Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity.
ASNase (
) substitution was approved in 2011 for ...allergic reactions.
has, however, been intermittently unavailable because of drug supply issues. The impact of
substitution or complete ASNase discontinuation is unknown.
Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute NCI standard risk SR: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to
but receiving all doses versus not receiving all ASNase doses.
We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio HR, 1.5; 95% CI, 1.2 to 1.9;
= .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with
substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6;
= .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6;
= .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7;
= .03).
Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of
shortages.
Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of IGH and TRG genes vs flow ...cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk SR; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.
•HTS identifies MRD at the conventional clinical cutoff in more patients than FC, and these patients have worse outcomes.•A subset of B-ALL patients essentially cured using current chemotherapy is identified at end of induction by HTS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Climate and land‐use/land‐cover change (“global change”) are restructuring biodiversity, globally. Broadly, environmental conditions are expected to become warmer, potentially drier (particularly in ...arid regions), and more anthropogenically developed in the future, with spatiotemporally complex effects on ecological communities. We used functional traits to inform Chesapeake Bay Watershed fish responses to future climate and land‐use scenarios (2030, 2060, and 2090). We modeled the future habitat suitability of focal species representative of key trait axes (substrate, flow, temperature, reproduction, and trophic) and used functional and phylogenetic metrics to assess variable assemblage responses across physiographic regions and habitat sizes (headwaters through large rivers). Our focal species analysis projected future habitat suitability gains for carnivorous species with preferences for warm water, pool habitats, and fine or vegetated substrates. At the assemblage level, models projected decreasing habitat suitability for cold‐water, rheophilic, and lithophilic individuals but increasing suitability for carnivores in the future across all regions. Projected responses of functional and phylogenetic diversity and redundancy differed among regions. Lowland regions were projected to become less functionally and phylogenetically diverse and more redundant while upland regions (and smaller habitat sizes) were projected to become more diverse and less redundant. Next, we assessed how these model‐projected assemblage changes 2005–2030 related to observed time‐series trends (1999–2016). Halfway through the initial projecting period (2005–2030), we found observed trends broadly followed modeled patterns of increasing proportions of carnivorous and lithophilic individuals in lowland regions but showed opposing patterns for functional and phylogenetic metrics. Leveraging observed and predicted analyses simultaneously helps elucidate the instances and causes of discrepancies between model predictions and ongoing observed changes. Collectively, results highlight the complexity of global change impacts across broad landscapes that likely relate to differences in assemblages' intrinsic sensitivities and external exposure to stressors.
We used functional traits to understand observed and predicted responses of stream fishes to climate and land‐use/land‐cover change. Future habitat suitability differed among tax: species with preferences for warm water, slower flows, and finer substrates were projected to gain habitat suitability, whereas those with preferences for cold‐water, faster flows, and clean, coarse substrates were projected lose suitable habitat. Projected biodiversity responses to global change varied among regions and habitat sizes, indicating the spatiotemporal complexity of ecological assemblages vulnerabilities to environmental stressors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
The BCL‐2 inhibitor venetoclax (ven) has revolutionized the treatment of acute myeloid leukemia (AML) in elderly adults, leading to its recent FDA approval for this population in ...combination regimens. Although extensive data exist for adult myeloid malignancies, there are limited preclinical data on the efficacy and/or dosing of venetoclax for pediatric myelodysplastic syndrome (MDS) or AML and thus little information to guide use of this regimen in pediatric patients. Our objective was to describe our single‐center experience with venetoclax in combination with the hypomethylating agent 5‐azacitidine (aza) in pediatric patients with MDS or AML.
Procedure
We conducted a retrospective chart review of patients treated at Children's Hospital Colorado prior to March 2020 with at least one cycle of ven/aza. Patients were included if between the ages of 1 and 25 years with a diagnosis of high‐grade MDS or AML. AML patients had relapsed or primary refractory disease or were deemed poor candidates for standard chemotherapy.
Results
Eight patients received ven/aza, two for high‐grade MDS and six for AML. Ven/aza was well tolerated by all patients. The most common adverse events seen with this regimen were gastrointestinal and hematologic. Morphologic responses were seen in six patients including both patients with MDS. All four AML responders became minimal residual disease negative. Three responders have thus far proceeded to allogeneic hematopoietic stem cell transplant following ven/aza.
Conclusions
Our clinical experience suggests that ven/aza is a safe and promising regimen that should be further explored with late‐phase clinical trials.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
5.
Boosted beta regression Schmid, Matthias; Wickler, Florian; Maloney, Kelly O ...
PloS one,
04/2013, Volume:
8, Issue:
4
Journal Article
Peer reviewed
Open access
Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured ...on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Technological advances in hydraulic fracturing and horizontal drilling have led to the exploration and exploitation of shale oil and gas both nationally and internationally. Extensive development of ...shale resources has occurred within the United States over the past decade, yet full build out is not expected to occur for years. Moreover, countries across the globe have large shale resources and are beginning to explore extraction of these resources. Extraction of shale resources is a multistep process that includes site identification, well pad and infrastructure development, well drilling, high-volume hydraulic fracturing and production; each with its own propensity to affect associated ecosystems. Some potential effects, for example from well pad, road and pipeline development, will likely be similar to other anthropogenic activities like conventional gas drilling, land clearing, exurban and agricultural development and surface mining (e.g., habitat fragmentation and sedimentation). Therefore, we can use the large body of literature available on the ecological effects of these activities to estimate potential effects from shale development on nearby ecosystems. However, other effects, such as accidental release of wastewaters, are novel to the shale gas extraction process making it harder to predict potential outcomes. Here, we review current knowledge of the effects of high-volume hydraulic fracturing coupled with horizontal drilling on terrestrial and aquatic ecosystems in the contiguous United States, an area that includes 20 shale plays many of which have experienced extensive development over the past decade. We conclude that species and habitats most at risk are ones where there is an extensive overlap between a species range or habitat type and one of the shale plays (leading to high vulnerability) coupled with intrinsic characteristics such as limited range, small population size, specialized habitat requirements, and high sensitivity to disturbance. Examples include core forest habitat and forest specialists, sagebrush habitat and specialists, vernal pond inhabitants and stream biota. We suggest five general areas of research and monitoring that could aid in development of effective guidelines and policies to minimize negative impacts and protect vulnerable species and ecosystems: (1) spatial analyses, (2) species-based modeling, (3) vulnerability assessments, (4) ecoregional assessments, and (5) threshold and toxicity evaluations.
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IJS, KILJ, NUK, PNG, UL, UM
Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also ...improve outcomes for those with standard-risk (SR) ALL.
AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases.
The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% (
= .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% (
= 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%;
= .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively.
The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.
Statistical modeling of ecological data is often faced with a large number of variables as well as possible nonlinear relationships and higher-order interaction effects. Gradient boosted trees (GBT) ...have been successful in addressing these issues and have shown a good predictive performance in modeling nonlinear relationships, in particular in classification settings with a categorical response variable. They also tend to be robust against outliers. However, their black-box nature makes it difficult to interpret these models. We introduce several recently developed statistical tools to the environmental research community in order to advance interpretation of these black-box models. To analyze the properties of the tools, we applied gradient boosted trees to investigate biological health of streams within the contiguous USA, as measured by a benthic macroinvertebrate biotic index. Based on these data and a simulation study, we demonstrate the advantages and limitations of partial dependence plots (PDP), individual conditional expectation (ICE) curves and accumulated local effects (ALE) in their ability to identify covariate-response relationships. Additionally, interaction effects were quantified according to interaction strength (IAS) and Friedman's Formula omitted statistic. Interpretable machine learning techniques are useful tools to open the black-box of gradient boosted trees in the environmental sciences. This finding is supported by our case study on the effect of impervious surface on the benthic condition, which agrees with previous results in the literature. Overall, the most important variables were ecoregion, bed stability, watershed area, riparian vegetation and catchment slope. These variables were also present in most identified interaction effects. In conclusion, graphical tools (PDP, ICE, ALE) enable visualization and easier interpretation of GBT but should be supported by analytical statistical measures. Future methodological research is needed to investigate the properties of interaction tests. Supplementary materials accompanying this paper appear on-line.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Rapid growth in unconventional oil and gas (UOG) has produced jobs, revenue, and energy, but also concerns over spills and environmental risks. We assessed spill data from 2005 to 2014 at 31 481 UOG ...wells in Colorado, New Mexico, North Dakota, and Pennsylvania. We found 2–16% of wells reported a spill each year. Median spill volumes ranged from 0.5 m3 in Pennsylvania to 4.9 m3 in New Mexico; the largest spills exceeded 100 m3. Seventy-five to 94% of spills occurred within the first three years of well life when wells were drilled, completed, and had their largest production volumes. Across all four states, 50% of spills were related to storage and moving fluids via flowlines. Reporting rates varied by state, affecting spill rates and requiring extensive time and effort getting data into a usable format. Enhanced and standardized regulatory requirements for reporting spills could improve the accuracy and speed of analyses to identify and prevent spill risks and mitigate potential environmental damage. Transparency for data sharing and analysis will be increasingly important as UOG development expands. We designed an interactive spills data visualization tool (http://snappartnership.net/groups/hydraulic-fracturing/webapp/spills.html) to illustrate the value of having standardized, public data.
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IJS, KILJ, NUK, PNG, UL, UM
Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor ...2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.
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