Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Data from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.</p> <p>Purpose</p> <p>To assess the consistency of treatment benefit across patient subsets and the robustness of data with respect to trial centers and endpoints.</p> <p>Methods</p> <p>Forest plots were constructed with hazard ratios (HRs) of HDC/IL-2 treatment effects versus no treatment (control) for prospectively defined patient subsets. Inconsistency coefficients (I²) and interaction tests (X²) were used to detect any differences in benefit among subsets. Robustness of results to the elimination of individual study centers was performed using "leave-one-center-out" analyses. Associations between treatment effects on the endpoints were evaluated using weighted linear regression between HRs for LFS and OS estimated within countries.</p> <p>Results</p> <p>The benefit of HDC/IL-2 over controls was statistically consistent across all subsets defined by baseline prognostic variables. I²and <it>P</it>-values of X²ranged from 0.00 to 0.51 and 0.14 to 0.91, respectively. Treatment effects were statistically significant in 14 of 28 subsets analyzed. The "leave-one-center-out" analysis confirmed that no single center dominated (<it>P</it>-values ranged from 0.004 to 0.020 [mean 0.009]). The HRs representing the HDC/IL-2 effects on LFS and OS were strongly correlated at the country level (R²= 0.84).</p> <p>Limitations</p> <p>Small sample sizes in some of the subsets analyzed.</p> <p>Conclusions</p> <p>These analyses confirm the consistency and robustness of the HDC/IL-2 effect as compared with no treatment. LFS may be an acceptable surrogate for OS in future AML trials. Analyses of consistency and robustness may aid interpretation of data from multicenter trials, especially in populations with rare diseases, when the size of randomized clinical trials is limited.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00003991">NCT00003991</a></p

Epitaxial growth of (001)-oriented Ba0.5Sr0.5TiO3 thin films on a-plane sapphire with an MgO/ZnO bridge layer

High quality (001)-oriented Ba0.5Sr0.5TiO3 (BST) thin films have been grown on a-plane sapphire(112¯0) by rf magnetron sputtering using a double bridge layer consisting of (0001)-oriented ZnO (50 nm) and (001)-oriented MgO (10 nm) prepared by plasma-assisted molecular beam epitaxy. X-ray diffraction revealed the formation of three sets of in-plane BST domains, offset from one another by 30°, which is consistent with the in-plane symmetry of the MgO layer observed by in situ reflective high electron energy diffraction. The in-plane epitaxial relationship of BST, MgO, and ZnO has been determined to be BST [110]//MgO [110]//ZnO [112¯0] and BST [110]/MgO [110]//ZnO [11¯00]. Capacitance-voltage measurements performed on BST coplanar interdigitated capacitor structures revealed a high dielectric tunability of up to 84% at 1 MHz

Effect of large strain on dielectric and ferroelectric properties of Ba0.5Sr0.5TiO3 thin films

BaxSr1−xTiO3 is ideally suited as a tunable medium for radio frequency passive component. In this context we have studied the effect of biaxial strain on the dielectric and ferroelectricproperties of Ba0.5Sr0.5TiO3thin filmsgrown epitaxially on SrTiO3 (001) substrates. The lattice parameters of the films determined by high-resolution x-ray diffraction with the thickness varying from 160 to 1000 nm indicated large biaxial compressive strain which decreased from 2.54% to 1.14% with increasing film thickness. Temperature-dependent measurements of the dielectric constant in our strained Ba0.5Sr0.5TiO3thin films revealed a significant increase in the Curie temperature as the film thickness is below 500 nm. Enhanced ferroelectric behavior was observed for highly strained films with a remanent polarization of 15 μC/cm2 in the 160-nm-thick layer. However, the thick films(≥500 nm) exhibited weak temperature dependence of the dielectric constant without any pronounced peak corresponding to the Curie temperature, which may suggest inhomogeneous strain distribution in the thick films

Black carbon in the Southern Andean snowpack

The Andean snowpack is an important source of water for many communities. As other snow-covered regions around the world, the Andes are sensitive to black carbon (BC) deposition from fossil fuel and biomass combustion. BC darkens the snow surface, reduces the albedo, and accelerates melting. Here, we report on measurements of the BC content conducted by using the meltwater filtration (MF) technique in snow samples collected across a transect of more than 2500 km from the mid-latitude Andes to the southern tip of South America. Addressing some of the key knowledge gaps regarding the effects of the BC deposition on the Andean snow, we identified BC-impacted areas, assessed the BC-related albedo reduction, and estimated the resulting snow losses. We found that BC concentrations in our samples generally ranged from 2 to 15 ng g-1, except for the nearly BC-free Patagonian Icefields and for the BC-impacted sites nearby Santiago (a metropolis of 6 million inhabitants). We estimate that the seasonal snowpack shrinking attributable to the BC deposition ranges from 4 mm water equivalent (w.e.) at relatively clean sites in Patagonia to 241 mm w.e. at heavily impacted sites close to Santiago. © 2022 The Author(s). Published by IOP Publishing Ltd

Black carbon in the Southern Andean snowpack

The Andean snowpack is an important source of water for many communities. As other snow-covered regions around the world, the Andes are sensitive to black carbon (BC) deposition from fossil fuel and biomass combustion. BC darkens the snow surface, reduces the albedo, and accelerates melting. Here, we report on measurements of the BC content conducted by using the meltwater filtration (MF) technique in snow samples collected across a transect of more than 2500 km from the mid-latitude Andes to the southern tip of South America. Addressing some of the key knowledge gaps regarding the effects of the BC deposition on the Andean snow, we identified BC-impacted areas, assessed the BC-related albedo reduction, and estimated the resulting snow losses. We found that BC concentrations in our samples generally ranged from 2 to 15 ng g-1, except for the nearly BC-free Patagonian Icefields and for the BC-impacted sites nearby Santiago (a metropolis of 6 million inhabitants). We estimate that the seasonal snowpack shrinking attributable to the BC deposition ranges from 4 mm water equivalent (w.e.) at relatively clean sites in Patagonia to 241 mm w.e. at heavily impacted sites close to Santiago. © 2022 The Author(s). Published by IOP Publishing Ltd

Independent Prognostic Significance of Monosomy 17 and Impact of Karyotype Complexity in Monosomal Karyotype/Complex Karyotype Acute Myeloid Leukemia: Results from Four ECOG-ACRIN Prospective Therapeutic Trials

The presence of a monosomal karyotype (MK+) and/or a complex karyotype (CK+) identifies subcategories of AML with poor prognosis. The prognostic significance of the most common monosomies (monosomy 5, monosomy 7, and monosomy 17) within MK+/CK+ AML is not well defined. We analyzed data from 1,592 AML patients age 17–93 years enrolled on ECOG-ACRIN therapeutic trials. The majority of MK+ patients (182/195; 93%) were MK+/CK+ with 87% (158/182) having ≥5 clonal abnormalities (CK≥ 5). MK+ patients with karyotype complexity ≤4 had a median overall survival (OS) of 0.4y compared to 1.0y for MK- with complexity ≤4 (p < 0.001), whereas no OS difference was seen in MK+ vs. MK- patients with CK≥ 5 (p = 0.82). Monosomy 5 (93%; 50/54) typically occurred within a highly complex karyotype and had no impact on OS (0.4y; p = 0.95). Monosomy 7 demonstrated no impact on OS in patients with CK≥ 5 (p = 0.39) or CK ≤ 4 (p = 0.44). Monosomy 17 appeared in 43% (68/158) of CK≥ 5 patients and demonstrated statistically significant worse OS (0.4y) compared to CK≥ 5 patients without monosomy 17 (0.5y; p = 0.012). Our data suggest that the prognostic impact of MK+ is limited to those with less complex karyotypes and that monosomy 17 may independently predict for worse survival in patients with AML

Measuring the Loschmidt amplitude for finite-energy properties of the Fermi-Hubbard model on an ion-trap quantum computer

Calculating the equilibrium properties of condensed matter systems is one of the promising applications of near-term quantum computing. Recently, hybrid quantum-classical time-series algorithms have been proposed to efficiently extract these properties from a measurement of the Loschmidt amplitude $\langle \psi| e^{-i \hat H t}|\psi \rangle$ from initial states $|\psi\rangle$ and a time evolution under the Hamiltonian $\hat H$ up to short times $t$. In this work, we study the operation of this algorithm on a present-day quantum computer. Specifically, we measure the Loschmidt amplitude for the Fermi-Hubbard model on a $16$-site ladder geometry (32 orbitals) on the Quantinuum H2-1 trapped-ion device. We assess the effect of noise on the Loschmidt amplitude and implement algorithm-specific error mitigation techniques. By using a thus-motivated error model, we numerically analyze the influence of noise on the full operation of the quantum-classical algorithm by measuring expectation values of local observables at finite energies. Finally, we estimate the resources needed for scaling up the algorithm.Comment: 18 pages, 12 figure

Black carbon footprint of human presence in Antarctica

Black carbon (BC) from fossil fuel and biomass combustion darkens the snow and makes it melt sooner. The BC footprint of research activities and tourism in Antarctica has likely increased as human presence in the continent has surged in recent decades. Here, we report on measurements of the BC concentration in snow samples from 28 sites across a transect of about 2,000 km from the northern tip of Antarctica (62°S) to the southern Ellsworth Mountains (79°S). Our surveys show that BC content in snow surrounding research facilities and popular shore tourist-landing sites is considerably above background levels measured elsewhere in the continent. The resulting radiative forcing is accelerating snow melting and shrinking the snowpack on BC-impacted areas on the Antarctic Peninsula and associated archipelagos by up to 23 mm water equivalent (w.e.) every summer

NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT