy), whereas the mean transverse momentum (⟨pT⟩) shows a flat behavior as a function of rapidity. The rapidity asymmetry (Yasym) at low pT ( < 5 GeV/c) is more significant for higher multiplicity classes. At high pT, no significant rapidity asymmetry is observed in any of the multiplicity classes. Both K∗(892)0 and ϕ(1020) show similar Yasym. The nuclear modification factor (QCP) as a function of pT shows a Cronin-like enhancement at intermediate pT, which is more prominent at higher rapidities (Pb-going direction) and in higher multiplicity classes. At high pT (> 5 GeV/c), the QCP values are greater than unity and no significant rapidity dependence is observed.
The transverse-momentum (pT) spectra of K∗(892)0 and ϕ(1020) measured with the ALICE detector up to pT = 16 GeV/c in the rapidity range −1.2<y<0.3, in p-Pb collisions at the center-of-mass energy per nucleon-nucleon collision sNN−−−√ = 5.02 TeV are presented as a function of charged particle multiplicity and rapidity. The measured pT distributions show a dependence on both multiplicity and rapidity at low pT whereas no significant dependence is observed at high pT. A rapidity dependence is observed in the pT-integrated yield (dN/dy), whereas the mean transverse momentum (⟨pT⟩) shows a flat behavior as a function of rapidity. The rapidity asymmetry (Yasym) at low pT ( < 5 GeV/c) is more significant for higher multiplicity classes. At high pT, no significant rapidity asymmetry is observed in any of the multiplicity classes. Both K∗(892)0 and ϕ(1020) show similar Yasym. The nuclear modification factor (QCP) as a function of pT shows a Cronin-like enhancement at intermediate pT, which is more prominent at higher rapidities (Pb-going direction) and in higher multiplicity classes. At high pT (> 5 GeV/c), the QCP values are greater than unity and no significant rapidity dependence is observed.
The event-by-event correlations between three flow amplitudes are measured for the first time in Pb--Pb collisions, using higher-order Symmetric Cumulants. We find that different three-harmonic correlations develop during the collective evolution of the medium, when compared with correlations that exist in the initial state. These new results cannot be interpreted in terms of previous lower-order flow measurements, since contributions from two-harmonic correlations are explicitly removed in the new observables. Comparison with Monte Carlo simulations provides new and independent constraints for the initial conditions and system properties of nuclear matter created in heavy-ion collisions.
The event-by-event correlations between three flow amplitudes are measured for the first time in Pb--Pb collisions, using higher-order Symmetric Cumulants. We find that different three-harmonic correlations develop during the collective evolution of the medium, when compared with correlations that exist in the initial state. These new results cannot be interpreted in terms of previous lower-order flow measurements, since contributions from two-harmonic correlations are explicitly removed in the new observables. Comparison with Monte Carlo simulations provides new and independent constraints for the initial conditions and system properties of nuclear matter created in heavy-ion collisions.
Long- and short-range correlations for pairs of charged particles are studied via two-particle angular correlations in pp collisions at s√=13 TeV and p−Pb collisions at sNN−−−√=5.02 TeV. The correlation functions are measured as a function of relative azimuthal angle Δφ and pseudorapidity separation Δη for pairs of primary charged particles within the pseudorapidity interval |η|<0.9 and the transverse-momentum interval 1<pT<4 GeV/c. Flow coefficients are extracted for the long-range correlations (1.6<|Δη|<1.8) in various high-multiplicity event classes using the low-multiplicity template fit method. The method is used to subtract the enhanced yield of away-side jet fragments in high-multiplicity events. These results show decreasing flow signals toward lower multiplicity events. Furthermore, the flow coefficients for events with hard probes, such as jets or leading particles, do not exhibit any significant changes compared to those obtained from high-multiplicity events without any specific event selection criteria. The results are compared with hydrodynamic-model calculations, and it is found that a better understanding of the initial conditions is necessary to describe the results, particularly for low-multiplicity events.
Long- and short-range correlations for pairs of charged particles are studied via two-particle angular correlations in pp collisions at √sNN = 13 TeV and p–Pb collisions at √s = 5.02 TeV. The correlation functions are measured as a function of relative azimuthal angle ∆φ and pseudorapidity separation ∆η for pairs of primary charged particles within the pseudorapidity interval |η| < 0.9 and the transverse-momentum interval 1 < pT < 4 GeV/c. Flow coefficients are extracted for the long-range correlations (1.6 < |∆η| < 1.8) in various high-multiplicity event classes using the low-multiplicity template fit method. The method is used to subtract the enhanced yield of away-side jet fragments in high-multiplicity events. These results show decreasing flow signals toward lower multiplicity events. Furthermore, the flow coefficients for events with hard probes, such as jets or leading particles, do not exhibit any significant changes compared to those obtained from high-multiplicity events without any specific event selection criteria. The results are compared with hydrodynamic-model calculations, and it is found that a better understanding of the initial conditions is necessary to describe the results, particularly for low-multiplicity events.