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[abstract] => Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranical direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes. This change is not accompanied by large increases in neuronal activity, as visualized using the cFos Targeted Recombination in Active Populations (cFosTRAP2) mouse line, or activation of microglia, which was assessed with IBA-1 staining. Using a model (SONIC) based on the neuronal intramembrane cavitation excitation (NICE) theory of ultrasound neuromodulation, we find that the predicted activity pattern of dLGN neurons upon sonication is state-dependent with a range of activity that falls within the parameter space conducive for inducing long-term synaptic depression. Our results suggest that noninvasive transcranial LIFU stimulation has a potential for recovering long-term plasticity of thalamocortical synapses in the post-critical period adult brain. Significance Statement Recovery of adult sensory cortical function is thought to be limited by the developmental decline in cortical plasticity mechanisms. In particular, thalamocortical (TC) synapses in the primary sensory cortices lose their ability to undergo experience-dependent plasticity quite early in postnatal development. As such, recovery of adult sensory cortical function is often accompanied by restoration of thalamocortical plasticity. Here we used a noninvasive transcranial low-intensity focused ultrasound (LIFU) stimulation, which can produce neuromodulation of localized structures deep in the brain, to elicit long-term depression of TC synapses in the primary visual cortex of adult mice. Our results suggest that transcranial LIFU stimulation could be a useful therapeutic that can produce long-term plasticity of neural circuits to restore adult brain functions.Risk stratification is crucial to the successful treatment of ALL. Although numerous risk factors have been identified, an optimal prognostic model for integrating variables has not been developed. We used individual patient data from four contemporary academic national clinical trials: UKALL14, NILG-ALL10/07, GIMEMA-LAL1913, PETHEMA-ALL-HR2011 to generate and validate the EWALL prognostic index (EWALL-PI) which is based on white blood cell count, genetics, and end of induction minimal residual disease. Individual patient risk scores were calculated for 778 patients in complete remission aged 15-67 years old using the validated UKALL-PI formula; applying minor modifications to reflect differences between paediatric and adult ALL. Per-trial analysis revealed that EWALL-PI correlated with relapse and death. Regression analysis revealed that each unit increase in EWALL-PI increased the risk of relapse or death by ~30% with no evidence of heterogeneity across trials or patient subgroups. EWALL-PI-defined risk models outperformed the stratification algorithms used by each trial. Threshold analysis revealed an EWALL-PI threshold that divided B and T-cell patients into standard (EWALL-PI <2·50) and high (EWALL-PI ≥2·50) risk groups. Per-trial analysis showed that high-risk patients had a significantly increased relapse rate and inferior survival compared with standard-risk patients (subdistribution hazard ratio ranged from 1.85 to 3.28 for relapse and hazard ratio 1.73 to 3.03 for death). Subgroup analysis confirmed the robustness of these risk groups by sex, age, white cell count and lineage. In conclusion, we validated an integrated risk model across four independent adult ALL clinical trials demonstrating its utility defining clinically relevant risk groups.
[DOI] => 10.1182/bloodadvances.2023011661
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[title] => Array
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[0] => A robust and validated integrated prognostic index for defining risk groups in adult ALL: A EWALL collaborative study.
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[abstract] => SUMMARY Dendritic spines are structural correlates of excitatory synapses maintaining stable synaptic communications. However, this strong spine-synapse relationship was mainly characterized in excitatory pyramidal neurons (PyNs), raising a possibility that inferring synaptic density from dendritic spine number may not be universally applied to all neuronal types. Here we found that the ectopic expression of H-Ras increased dendritic spine numbers regardless of cortical cell types such as layer 2/3 pyramidal neurons (PyNs), parvalbumin (PV)- and vasoactive intestinal peptide (VIP)-positive interneurons (INs) in the primary motor cortex (M1). The probability of detecting dendritic spines was positively correlated with the magnitude of H-Ras activity, suggesting elevated local H-Ras activity is involved in the process of dendritic spine formation. H-Ras overexpression caused high spine turnover rate via adding more spines rather than eliminating them. Two-photon photolysis of glutamate triggeredde novo dendritic spine formation in mature neurons, suggesting H-Ras induced spine formation is not restricted to the early development. In PyNs and PV-INs, but not VIP-INs, we observed a shift in average spine neck length towards longer filopodia-like phenotypes. The portion of dendritic spines lacking key excitatory synaptic proteins were significantly increased in H-Ras transfected neurons, suggesting that these increased spines have other distinct functions. High spine density caused by H-Ras did not result in change in the frequency or the amplitude of miniature excitatory postsynaptic currents (mEPSCs). Thus, our results propose that dendritic spines possess more multifaceted functions beyond the morphological proxy of excitatory synapse.
[DOI] => 10.1101/2023.07.21.550095
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[0] => Exuberantde novodendritic spine growth in mature neurons
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We report the most sensitive upper limits to date on the 21 cm epoch of reionization power spectrum using 94 nights of observing with Phase I of the Hydrogen Epoch of Reionization Array (HERA). Using similar analysis techniques as in previously reported limits, we find at 95% confidence that Δ2 (k = 0.34 h Mpc−1 ) ≤ 457 mK2 at z = 7.9 and that Δ2 (k = 0.36 h Mpc−1 ) ≤ 3496 mK2 at z = 10.4, an improvement by a factor of 2.1 and 2.6, respectively. These limits are mostly consistent with thermal noise over a wide range of k after our data quality cuts, despite performing a relatively conservative analysis designed to minimize signal loss. Our results are validated with both statistical tests on the data and end-to-end pipeline simulations. We also report updated constraints on the astrophysics of reionization and the cosmic dawn. Using multiple independent modeling and inference techniques previously employed by HERA Collaboration, we find that the intergalactic medium must have been heated above the adiabatic cooling limit at least as early as z = 10.4, ruling out a broad set of so-called “cold reionization” scenarios. If this heating is due to high-mass X-ray binaries during the cosmic dawn, as is generally believed, our result’s 99% credible interval excludes the local relationship between soft X-ray luminosity and star formation and thus requires heating driven by evolved low-metallicity stars.
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[abstract] => ABSTRACT
Radio interferometers aiming to measure the power spectrum of the redshifted 21 cm line during the Epoch of Reionization (EoR) need to achieve an unprecedented dynamic range to separate the weak signal from overwhelming foreground emissions. Calibration inaccuracies can compromise the sensitivity of these measurements to the effect that a detection of the EoR is precluded. An alternative to standard analysis techniques makes use of the closure phase, which allows one to bypass antenna-based direction-independent calibration. Similarly to standard approaches, we use a delay spectrum technique to search for the EoR signal. Using 94 nights of data observed with Phase I of the Hydrogen Epoch of Reionization Array (HERA), we place approximate constraints on the 21 cm power spectrum at z = 7.7. We find at 95 per cent confidence that the 21 cm EoR brightness temperature is ≤(372)2 ‘pseudo’ mK2 at 1.14 ‘pseudo’ h Mpc−1, where the ‘pseudo’ emphasizes that these limits are to be interpreted as approximations to the actual distance scales and brightness temperatures. Using a fiducial EoR model, we demonstrate the feasibility of detecting the EoR with the full array. Compared to standard methods, the closure phase processing is relatively simple, thereby providing an important independent check on results derived using visibility intensities, or related.
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[abstract] => ABSTRACT To mitigate the effects of Radio Frequency Interference (RFI) on the data analysis pipelines of 21 cm interferometric instruments, numerous inpaint techniques have been developed. In this paper, we examine the qualitative and quantitative errors introduced into the visibilities and power spectrum due to inpainting. We perform our analysis on simulated data as well as real data from the Hydrogen Epoch of Reionization Array (HERA) Phase 1 upper limits. We also introduce a convolutional neural network that is capable of inpainting RFI corrupted data. We train our network on simulated data and show that our network is capable of inpainting real data without requiring to be retrained. We find that techniques that incorporate high wavenumbers in delay space in their modelling are best suited for inpainting over narrowband RFI. We show that with our fiducial parameters discrete prolate spheroidal sequences (dpss) and clean provide the best performance for intermittent RFI while Gaussian progress regression (gpr) and least squares spectral analysis (lssa) provide the best performance for larger RFI gaps. However, we caution that these qualitative conclusions are sensitive to the chosen hyperparameters of each inpainting technique. We show that all inpainting techniques reliably reproduce foreground dominated modes in the power spectrum. Since the inpainting techniques should not be capable of reproducing noise realizations, we find that the largest errors occur in the noise dominated delay modes. We show that as the noise level of the data comes down, clean and dpss are most capable of reproducing the fine frequency structure in the visibilities.
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[abstract] => ABSTRACT
Combining the visibilities measured by an interferometer to form a cosmological power spectrum is a complicated process. In a delay-based analysis, the mapping between instrumental and cosmological space is not a one-to-one relation. Instead, neighbouring modes contribute to the power measured at one point, with their respective contributions encoded in the window functions. To better understand the power measured by an interferometer, we assess the impact of instrument characteristics and analysis choices on these window functions. Focusing on the Hydrogen Epoch of Reionization Array (HERA) as a case study, we find that long-baseline observations correspond to enhanced low-k tails of the window functions, which facilitate foreground leakage, whilst an informed choice of bandwidth and frequency taper can reduce said tails. With simple test cases and realistic simulations, we show that, apart from tracing mode mixing, the window functions help accurately reconstruct the power spectrum estimator of simulated visibilities. The window functions depend strongly on the beam chromaticity and less on its spatial structure – a Gaussian approximation, ignoring side lobes, is sufficient. Finally, we investigate the potential of asymmetric window functions, down-weighting the contribution of low-k power to avoid foreground leakage. The window functions presented here correspond to the latest HERA upper limits for the full Phase I data. They allow an accurate reconstruction of the power spectrum measured by the instrument and will be used in future analyses to confront theoretical models and data directly in cylindrical space.
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We present a Bayesian jackknife test for assessing the probability that a data set contains biased subsets, and, if so, which of the subsets are likely to be biased. The test can be used to assess the presence and likely source of statistical tension between different measurements of the same quantities in an automated manner. Under certain broadly applicable assumptions, the test is analytically tractable. We also provide an open-source code, chiborg, that performs both analytic and numerical computations of the test on general Gaussian-distributed data. After exploring the information theoretical aspects of the test and its performance with an array of simulations, we apply it to data from the Hydrogen Epoch of Reionization Array (HERA) to assess whether different sub-seasons of observing can justifiably be combined to produce a deeper 21 cm power spectrum upper limit. We find that, with a handful of exceptions, the HERA data in question are statistically consistent and this decision is justified. We conclude by pointing out the wide applicability of this test, including to CMB experiments and the H0 tension.
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We introduce CALibration AMITY (calamity ), a precision bandpass calibration method for radio interferometry. calamity can solve for direction-independent gains with arbitrary frequency structure to the high precision required for 21 cm cosmology with minimal knowledge of foregrounds or antenna beams and does not require any degree of redundancy (repeated identical measurements of the same baseline). We have achieved this through two key innovations. First, we model the foregrounds on each baseline independently using a flexible and highly efficient set of basis functions that have minimal overlap with 21 cm modes and enforce spectral smoothness in the calibrated foregrounds. Second, we use an off-the-shelf GPU accelerated API (tensorflow ) to solve for per-baseline foregrounds simultaneously with per-frequency antenna gains in a single optimization loop. GPU acceleration is critical for our technique to be able to solve for the large numbers of foreground and gain parameters simultaneously across all frequencies for an interferometer with ≳10 antennas in a reasonable amount of time. In this paper, we give an overview of our technique and, using realistic simulations, demonstrate its performance in solving for and removing pathological gain structures down to 4.5 orders of magnitude below the level of foregrounds and consistent with our simulated thermal noise limit. If readers want to start using calamity now, they can find a tutorial notebook online.
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[abstract] => Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain. SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.ABSTRACT We derive a general formalism for interferometric visibilities, which considers first-order antenna–antenna coupling and assumes steady-state, incident radiation. We simulate such coupling features for non-polarized skies on a compact, redundantly spaced array and present a phenomenological analysis of the coupling features. Contrary to previous studies, we find mutual coupling features manifest themselves at non-zero fringe rates. We compare power-spectrum results for both coupled and non-coupled (noiseless, simulated) data and find coupling effects to be highly dependent on local sidereal time (LST), baseline length, and baseline orientation. For all LSTs, lengths, and orientations, coupling features appear at delays which are outside the foreground ‘wedge’, which has been studied extensively and contains non-coupled astrophysical foreground features. Further, we find that first-order coupling effects threaten our ability to average data from baselines with identical length and orientation. Two filtering strategies are proposed which may mitigate such coupling systematics. The semi-analytic coupling model herein presented may be used to study mutual coupling systematics as a function of LST, baseline length, and baseline orientation. Such a model is not only helpful to the field of 21cm cosmology, but any study involving interferometric measurements, where coupling effects at the level of at least 1 part in 104 could corrupt the scientific result. Our model may be used to mitigate coupling systematics in existing radio interferometers and to design future arrays where the configuration of array elements inherently mitigates coupling effects at desired LSTs and angular resolutions.
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[abstract] => Abstract
We report upper limits on the Epoch of Reionization 21 cm power spectrum at redshifts 7.9 and 10.4 with 18 nights of data (∼36 hr of integration) from Phase I of the Hydrogen Epoch of Reionization Array (HERA). The Phase I data show evidence for systematics that can be largely suppressed with systematic models down to a dynamic range of ∼109 with respect to the peak foreground power. This yields a 95% confidence upper limit on the 21 cm power spectrum of
Δ
21
2
≤
(
30.76
)
2
mK
2
at k = 0.192 h Mpc−1 at z = 7.9, and also
Δ
21
2
≤
(
95.74
)
2
mK
2
at k = 0.256 h Mpc−1 at z = 10.4. At z = 7.9, these limits are the most sensitive to date by over an order of magnitude. While we find evidence for residual systematics at low line-of-sight Fourier k
∥ modes, at high k
∥ modes we find our data to be largely consistent with thermal noise, an indicator that the system could benefit from deeper integrations. The observed systematics could be due to radio frequency interference, cable subreflections, or residual instrumental cross-coupling, and warrant further study. This analysis emphasizes algorithms that have minimal inherent signal loss, although we do perform a careful accounting in a companion paper of the small forms of loss or bias associated with the pipeline. Overall, these results are a promising first step in the development of a tuned, instrument-specific analysis pipeline for HERA, particularly as Phase II construction is completed en route to reaching the full sensitivity of the experiment.
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[abstract] => Abstract
We describe the validation of the HERA Phase I software pipeline by a series of modular tests, building up to an end-to-end simulation. The philosophy of this approach is to validate the software and algorithms used in the Phase I upper-limit analysis on wholly synthetic data satisfying the assumptions of that analysis, not addressing whether the actual data meet these assumptions. We discuss the organization of this validation approach, the specific modular tests performed, and the construction of the end-to-end simulations. We explicitly discuss the limitations in scope of the current simulation effort. With mock visibility data generated from a known analytic power spectrum and a wide range of realistic instrumental effects and foregrounds, we demonstrate that the current pipeline produces power spectrum estimates that are consistent with known analytic inputs to within thermal noise levels (at the 2σ level) for k > 0.2h Mpc−1 for both bands and fields considered. Our input spectrum is intentionally amplified to enable a strong “detection” at k ∼ 0.2 h Mpc−1 —at the level of ∼25σ —with foregrounds dominating on larger scales and thermal noise dominating at smaller scales. Our pipeline is able to detect this amplified input signal after suppressing foregrounds with a dynamic range (foreground to noise ratio) of ≳107 . Our validation test suite uncovered several sources of scale-independent signal loss throughout the pipeline, whose amplitude is well-characterized and accounted for in the final estimates. We conclude with a discussion of the steps required for the next round of data analysis.
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[abstract] => Abstract We present a framework for identifying and flagging malfunctioning antennas in large radio interferometers. We outline two distinct categories of metrics designed to detect outliers along known failure modes of large arrays: cross‐correlation metrics, based on all antenna pairs, and auto‐correlation metrics, based solely on individual antennas. We define and motivate the statistical framework for all metrics used, and present tailored visualizations that aid us in clearly identifying new and existing systematics. We implement these techniques using data from 105 antennas in the Hydrogen Epoch of Reionization Array (HERA) as a case study. Finally, we provide a detailed algorithm for implementing these metrics as flagging tools on real data sets.
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[abstract] => Abstract
Recently, the Hydrogen Epoch of Reionization Array (HERA) has produced the experiment’s first upper limits on the power spectrum of 21 cm fluctuations at z ∼ 8 and 10. Here, we use several independent theoretical models to infer constraints on the intergalactic medium (IGM) and galaxies during the epoch of reionization from these limits. We find that the IGM must have been heated above the adiabatic-cooling threshold by z ∼ 8, independent of uncertainties about IGM ionization and the radio background. Combining HERA limits with complementary observations constrains the spin temperature of the z ∼ 8 neutral IGM to 27 K
〈
T
¯
S
〉
630 K (2.3 K
〈
T
¯
S
〉
640 K) at 68% (95%) confidence. They therefore also place a lower bound on X-ray heating, a previously unconstrained aspects of early galaxies. For example, if the cosmic microwave background dominates the z ∼ 8 radio background, the new HERA limits imply that the first galaxies produced X-rays more efficiently than local ones. The z ∼ 10 limits require even earlier heating if dark-matter interactions cool the hydrogen gas. If an extra radio background is produced by galaxies, we rule out (at 95% confidence) the combination of high radio and low X-ray luminosities of L
r ,ν
/SFR > 4 × 1024 W Hz−1
M
⊙
−
1
yr and L
X
/SFR < 7.6 × 1039 erg s−1
M
⊙
−
1
yr. The new HERA upper limits neither support nor disfavor a cosmological interpretation of the recent Experiment to Detect the Global EOR Signature (EDGES) measurement. The framework described here provides a foundation for the interpretation of future HERA results.
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On behalf of the GRAALL group, the Czech Republic ALL group, the Finland ALL group and the EWALL group.
Introduction. Treatment of older patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains an unmet medical need. Inotuzumab ozogamicin (INO), an anti-CD22 antibody conjugated to calicheamicin, is approved for the treatment of relapsed/refractory BCP-ALL in adults, sinusoidal obstruction syndrome (SOS) being the major adverse event associated with INO. A previous first line study conducted by the MDACC in pts 60 years or older successfully used INO in combination with a lower intensity version of the hyper-CVAD (mini-hyper-CVD). Due to the occurrence of SOS, the total doses were fixed at 1.3 mg/m² for cycle 1 followed by 3 cycles at 1 mg/m² (Kantarjian H et al. Lancet Oncol, 2018). Here, we aimed to assess the activity and safety of fractionated INO at a reduced dosage in combination with low-intensity chemotherapy as frontline therapy for older pts with CD22+ Philadelphia chromosome-negative (Ph-neg) BCP-ALL.
Methods. EWALL-INO is a single arm prospective phase 2 multicentric study conducted in European centers belonging to the EWALL group. Eligibility criteria were pts aged 55y or older, performance status ≤2, and newly diagnosed CD22+ (20% or more of positive blast cells) Ph-neg BCP-ALL without central nervous system involvement. After a prephase including 5 days (D) of dexamethasone (DEX) 10mg per D and a single intrathecal injection (IT), the induction regimen was begun and split in 2 parts. Induction part I (Induc1) consisted of one triple IT, vincristine (VCR) 2 mg (1 mg over 70y) D1 D8 D15 D22 and DEX 20 mg D1D2 D8D9 D15D16 D22D23 combined with 3 injections of INO (0.8 mg/m² D1, 0.5 mg/m² D8 and D15). Induction part II (Induc2) was offered to pts in CR or CRp (CR with platelets < 100 G/l) after Induc1 or as salvage therapy. Induc2 consisted of DEX 20mg D1D8, cyclophosphamide (CY) 300 mg/m² D1 to D3, one triple IT D2 and 2 injections of INO (0.5 mg/m² D1 and D8). Pts in CR/CRp were programmed to receive 6 blocks of consolidation (Ara-C 1.5g/m²/12h adapted to renal clearance D1D2 and DEX 10mg/12h D1D2, cycles 1 and 4; Methotrexate (MTX) 1.5 g/m² over 24h D1, VCR 1 or 2 mg D1, one triple IT D2 and 6-mercaptopurin (6-MP) D1 to D7, cycles 2 and 5; CY 500 mg/m² D1D2, VP16 75 mg/m² D1D2, one triple IT D2 and MTX 25 mg/m² D1, cycles 3 and 6) followed by a POMP maintenance (VCR, 6-MP, MTX, DEX) during 18 months. Allograft was allowed after at least 3 blocks of consolidation at the discretion of the investigators. The evaluable population was pts who received at least 1 dose of INO. Analyses were by modified intention to treat and performed JUN 28, 2021. All pts gave informed consent. The study is registered at ClinicalTrials.gov under the NCT number: NCT03249870.
Results. Between DEC 29, 2017 and JUN 22, 2021, 115 pts (out of 130 planned pts) were enrolled including 6 pts with screen failure. The first 90 eligible pts (up to MAR 1, 2021) were considered for this analysis to obtain a minimum of 4 months follow-up. Median age was 69y (range 55-84) and median follow-up for alive pts was 1.18 years (range 0.3-3.5). At time of analysis, 90 and 88 pts had started induc1 and induc2, respectively. Treatment related mortality was 2.2% (2/90) and CR/CRp rate was 85.5% (77/90, 6 CRp) after induc1. Three cases relapsed between induc1 and induc2 and 5 pts were salvaged by induc2 allowing to a CR/CRp rate of 87.7% (79/90, 8 CRp) after induc2. One pts died from refractory disease during induc2. One, 2, 3 4 and 5 injections of INO were administered to 2 (2.2%), 2(2.2%), 11 (12.2%), 2 (2.2%) and 73 pts (81.1%) respectively. Only 6 pts were allografted. One-year OS was estimated to be 78.5% (95%CI 68-85.9) and median OS was not reached. One-year relapse free survival was 74.5% (95CI 63.5-82.6) (Figure 1). Grade 3-4 liver toxicity was observed in 8 pts (8.8%) during the study including 3 pts (3.3%) developing SOS, 2 related to INO during induc1 and one occurred after transplant. Twenty-nine pts died during the follow-up, 16 from relapses (overall incidence 18%) and 13 from adverse events (overall incidence 14.4%), including one COVID19 fatal infection during consolidation.
Conclusion. Fractionated inotuzumab ozogamicin at reduced doses (0.8/0.5/0.5/0.5 mg/m²) combined with low-intensity chemotherapy is a very active and well tolerated frontline therapy for older patients with CD22+ Ph-neg BCP-ALL.
Figure 1 Figure 1.
Disclosures
Doubek: Janssen-Cilag, AbbVie, AstraZeneca, Amgen, Gilead, Novartis: Honoraria, Research Funding. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Raffoux: ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy. Boissel: CELGENE: Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; SANOFI: Honoraria. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding.
OffLabel Disclosure:
Inotuzumab ozogamicin as first line therapy in newly diagnosed CD22+ Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia
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Precision calibration poses challenges to experiments probing the redshifted 21-cm signal of neutral hydrogen from the Cosmic Dawn and Epoch of Reionization (z ∼ 30–6). In both interferometric and global signal experiments, systematic calibration is the leading source of error. Though many aspects of calibration have been studied, the overlap between the two types of instruments has received less attention. We investigate the sky based calibration of total power measurements with a HERA dish and an EDGES-style antenna to understand the role of autocorrelations in the calibration of an interferometer and the role of sky in calibrating a total power instrument. Using simulations we study various scenarios such as time variable gain, incomplete sky calibration model, and primary beam model. We find that temporal gain drifts, sky model incompleteness, and beam inaccuracies cause biases in the receiver gain amplitude and the receiver temperature estimates. In some cases, these biases mix spectral structure between beam and sky resulting in spectrally variable gain errors. Applying the calibration method to the HERA and EDGES data, we find good agreement with calibration via the more standard methods. Although instrumental gains are consistent with beam and sky errors similar in scale to those simulated, the receiver temperatures show significant deviations from expected values. While we show that it is possible to partially mitigate biases due to model inaccuracies by incorporating a time-dependent gain model in calibration, the resulting errors on calibration products are larger and more correlated. Completely addressing these biases will require more accurate sky and primary beam models.
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[abstract] => Cortical areas are highly interconnected both via cortical and subcortical pathways, and primary sensory cortices are not isolated from this general structure. In primary sensory cortical areas, these pre-existing functional connections serve to provide contextual information for sensory processing and can mediate adaptation when a sensory modality is lost. Cross-modal plasticity in broad terms refers to widespread plasticity across the brain in response to losing a sensory modality, and largely involves two distinct changes: cross-modal recruitment and compensatory plasticity. The former involves recruitment of the deprived sensory area, which includes the deprived primary sensory cortex, for processing the remaining senses. Compensatory plasticity refers to plasticity in the remaining sensory areas, including the spared primary sensory cortices, to enhance the processing of its own sensory inputs. Here, we will summarize potential cellular plasticity mechanisms involved in cross-modal recruitment and compensatory plasticity, and review cortical and subcortical circuits to the primary sensory cortices which can mediate cross-modal plasticity upon loss of vision.
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[abstract] => ABSTRACT
We introduce DPSS Approximate lazY filtEriNg of foregroUnds (dayenu), a linear, spectral filter for H i intensity mapping that achieves the desirable foreground mitigation and error minimization properties of inverse co-variance weighting with minimal modelling of the underlying data. Beyond 21-cm power-spectrum estimation, our filter is suitable for any analysis where high dynamic-range removal of spectrally smooth foregrounds in irregularly (or regularly) sampled data is required, something required by many other intensity mapping techniques. Our filtering matrix is diagonalized by Discrete Prolate Spheroidal Sequences which are an optimal basis to model band-limited foregrounds in 21-cm intensity mapping experiments in the sense that they maximally concentrate power within a finite region of Fourier space. We show that dayenu enables the access of large-scale line-of-sight modes that are inaccessible to tapered discrete Fourier transform estimators. Since these modes have the largest SNRs,dayenu significantly increases the sensitivity of 21-cm analyses over tapered Fourier transforms. Slight modifications allow us to use dayenu as a linear replacement for iterative delay clean ing (dayenurest). We refer readers to the Code section at the end of this paper for links to examples and code.
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The detection of the Epoch of Reionization (EoR) delay power spectrum using a ‘foreground avoidance method’ highly depends on the instrument chromaticity. The systematic effects induced by the radio telescope spread the foreground signal in the delay domain, which contaminates the EoR window theoretically observable. Applied to the Hydrogen Epoch of Reionization Array (HERA), this paper combines detailed electromagnetic and electrical simulations in order to model the chromatic effects of the instrument, and quantify its frequency and time responses. In particular, the effects of the analogue receiver, transmission cables, and mutual coupling are included. These simulations are able to accurately predict the intensity of the reflections occurring in the 150-m cable which links the antenna to the backend. They also show that electromagnetic waves can propagate from one dish to another one through large sections of the array due to mutual coupling. The simulated system time response is attenuated by a factor 104 after a characteristic delay which depends on the size of the array and on the antenna position. Ultimately, the system response is attenuated by a factor 105 after 1400 ns because of the reflections in the cable, which corresponds to characterizable k∥-modes above 0.7 $h\,\,\rm {Mpc}^{-1}$ at 150 MHz. Thus, this new study shows that the detection of the EoR signal with HERA Phase I will be more challenging than expected. On the other hand, it improves our understanding of the telescope, which is essential to mitigate the instrument chromaticity.
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In 21-cm cosmology, precision calibration is key to the separation of the neutral hydrogen signal from very bright but spectrally smooth astrophysical foregrounds. The Hydrogen Epoch of Reionization Array (HERA), an interferometer specialized for 21-cm cosmology and now under construction in South Africa, was designed to be largely calibrated using the self-consistency of repeated measurements of the same interferometric modes. This technique, known as redundant-baseline calibration resolves most of the internal degrees of freedom in the calibration problem. It assumes, however, on antenna elements with identical primary beams placed precisely on a redundant grid. In this work, we review the detailed implementation of the algorithms enabling redundant-baseline calibration and report results with HERA data. We quantify the effects of real-world non-redundancy and how they compare to the idealized scenario in which redundant measurements differ only in their noise realizations. Finally, we study how non-redundancy can produce spurious temporal structure in our calibration solutions – both in data and in simulations – and present strategies for mitigating that structure.
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The central challenge in 21 cm cosmology is isolating the cosmological signal from bright foregrounds. Many separation techniques rely on the accurate knowledge of the sky and the instrumental response, including the antenna primary beam. For drift-scan telescopes, such as the Hydrogen Epoch of Reionization Array (HERA), that do not move, primary beam characterization is particularly challenging because standard beam-calibration routines do not apply (Cornwell et al.) and current techniques require accurate source catalogs at the telescope resolution. We present an extension of the method from Pober et al. where they use beam symmetries to create a network of overlapping source tracks that break the degeneracy between source flux density and beam response and allow their simultaneous estimation. We fit the beam response of our instrument using early HERA observations and find that our results agree well with electromagnetic simulations down to a −20 dB level in power relative to peak gain for sources with high signal-to-noise ratio. In addition, we construct a source catalog with 90 sources down to a flux density of 1.4 Jy at 151 MHz.
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We analyze data from the Hydrogen Epoch of Reionization Array (HERA). This is the third in a series of papers on the closure phase delay spectrum technique designed to detect the H i 21 cm emission from cosmic reionization. We present the details of the data and models employed in the power spectral analysis and discuss limitations to the process. We compare images and visibility spectra made with HERA data to parallel quantities generated from sky models based on the Galactic and Extra-Galactic All-Sky MWA (GLEAM) survey, incorporating the HERA telescope model. We find reasonable agreement between images made from HERA data with those generated from the models, down to the confusion level. For the visibility spectra, there is broad agreement between model and data across the full band of ∼80 MHz. However, models with only GLEAM sources do not reproduce a roughly sinusoidal spectral structure at the tens of percent level seen in the observed visibility spectra on scales of ∼10 MHz on 29 m baselines. We find that this structure is likely due to diffuse Galactic emission, predominantly the Galactic plane, filling the far sidelobes of the antenna primary beam. We show that our current knowledge of the frequency dependence of the diffuse sky radio emission, and the primary beam at large zenith angles, is inadequate to provide an accurate reproduction of the diffuse structure in the models. We discuss some implications arising due to this missing structure in the models, in terms of calibration, and in the search for the H i 21 cm signal, as well as possible mitigation techniques.
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We discuss absolute calibration strategies for Phase I of the Hydrogen Epoch of Reionization Array (HERA), which aims to measure the cosmological 21 cm signal from the Epoch of Reionization. HERA is a drift-scan array with a 10° wide field of view, meaning bright, well-characterized point-source transits are scarce. This, combined with HERA’s redundant sampling of the uv plane and the modest angular resolution of the Phase I instrument, make traditional sky-based and self-calibration techniques difficult to implement with high dynamic range. Nonetheless, in this work, we demonstrate calibration for HERA using point-source catalogs and electromagnetic simulations of its primary beam. We show that unmodeled diffuse flux and instrumental contaminants can corrupt the gain solutions and present a gain-smoothing approach for mitigating their impact on the 21 cm power spectrum. We also demonstrate a hybrid sky and redundant calibration scheme and compare it to pure sky-based calibration, showing only a marginal improvement to the gain solutions at intermediate delay scales. Our work suggests that the HERA Phase I system can be well calibrated for a foreground avoidance power spectrum estimator by applying direction-independent gains with a small set of degrees of freedom across the frequency and time axes.
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We present a study of internal reflection and cross-coupling systematics in Phase I of the Hydrogen Epoch of Reionization Array (HERA). In a companion paper, we outlined the mathematical formalism for such systematics and presented algorithms for modeling and removing them from the data. In this work, we apply these techniques to data from HERA’s first observing season as a method demonstration. The data show evidence for systematics that, without removal, would hinder a detection of the 21 cm power spectrum for the targeted Epoch of Reionization (EoR) line-of-sight modes in the range 0.2 h
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The key challenge in the observation of the redshifted 21-cm signal from cosmic reionization is its separation from the much brighter foreground emission. Such separation relies on the different spectral properties of the two components, although, in real life, the foreground intrinsic spectrum is often corrupted by the instrumental response, inducing systematic effects that can further jeopardize the measurement of the 21-cm signal. In this paper, we use Gaussian Process Regression to model both foreground emission and instrumental systematics in ∼2 h of data from the Hydrogen Epoch of Reionization Array. We find that a simple co-variance model with three components matches the data well, giving a residual power spectrum with white noise properties. These consist of an ‘intrinsic’ and instrumentally corrupted component with a coherence scale of 20 and 2.4 MHz, respectively (dominating the line-of-sight power spectrum over scales k∥ ≤ 0.2 h cMpc−1) and a baseline-dependent periodic signal with a period of ∼1 MHz (dominating over k∥ ∼ 0.4–0.8 h cMpc−1), which should be distinguishable from the 21-cm Epoch of Reionization signal whose typical coherence scale is ∼0.8 MHz.
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We use a semi-analytic model to explore the potential impact of a brief and violent period of radio-loud accretion on to black holes (The Radio Scream) during the Cosmic Dawn on the H i hyperfine 21 cm signal. We find that radio emission from supermassive black hole seeds can impact the global 21 cm signal at the level of tens to hundreds of per cent provided that they were as radio loud as $z$ ≈ 1 black holes and obscured by gas with column depths of NH ≳ 1023 cm−2. We determine plausible sets of parameters that reproduce some of the striking features of the EDGES absorption feature including its depth, timing, and side steepness while producing radio/X-ray backgrounds and source counts that are consistent with published limits. Scenarios yielding a dramatic 21 cm signature also predict large populations of ∼$\mu$Jy point sources that will be detectable in future deep surveys from the Square Kilometer Array (SKA). Thus, 21 cm measurements, complemented by deep point-source surveys, have the potential to constrain optimistic scenarios where supermassive black hole progenitors were radio loud.
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[abstract] => Abstract
Foreground power dominates the measurements of interferometers that seek a statistical detection of highly-redshifted H i emission from the Epoch of Reionization (EoR). The chromaticity of the instrument creates a boundary in the Fourier transform of frequency (proportional to k
∥ ) between spectrally smooth emission, characteristic of the strong synchrotron foreground (the “wedge”), and the spectrally structured emission from H i in the EoR (the “EoR window”). Faraday rotation can inject spectral structure into otherwise smooth polarized foreground emission, which through instrument effects or miscalibration could possibly pollute the EoR window. For instruments pursuing a “foreground avoidance” strategy of simply measuring in the EoR window, and not attempting to model and remove foregrounds, as is the plan for the first stage of the Hydrogen Epoch of Reionization Array (HERA), characterizing the intrinsic instrument polarization response is particularly important. Using data from the HERA 19-element commissioning array, we investigate the polarization response of this new instrument in the power-spectrum domain. We perform a simple image-based calibration based on the unpolarized diffuse emission of the Global Sky Model, and show that it achieves qualitative redundancy between the nominally redundant baselines of the array and reasonable amplitude accuracy. We construct power spectra of all fully polarized coherencies in all pseudo-Stokes parameters, and discuss the achieved isolation of foreground power due to the intrinsic spectral smoothness of the foregrounds, the instrument chromaticity, and the calibration. We compare to simulations based on an unpolarized diffuse sky model and detailed electromagnetic simulations of the dish and feed, confirming that in Stokes I , the calibration does not add significant spectral structure beyond that expected from the interferometer array configuration and the modeled primary beam response. Furthermore, this calibration is stable over the 8 days of observations considered. Excess power is seen in the power spectra of the linear polarization Stokes parameters, which is not easily attributable to leakage via the primary beam, and results from some combination of residual calibration errors and actual polarized emission. Stokes V is found to be highly discrepant from the expectation of zero power, strongly pointing to the need for more accurate polarized calibration.
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[abstract] => ABSTRACT
Radio frequency interference (RFI) is an ever-present limiting factor among radio telescopes even in the most remote observing locations. When looking to retain the maximum amount of sensitivity and reduce contamination for Epoch of Reionization studies, the identification and removal of RFI is especially important. In addition to improved RFI identification, we must also take into account computational efficiency of the RFI-Identification algorithm as radio interferometer arrays such as the Hydrogen Epoch of Reionization Array (HERA) grow larger in number of receivers. To address this, we present a deep fully convolutional neural network (DFCN) that is comprehensive in its use of interferometric data, where both amplitude and phase information are used jointly for identifying RFI. We train the network using simulated HERA visibilities containing mock RFI, yielding a known ‘ground truth’ data set for evaluating the accuracy of various RFI algorithms. Evaluation of the DFCN model is performed on observations from the 67 dish build-out, HERA-67, and achieves a data throughput of 1.6 × 105 HERA time-ordered 1024 channelled visibilities per hour per GPU. We determine that relative to an amplitude only network including visibility phase adds important adjacent time–frequency context which increases discrimination between RFI and non-RFI. The inclusion of phase when predicting achieves a recall of 0.81, precision of 0.58, and F2 score of 0.75 as applied to our HERA-67 observations.
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Background. Tyrosine kinase inhibitors (TKI) are standard front-line therapy for patients with BCR-ABL1/Philadelphia positive ALL (Ph+ ALL), but the relative merits of available TKIs remain uncertain. Nilotinib is a potent inhibitor of BCR-ABL1 with broader activity against ABL kinase domain mutations than imatinib and greater selectivity than dasatinib or ponatinib. As there is a paucity of data on nilotinib as first-line therapy for Ph+ ALL, the EWALL (European Working Group for Adult ALL) conducted an international clinical trial to evaluate efficacy and safety of the combination of nilotinib with low intensity chemotherapy.
Patients and Methods. After a prephase with dexamethasone (DEX) and cyclophosphamide, nilotinib (400 mg BID) was given concurrently with the same chemotherapy backbone employed in the EWALL-PH01 assessing the combination with dasatinib (Rousselot et al, Blood 2016;128:774-82). Induction consisted of nilotinib combined with weekly vincristine (VCR, 1mg iv) and oral dexamethasone 40mg 2 days (20 mg over 70y). Nilotinib was continued throughout six consolidation cycles, followed by 24 months maintenance therapy with nilotinib, 6-MP, MTX and DEX/VCR boosts. Stem cell transplantation (SCT) was permitted as considered appropriate. BCR-ABL1 RTQ-PCR and kinase domain resistance mutations were centrally monitored. Primary endpoint was event-free survival (EFS) at 12 months, secondary endpoints included rates of CR, major and complete molecular response, relapse free survival (RFS), EFS and overall survival (OS).
Results. 72/79 enrolled pts. were evaluable for response, 3 withdrew consent, 4 did not meet eligibility criteria. Median age was 65.5 (55-85) years, male/female ratio 0.85, ECOG status 0 or 1 in 89% of pts., median CIRS comorbidity score 5(0-19). Baseline vascular risk factors including high blood pressure (grade ≥2) were present in 36% of pts.. Sixty-eight of 72 pts. (94.4%) achieved CR, one died during induction and one was refractory, 2 pts. discontinued study therapy. Non-hematologic adverse events (AE) grades 3/4 during induction (in ≥ 5% of pts. irrespective of causality) included infections (n=20), elevated transaminases or bilirubin (n=18) and gastrointestinal AEs (n=12). The spectrum of AEs was similar during consolidation, without concerns related to cardiovascular events. 24 pts. (61y; 55-69y) underwent allogeneic (9 MUD, 12 SIB, 3 Haplo) and 3 autologous SCT. 21 pts. received reduced intensity conditioning (including 8Gy TBI, n=11) regimens. Among all pts., relapse was the main cause of treatment failure (n=23; 17 BM, 2 CNS, 3 other sites, 1 na), 11 pts. died in CR (6 after HSCT), 34 are in ongoing CR. Based on Kaplan Meier analysis, EFS (events being resistant disease, relapse or death) at 12 months was 74%, with median follow-up of 39 (24-66) months for surviving pts., EFS and OS at 4 years was 42%, and 47%, respectively. By landmark analyses using median time to HSCT as cutoff, cumulative incidence of relapse in transplanted vs. non-transplanted pts. was 32% and 47%, OS at 4 years was 61% and 39%, median OS was not reached versus 3.6 years, respectively (p=ns). The proportion of pts. with a BCR-ABL1/ABL1 ratio ≤0.1% increased from 41% after induction to 86% after consolidation 2; that of pts. with undetectable or non-quantifiable BCR-ABL1 transcripts (sensitivity ≥10-4) increased from 14% to 58%.
Conclusions. Nilotinib combined with low-intensity chemotherapy is well tolerated and highly effective in elderly pts. with Ph-positive ALL. OS and EFS compare favorably with previous similar studies testing imatinib or dasatinib. With 32% of pts. undergoing allogeneic HSCT and 61% survival at 4 years, transplantation is a viable option in this elderly cohort of pts..
Disclosures
Ottmann: Celgene: Consultancy, Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Fusion Pharma: Consultancy, Research Funding. Pfeifer:Novartis: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanhes:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goekbuget:Pfizer: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Celgene: Consultancy; Kite / Gilead: Consultancy; Amgen: Consultancy, Other: Travel support, Research Funding. Dombret:Jazz Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Shire-Baxalta: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau.
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We estimate the 21 cm radio background from accretion onto the first intermediate-mass black holes between z ≈ 30 and z ≈ 16. Combining potentially optimistic, but plausible, scenarios for black hole formation and growth with empirical correlations between luminosity and radio emission observed in low-redshift active galactic nuclei, we find that a model of black holes forming in molecular cooling halos is able to produce a 21 cm background that exceeds the cosmic microwave background (CMB) at z ≈ 17, though models involving larger halo masses are not entirely excluded. Such a background could explain the surprisingly large amplitude of the 21 cm absorption feature recently reported by the EDGES collaboration. Such black holes would also produce significant X-ray emission and contribute to the 0.5–2 keV soft X-ray background at the level of ≈10−13 –10−12 erg s−1 cm−2 deg−2 , consistent with existing constraints. In order to avoid heating the intergalactic medium (IGM) over the EDGES trough, these black holes would need to be obscured by hydrogen column depths of N
H ∼ 5 × 1023 cm−2 . Such black holes would avoid violating constraints on the CMB optical depth from Planck if their UV photon escape fractions were below f
esc ≲ 0.1, which would be a natural result of N
H ∼ 5 × 1023 cm−2 being imposed by an unheated IGM.
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Interferometric arrays seeking to measure the 21 cm signal from the epoch of reionization (EOR) must contend with overwhelmingly bright emission from foreground sources. Accurate recovery of the 21 cm signal will require precise calibration of the array, and several new avenues for calibration have been pursued in recent years, including methods using redundancy in the antenna configuration. The newly upgraded Phase II of Murchison Widefield Array (MWA) is the first interferometer that has large numbers of redundant baselines while retaining good instantaneous UV coverage. This array therefore provides a unique opportunity to compare redundant calibration with sky-model-based algorithms. In this paper, we present the first results from comparing both calibration approaches with MWA Phase II observations. For redundant calibration, we use the package OMNICAL and produce sky-based calibration solutions with the analysis package Fast Holographic Deconvolution (FHD). There are three principal results: (1) We report the success of OMNICAL on observations of ORBComm satellites, showing substantial agreement between redundant visibility measurements after calibration. (2) We directly compare OMNICAL calibration solutions with those from FHD and demonstrate that these two different calibration schemes give extremely similar results. (3) We explore improved calibration by combining OMNICAL and FHD. We evaluate these combined methods using power spectrum techniques developed for EOR analysis and find evidence for marginal improvements mitigating artifacts in the power spectrum. These results are likely limited by the signal-to-noise ratio in the 6 hr of data used, but they suggest future directions for combining these two calibration schemes.
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We present new radio continuum observations of NGC 253 from the Murchison Widefield Array at frequencies between 76 and 227 MHz. We model the broadband radio spectral energy distribution for the total flux density of NGC 253 between 76 MHz and 11 GHz. The spectrum is best described as a sum of a central starburst and extended emission. The central component, corresponding to the inner 500 pc of the starburst region of the galaxy, is best modeled as an internally free–free absorbed synchrotron plasma, with a turnover frequency around 230 MHz. The extended emission component of the spectrum of NGC 253 is best described as a synchrotron emission flattening at low radio frequencies. We find that 34% of the extended emission (outside the central starburst region) at 1 GHz becomes partially absorbed at low radio frequencies. Most of this flattening occurs in the western region of the southeast halo, and may be indicative of synchrotron self-absorption of shock-reaccelerated electrons or an intrinsic low-energy cutoff of the electron distribution. Furthermore, we detect the large-scale synchrotron radio halo of NGC 253 in our radio images. At 154–231 MHz the halo displays the well known X-shaped/horn-like structure, and extends out to ∼8 kpc in the z -direction (from the major axis).
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The detection of redshifted 21 cm emission from the epoch of reionization (EoR) is a challenging task owing to strong foregrounds that dominate the signal. In this paper, we propose a general method, based on the delay spectrum approach, to extract H i power spectra that are applicable to tracking observations using an imaging radio interferometer ("Delay Spectrum with Imaging Arrays"). Our method is based on modeling the H i signal taking into account the impact of wide field effects such as the w -term, which are then used as appropriate weights in cross-correlating the measured visibilities. Our method is applicable to any radio interferometer that tracks a phase center and could be utilized for arrays such as the Murchison Widefield Array (MWA), Low Frequency Array (LOFAR), Giant Meterwave Radio Telescope (GMRT), Donald C. Backer Precision Array for Probing the Epoch of Reionization (PAPER), and HERA. In the literature the delay spectrum approach has been implemented for near-redundant baselines using drift scan observations. In this paper we explore the scheme for non-redundant tracking arrays. This is the first application of delay spectrum methodology to such data to extract the H i signal. We analyze 3 hr of MWA tracking data on the EoR1 field. We present both two-dimensional (
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We use time-domain electromagnetic simulations to determine the spectral characteristics of the Hydrogen Epoch of Reionization Arrays (HERA) antenna. These simulations are part of a multi-faceted campaign to determine the effectiveness of the dish’s design for obtaining a detection of redshifted 21 cm emission from the epoch of reionization. Our simulations show the existence of reflections between HERA’s suspended feed and its parabolic dish reflector that fall below −40 dB at 150 ns and, for reasonable impedance matches, have a negligible impact on HERA’s ability to constrain EoR parameters. It follows that despite the reflections they introduce, dishes are effective for increasing the sensitivity of EoR experiments at a relatively low cost. We find that electromagnetic resonances in the HERA feed’s cylindrical skirt, which is intended to reduce cross coupling and beam ellipticity, introduces significant power at large delays (−40 dB at 200 ns), which can lead to some loss of measurable Fourier modes and a modest reduction in sensitivity. Even in the presence of this structure, we find that the spectral response of the antenna is sufficiently smooth for delay filtering to contain foreground emission at line-of-sight wave numbers below k
∥ ≲ 0.2 h Mpc−1 , in the region where the current PAPER experiment operates. Incorporating these results into a Fisher Matrix analysis, we find that the spectral structure observed in our simulations has only a small effect on the tight constraints HERA can achieve on parameters associated with the astrophysics of reionization.
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We present deep polarimetric observations at 154 MHz with the Murchison Widefield Array (MWA), covering 625 deg2 centered on α = 0h and δ = −27°. The sensitivity available in our deep observations allows an in-band, frequency-dependent analysis of polarized structure for the first time at long wavelengths. Our analysis suggests that the polarized structures are dominated by intrinsic emission but may also have a foreground Faraday screen component. At these wavelengths, the compactness of the MWA baseline distribution provides excellent snapshot sensitivity to large-scale structure. The observations are sensitive to diffuse polarized emission at ∼54′ resolution with a sensitivity of 5.9 mJy beam−1 and compact polarized sources at ∼2.′4 resolution with a sensitivity of 2.3 mJy beam−1 for a subset (400 deg2 ) of this field. The sensitivity allows the effect of ionospheric Faraday rotation to be spatially and temporally measured directly from the diffuse polarized background. Our observations reveal large-scale structures (∼1°–8° in extent) in linear polarization clearly detectable in ∼2 minute snapshots, which would remain undetectable by interferometers with minimum baseline lengths of >110 m at 154 MHz. The brightness temperature of these structures is on average 4 K in polarized intensity, peaking at 11 K. Rotation measure synthesis reveals that the structures have Faraday depths ranging from −2 to 10 rad m−2 with a large fraction peaking at approximately +1 rad m−2 . We estimate a distance of 51 ± 20 pc to the polarized emission based on measurements of the in-field pulsar J2330–2005. We detect four extragalactic linearly polarized point sources within the field in our compact source survey. Based on the known polarized source population at 1.4 GHz and non-detections at 154 MHz, we estimate an upper limit on the depolarization ratio of 0.08 from 1.4 GHz to 154 MHz.
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We present the 21 cm power spectrum analysis approach of the Murchison Widefield Array Epoch of Reionization project. In this paper, we compare the outputs of multiple pipelines for the purpose of validating statistical limits cosmological hydrogen at redshifts between 6 and 12. Multiple independent data calibration and reduction pipelines are used to make power spectrum limits on a fiducial night of data. Comparing the outputs of imaging and power spectrum stages highlights differences in calibration, foreground subtraction, and power spectrum calculation. The power spectra found using these different methods span a space defined by the various tradeoffs between speed, accuracy, and systematic control. Lessons learned from comparing the pipelines range from the algorithmic to the prosaically mundane; all demonstrate the many pitfalls of neglecting reproducibility. We briefly discuss the way these different methods attempt to handle the question of evaluating a significant detection in the presence of foregrounds.
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Unaccounted for systematics from foregrounds and instruments can severely limit the sensitivity of current experiments from detecting redshifted 21 cm signals from the Epoch of Reionization (EoR). Upcoming experiments are faced with a challenge to deliver more collecting area per antenna element without degrading the data with systematics. This paper and its companions show that dishes are viable for achieving this balance using the Hydrogen Epoch of Reionization Array (HERA) as an example. Here, we specifically identify spectral systematics associated with the antenna power pattern as a significant detriment to all EoR experiments which causes the already bright foreground power to leak well beyond ideal limits and contaminate the otherwise clean EoR signal modes. A primary source of this chromaticity is reflections in the antenna-feed assembly and between structures in neighboring antennas. Using precise foreground simulations taking wide-field effects into account, we provide a generic framework to set cosmologically motivated design specifications on these reflections to prevent further EoR signal degradation. We show that HERA will not be impeded by such spectral systematics and demonstrate that even in a conservative scenario that does not perform removal of foregrounds, HERA will detect the EoR signal in line-of-sight k -modes,
Mpc−1 , with high significance. Under these conditions, all baselines in a 19-element HERA layout are capable of detecting EoR over a substantial observing window on the sky.
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In this paper we present observations, simulations, and analysis demonstrating the direct connection between the location of foreground emission on the sky and its location in cosmological power spectra from interferometric redshifted 21 cm experiments. We begin with a heuristic formalism for understanding the mapping of sky coordinates into the cylindrically averaged power spectra measurements used by 21 cm experiments, with a focus on the effects of the instrument beam response and the associated sidelobes. We then demonstrate this mapping by analyzing power spectra with both simulated and observed data from the Murchison Widefield Array. We find that removing a foreground model that includes sources in both the main field of view and the first sidelobes reduces the contamination in high k
∥ modes by several per cent relative to a model that only includes sources in the main field of view, with the completeness of the foreground model setting the principal limitation on the amount of power removed. While small, a percent-level amount of foreground power is in itself more than enough to prevent recovery of any Epoch of Reionization signal from these modes. This result demonstrates that foreground subtraction for redshifted 21 cm experiments is truly a wide-field problem, and algorithms and simulations must extend beyond the instrument’s main field of view to potentially recover the full 21 cm power spectrum.
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Detection of the cosmological neutral hydrogen signal from the Epoch of Reionization (EoR) and estimation of its basic physical parameters are principal scientific aims of many current low-frequency radio telescopes. Here we describe the Cosmological H i Power Spectrum Estimator (CHIPS), an algorithm developed and implemented with data from the Murchison Widefield Array, to compute the two-dimensional and spherically-averaged power spectrum of brightness temperature fluctuations. The principal motivations for CHIPS are the application of realistic instrumental and foreground models to form the optimal estimator, thereby maximizing the likelihood of unbiased signal estimation, and allowing a full covariant understanding of the outputs. CHIPS employs an inverse-covariance weighting of the data through the maximum likelihood estimator, thereby allowing use of the full parameter space for signal estimation (“foreground suppression”). We describe the motivation for the algorithm, implementation, application to real and simulated data, and early outputs. Upon application to a set of 3 hr of data, we set a 2σ upper limit on the EoR dimensionless power at
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[abstract] => Abstract The Murchison Widefield Array is a new low-frequency interferometric radio telescope built in Western Australia at one of the locations of the future Square Kilometre Array. We describe the automated radio-frequency interference detection strategy implemented for the Murchison Widefield Array, which is based on the aoflagger platform, and present 72–231 MHz radio-frequency interference statistics from 10 observing nights. Radio-frequency interference detection removes 1.1% of the data. Radio-frequency interference from digital TV is observed 3% of the time due to occasional ionospheric or atmospheric propagation. After radio-frequency interference detection and excision, almost all data can be calibrated and imaged without further radio-frequency interference mitigation efforts, including observations within the FM and digital TV bands. The results are compared to a previously published Low-Frequency Array radio-frequency interference survey. The remote location of the Murchison Widefield Array results in a substantially cleaner radio-frequency interference environment compared to Low-Frequency Array’s radio environment, but adequate detection of radio-frequency interference is still required before data can be analysed. We include specific recommendations designed to make the Square Kilometre Array more robust to radio-frequency interference, including: the availability of sufficient computing power for radio-frequency interference detection; accounting for radio-frequency interference in the receiver design; a smooth band-pass response; and the capability of radio-frequency interference detection at high time and frequency resolution (second and kHz-scale respectively).
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[abstract] => Abstract We compare first-order (refractive) ionospheric effects seen by the MWA with the ionosphere as inferred from GPS data. The first-order ionosphere manifests itself as a bulk position shift of the observed sources across an MWA field of view. These effects can be computed from global ionosphere maps provided by GPS analysis centres, namely the CODE. However, for precision radio astronomy applications, data from local GPS networks needs to be incorporated into ionospheric modelling. For GPS observations, the ionospheric parameters are biased by GPS receiver instrument delays, among other effects, also known as receiver DCBs. The receiver DCBs need to be estimated for any non-CODE GPS station used for ionosphere modelling. In this work, single GPS station-based ionospheric modelling is performed at a time resolution of 10 min. Also the receiver DCBs are estimated for selected Geoscience Australia GPS receivers, located at Murchison Radio Observatory, Yarragadee, Mount Magnet and Wiluna. The ionospheric gradients estimated from GPS are compared with that inferred from MWA. The ionospheric gradients at all the GPS stations show a correlation with the gradients observed with the MWA. The ionosphere estimates obtained using GPS measurements show promise in terms of providing calibration information for the MWA.
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[abstract] => Abstract
Despite a high complete hematologic remission (CHR) rate with imatinib-based therapy, the prognosis of elderly patients (pts.) with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) is poor, primarily due to relapse. Nilotinib (Tasigna®) is a potent ABL kinase inhibitor (TKI) approved for treatment of chronic and accelerated phase CML, but data on its efficacy in Ph+ ALL are limited. To study the activity of ABL-TKI in the front-line setting, the EWALL (European Working Group for Adult ALL) has developed a joint chemotherapeutic protocol for first-line therapy of elderly Ph+ ALL pts. (aged 55 years or more) that serves as a platform for the addition of targeted therapeutic agents. This chemotherapy backbone was used to test the efficacy and safety of the addition of nilotinib in elderly patients with newly diagnosed Ph+ ALL in a European, investigator-initiated trial.
Male or female pts. > 55 years with Ph+ and/or BCR-ABL1 positive ALL were eligible if they had not been previously treated except with corticosteroids, single dose vincristine or three doses of cyclophosphamide, had a WHO performance status of 0-2, adequate organ function and had signed written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of all participating centres. The trial was registered under NCT01528085. After a pre-phase with dexamethasone (Dex) 10 mg/m² d-7 to d-3 (cyclophosphamide 200mg/m² i.v. d-3 to d-1 optional), nilotinib was administered at 400 mg BID starting with induction therapy and given continuously thereafter. During induction, nilotinib was combined with IV injections of vincristine (VCR) 1 mg and Dex 40 mg on 2 days (20 mg over 70y), repeated weekly for 4 weeks. Consolidation cycles consisted of nilotinib 400 mg BID, methotrexate 1000 mg/m² IV d1 (500 mg/m² over 70y) and asparaginase 10,000 UI/m² IV d2 (5,000 UI/m² over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m²/12h IV d1, d3, d5 (500 mg/m² over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of nilotinib, 6-MP QD and methotrexate once weekly over 1 month every other month, and Dex/VCR in 2 month intervals for up to 24 months of treatment. The primary end-point is the rate of pts. without an event (defined as relapse, death, SAE or study treatment discontinuation) at 12 months, secondary endpoints include the rate of CHR after induction, death during induction or in CHR, event free (and overall survival, the rate of major (MMR) or complete molecular response (CMR) defined by BCR-ABL/ABL ratios < 0.1% and < 0.001%, respectively.
As of August 2014, 47 pts. (21 male, 26 female) have been enrolled. Median age is 66 years (55-85 years), twelve pts. are older than 70 years of age. To date, 43 pts. are evaluable for safety and 36 pts. are evaluable for efficacy. The CHR rate is 97% (35 of 36 pts. evaluable for response), one patient was refractory (3%). No patient died during induction therapy. With a median follow-up of 211 days, 31 of 35 evaluable pts. are in CCR and four pts. relapsed, two of whom had discontinued study treatment to undergo allogeneic SCT. 13 of the 36 pts. with documented induction response have discontinued study treatment prematurely, primarily because of transfer to allogeneic SCT (n=7), as explicitly permitted by the protocol. Six pts. discontinued for various other reasons. Eight of 35 CR pts. have completed the consolidation cycles and have entered maintenance phase, five pts. have completed protocol therapy. The rate of complete molecular remission (CMR) after induction (32 pts. evaluable) was 30%, with 2 pts. having undetectable BCR-ABL1 transcripts. During consolidation, 13 of 31 pts. (42%) had a CMR, and BCR-ABL transcripts were undetectable in 9 of 31 pts. (29%). Tolerability has been acceptable, with thirty-four SAEs reported so far, 11 during induction (of 43 pts.), 16 during consolidation (of 37 pts.), 6 during the maintenance phase and one following study discontinuation. Infectious events and neutropenic fever predominated, individual SAEs included metabolic, cardiovascular, neurologic, renal and hepatic events.
In conclusion, nilotinib in conjunction with chemotherapy according to the EWALL-PH-02 protocol is well tolerated and highly effective with a 97% CR in elderly pts. with newly diagnosed Ph+ ALL. Molecular response rates are high and MRD levels in responding pts. continue to decrease with time.
Disclosures
Ottmann: Novartis: Consultancy, Honoraria, Research Funding. Ribera:Novartis: Research Funding. Rousselot:Novartis: Research Funding.
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[abstract] => Abstract
Abstract 1473
Introduction:
L-asparaginase-loaded red blood cells (GRASPA®) has been shown to be a new available option for combining L-asparaginase with standard chemotherapy in different ALL population, including older patients with the disease. Tolerability and preliminary results of efficacy of GRASPA® in GRASPALL/GRAALL-SA2–2008 study have already been presented. We report below the 2-year follow-up efficacy results of this study.
Methods:
GRASPALL/GRAALL-SA2–2008 study aimed at determining optimal dose of GRASPA® that could be combined with standard EWALL chemotherapy backbone in patients aged >55y with newly diagnosed Ph-ALL. It was an open label Phase II dose escalation study. Primary endpoint combined tolerance and efficacy (asparagine depletion ≥7 days). Three doses of L-Asparaginase-Loaded Red Blood Cells (50, 100 and 150 IU/kg), infused twice during induction cycles, were investigated. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone d1–2/8–11, vincristine d1,8, and idarubicine d1–2/8–9) and induction-2 (cyclophosphamide d15–17 and cytarabine d16–19/23–26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (d1) / E.coli asparaginase (d2) and high-dose cytarabine (d1, 3, 5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for 2 years. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival were secondary endpoints.
Results:
Between March 2009 and October 2010, 30 patients were recruited in 20 centres in France by the GRAALL network. The 50, 100 and 150 dose levels included 3, 13 and 14 patients, respectively. Median age was 67 years (range 59–77). No differences in baseline characteristics were observed across the 3 dose level groups.
The tolerability with L-Asparaginase-related side effects is reported below:
Overall L-asp expected adverse events tended to be lower in the 100 UI/kg group.
Regarding the efficacy and benefit/risk, asparagines depletion, remission rate, EFS and OS are reported below:
Three patients received the dose of 50 UI/kg but this dose was insufficient to reach a 7-day asparagine depletion.
Survival analysis showed that the dose of 100IU/kg was associated with median OS of 15.6 months an absolute value that compared favorably with historical controls: 8,8 mo (Rousselot et al. Drugs Aging,2011) and 10,5 mo (Hunault et al. Haematologica,2011)
Conclusion:
GRASPA® at a dose of 100 UI/kg appears to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older patients with Ph- ALL with a sustained asparagine depletion and a good efficacy/safety profile.
Disclosures:
Godfrin: ERYTECH Pharma: COO Other.
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Abstract 666
Background.
Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. The EWALL group for adult ALL decided to run a study at the European level evaluating the combination of dasatinib and chemotherapy for Philadelphia positive (Ph+) ALL patients (pts) aged 55 and over.
Aim.
To analyse efficacy of Dasatinib combined to low intensity chemotherapy and to test factors associated with outcome. (EudraCT 2006–005694-21).
Methods.
After prephase, dasatinib was administered at 140 mg QD (100 mg over 70y) during the induction period in combination with weekly vincristine (VCR) 1 mg IV and dexamethasone (DEX) 40 mg for 2 days (20 mg over 70y) for 4 weeks. Consolidation
Disclosures:
Rousselot: BMS, Novartis: Research Funding. Gambacorti-Passerini:BMS, Novartis: Research Funding.
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[abstract] => Abstract
Abstract 2535
Background:
Minimal residual disease is well established as an important prognostic parameter in a number of hematologic diseases and is used for stratification and treatment decisions in adult and childhood acute lymphoblastic leukaemia (ALL). DNA- based PCR analysis of Ig-/TCR-rearrangements have been well standardised during the last decade, resulting in robust systems for MRD analysis with an intra- and inter-assay variability of less than half a log and low false positivity. In Ph+ALL, MRD analysis relies on RNA-based RT-PCR techniques that are highly sensitive but as yet lack standardisation between laboratories. Since laboratories differ substantially in both their methodology and analysis strategy, interpretation and meaningful comparison of results between laboratories and from different studies is difficult or impossible. Moreover, and in contrast to CML, there are no generally accepted definitions of molecular response that could identify thresholds on which to base therapeutic decisions.
Aims:
To assess i) the variability of BCR-ABL quantification between laboratories with recognized expertise in bcr-abl analysis, ii) identify optimal laboratory methods and iii) to standardize analysis and interpretation of RT-PCR results for Ph+ALL, the EWALL and ESG-MRD-ALL consortia initiated a multinational project for quality assurance involving more than 30 laboratories from 14 countries worldwide. We here report the results of the first six m-BCR-ABL laboratory control rounds, performed between march 2008 and august 2011, that focussed on inter-intraassay variability of rt-PR techniques, comparison of housekeeping genes, plasmids, platforms and reagents.
Methods:
Serial dilutions of the BCR-ABL positive cell line Sup B15 with the BCR-ABL negative cell line Nalm 6 covering 5 logs were produced. In the 6 lab rounds, 1355 aliquots, each generated from with a total amount of 5 × 10E+06 cells in a final volume of 1 ml were produced, stabilized in TRIZOL or buffer RLT and frozen at −20°C until shipment or centralized isolation of RNA and reverse transcribed. Participants were asked to process the material using predefined procedures.
Results:
In the first QC round a major finding was the high variability in RNA-yield between laboratories despite using the same extraction method, with an up to 3 log difference in ABL copy numbers. In addition, there was rare false-positivity and false negativity (specifity 94.8%). With centrally produced cDNA the variability improved and there was a lower frequency of false-positivity reaching 100% specifity in QC 2. By using standardized assays, in 12 of 33 laboratories no conversion factor is needed, 20 of 33 laboratories are at the moment within one log difference when comparing the BCR-ABL/ABL ratios. Comparison of housekeeping genes (ABL/GUS) revealed non-linearity at high transcript levels resulting in an underestimation of intraindividual log reductions and may be relevant when assessing disease prognosis. The quantitative range was generally above 10E-04.
Conclusion:
Initiation of laboratory control rounds and implementation of standardized methodology improved the variability and reduced the frequency of false-positive results. Sensitivity of current techniques is still unsatisfactory for diseases with aggressive growth kinetics such as Ph*ALL. Further standardisation of technical and analytical methodology will provide the basis for defining levels of molecular remission and relapse and help to ensure comparability between laboratories and clinical trials at the European level.
Disclosures:
Goekbuget: Micromet: Consultancy. Ottmann:Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding.
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[abstract] => Abstract
Abstract 2579
Introduction:
In adults with Ph- ALL, the clinical benefit of L-asparaginase is hampered by its toxicity. With its improved efficacy/tolerability potential, L-asparaginase-loaded red blood cells (GRASPA®) could be a suitable option for combining L-asparaginase with standard chemotherapy, especially in older patients with the disease.
Methods:
The GRASPALL/GRAALL-SA2-2008 was an open label Phase II dose escalation study conducted by the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) in patients aged >55y with newly diagnosed ALL Ph-. The aim was to determine the optimal dose of GRASPA® that could be combined with the standard EWALL chemotherapy backbone in these patients. The primary composite endpoint included tolerance and efficacy, the latter being defined as the achievement of target asparagine depletion for at least 7 days. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival and anti L-asparaginase antibody titer (Abs), were secondary endpoints. Three doses of Graspa® (50, 100 and 150 IU/kg), infused at d3 and d6 of two successive induction cycles, were investigated, using a Bayesian experimental plan. After each 3-pt cohort, an independent Data Safety Monitoring Board reviewed study drug tolerance before opening the next dose. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone 10 mg/m2 d1-2,/8-11, vincristine 1 mg d1,8, and idarubicine 10 mg d1-2/8-9) and induction-2 (cyclophosphamide 500 mg/m2 d15-17 and cytarabine 60 mg/m2 d16-19/23-26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (1 g/m2 d1), E.coli asparaginase (10,000 IU/m2 d2) and high-dose cytarabine (1 g/m2/q12 hrs d1,3,5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for a total duration of 2 years. Dose reductions were recommended for pts aged >70y.
Results:
Between March 2009 and October 2010, 30 pts were recruited in 20 GRAALL centers. The 50, 100 and 150 dose levels included 3, 13 and 14 pts, respectively. Median age was 67 years (range 59–77). Twenty-six pts had B-lineage ALL and 4 had T-ALL. No differences in baseline characteristics were observed across the 3 dose level groups. Overall, 0 (0%), 2 (15%) and 5 (36%) pts presented limiting toxicities in the 50, 100 and 150 dose level, respectively. Because of insufficient efficacy, only 3 pts received the lower 50 IU/kg dose. At the higher 100 and 150 dose levels, 85% and 71% pts reached target asparagine depletion at d7, respectively. In these two 100 and 150 IU/kg groups, grade 3/4 infections were observed in 69% and 71% pts and invasive fungal infection in 23% and 43% pts, respectively. Incidences of adverse events tended to be lower in the 100 IU/kg group:
Anti L-asparaginase Abs were detected in 0/3, 2/13 and 1/14 pts after induction-1 and 1/2, 3/9 and 5/9 pts after induction-2, in the 50, 100 and 150 dose level group, respectively. Nevertheless, no clinical allergy was observed after the second drug infusion, but allergic reactions to native E-Coli L-asparaginase were observed in 5/19 pts after consolidation 1. Grade 3–4 infections and renal methotrexate toxicities were observed in 11% (11/99) and 10% (11/51) of consolidations courses.
Responses to therapy were as follows:
Conclusion:
Two infusions of 100 IU/kg GRASPA® appear to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older pts with Ph- ALL. Larger prospective evaluations of this new L-asparaginase formulation are warranted.
Disclosures:
Liens: ERYTECH Pharma: Employment, Equity Ownership. Godfrin:ERYTECH Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Abstract 172
Background.
Dasatinib (Sprycel®) is a potent inhibitor of BCR-ABL and SRC family kinases. Based on the rapid and clinically meaningful activity observed when dasatinib was used as a single agent a consensus has been reached by the EWALL (European Working Group for Adult ALL) to conduct an international study evaluating the combination of dasatinib and low-intensity chemotherapy in patients with Ph+ ALL aged 55 years or more.
Patients and Methods.
After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, dasatinib was administered at 140 mg QD (100 mg in patients over 70y) during the induction period in combination with IV injections of vincristine 1 mg and dexamethasone 40 mg 2 days (20 mg over 70y) repeated weekly for 4 weeks. Consolidation cycles consisted of dasatinib 100 mg/d administered sequentially with methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and L-asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 and cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted of dasatinib alternating with 6-MP and methotrexate orally every other month and dexamethasone/vincristine once every 2 months for up to 24 months. Patients were molecularly monitored by a central laboratory for BCR-ABL RTQ-PCR and T315I resistance mutation ASO RTQ-PCR.
Results.
Seventy one patients were included from August 2007 to study termination in May 2010. Median age was 69.1 years (range: 58–83). Median follow-up was 16.3 months. At diagnosis, the Ph chromosome was associated with other abnormalities (complex, -7, Ph duplication or others) in 64.5% of cases. The CR rate after induction was 90% and 55.7% of the patients achieved a BCR-ABL/ABL ratio ≤0.1% at the time of CR. Failure to achieve CR was mainly related to death (n=5.7%). Serious adverse events (SAEs) during induction were infections (11%), elevated transaminases (7%), hemorrhage (5.6%), renal failure due to tumor lysis syndrome (4.2%) and cardiovascular events (5.6%). Only 2 pleural effusions were observed. During consolidation and maintenance, most frequent SAEs were infections (33.3%). One pleural effusion was observed. Nineteen patients relapsed after a median response duration of 19.2 weeks and 12 of them died. Thirteen patients presented mutations in the BCR-ABL TK domain at relapse (12 T315I, 1 F317L), no mutation was detected in 3 patients and results are pending in 3 patients. T315I ASO RTQ-PCR analysis during follow-up was predictive for relapse. The rise of the T315I signal over 0.1% was always associated with relapse and occurred 1 to 3 months before relapse in 6 of the 12 T315I cases and concomitantly in the 6 remaining patients. Four patients received RIC allogenic stem cell transplantation and were censored at the time of SCT. Median RFS and OS were 22.1 and 27.1 months, respectively. Cytogenetics findings at diagnosis were good predictors for RFS: the median RFS for patients with isolated Ph was not reached while it was 19.2 months in patients with additional cytogenetic abnormalities (p=0.03)). Molecular BCR-ABL transcript level after induction had no effect on RFS. However, a BCR-ABL ratio ≤0.1% after induction and then confirmed during consolidation was significantly associated with a better RFS (5.1 months versus not reached, p=0.006).
Conclusions.
Dasatinib combined with low-intensity chemotherapy is highly effective in elderly patients with Ph-positive ALL with a 90% CR rate and a 22.1 months RFS. Cytogenetics at diagnosis is a strong predictive factor for RFS. Most relapses were associated with the T315I mutation. Serial monitoring for T315I allowed us to predict for hematological relapse and may offer an opportunity to adapt therapy before relapse.
Disclosures:
Rousselot: Bristol Myers Squibb: Research Funding. Off Label Use: Dasatinib as first line therapy in Ph ALL.
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Abstract 2130
The use of granulocyte colony stimulating factor (G-CSF), either filgrastim or lenograstim, along with induction and consolidation of adults with acute lymphoblastic leukemia (ALL) was a subject of several trials documenting significant shortening of neutropenia, reduced rate of infections and better adherence to chemotherapy protocol. The above studies, however, were not powered to detect differences with regard to long-term outcome.
We performed a joint analysis of follow-up data from five multicenter prospective, randomized trials performed in France, Poland, Sweden, Austria and Australia. Among 347 adults with ALL (median age 33 years), 185 were assigned to receive prophylactically G-CSF while 162 patients were treated without G-CSF support. G-CSF was administered either in parallel to chemotherapy or in a sequential mode.
With the median follow-up of 3.2 years, the remission duration was significantly longer for patients receiving G-CSF compared to controls (33 vs. 17 months, p=0.007). The difference was particularly pronounced for T-ALL (median not reached vs. 13 m., p=0.01) and a trend was observed for B-ALL (22 vs. 17 m., p=0.11). The 5-years probability of leukemia-free survival (LFS) was 38% for patients assigned to the G-CSF arm and 23% for the remaining subjects (p=0.01). There was also a tendency to increased overall survival (OS) rate in favor of patients receiving G-CSF (45% vs. 39%, p=0.17), which reached statistical significance in a subgroup of T-ALL (54% vs. 33%, p=0.03). In a multivariate analysis adjusted to age, initial WBC and the presence of Ph chromosome the prophylactic use of G-CSF was associated with reduced risk of relapse (HR=0.65, p=0.01) and treatment failure (HR=0.7, p=0.02). The differences remained significant when the observations were censored at the time of alloHSCT.
We conclude that the prophylactic use of G-CSF during induction and consolidation of adults with ALL is associated with reduced risk of relapse and improved LFS. The possible explanation could be better adherence to chemotherapy schedules, as demonstrated in previous studies. Patients with T-ALL appear to particularly benefit from the use of G-CSF.
Disclosures:
No relevant conflicts of interest to declare.
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[abstract] => Abstract
Dasatinib (Sprycel®, Bristol-Myers Squibb) is a potent multi-targeted kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. Despite a 33% complete hematological response (CHR) rate in a Phase 2 study in patients with Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL) intolerant or resistant to imatinib, the median duration of progression-free survival (PFS) was 3.3 months (Ottmann et al. Blood. 2007;110:2309-2315). Second-generation TKI may thus have a place in the management of these patients. As a European consensus has been reached by the EWALL to adopt a common first-line chemotherapeutic schedule for elderly patients (aged 55 years or more) with Ph-positive ALL, this schedule was used here to test the addition of dasatinib. After a prephase with dexamethasone 10 mg/m2 d-7 to d-3, the induction phase consisted in IV injections of vincristine 1 mg combined with 2 days of dexamethasone 40 mg PO repeated weekly for 4 weeks followed by consolidation cycles including methotrexate 1000 mg/m2 IV d1 (500 mg/m2 over 70y) and asparaginase 10,000 UI/m2 IM d2 (5,000 UI/m2 over 70y) for cycles 1, 3 and 5 alternating with cytarabine 1,000 mg/m2/12h IV d1, d3, d5 (500 mg/m2 over 70y) for cycles 2, 4 and 6. Maintenance phase consisted in 6-MP 60 mg/m2/d and methotrexate 25 mg/m2/week orally 1 month every other month and dexamethasone/vincristine in 2 months intervals during the first year and in 3 months intervals during the second year. Dasatinib (provided by Bristol-Myers Squibb) was administered at 140 mg per day (QD) during the induction period in combination with chemotherapy and at 100 mg/d sequentially with the chemotherapy courses during consolidation and maintenance. BCRABL analysis was performed according to the European Leukemia Net recommendations in two centralized laboratories.
A total of 22 patients were included from August 2007 to June 2008. Median age was 71 years (range, 61 to 83), sex ratio (M/F) was 0,46, and median follow-up was 5.8 months. The Ph+ chromosome was associated with complex abnormalities in 58% of cases and 84% of the patients were m-BCR. The CHR rate was 95.2% (20 out of 21 evaluable patients). The only case of induction failure was due to death. The rate of complete molecular remission (CMR) after induction was 33% in blood and 28% in bone marrow and MRD level continued to decrease with time. Only one relapse was observed before the consolidation phase. No other relapse occurred for the 13 patients in CHR still in study after a median follow-up of 3.6 months. One patient died during induction from invasive aspergillosis, 3 deaths occurred in CR, 2 before consolidation due to pulmonary embolism and physical deterioration, and one during maintenance from pneumonia. Serious adverse events (SAEs) were reported in 7 out of 22 patients during induction (31.8%) and in 2 out of 13 patients during maintenance and consolidation (15.3%). SAEs consisted in renal failure (n=3, 2 from acute lysis syndrome and 1 tubular necrosis), invasive aspergillosis (n=1), pulmonary embolism (n=2), pneumonia (n=1), atrial arythmia (n=2), pleural effusion (n=1), microangiopathy (n=1), cytolytic hepatitis (n=1) and physical deterioration (n=1). Eight patients discontinued the study after induction (35%). Primary reasons for discontinuation were SAEs (n=4), death (n=3) and relapse (n=1).
The EWALL-PH-01 protocol is highly effective with a 95.2% RCH rate in elderly patients with Ph-positive ALL. Of importance, responses appeared to be durable and MRD level was decreasing over time. An expected 40% rate of SAEs was observed in this elderly population. Reduced doses of therapy are now applied for patients over 70y (20 mg for dexamethasone, 100 mg/d for dasatinib).
[DOI] => 10.1182/blood.v112.11.2920.2920
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[abstract] => We introduce EWall, an experimental visual analytics environment for the support of remote-collaborative sense-making activities. EWall is designed to foster and support ‘ object focused thinking’, where users represent and understand information as objects, construct and recognize contextual relationships among objects, as well as communicate through objects. EWall also offers a unified infrastructure for the implementation and testing of computational agents that consolidate user contributions and manage the flow of information among users through the creation and management of a ‘ virtual transactive memory’. EWall users operate their individual graphical interfaces to collect, abstract, organize and comprehend task-relevant information relative to their areas of expertise. A first type of computational agents infers possible relationships among information items through the analysis of the spatial and temporal organization and collaborative use of information. All information items and relationships converge in a shared database. A second type of computational agents evaluates the contents of the shared database and provides individual users with a customized selection of potentially relevant information. A learning mechanism allows the computational agents to adapt to particular users and circumstances. EWall is designed to enable individual users to navigate vast amounts of shared information effectively and help remotely dispersed team members combine their contributions, work independently without diverting from common objectives, and minimize the necessary amount of verbal communication.
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- No errors