A Validation Roadmap of Multi-Physics Simulators of the Resonator of MW-Class CW Gyrotrons for Fusion Applications

For a few years the multi-physics modelling of the resonance cavity (resonator) of MW-class continuous-wave gyrotrons, to be employed for electron cyclotron heating and current drive in magnetic confinement fusion machines, has gained increasing interest. The rising target power of the gyrotrons, which drives progressively higher Ohmic losses to be removed from the resonator, together with the need for limiting the resonator deformation as much as possible, has put more emphasis on the thermal-hydraulic and thermo-mechanic modeling of the cavity. To cope with that, a multi-physics simulator has been developed in recent years in a shared effort between several European institutions (the Karlsruher Institut für Technologie and Politecnico di Torino, supported by Fusion for Energy). In this paper the current status of the tool calibration and validation is addressed, aiming at highlighting where any direct or indirect comparisons with experimental data are missing and suggesting a possible roadmap to fill that gap, taking advantage of forthcoming tests in Europe.

Efficacy and Safety of Innovative Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

Indirect Treatment Comparisons of Daratumumab, Pomalidomide, and Dexamethasone Versus Daratumumab, Bortezomib, and Dexamethasone or Bortezomib and Dexamethasone in Patients with Difficult-to-Treat Relapsed/Refractory Multiple Myeloma

Introduction: The phase 3 APOLLO study demonstrated significantly better progression-free survival (PFS) and clinical responses with daratumumab, pomalidomide, and dexamethasone (D-Pd) vs pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory multiple myeloma (RRMM). Based on these results, D-Pd became 1 of many treatment regimens approved in this patient population. In the absence of head-to-head data, indirect comparisons can provide important information to help optimize treatment for patients with RRMM. However, indirect comparisons of aggregated clinical trial data can be subject to selection and confounding bias, thus limiting the conclusions that can be drawn from the comparison. Several statistical methodologies are available that can be used to control for baseline differences and estimate the relative treatment effect of different treatment regimens. Here, we report the results of indirect comparisons that used patient-level data to compare improvement in PFS with D-Pd vs daratumumab, bortezomib, and dexamethasone (D-Vd) and D-Pd vs Vd in patients with RRMM with prior immunomodulatory drug (IMiD) and proteasome inhibitor (PI) exposure. Methods: Data for the D-Pd cohort came from the APOLLO (NCT03180736) and EQUULEUS (NCT01998971) studies. APOLLO is a randomized, open-label, phase 3 trial in which patients with RRMM and ≥1 prior line of therapy (LOT) including lenalidomide and a PI were randomized to D-Pd (N=151) or Pd (N=153). EQULEUUS was a nonrandomized, open-label, phase 1b trial that evaluated D-Pd in 103 patients with RRMM and ≥1 prior LOT, including lenalidomide and a PI. Data for the D-Vd and Vd cohorts came from CASTOR (NCT02136134), a randomized, open-label, phase 3 trial comparing D-Vd (N=251) vs Vd (N=247) in patients with RRMM and ≥1 prior LOT. Harmonized eligibility criteria (≥1 prior LOT including an IMiD and a PI; no prior pomalidomide) were applied prior to weighting/matching. Stabilized inverse probability of treatment weighting (sIPTW), propensity score matching (PSM), and cardinality matching (CM) were explored to adjust for imbalances in patient characteristics at baseline. Propensity scores were estimated using logistic regression for sIPTW and PSM. CM is an optimization-based method to find the mathematically-guaranteed largest matched sample meeting prespecified maximum standardized mean difference criteria for matching covariates, thereby overcoming limitations of PSM associated with limited covariate overlap, which was identified in this sample. Age, sex, cytogenetic risk (high/standard/missing), Eastern Cooperative Oncology Group performance status (0, 1, or 2), International Staging System (ISS) stage (I, II, III, or missing), MM type (IgG/non-IgG/missing), prior autologous stem cell transplant (yes/no), number of prior LOT (1, 2-3, or ≥4), refractory to lenalidomide status (yes/no/not received), refractory to IMiD/PI status (IMiD only, PI only, both, neither), and years since diagnosis were considered for adjustment. The analysis focused on PFS; overall survival was not analyzed as these data are immature. Results: After harmonized eligibility criteria were applied, 253, 104, and 122 patients from the D-Pd, D-Vd, and Vd cohorts, respectively, were included for comparison. A naïve comparison of baseline characteristics identified differences between D-Pd and D-Vd/Vd cohorts. After sIPTW, PSM, and CM adjusting, some imbalances between the D-Pd and D-Vd/Vd cohorts remained. ISS stage and MM type could not be adjusted for due to the amount of missing data in EQUULEUS. The CM method yielded better balance than sIPTW. The effective sample sizes (ESS) for each method are shown in the Table. The ESS for PSM was too low for comparison of PFS. PFS hazard ratios favored D-Pd over D-Vd and Vd and were statistically significant for sIPTW and CM (Figure). Conclusions: This indirect treatment comparison showed a PFS benefit for D-Pd compared with well-established SOC regimens D-Vd and Vd in patients with RRMM with previous exposure to an IMiD and a PI. Although the low ESS of sIPTW and PSM is a limitation, these findings provide support in favor of using D-Pd in a population of patients with difficult-to-treat MM. Figure 1 Figure 1. Disclosures He: Janssen: Current Employment, Current equity holder in publicly-traded company. Heeg: Janssen: Research Funding. Kampfenkel: Janssen: Current Employment. Dwarakanathan: Janssen: Other: Data related vendor services. Johnston: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Mendes: Janssen-Cilag Farmacêutica: Current Employment. Lam: Janssen: Current Employment, Current equity holder in publicly-traded company. Bathija: Janssen: Current Employment; Parexel International: Ended employment in the past 24 months.

Efficacy and Safety of Experimental Chimeric Antigen Receptor (CAR) T-cells versus Axicabtagene ciloleucel (Yescarta) for the Treatment of Relapsed/Refractory Large B-Cell Lymphoma (LBCL): Matching Adjusted Indirect Comparisons (MAICs) and Systematic Review.

Despite favorable results of CAR T-cell therapy for relapsed/refractory large B-cell lymphoma (R/R LBCL), several challenges remain, including incomplete response, immune-mediated toxicity, and antigen-loss relapse. We delineated the relative clinical benefit of the novel approaches compared to the currently approved CAR T-cell therapies. In the absence of head-to-head comparisons and randomized controlled trials, we performed Matching Adjusted Indirect Comparisons to quantify the relative efficacy and safety of experimental CARs against Axicabtagene ciloleucel (Yescarta), the first FDA-approved CAR. A total of 182 R/R LBCL patients from 15 clinical trials with individual patient data (IPD) were pooled into eight populations by their CAR T-cell constructs and +/- ASCT status. The study endpoints were Progression-Free Survival (PFS), grade ≥ 3 cytokine release syndrome (CRS), and grade ≥ 3 neurotoxicity (NT). Tandem CD19.CD20.4-1BBζ CARs indicated favorable efficacy and safety, whereas the co-infusion of CD19 & CD20 with 4-1BBζ showed no clinical benefit compared to Yescarta. Third generation CD19. CD28. 4-1BBζ, and sequential administration of autologous stem cell transplantation (ASCT) and CD19. CARs presented statistically insignificant yet improved PFS and safety except for ASCT combined intervention which had suggestively higher NT risk than Yescarta. CARs with modified co-stimulatory domains to reduce toxicity (Hu19. CD8.28Zζ and CD19. BBz.86ζ) presented remarkable safety with no severe adverse events; however, both presented worse PFS than Yescarta. Third-generation CARs demonstrated statistically significantly lower NT than Yescarta. CD20. 4-1BBζ data suggested targeting CD20 antigen alone lacks clinical or safety benefit compared to Yescarta. Further comparisons with other FDA-approved CARs are needed.

Mass Composition of UHECRs from Xmax Distributions Recorded by the Pierre Auger and Telescope Array Observatories

In this paper we infer the mass composition of the ultra high energy cosmic rays (UHECRs) from measurements of Xmax distributions recorded at the Pierre Auger (2014) and Telescope Array (TA) (2016) Observatories, by fitting them with all possible combinations of Monte Carlo (MC) templates from a large set of primary species (p, He, C, N, O, Ne, Si and Fe), as predicted by EPOS-LHC, QGSJETII-04 and Sibyll 2.1 hadronic interaction models. We use the individual fractions of nuclei reconstructed from one experiment in each energy interval to build equivalent MC Xmax distributions, which we compare with the experimental Xmax distributions of the other experiment, applying different statistical tests of compatibility. The results obtained from both experiments confirm that the mass composition of the UHECRs is dominated (≳70%) by protons and He nuclei in the energy range investigated lgE(eV) = [17.8–19.3] (Auger) and lgE(eV) = [18.2–19.0] (TA). The indirect comparisons between the Xmax distributions recorded by the two experiments show that the degree of compatibility of the two datasets is good, even excellent in some high energy intervals, especially above the ankle (lgE(eV)∼18.7). However, our study reveals that, at low energies, further effort in data analysis is required in order to harmonize the results of the two experiments.

Effect of dexmedetomidine on hemodynamics in patients undergoing hysterectomy: a meta-analysis and systematic review

Objective We conducted a meta-analysis and systematic review to evaluate the effects of dexmedetomidine on the hemodynamics of patients undergoing hysterectomy. Methods We searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases for clinical randomized controlled trials (RCTs) that allowed direct or indirect comparisons of hemodynamic indicators. We also searched nine English-language databases up to April 2021 to identify relevant research. The Cochrane risk-of-bias tool for RCTs was applied to assess the methodological quality of the eligible studies. The meta-analysis was conducted using RevMan 5.4 software. Results Nine trials were included in this systematic review. The effect of dexmedetomidine on heart rate during surgery was significantly smaller than that of other sedatives. Intraoperative systolic and diastolic blood pressure and mean arterial pressure were more stable in the dexmedetomidine group compared with the control group. The postoperative modified Observer’s Assessment of Alertness Score was also better in the dexmedetomidine compared with the control group. Conclusions Dexmedetomidine increases hemodynamic stability in patients undergoing hysterectomy, reduces the cardiovascular stress response during surgery, and effectively prevents postoperative adverse reactions, with good safety.