Decitabine in Older Patients with AML: Quality of Life Results of the EORTC-GIMEMA-GMDS-SG Randomized Phase III Trial.

We hypothesized that fit older patients with acute myeloid leukemia (AML) treated with decitabine (DEC) would report better health-related quality of life (HRQoL) outcomes compared to those receiving intensive chemotherapy (IC). We conducted a phase 3 randomized trial to compare DEC (10-day schedule) to IC (3+7) in older fit AML patients. HRQoL was a secondary endpoint, and it was assessed with the EORTC QLQ-C30 and the QLQ-ELD14. The following scales were a priori selected for defining the primary endpoint: physical and role functioning, fatigue, pain, and burden of illness. HRQoL was assessed at baseline, at regeneration from cycle 2, and at 6 and 12 months after randomization, and also prior to allo-HSCT and 100 days after transplantation. Overall, 606 patients underwent randomization. At 2 months, the risk of HRQoL deterioration was lower in the DEC arm than in the 3+7 arm (76% [95% CI, 69 to 82] v 88% [95% CI, 82 to 93]; odds ratio, 0.43 [95% CI, 0.24 to 0.76], P=.003). No statistically significant HRQoL differences were observed between treatment arms at the long-term evaluation combining assessments at 6 and 12 months. HRQoL deteriorations between baseline and post-allo-HSCT were observed in both arms. However, these deteriorations were not clinically meaningful in patients randomized to DEC, while this was the case for those in the 3+7 arm, in four out of the five primary HRQoL scales. Our HRQoL findings suggest that lower-intensity treatment with DEC, may be preferable to current standard IC (3+7), in fit older AML patients. ClinicalTrials.gov (NCT02172872).

Experimental Tuning of Transport Regimes in Hyperuniform Disordered Photonic Materials.

We present wave transport experiments in hyperuniform disordered arrays of cylinders with high dielectric permittivity. Using microwaves, we show that the same material can display transparency, photon diffusion, Anderson localization, or a full band gap, depending on the frequency ν of the electromagnetic wave. Interestingly, we find a second weaker band gap, which appears to be related to the second peak of the structure factor. Our results emphasize the importance of spatial correlations on different length scales for the formation of photonic band gaps.

Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells.

Nucleophosmin-1 (NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). Addition of retinoic acid (RA) to chemotherapy was proposed to improve survival of some of these patients. Here, we found that RA or arsenic trioxide synergistically induce proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. NPM1 mutation not only delocalizes NPM1 from the nucleolus, but it also disorganizes promyelocytic leukemia (PML) nuclear bodies. Combined RA/arsenic treatment significantly reduced bone marrow blasts in 3 patients and restored the subnuclear localization of both NPM1 and PML. These findings could explain the proposed benefit of adding RA to chemotherapy in NPM1 mutant AMLs, and warrant a broader clinical evaluation of regimen comprising a RA/arsenic combination.

10-day decitabine versus 3 + 7 chemotherapy followed by allografting in older patients with acute myeloid leukaemia: an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes. METHODS: This open-label, randomised, controlled, phase 3 trial was conducted at 54 hospitals in nine European countries. Patients aged 60 years and older who were newly diagnosed with acute myeloid leukaemia and had not yet been treated were enrolled if they had an Eastern Cooperative Oncology Group performance status of 2 or less and were eligible for intensive chemotherapy. Patients were randomly assigned (1:1) to receive decitabine or standard chemotherapy (known as 3 + 7). For the decitabine group, decitabine (20 mg/m2) was administered for the first 10 days in the first 28-day cycle, followed by 28-day cycles consisting of 5 days or 10 days of decitabine. For the 3 + 7 group, daunorubicin (60 mg/m2) was administered over the first 3 days and cytarabine (200 mg/m2) over the first 7 days, followed by 1-3 additional chemotherapy cycles. Allogeneic HSCT was strongly encouraged. Overall survival in the intention-to-treat population was the primary endpoint. Safety was assessed in all patients who received the allocated treatment. This trial is registered at ClinicalTrials.gov, NCT02172872, and is closed to new participants. FINDINGS: Between Dec 1, 2014, and Aug 20, 2019, 606 patients were randomly assigned to the decitabine (n=303) or 3 + 7 (n=303) group. Following an interim analysis which showed futility, the IDMC recommended on May 22, 2019, that the study continued as planned considering the risks and benefits for the patients participating in the study. The cutoff date for the final analysis presented here was June 30, 2021. At a median follow-up of 4·0 years (IQR 2·9-4·8), 4-year overall survival was 26% (95% CI 21-32) in the decitabine group versus 30% (24-35) in the 3 + 7 group (hazard ratio for death 1·04 [95% CI 0·86-1·26]; p=0·68). Rates of on-protocol allogeneic HSCT were similar between groups (122 [40%] of 303 patients for decitabine and 118 [39%] of 303 patients for 3+7). Rates of grade 3-5 adverse events were 254 (84%) of 302 patients in the decitabine group and 279 (94%) of 298 patients in the 3 + 7 group. The rates of grade 3-5 infections (41% [125 of 302] vs 53% [158 of 298]), oral mucositis (2% [seven of 302] vs 10% [31 of 298]) and diarrhoea (1% [three of 302] vs 8% [24 of 298]) were lower in the decitabine group than in the 3 + 7 group. Treatment-related deaths were reported for 12% (35 of 302) of patients in the decitabine group and 14% (41 of 298) in the 3 + 7 group. INTERPRETATION: 10-day decitabine did not improve overall survival but showed a better safety profile compared with 3 + 7 chemotherapy in older patients with acute myeloid leukaemia eligible for intensive chemotherapy. Decitabine could be considered a better-tolerated and sufficiently efficacious alternative to 3 + 7 induction in fit older patients with acute myeloid leukaemia without favourable genetics. FUNDING: Janssen Pharmaceuticals.

Diffuse field cross-correlations: Scattering theory and electromagnetic experiments.

The passive estimation of impulse responses from ambient noise correlations arouses increasing interest in seismology, acoustics, optics, and electromagnetism. Assuming the equipartition of the noise field, the cross-correlation function measured with noninvasive receiving probes converges towards the difference of the causal and anticausal Green's functions. Here, we consider the case when the receiving field probes are antennas which are well coupled to a complex medium-a scenario of practical relevance in electromagnetism. We propose a general approach based on the scattering matrix formalism to explore the convergence of the cross-correlation function. The analytically derived theoretical results for chaotic systems are confirmed in microwave measurements within a mode-stirred reverberation chamber. This study provides fundamental insight into the Green's function retrieval technique and paves the way for a new technique to characterize electromagnetic antennas.

Implementing nonuniversal features with a random matrix theory approach: Application to space-to-configuration multiplexing.

We consider the efficiency of multiplexing spatially encoded information across random configurations of a metasurface-programmable chaotic cavity in the microwave domain. The distribution of the effective rank of the channel matrix is studied to quantify the channel diversity and to assess a specific system's performance. System-specific features such as unstirred field components give rise to nontrivial interchannel correlations and need to be properly accounted for in modeling based on random matrix theory. To address this challenge, we propose a two-step hybrid approach. Based on an ensemble of experimentally measured scattering matrices for different random metasurface configurations, we first learn a system-specific pair of coupling matrix and unstirred contribution to the Hamiltonian, and then add an appropriately weighted stirred contribution. We verify that our method is capable of reproducing the experimentally found distribution of the effective rank with good accuracy. The approach can also be applied to other wave phenomena in complex media.

Controlled excitation of scar modes in passive and active multimode chaotic fiber.

A multimode optical fiber with a D-shaped cross section is an experimental paradigm of a wave system with chaotic ray dynamics. We show that seldom but usable modes, called scar modes, localized along some particular direction of the geometric trajectories, can be selectively excited. We report numerical simulations that demonstrate the importance of the so-called self-focal point in the scar mode selection process. We use a localized illumination in a passive fiber, or a localized gain in a ytterbium-doped fiber, located in the vicinity of this special point to control scar mode selection.

Fluctuations in an established transmission in the presence of a complex environment.

In various situations where wave transport is preeminent, like in wireless communication, a strong established transmission is present in a complex scattering environment. We develop a nonperturbative approach to describe emerging fluctuations which combines a transmitting channel and a chaotic background in a unified effective Hamiltonian. Modeling such a background by random matrix theory, we derive exact results for both transmission and reflection distributions at arbitrary absorption that is typically present in real systems. Remarkably, in such a complex scattering situation, the transport is governed by only two parameters: an absorption rate and the ratio of the so-called spreading width to the natural width of the transmission line. In particular, we find that the established transmission disappears sharply when this ratio exceeds unity. The approach exemplifies the role of the chaotic background in dephasing the deterministic scattering.

Diffractive orbits in the length spectrum of a two-dimensional microwave cavity with a small scatterer.

In a two-dimensional rectangular microwave cavity dressed with one pointlike scatterer, a semiclassical approach is used to analyze the spectrum in terms of periodic orbits and diffractive orbits. We show, both numerically and experimentally, how the latter can be accounted for in the so-called length spectrum, which is retrieved from two-point correlations of a finite-range frequency spectrum. Beyond its fundamental interest, this first experimental evidence of the role played by diffractive orbits in the spectrum of an actual cavity, can be the first step towards a technique to detect and track small defects in wave cavities.

Complete S matrix in a microwave cavity at room temperature.

We experimentally study the widths of resonances in a two-dimensional microwave cavity at room temperature. By developing a model for the coupling antennas, we are able to discriminate their contribution from those of Ohmic losses to the broadening of resonances. Concerning Ohmic losses, we experimentally put to evidence two mechanisms: damping along propagation and absorption at the contour, the latter being responsible for variations of widths from mode to mode due to its dependence on the spatial distribution of the field at the contour. A theory, based on an S -matrix formalism, is given for these variations. It is successfully validated through measurements of several hundreds of resonances in a rectangular cavity.

Speckle statistics in a chaotic multimode fiber.

Wave chaos is devoted to the study of wave motion when the geometrical limit of rays is chaotic. Imprints of ray chaos may be found either in spectral and spatial properties of modes or in spatio-temporal evolution of wave packets. In this paper, we present a thorough experimental and theoretical analysis of field statistics for light propagating in a multimode fiber with a noncircular cross section. This optical fiber serves as a powerful tool to image waves in a system where light rays exhibit a chaotic dynamics. We show that, in the speckle regime, the experimentally measured statistical properties of intensity patterns are well accounted for by a "random Gaussian" hypothesis. A comparison is also made in the case of regular ray motion by using a circular optical fiber. Possible extensions and applications of the tools and concepts of wave chaos are mentioned in modern communication technology.

Transient chaos in room acoustics.

The decay of sound in an auditorium due to absorption is central to the theory and practice of room acoustics. Within geometrical acoustics, this problem involves the partial trapping of chaotic ray trajectories in billiards, hence transient chaos. We first present a theoretical and numerical analysis of the decay of rays in 2-D chaotic billiards (2-D room acoustic models) and show that the existence of fluctuations (in the mean-free path and in the rate of phase space exploration) leads to modifications from the standard statistical theory. An ergodic wave theory of room acoustics based on a wave formulation is then discussed and tested by direct numerical calculations of the eigenmodes in 2-D billiards. Finally, we present a semiclassical calculation of the acoustic Green's functions in the time domain, based on a summation over rays, viewed as generalized wave impulses, and successfully compare its predictions with a direct numerical integration of the wave equation. This formalism provides a framework to link the geometrical ray description to the ergodic wave theory.

Stereospecific Migration of P from N to C sp 2: Ring-Expansion Reaction of Chiral Diazaphospholidine Oxides.

An addition-pseudorotation-elimination pathway is proposed for the first stereospecific ring-expansion reaction of chiral diazaphospholidine oxides by a 1,3-migration of P from N to C sp 2 [Eq. (1)]. R=H, Ph; LDA=lithium diisopropylamide.

Statistics of resonance states in a weakly open chaotic cavity with continuously distributed losses.

In this Rapid Communication, we demonstrate that a non-Hermitian random matrix description can account for both spectral and spatial statistics of resonance states in a weakly open chaotic wave system with continuously distributed losses. More specifically, the statistics of resonance states in an open two-dimensional chaotic microwave cavity are investigated by solving the Maxwell equations with lossy boundaries subject to Ohmic dissipation. We successfully compare the statistics of its complex-valued resonance states and associated widths with analytical predictions based on a non-Hermitian effective Hamiltonian model defined by a finite number of fictitious open channels.

Approximate equivalence between guided modes in a low-contrast photonic bandgap fiber and Maxwell TM modes of a high-contrast two-dimensional photonic structure.

We present a formal analogy between the eigenvalue problem for guided scalar modes in a low-contrast photonic bandgap fiber and quasi-stationary TM modes of a two-dimensional (2D) photonic structure. Using this analogy, we numerically study the confinement losses of disordered microstructured fibers through the leakage rate of an open 2D system with high refractive index inclusions. Our results show that for large values of the disorder, the confinement losses increase. However, they also suggest that losses might be improved in strongly disordered fibers by exploring ranges of physical parameters where Anderson localization sets in.

Avoided-level-crossing statistics in open chaotic billiards.

We investigate a two-level model with a large number of open decay channels in order to describe avoided level crossing statistics in open chaotic billiards. This model allows us to describe the fundamental changes in the probability distribution of the avoided level crossings compared with the closed case. Explicit expressions are derived for systems with preserved and broken time-reversal symmetry. We find that the decay process induces a modification at small spacings of the probability distribution of the avoided level crossings due to an attraction of the resonances. The theoretical predictions are in complete agreement with the recent experimental results of Dietz [Phys. Rev. E 73, 035201 (2006)].

Statistics of resonance states in open chaotic systems: a perturbative approach.

We investigate the statistical properties of the complexness parameter which characterizes uniquely complexness (nonorthogonality) of resonance eigenstates of open chaotic systems. Specifying to the regime of weakly overlapping resonances, we apply the random matrix theory to the effective Hamiltonian formalism and derive analytically the probability distribution of the complexness parameter for two statistical ensembles describing the systems invariant under time reversal. For those with rigid spectra, we consider a Hamiltonian characterized by a picket-fence spectrum without spectral fluctuations. Then, in the more realistic case of a Hamiltonian described by the Gaussian orthogonal ensemble, we reveal and discuss the role of spectral fluctuations.

When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group).

10-20% of APL patients relapse and the challenge remains to early identify these patients to improve survival rate. We report PML-RARalpha transcript detection by RQ-PCR in 260 consecutive APL patients (n = 970 samples). 223 patients with samples of sufficient RNA quality to demonstrate they reached molecular remission were monitored for MRD. During follow-up, 38 of these patients were tested positive for PML-RARalpha mRNA. 13 out of the 38 patients (34%) effectively developed hematological relapse. In the first positive sample, specific PML-RARalpha NCN thresholds over which, or under which, patients could effectively be predicted to relapse or not, were identified and subsequently validated in a second cohort.

Selective amplification of scars in a chaotic optical fiber.

In this Letter we propose an original mechanism to select scar modes through coherent gain amplification in a multimode D-shaped fiber. More precisely, we demonstrate the selective amplification of scar modes by positioning a gain region in the vicinity of the self-focal point of the shortest periodic orbit in the transverse motion.