Substantial heterogeneity within mutant TP53 acute myeloid leukemia (AML) and myelodysplastic syndrome with excess of blast (MDS-EB) precludes the exact assessment of prognostic impact for individual ...patients. We performed in-depth clinical and molecular analysis of mutant TP53 AML and MDS-EB to dissect the molecular characteristics in detail and determine its impact on survival. We performed next-generation sequencing on 2200 AML/MDS-EB specimens and assessed the TP53 mutant allelic status (mono- or bi-allelic), the number of TP53 mutations, mutant TP53 clone size, concurrent mutations, cytogenetics, and mutant TP53 molecular minimal residual disease and studied the associations of these characteristics with overall survival. TP53 mutations were detected in 230 (10.5%) patients with AML/MDS-EB with a median variant allele frequency of 47%. Bi-allelic mutant TP53 status was observed in 174 (76%) patients. Multiple TP53 mutations were found in 49 (21%) patients. Concurrent mutations were detected in 113 (49%) patients. No significant difference in any of the aforementioned molecular characteristics of mutant TP53 was detected between AML and MDS-EB. Patients with mutant TP53 have a poor outcome (2-year overall survival, 12.8%); however, no survival difference between AML and MDS-EB was observed. Importantly, none of the molecular characteristics were significantly associated with survival in mutant TP53 AML/MDS-EB. In most patients, TP53 mutations remained detectable in complete remission by deep sequencing (73%). Detection of residual mutant TP53 was not associated with survival. Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival. Therefore, mutant TP53 AML/MDS-EB should be considered a distinct molecular disease entity.
•Mutant TP53 AML and MDS-EB do not differ with respect to molecular characteristics and survival.•Mutant TP53 AML/MDS-EB should be considered a single molecular disease entity.
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Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) were recently demonstrated in acute myeloid leukemia (AML), but their prevalence and prognostic impact remain to be explored in ...large extensively characterized AML series, and also in various other hematologic malignancies. Here, we demonstrate in 893 newly diagnosed cases of AML mutations in the IDH1 (6%) and IDH2 (11%) genes. Moreover, we identified IDH mutations in 2 JAK2 V617F myeloproliferative neoplasias (n = 96), a single case of acute lymphoblastic leukemia (n = 96), and none in chronic myeloid leukemias (n = 81). In AML, IDH1 and IDH2 mutations are more common among AML with normal karyotype and NPM1mutant genotypes. IDH1 mutation status is an unfavorable prognostic factor as regards survival in a composite genotypic subset lacking FLT3ITD and NPM1mutant. Thus, IDH1 and IDH2 mutations are common genetic aberrations in AML, and IDH1 mutations may carry prognostic value in distinct subtypes of AML.
The applicability of
-internal tandem duplications (
-ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by ...patient-specific duplications and potential instability of
-ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based
-ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant
and multiparameter flow cytometry.
In 161 patients with de novo
-ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment.
-ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS).
NGS-based
-ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of
-ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75%
-ITD MRD
33% no
-ITD MRD;
< .001) and inferior OS (4-year OS, 31%
-ITD MRD
57% no
-ITD MRD;
< .001). In multivariate analysis, detection of
-ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55;
< .001) and OS (hazard ratio 2.51;
= .002). Strikingly,
-ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the
-ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant
detection or multiparameter flow cytometry.
NGS-based detection of
-ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for
-ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.
Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been described in various types of myeloid malignancies, including acute myeloid leukemia. Analysis of novel markers, such as ...ASXL1 mutations, in independent clinical trials is indispensable before considering them for clinical decision-making. We analyzed 882 well-characterized acute myeloid leukemia cases to determine the prevalence and prognostic impact of ASXL1 exon12 mutations. Truncating ASXL1 mutations were present in 46 cases (5.3%). ASXL1 mutations were inversely associated with FLT3 internal tandem duplications and mutually exclusive with NPM1 mutations. ASXL1 mutations were an unfavorable prognostic factor as regards survival (median overall survival 15.9 months vs. 22.3 months; P=0.019), with a significantly lower complete response rate (61% vs. 79.6%; P=0.004). In multivariate analyses, ASXL1 mutations were independently associated with inferior poor overall survival (HR 1.52, P=0.032). In conclusion, ASXL1 mutations are common mutations in acute myeloid leukemia and indicate a poor therapy outcome.
The scattering trans-Neptunian Objects (TNOs) can be measured to smaller sizes than any other distant small-body population. We use the largest sample yet obtained, 68 discoveries, primarily by the ...Outer Solar System Origins Survey (OSSOS), to constrain the slope of its luminosity distribution, with sensitivity to much fainter absolute H-magnitudes than previous work. Using the analysis technique in Shankman et al., we confirm that a single slope for the H-distribution is not an accurate representation of the scattering TNOs and Centaurs, and that a break in the distribution is required, in support of previous conclusions. A bright-end slope of b = 0.9 transitioning to a faint-end slope f of 0.4-0.5 with a differential number contrast c from 1 (a knee) to 10 (a divot) provides an acceptable match to our data. We find that break magnitudes Hb of 7.7 and 8.3, values both previously suggested for dynamically hot Kuiper Belt populations, are equally non-rejectable for a range of f and c in our statistical analysis. Our preferred divot H-distribution transitions to f = 0.5 with a divot of contrast c = 3 at Hb = 8.3, while our preferred knee H-distribution transitions to f = 0.4 at Hb = 7.7. The intrinsic population of scattering TNOs required to match the OSSOS detections is 3 × 106 for Hr < 12, and 9 × 104 for Hr < 8.66 (D 100 km), with Centaurs having an intrinsic population two orders of magnitude smaller.
ABSTRACT We report the discovery, tracking, and detection circumstances for 85 trans-Neptunian objects (TNOs) from the first 42 deg2 of the Outer Solar System Origins Survey. This ongoing r-band ...solar system survey uses the 0.9 deg2 field of view MegaPrime camera on the 3.6 m Canada-France-Hawaii Telescope. Our orbital elements for these TNOs are precise to a fractional semimajor axis uncertainty <0.1%. We achieve this precision in just two oppositions, as compared to the normal three to five oppositions, via a dense observing cadence and innovative astrometric technique. These discoveries are free of ephemeris bias, a first for large trans-Neptunian surveys. We also provide the necessary information to enable models of TNO orbital distributions to be tested against our TNO sample. We confirm the existence of a cold "kernel" of objects within the main cold classical Kuiper Belt and infer the existence of an extension of the "stirred" cold classical Kuiper Belt to at least several au beyond the 2:1 mean motion resonance with Neptune. We find that the population model of Petit et al. remains a plausible representation of the Kuiper Belt. The full survey, to be completed in 2017, will provide an exquisitely characterized sample of important resonant TNO populations, ideal for testing models of giant planet migration during the early history of the solar system.
Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this ...comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein-coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.
We use published models of the early solar system evolution with a slow, long-range and grainy migration of Neptune to predict the orbital element distributions and the number of modern-day Centaurs. ...The model distributions are biased by the Outer Solar System Origins Survey (OSSOS) simulator and compared with the OSSOS Centaur detections. We find an excellent match to the observed orbital distribution, including the wide range of orbital inclinations which was the most troublesome characteristic to fit in previous models. A dynamical model, in which the original population of outer disk planetesimals was calibrated from Jupiter trojans, is used to predict that OSSOS should detect 11 4 Centaurs with semimajor axes of a < 30 au, perihelion distances of q > 7.5 au, and diameter of D > 10 km (absolute magnitude Hr < 13.7 for a 6% albedo). This is consistent with 15 actual OSSOS Centaur detections with Hr < 13.7. The population of Centaurs is estimated to be 21,000 8000 for D > 10 km. The inner scattered disk at 50 < a < 200 au should contain (2.0 0.8) × 107 D > 10 km bodies and the Oort cloud should contain (5.0 1.9) × 108 D > 10 km comets. Population estimates for different diameter cutoffs can be obtained from the size distribution of Jupiter trojans (N(>D) ∝ D−2.1 for 5 < D < 100 km). We discuss model predictions for the Large Synoptic Survey Telescope observations of Centaurs.
ABSTRACT The first two observational sky "blocks" of the Outer Solar System Origins Survey (OSSOS) have significantly increased the number of well characterized observed trans-Neptunian objects ...(TNOs) in Neptune's mean motion resonances. We describe the 31 securely resonant TNOs detected by OSSOS so far, and we use them to independently verify the resonant population models from the Canada-France Ecliptic Plane Survey (CFEPS), with which we find broad agreement. We confirm that the 5:2 resonance is more populated than models of the outer solar system's dynamical history predict; our minimum population estimate shows that the high-eccentricity (e > 0.35) portion of the resonance is at least as populous as the 2:1 and possibly as populated as the 3:2 resonance. One OSSOS block was well suited for detecting objects trapped at low libration amplitudes in Neptune's 3:2 resonance, a population of interest in testing the origins of resonant TNOs. We detected three 3:2 objects with libration amplitudes below the cutoff modeled by CFEPS; OSSOS thus offers new constraints on this distribution. The OSSOS detections confirm that the 2:1 resonance has a dynamically colder inclination distribution than either the 3:2 or 5:2 resonances. Using the combined OSSOS and CFEPS 2:1 detections, we constrain the fraction of 2:1 objects in the symmetric mode of libration to 0.2-0.85; we also constrain the fraction of asymmetric librators in the leading island, which has been theoretically predicted to vary depending on Neptune's migration history, to be 0.05-0.8. Future OSSOS blocks will improve these constraints.
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