Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.
We evaluated infection-related complications that were grade ...≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.
Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n= 389), followed by ear (n= 151), bloodstream (n= 147), and gastrointestinal tract (n= 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n= 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1–9.9 years at diagnosis was associated with febrile neutropenia (P= 0.002) during induction and febrile neutropenia and documented infection (both P< 0.001) during later continuation. White race was associated with documented infection (P= 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P< 0.001) and documented infections (P= 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P< 0.001).
The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.
The second-generation of gravitational-wave detectors are just starting operation, and have already yielding their first detections. Research is now concentrated on how to maximize the scientific ...potential of gravitational-wave astronomy. To support this effort, we present here design targets for a new generation of detectors, which will be capable of observing compact binary sources with high signal-to-noise ratio throughout the Universe.
We present IRAM-30 m Telescope 12CO and 13CO observations of a sample of 55 luminous and ultraluminous infrared galaxies (LIRGs and ULIRGs) in the local universe. This sample is a subset of the Great ...Observatory All-Sky LIRG Survey (GOALS), for which we use ancillary multi-wavelength data to better understand their interstellar medium and star formation properties. Fifty-three (96%) of the galaxies are detected in 12CO, and 29 (52%) are also detected in 13CO above a 3σ level. The median full width at zero intensity (FWZI) velocity of the CO line emission is 661 km s−1, and ∼54% of the galaxies show a multi-peak CO profile. Herschel photometric data is used to construct the far-IR spectral energy distribution of each galaxy, which are fit with a modified blackbody model that allows us to derive dust temperatures and masses, and infrared luminosities. We make the assumption that the gas-to-dust mass ratio of (U)LIRGs is comparable to local spiral galaxies with a similar stellar mass (i.e., gas/dust of mergers is comparable to their progenitors) to derive a CO-to-H2 conversion factor of ⟨α⟩ = 1.8−0.8+1.3 M⊙ ⟨ α ⟩ = 1 . 8 − 0.8 + 1.3 M ⊙ $ \langle\alpha\rangle=1.8^{+1.3}_{-0.8}\,M_\odot $ (K km s−1 pc2)−1; such a value is comparable to that derived for (U)LIRGs based on dynamical mass arguments. We derive gas depletion times of 400 − 600 Myr for the (U)LIRGs, compared to the 1.3 Gyr for local spiral galaxies. Finally, we re-examine the relationship between the 12CO/13CO ratio and dust temperature, confirming a transition to elevated ratios in warmer systems.
With improved contemporary therapy, we reassess long-term outcome in patients completing treatment for childhood acute lymphoblastic leukemia (ALL) to determine when cure can be declared with a high ...degree of confidence. In six successive clinical trials between 1984 and 2007, 1291 (84.5%) patients completed all therapies in continuous complete remission. The post-therapy cumulative risk of relapse or development of a second neoplasm and the event-free survival rate and overall survival were analyzed according to the presenting features and the three treatment periods defined by relative outcome. Over the three treatment periods, there has been progressive increase in the rate of event-free survival (65.2% vs 74.8% vs 85.1% (P<0.001)) and overall survival (76.5% vs 81.1% vs 91.7% (P<0.001)) at 10 years. The most important predictor of outcome after completion of therapy was the type of treatment. In the most recent treatment period, which omitted the use of prophylactic cranial irradiation, the post-treatment cumulative risk of relapse was 6.4%, death in remission 1.5% and development of a second neoplasm 2.3% at 10 years, with all relapses except one occurring within 4 years of therapy. None of the 106 patients with the t(9;22)/BCR-ABL1, t(1;19)/TCF3-PBX1 or t(4;11)/MLL-AFF1 had relapsed after 2 years from completion of therapy. These findings demonstrate that with contemporary effective therapy that excludes cranial irradiation, approximately 6% of children with ALL may relapse after completion of treatment, and those who remain in remission at 4 years post treatment may be considered cured (that is, less than 1% chance of relapse).
Endometrial cancer (EC) is often the sentinel cancer in women with Lynch syndrome (LS). However, efforts to implement universal LS screening in EC patients have been hampered by a lack of evidence ...detailing the proportion of EC patients that would be expected to screen positive for LS.
Studies were identified by electronic searches of Medline, Embase, Cochrane CENTRAL and Web of Science. Proportions of test positivity were calculated by random and fixed-effects meta-analysis models. I
score was used to assess heterogeneity across studies.
Fifty-three studies, including 12,633 EC patients, met the inclusion criteria. The overall proportion of endometrial tumors with microsatellite instability or mismatch repair (MMR) deficiency by immunohistochemistry (IHC) was 0.27 (95% confidence interval CI 0.25-0.28, I
: 71%) and 0.26 (95% CI 0.25-0.27, I
: 88%), respectively. Of those women with abnormal tumor testing, 0.29 (95% CI 0.25-0.33, I
: 83%) had LS-associated pathogenic variants on germline testing; therefore around 3% of ECs can be attributed to LS. Preselection of EC cases did increase the proportion of germline LS diagnoses.
The current study suggests that prevalence of LS in EC patients is approximately 3%, similar to that of colorectal cancer patients; therefore our data support the implementation of universal EC screening for LS.
Widely used as anticancer and immunosuppressive agents, thiopurines have narrow therapeutic indices owing to frequent toxicities, partly explained by TPMT genetic polymorphisms. Recent studies ...identified germline NUDT15 variation as another critical determinant of thiopurine intolerance, but the underlying molecular mechanisms and the clinical implications of this pharmacogenetic association remain unknown. In 270 children enrolled in clinical trials for acute lymphoblastic leukemia in Guatemala, Singapore and Japan, we identified four NUDT15 coding variants (p.Arg139Cys, p.Arg139His, p.Val18Ile and p.Val18_Val19insGlyVal) that resulted in 74.4-100% loss of nucleotide diphosphatase activity. Loss-of-function NUDT15 diplotypes were consistently associated with thiopurine intolerance across the three cohorts (P = 0.021, 2.1 × 10(-5) and 0.0054, respectively; meta-analysis P = 4.45 × 10(-8), allelic effect size = -11.5). Mechanistically, NUDT15 inactivated thiopurine metabolites and decreased thiopurine cytotoxicity in vitro, and patients with defective NUDT15 alleles showed excessive levels of thiopurine active metabolites and toxicity. Taken together, these results indicate that a comprehensive pharmacogenetic model integrating NUDT15 variants may inform personalized thiopurine therapy.
We report the discovery of TOI 837b and its validation as a transiting planet. We characterize the system using data from the NASA Transiting Exoplanet Survey Satellite mission, the ESA Gaia mission, ...ground-based photometry from El Sauce and ASTEP400, and spectroscopy from CHIRON, FEROS, and Veloce. We find that TOI 837 is a T = 9.9 mag G0/F9 dwarf in the southern open cluster IC 2602. The star and planet are therefore million years old. Combining the transit photometry with a prior on the stellar parameters derived from the cluster color-magnitude diagram, we find that the planet has an orbital period of and is slightly smaller than Jupiter ( ). From radial velocity monitoring, we limit to less than 1.20 MJup (3 ). The transits either graze or nearly graze the stellar limb. Grazing transits are a cause for concern, as they are often indicative of astrophysical false-positive scenarios. Our follow-up data show that such scenarios are unlikely. Our combined multicolor photometry, high-resolution imaging, and radial velocities rule out hierarchical eclipsing binary scenarios. Background eclipsing binary scenarios, though limited by speckle imaging, remain a 0.2% possibility. TOI 837b is therefore a validated adolescent exoplanet. The planetary nature of the system can be confirmed or refuted through observations of the stellar obliquity and the planetary mass. Such observations may also improve our understanding of how the physical and orbital properties of exoplanets change in time.
The observation of hyperfine structure in atomic hydrogen by Rabi and co-workers and the measurement of the zero-field ground-state splitting at the level of seven parts in 10
are important ...achievements of mid-twentieth-century physics. The work that led to these achievements also provided the first evidence for the anomalous magnetic moment of the electron, inspired Schwinger's relativistic theory of quantum electrodynamics and gave rise to the hydrogen maser, which is a critical component of modern navigation, geo-positioning and very-long-baseline interferometry systems. Research at the Antiproton Decelerator at CERN by the ALPHA collaboration extends these enquiries into the antimatter sector. Recently, tools have been developed that enable studies of the hyperfine structure of antihydrogen-the antimatter counterpart of hydrogen. The goal of such studies is to search for any differences that might exist between this archetypal pair of atoms, and thereby to test the fundamental principles on which quantum field theory is constructed. Magnetic trapping of antihydrogen atoms provides a means of studying them by combining electromagnetic interaction with detection techniques that are unique to antimatter. Here we report the results of a microwave spectroscopy experiment in which we probe the response of antihydrogen over a controlled range of frequencies. The data reveal clear and distinct signatures of two allowed transitions, from which we obtain a direct, magnetic-field-independent measurement of the hyperfine splitting. From a set of trials involving 194 detected atoms, we determine a splitting of 1,420.4 ± 0.5 megahertz, consistent with expectations for atomic hydrogen at the level of four parts in 10
. This observation of the detailed behaviour of a quantum transition in an atom of antihydrogen exemplifies tests of fundamental symmetries such as charge-parity-time in antimatter, and the techniques developed here will enable more-precise such tests.
Abstract
We present the results of a Hubble Space Telescope WFC3 near-UV and Advanced Camera for Surveys Wide Field Channel optical study into the star cluster populations of a sample of 10 luminous ...infrared galaxies (LIRGs) in the Great Observatories All-Sky LIRG Survey. Through integrated broadband photometry we have derived ages, masses, and extinctions for a total of 1027 star clusters in galaxies with
d
L
< 110 Mpc in order to avoid issues related to cluster bending. The measured cluster age distribution slope of
dN
/
d
τ
∝
τ
−
0.5
+
/
−
0.12
is steeper than what has been observed in lower-luminosity star-forming galaxies. Further, differences in the slope of the observed cluster age distribution between inner- (
dN
/
d
τ
∝
τ
−
1.07
+
/
−
0.12
) and outer-disk (
dN
/
d
τ
∝
τ
−
0.37
+
/
−
0.09
) star clusters provide evidence of mass-dependent cluster destruction in the central regions of LIRGs driven primarily by the combined effect of strong tidal shocks and encounters with massive giant molecular clouds. Excluding the nuclear ring surrounding the Seyfert 1 nucleus in NGC 7469, the derived cluster mass function (CMF;
dN
/
dM
∝
M
α
) offers marginal evidence for a truncation in the power law at
M
t
∼ 2×10
6
M
⊙
for our three most
cluster-rich
sources, which are all classified as early stage mergers. Finally, we find evidence of a flattening of the CMF slope of
dN
/
dM
∝
M
−
1.42
±
0.1
for clusters in late-stage mergers relative to early stage (
α
= −1.65 ± 0.02), which we attribute to an increase in the formation of massive clusters over the course of the interaction.
We present HST narrowband near-infrared imaging of Pa and Paβ emission of 48 local luminous infrared galaxies (LIRGs) from the Great Observatories All-Sky LIRG Survey. These data allow us to measure ...the properties of 810 spatially resolved star-forming regions (59 nuclei and 751 extranuclear clumps) and directly compare their properties to those found in both local and high-redshift star-forming galaxies. We find that in LIRGs the star-forming clumps have radii ranging from ∼90 to 900 pc and star formation rates (SFRs) of ∼1 × 10−3 to 10 M yr−1, with median values for extranuclear clumps of 170 pc and 0.03 M yr−1. The detected star-forming clumps are young, with a median stellar age of 8.7 Myr, and have a median stellar mass of 5 × 105 M . The SFRs span the range of those found in normal local star-forming galaxies to those found in high-redshift star-forming galaxies at z = 1-3. The luminosity function of the LIRG clumps has a flatter slope than found in lower-luminosity, star-forming galaxies, indicating a relative excess of luminous star-forming clumps. In order to predict the possible range of star-forming histories and gas fractions, we compare the star-forming clumps to those measured in the MassiveFIRE high-resolution cosmological simulation. The star-forming clumps in MassiveFIRE cover the same range of SFRs and sizes found in the local LIRGs and have total gas fractions that extend from 10% to 90%. If local LIRGs are similar to these simulated galaxies, we expect that future observations with ALMA will find a large range of gas fractions, and corresponding star formation efficiencies, among the star-forming clumps in LIRGs.
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