Combination Early-Phase Trials of Anticancer Agents in Children and Adolescents

Trials; Anticancer agents; ChildrenEnsayos; Agentes anticancerígenos; NiñosAssajos; Agents anticancerígens; NensPURPOSE There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders. METHODS After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved. RESULTS Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements. CONCLUSION An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer

Currents and Superpotentials in classical gauge invariant theories I. Local results with applications to Perfect Fluids and General Relativity

E. Noether's general analysis of conservation laws has to be completed in a Lagrangian theory with local gauge invariance. Bulk charges are replaced by fluxes of superpotentials. Gauge invariant bulk charges may subsist when distinguished one-dimensional subgroups are present. As a first illustration we propose a new {\it Affine action} that reduces to General Relativity upon gauge fixing the dilatation (Weyl 1918 like) part of the connection and elimination of auxiliary fields. It allows a comparison of most gravity superpotentials and we discuss their selection by the choice of boundary conditions. A second and independent application is a geometrical reinterpretation of the convection of vorticity in barotropic nonviscous fluids. We identify the one-dimensional subgroups responsible for the bulk charges and thus propose an impulsive forcing for creating or destroying selectively helicity. This is an example of a new and general Forcing Rule.Comment: 64 pages, LaTeX. Version 2 has two more references and one misprint corrected. Accepted in Classical and Quantum Gravit

Covariant theory of asymptotic symmetries, conservation laws and central charges

Under suitable assumptions on the boundary conditions, it is shown that there is a bijective correspondence between equivalence classes of asymptotic reducibility parameters and asymptotically conserved n-2 forms in the context of Lagrangian gauge theories. The asymptotic reducibility parameters can be interpreted as asymptotic Killing vector fields of the background, with asymptotic behaviour determined by a new dynamical condition. A universal formula for asymptotically conserved n-2 forms in terms of the reducibility parameters is derived. Sufficient conditions for finiteness of the charges built out of the asymptotically conserved n-2 forms and for the existence of a Lie algebra g among equivalence classes of asymptotic reducibility parameters are given. The representation of g in terms of the charges may be centrally extended. An explicit and covariant formula for the central charges is constructed. They are shown to be 2-cocycles on the Lie algebra g. The general considerations and formulas are applied to electrodynamics, Yang-Mills theory and Einstein gravity.Comment: 86 pages Latex file; minor correction

The nonstructural NS1 protein of influenza viruses modulates TP53 splicing through host factor CPSF4

International audienceInfluenza A viruses (IAV) are known to modulate and "hijack" several cellular host mechanisms, including gene splicing and RNA maturation machineries. These modulations alter host cellular responses and enable an optimal expression of viral products throughout infection. The interplay between the host protein p53 and IAV, in particular through the viral nonstructural protein NS1, has been shown to be supportive for IAV replication. However, it remains unknown whether alternatively spliced isoforms of p53, known to modulate p53 transcriptional activity, are affected by IAV infection and contribute to IAV replication. Using a TP53 minigene, which mimics intron 9 alternative splicing, we have shown here that the NS1 protein of IAV changes the expression pattern of p53 isoforms. Our results demonstrate that CPSF4 (cellular protein cleavage and polyadenylation specificity factor 4) independently and the interaction between NS1 and CPSF4 modulate the alternative splicing of TP53 transcripts, which may result in the differential activation of p53-responsive genes. Finally, we report that CPSF4 and most likely beta and gamma spliced p53 isoforms affect both viral replication and IAV-associated type I interferon secretion. All together, our data show that cellular p53 and CPSF4 factors, both interacting with viral NS1, have a crucial role during IAV replication that allows IAV to interact with and alter the expression of alternatively spliced p53 isoforms in order to regulate the cellular innate response, especially via type I interferon secretion, and perform efficient viral replication

Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): A report from the therapeutic advances in childhood leukemia (TACL) consortium

Background Outcomes remain poor for children after relapse of acute lymphoblastic leukemia (ALL), especially after early marrow relapse. Bortezomib is a proteasome inhibitor with in vitro synergy with corticosteroids and clinical activity in human lymphoid malignancies. Procedure This is a Phase I study of escalating doses bortezomib administered days 1, 4, 8, and 11, added to 4-drug induction chemotherapy with vincristine, dexamethasone, pegylated L -asparaginase, and doxorubicin (VXLD) in children with relapsed ALL. Results Ten patients were enrolled, five in first marrow relapse, and five in second relapse. Four patients were enrolled at dose level 1 (bortezomib 1 mg/m 2 ). One patient was not evaluable for toxicity because of omitted dexamethasone doses. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (bortezomib 1.3 mg/m 2 ). One patient had dose-limiting hypophosphatemia and rhabdomyolysis after 1 dose of bortezomib, and died from a diffuse zygomyces infection on day 17. Five additional patients were enrolled with no subsequent DLTs. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Two patients had mild peripheral neuropathy (grades 1 and 2). Six of nine evaluable patients (67%) achieved a complete response (CR), and one had a bone marrow CR with persistent central nervous system leukemia. Conclusions The combination of bortezomib (1.3 mg/m 2 ) with VXLD is active with acceptable toxicity in pretreated pediatric patients with relapsed ALL. We are expanding the 1.3 mg/m 2 cohort for a phase II estimate of response. Study registered at ClinicalTrials.gov ( http://clinicaltrials.gov/ct2/show/NCT00440726 ). Pediatr Blood Cancer 2010;55:254–259. © 2010 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77437/1/22456_ftp.pd

Phase error estimation for synthetic aperture imagery.

The estimation of phase errors in synthetic aperture imagery is important for high quality images. Many methods of autofocus, or the estimation of phase errors from the measured data, are developed using certain assumptions about the imaged scene. This thesis develops improved methods of phase estimation which make full use of the information in the recorded signal. This results in both a more accurate estimate of the image phase error and improved imagery compared to using standard techniques. The standard phase estimation kernel used in echo-correlation techniques is shear-average. This technique averages the phase-difference between each ping over all range-bins, weighted by the signal strength. It is shown in this thesis that this is not the optimal method of weighting each phase estimate. In images where the signal to clutter ratio (SCR) is not proportional to the signal amplitude, shear-average does not meet the predicted error bound. This condition may be met by many image types, including those with shadows, distributed targets and varying surface structure. By measuring the average coherence between echos at each range-bin, it is possible to accurately estimate the variance of each phase estimate, and weight accordingly. A weighted phase-difference estimation (WPDE) using this coherence weighting meets the performance bound for all images tested. Thus an improved performance over shear-average is shown for many image types. The WPDE phase estimation method can be used within the framework of many echo-correlation techniques, such as phase-gradient autofocus (PGA), phase curvature estimation, redundant phase-centre or displaced phase-centre algorithms. In addition, a direct centre-shifting method is developed which reduces bias compared to the centre-shifting method used in PGA. For stripmap images, a weighted phase curvature estimator shows better performance than amplitude weighted shear-average for images with high SCR. A different method of phase estimation, known as sharpness maximisation, perturbs an estimate of the phase error to maximise the sharpness of the reconstructed image. Several improvements are made to the technique of sharpness maximisation. These include the reduction of over-sharpening using regularisation and an improvement in accuracy of the phase estimate using range-weighting based on the coherence measure. A cascaded parametric optimisation method is developed which converges significantly faster than standard optimisation methods for stripmap images. A number of novel insights into the method of sharpness maximisation are presented. A derivation of the phase that gives maximum intensity squared sharpness is extended from a noncoherent imaging system to a coherent spotlight system. A bound on the performance of sharpness-maximisation is presented. A method is developed which allows the direct calculation of the result of a sharpness maximisation for a single ping of a spotlight synthetic aperture image. The phase correction that maximises sharpness can be directly calculated from the signal in a manner similar to a high-order echo-correlation. This calculation can be made for all pings in a recursive manner. No optimisation is required, resulting in a significantly faster phase estimation. The techniques of sharpness maximisation and echo-correlation can be shown to be closely related. This is confirmed by direct comparisons of the results. However, the classical intensity-squared sharpness measure gives poorer results than WPDE and different sharpness measures tested for a distributed target. The standard methods of shear average and maximisation of the intensity-squared sharpness measure, both perform well below the theoretical performance bound. Two of the techniques developed, WPDE and direct entropy minimisation perform at the bound, showing improved performance over standard techniques. The contributions of this thesis add considerably to the body of knowledge on the technique of sharpness maximisation. This allows an improvement in the accuracy of some phase estimation methods, as well as an increase in the understanding of how these techniques work on coherent imagery in general

Star-gas misalignment in galaxies: I. The properties of galaxies from the Horizon-AGN simulation and comparisons to SAMI

Recent integral field spectroscopy observations have found that about 11% of galaxies show star-gas misalignment. The misalignment possibly results from external effects such as gas accretion, interaction with other objects, and other environmental effects, hence providing clues to these effects. We explore the properties of misaligned galaxies using Horizon-AGN, a large-volume cosmological simulation, and compare the result with the result of the Sydney-AAO Multi-object integral field spectrograph (SAMI) Galaxy Survey. Horizon-AGN can match the overall misalignment fraction and reproduces the distribution of misalignment angles found by observations surprisingly closely. The misalignment fraction is found to be highly correlated with galaxy morphology both in observations and in the simulation: early-type galaxies are substantially more frequently misaligned than late-type galaxies. The gas fraction is another important factor associated with misalignment in the sense that misalignment increases with decreasing gas fraction. However, there is a significant discrepancy between the SAMI and Horizon-AGN data in the misalignment fraction for the galaxies in dense (cluster) environments. We discuss possible origins of misalignment and disagreement.Comment: 23 pages with 15 figures. Accepted for publication in Ap

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae. VIII: The Eighth Year (2015-2016)

Continuing the project described by Kato et al. (2009, arXiv:0905.1757), we collected times of superhump maxima for 128 SU UMa-type dwarf novae observed mainly during the 2015-2016 season and characterized these objects. The data have improved the distribution of orbital periods, the relation between the orbital period and the variation of superhumps, the relation between period variations and the rebrightening type in WZ Sge-type objects. Coupled with new measurements of mass ratios using growing stages of superhumps, we now have a clearer and statistically greatly improved evolutionary path near the terminal stage of evolution of cataclysmic variables. Three objects (V452 Cas, KK Tel, ASASSN-15cl) appear to have slowly growing superhumps, which is proposed to reflect the slow growth of the 3:1 resonance near the stability border. ASASSN-15sl, ASASSN-15ux, SDSS J074859.55+312512.6 and CRTS J200331.3-284941 are newly identified eclipsing SU UMa-type (or WZ Sge-type) dwarf novae. ASASSN-15cy has a short (~0.050 d) superhump period and appears to belong to EI Psc-type objects with compact secondaries having an evolved core. ASASSN-15gn, ASASSN-15hn, ASASSN-15kh and ASASSN-16bu are candidate period bouncers with superhump periods longer than 0.06 d. We have newly obtained superhump periods for 79 objects and 13 orbital periods, including periods from early superhumps. In order that the future observations will be more astrophysically beneficial and rewarding to observers, we propose guidelines how to organize observations of various superoutbursts.Comment: 123 pages, 162 figures, 119 tables, accepted for publication in PASJ (including supplementary information