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Objective Pediatric patients with relapsed or refractory acute lymphoblastic leukemia have a poor prognosis. We here assess the response rates, adverse events, and long-term follow-up of pediatric patients with relapsed/refractory acute lymphoblastic leukemia receiving blinatumomab. Methods Retrospective analysis of a single-center experience with blinatumomab in 38 patients over a period of 10 years. Results The median age at onset of therapy was 10 years (1-21 years). Seventy-one percent of patients had undergone at least one hematopoietic stem cell transplantation (HSCT) prior to treatment with blinatumomab. We observed a response to blinatumomab in 13/38 patients (34%). The predominant side effect was febrile reactions, nearly half of the patients developed a cytokine release syndrome. Eight events of neurotoxicity were registered over the 78 cycles (15%). To date, nine patients (24%) are alive and in complete molecular remission. All survivors underwent haploidentical HSCT after treatment with blinatumomab. Conclusions Despite heavy pretreatment of most of our patients, severe adverse events were rare and response rates encouraging. Blinatumomab is a valuable bridging salvage therapy for relapsed or refractory patients to a second or even third HSCT.

Managing public health risks from environmental contaminants has historically relied on a risk assessment process defined by the regulatory context in which these risks are assessed. Risk assessment guidance follows a straightforward, chemical-by-chemical approach to inform regulatory decisions around the question “what is the risk-based concentration protective of human and ecological health outcomes?” Here we briefly summarize regulatory risk assessment in the context of innovative risk assessment approaches based on an evolving understanding of the underlying scientific disciplines that support risk analysis more broadly. We discuss scientific versus regulatory tensions in the application of these approaches for future risk assessments, and challenges in translating our improved understanding of the underlying scientific complexity to the regulatory landscape to better inform decision making that extends beyond conventional regulatory mandates.

The population level is often the biological endpoint addressed in ecological risk assessments (ERAs). However, ERAs tend to ignore the metapopulation structure, which precludes an understanding of how population viability is affected by multiple stressors (e.g., toxicants and environmental conditions) at large spatial scales. Here we integrate metapopulation model simulations into a regional-scale, multiple stressors risk assessment (Bayesian network relative risk model [BN-RRM]) of organophosphate (OP) exposure, water temperature, and DO impacts on Chinook salmon (Oncorhynchus tshawytscha). A matrix metapopulation model was developed for spring Chinook salmon in the Yakima River Basin (YRB), Washington, USA, including 3 locally adapted subpopulations and hatchery fish that interact with those subpopulations. Three metapopulation models (an exponential model, a ceiling density-dependent model, and an exponential model without dispersal) were integrated into the BN-RRM to evaluate the effects of population model assumptions on risk calculations. Risk was defined as the percent probability that the abundance of a subpopulation would decline from their initial abundance (500 000). This definition of risk reflects the Puget Sound Partnership's management goal of achieving "no net loss" of Chinook abundance. The BN-RRM model results for projection year 20 showed that risk (in % probability) from OPs and environmental stressors was higher for the wild subpopulations-the American River (50.9%-97.7%) and Naches (39.8%-84.4%) spring Chinook-than for the hatchery population (CESRF 18.5%-46.5%) and the Upper Yakima subpopulation (21.5%-68.7%). Metapopulation risk was higher in summer (58.1%-68.7%) than in winter (33.6%-53.2%), and this seasonal risk pattern was conserved at the subpopulation level. To reach the management goal in the American River spring Chinook subpopulation, the water temperature conditions in the Lower Yakima River would need to decrease. We demonstrate that 1) relative risk can vary across a metapopulation's spatial range, 2) dispersal among patches impacts subpopulation abundance and risk, and 3) local adaptation within a salmon metapopulation can profoundly impact subpopulation responses to equivalent stressors. Integr Environ Assess Manag 2021;17:95-109. © 2020 SETAC.

Aneuploidy is common in paediatric B-cell precursor acute lymphoblastic leukaemia (ALL). Specific subgroups, such as high hyperdiploidy (>50 chromosomes or DNA Index ≥1·16) and hypodiploidy (

The prognosis in children with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) is poor. Nelarabine (Ara-G) has successfully been used as salvage therapy in these children, but has been associated with significant, even fatal, neurotoxicities. We retrospectively analysed 52 patients with r/r T-ALL/T-LBL aged ≤19 years who were treated with Ara-G alone (n = 25) or in combination with cyclophosphamide and etoposide (n = 27). The majority of patients (45/52) received 1-2 cycles of Ara-G. Seventeen patients (32·7%) had refractory disease, 28 (53·8%) were in first relapse and 7 (13·5%) were in second relapse. A response to Ara-G was achieved in 20 patients and 15 (28·8%) were in remission at last follow-up. Twelve patients (23·1%) had neurotoxic adverse effects (neuro-AE) of any grade, of whom 7 (13·5%) developed neurotoxicity ≥ grade III. The most frequent neuro-AEs were peripheral motor neuropathy (19·2%), peripheral sensory neuropathy (11·5%) and seizures (9·6%). Three patients died of central neuro-AE after 1-2 cycles of combination therapy. Patients with neurotoxicity were significantly older (median 15·17 years) than those without (10·34 years, P = 0·017). No differences were observed between mono- and combination therapy concerning outcome and neuro-AE. The incidence of neuro-AE was not associated with concurrent intrathecal therapy or prior central nervous system irradiation.

Bioaccumulation models quantify the relationship between sediment and water exposure concentrations and resulting tissue levels of chemicals in aquatic organisms and represent a key link in the suite of tools used to support decision making at contaminated sediment sites. Predicted concentrations in the aquatic food web provide exposure estimates for human health and ecological risk assessments, which, in turn, provide risk-based frameworks for evaluating potential remedial activities and other management alternatives based on the fish consumption pathway. Despite the widespread use of bioaccumulation models to support remedial decision making, concerns remain about the predictive power of these models. A review of the available literature finds the increased mathematical complexity of typical bioaccumulation model applications is not matched by the deterministic exposure concentrations used to drive the models. We tested a spatially explicit exposure model (FishRand) at 2 nominally contaminated sites and compared results to estimates of bioaccumulation based on conventional, nonspatial techniques, and monitoring data. Differences in predicted fish tissue concentrations across applications were evident, although these demonstration sites were only mildly contaminated and would not warrant management actions on the basis of fish consumption. Nonetheless, predicted tissue concentrations based on the spatially explicit exposure characterization consistently outperformed conventional, nonspatial techniques across a variety of model performance metrics. These results demonstrate the improved predictive power as well as greater flexibility in evaluating the impacts of food web exposure and fish foraging behavior in a heterogeneous exposure environment. Integr Environ Assess Manag 2017;13:1023-1037. © 2017 SETAC.

Linked socioecological systems consist of economies in societies in nature and make explicit the relationship between the natural environment and human well-being using the language of ecosystem services. A growth-based economy within a constrained biophysical planet (e.g., human activities) has led to a need for ecosystem resilience. Valuation of ecosystem services using the language of economics appears insufficient in the face of human activity. All ecosystems are resilient but will demonstrate that resilience in unexpected and potentially unwanted ways, particularly as human pressures and influences lead to tipping points of extinction (e.g., complete die-off of coral reefs) in these linked socioecological systems. Structured approaches for evaluating the risks, benefits, and impacts of human activities exist but are not effectively applied and when applied, focus on downstream outcomes rather than on upstream actions (e.g., responding to climate change impacts rather than addressing causes of climate change). Ecosystem resilience in the face of unprecedented environmental challenges may not result in the hoped-for set of ecosystem services. Integr Environ Assess Manag 2018;14:598-600. © 2018 SETAC.

The ecosystem services (ES) concept holds much promise for environmental decision making. Even so, the concept has yet to gain full traction in the decisions and policies of environmental agencies in the United States, Europe, and elsewhere. In this paper we examine the opportunities for and implications of including ES in risk assessments and the risk management decisions that they inform. We assert that use of ES will: 1) lead to more comprehensive environmental protection; 2) help to articulate the benefits of environmental decisions, policies, and actions; 3) better inform the derivation of environmental quality standards; 4) enable integration of human health and ecological risk assessment; and 5) facilitate horizontal integration of policies, regulations, and programs. We provide the technical basis and supporting rationale for each assertion, relying on examples taken from experiences in the United States and European Union. Specific recommendations are offered for use of ES in risk assessment and risk management, and issues and challenges to advancing use of ES are described together with some of the science needed to improve the value of the ES concept to environmental protection. Integr Environ Assess Manag 2017;13:62–73. © 2016 SETAC.

Background The risk of early death (ED) by bleeding/leukostasis is high in patients with AML with hyperleukocytosis (>100,000/μl). Within the pediatric AML-BFM (Berlin-Frankfurt-Munster) 98/04 studies, emergency strategies for these children included exchange transfusion (ET) or leukapheresis (LPh). Risk factors for ED and interventions performed were analyzed. Patients Two hundred thirty-eight of 1,251 (19%) patients with AML presented with hyperleukocytosis; 23 of 1,251 (1.8%) patients died of bleeding/leukostasis. Results ED due to bleeding/leukostasis was highest at white blood cell (WBC) count >200,000/μl (14.3%). ED rates were even higher (20%) in patients with FAB (French-American-British) M4/M5 and hyperleukocytosis >200,000/μl. Patients with WBC >200,000/μl did slightly better with ET/LPh compared to those without ET/LPh (ED rate 7.5% vs. 21.2%, P = 0.055). Multivariate WBC >200,000/μl was of strongest prognostic significance for ED (P(χ2) 200,000/μl, and in FAB M4/M5 even at lower WBC.

Current risk assessment guidance calls for an individual chemical-by-chemical approach that fails to capture potential interactive effects of exposure to environmental mixtures and genetic variability. We conducted a review of the literature on relationships between prenatal and early life exposure to mixtures of lead (Pb), arsenic (As), cadmium (Cd), and manganese (Mn) with neurodevelopmental outcomes. We then used an adverse outcome pathway (AOP) framework to integrate lines of evidence from multiple disciplines based on evolving guidance developed by the Organization for Economic Cooperation and Development (OECD). Toxicological evidence suggests a greater than additive effect of combined exposures to As-Pb-Cd and to Mn with any other metal, and several epidemiologic studies also suggest synergistic effects from binary combinations of Pb-As, Pb-Cd, and Pb-Mn. The exposure levels reported in these epidemiologic studies largely fall at the high-end (e.g., 95th percentile) of biomonitoring data from the National Health and Nutrition Examination Survey (NHANES), suggesting a small but significant potential for high-end exposures. This review integrates multiple data sources using an AOP framework and provides an initial application of the OECD guidance in the context of potential neurodevelopmental toxicity of several metals, recognizing the evolving nature of regulatory interpretation and acceptance.

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from 80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals.

Summary Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin-Frankfurt-Munster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event-free (EFS) and overall survival (OS) than the control group without DS (EFS 17 ± 08% vs. non-DS 41 ± 06%, P = 0·006; OS 17 ± 09% vs. non-DS 51 ± 06%, P

Ecosystem services as a concept and guiding principle are enjoying wide popularity and endorsement from high-level policy thinkers to industry as support for sustainability goals continue to grow. However, explicit incorporation of ecosystem services into decision making still lacks practical implementation at more local scales and faces significant regulatory and technical constraints. Risk assessment represents an example of a regulatory process for which guidance exists that makes it challenging to incorporate ecosystem service endpoints. Technical constraints exist in the quantification of the relationships between ecological functions and services and endpoints valued by humans, and the complexity of those interactions with respect to bundling and stacking. In addition, ecosystem services, by their very definition, represent an anthropogenic construct with no inherent ecological value, which, in practical terms, requires a far more inclusionary decision making process explicitly incorporating a greater diversity of stakeholder values. Despite these constraints, it is possible, given a commitment to sustainable decision making, to simplify the process based on strategic outcomes (e.g., identifying desired end-states in general terms). Decision analytic techniques provide a mechanism for evaluating tradeoffs across key ecosystem services valued by stakeholders and to develop criteria drawn from the entire spectrum of stakeholders in evaluating potential alternatives. This article highlights several examples of ways in which ecosystem service endpoints can be incorporated into the decision-making process. Integr Environ Assess Manag 2013; 9: 260–268. © 2013 SETAC

Background The treatment of childhood B-cell precursor acute lymphoblastic leukemia (ALL) after isolated extramedullary or late relapse is mostly based on chemotherapy or allogeneic transplantation. The aim of this study is to provocatively assess the role of purified autologous transplantation compared with best chemotherapy results in the same setting. Procedure We reported a series of 30 pediatric patients who underwent purified peripheral blood autologous transplantation for ALL in CR2, after isolated extramedullary (7), or late medullary (23) relapse from January 1997 and March 2004. Among 246 patients treated with chemotherapy within Berlin–Frankfurt–Munster relapse protocols during the same period, we found 103 controls who matched our 30 cases, according to site of relapse, CR1 duration, time elapsed in CR2, and period of relapse. Results Event-free survival and survival at 5 years after relapse were 73.3% (SE 8.1) and 86.5% (SE 8.2) for auto-transplanted cases and 40.0% (SE 9.7) and 62.5%(SE 9.6) for chemotherapy-treated controls (P-values: 0.012 and 0.025, respectively). The risk of relapse after auto-transplantation at 1 and 4 years was approximately half and one-fifth, respectively, of the same risk obtained with chemotherapy. Conclusions This matched analysis showed an advantage of purified autologous transplantation compared with chemotherapy in low-risk relapsed ALL, possibly explained by the single-center effect, the myeloablation of total body irradiation, the documented low tumor burden at mobilization and the stem cell isolation procedure. Pediatr Blood Cancer 2011; 57: 654–659. © 2011 Wiley-Liss, Inc.

BACKGROUND: Cancer-associated thrombosis and enduring inflammation are strongly associated with cancer progression and metastasis. Heparin is the mostly clinically used anticoagulant/antithrombotic drug, and has recently been shown to exhibit antimetastatic and anti-inflammatory activities that are linked to inhibition of P-selectin and/or L-selectin. P-selectin-mediated platelet-tumor cell and tumor cell-endothelium interactions facilitate the initial steps of metastasis. OBJECTIVES AND METHODS: The aim of the present study was to determine the capacity of dermatan sulfates to inhibit P-selectin and to test their potential to affect thrombosis, inflammation and metastasis in respective experimental mouse models. RESULTS: Two dermatan sulfates isolated from the ascidians Styela plicata and Phallusia nigra, composed of the same disaccharide core structure (IdoA2-GalNAc)(n) , but sulfated at carbon 4 or 6 of the GalNAc, respectively, have opposed heparin cofactor II (HCII) activities and are potent inhibitors of P-selectin. The ascidian dermatan sulfates effectively attenuated metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model. Moreover, both glycosaminoglycans reduced thrombus size in an FeCl(3) -induced arterial thrombosis model, irrespective of their HCII activities. The analysis of arterial thrombi demonstrated markedly reduced platelet deposition after dermatan sulfate treatment, suggesting that the glycosaminoglycan inhibited P-selectin and thereby the binding of activated platelets during thrombus formation. CONCLUSIONS: Collectively, these findings provide evidence that specific inhibition of P-selectin represents a potential therapeutic target in thrombosis, inflammation and metastasis, and that ascidian dermatan sulfates may serve as antiselectin agents. © 2011 International Society on Thrombosis and Haemostasis.

A central problem in evolutionary biology is identifying factors that promote the evolution of reproductive isolation. Among mosses, biogeographic evidence indicates that the potential for migration is great, suggesting that biological factors other than geographic isolation may be critical for speciation in this group. The moss Physcomitrella patens (Funariaceae) has long been used as a model for interspecies hybridization and has recently emerged as an important model system for comparative genomics. We report genealogical analyses of six loci from several populations of P. patens and related species in the genus Physcomitrium. These results unambiguously indicate that the so-called genus Physcomitrella arose at least three times from distinct ancestors within the genus Physcomitrium. In spite of the evidence for natural hybridization in the Physcomitrella-Physcomitrium complex, genealogical and experimental hybridization data indicate that the taxonomically defined species are reproductively isolated. However, these analyses suggest that Physcomitrium eurystomum was formed from a hybridization event between two early diverging lineages in the complex, and that the ancestral population size of these lineages was much smaller than the current population sizes. We discuss these findings in the context of the inferred mating system in the Physcomitrella-Physcomitrium complex and patterns of speciation and diversification.

The moss Physcomitrella patens is a model for the study of plant cell biology and, by virtue of its basal position in land plant phylogeny, for comparative analysis of the evolution of plant gene function and development. It is ideally suited for ‘reverse genetic’ analysis by virtue of its outstanding ability to undertake targeted transgene integration by homologous recombination. However, gene identification through mutagenesis and map-based cloning has hitherto not been possible, due to the lack of a genetic linkage map. Using molecular markers [amplified fragment length polymorphisms (AFLP) and simple sequence repeats (SSR)] we have generated genetic linkage maps for Physcomitrella. One hundred and seventy-nine gene-specific SSR markers were mapped in 46 linkage groups, and 1574 polymorphic AFLP markers were identified. Integrating the SSR- and AFLP-based maps generated 31 linkage groups comprising 1420 markers. Anchorage of the integrated linkage map with gene-specific SSR markers coupled with computational prediction of AFLP loci has enabled its correspondence with the newly sequenced Physcomitrella genome. The generation of a linkage map densely populated with molecular markers and anchored to the genome sequence now provides a resource for forward genetic interrogation of the organism and for the development of a pipeline for the map-based cloning of Physcomitrella genes. This will radically enhance the potential of Physcomitrella for determining how gene function has evolved for the acquisition of complex developmental strategies within the plant kingdom.

Biomagnification of organochlorine and other persistent organic contaminants by higher trophic level organisms represents one of the most significant sources of uncertainty and variability in evaluating potential risks associated with disposal of dredged materials. While it is important to distinguish between population variability (e.g., true population heterogeneity in fish weight, and lipid content) and uncertainty (e.g., measurement error), they can be operationally difficult to define separately in probabilistic estimates of human health and ecological risk. We propose a disaggregation of uncertain and variable parameters based on: (1) availability of supporting data; (2) the specific management and regulatory context (in this case, of the U.S. Army Corps of Engineers/U.S. Environmental Protection Agency tiered approach to dredged material management); and (3) professional judgment and experience in conducting probabilistic risk assessments. We describe and quantitatively evaluate several sources of uncertainty and variability in estimating risk to human health from trophic transfer of polychlorinated biphenyls (PCBs) using a case study of sediments obtained from the New York-New Jersey Harbor and being evaluated for disposal at an open water off-shore disposal site within the northeast region. The estimates of PCB concentrations in fish and dietary doses of PCBs to humans ingesting fish are expressed as distributions of values, of which the arithmetic mean or mode represents a particular fractile. The distribution of risk values is obtained using a food chain biomagnification model developed by Gobas ( 1 , 2 ) by specifying distributions for input parameters disaggregated to represent either uncertainty or variability. Only those sources of uncertainty that could be quantified were included in the analysis. Results for several different two-dimensional Latin Hypercube analyses are provided to evaluate the influence of the uncertain versus variable disaggregation of model parameters. The analysis suggests that variability in human exposure parameters is greater than the uncertainty bounds on any particular fractile, given the described assumptions.

In recent years, a variety of approaches to deriving sediment quality guidelines have been developed. One approach relies on establishing an empirical relationship between the concentration of a contaminant in sediment and the condition of some biological indicator, for example, combining measured sediment concentrations of contaminants combined with data on colocated benthic species to measure in situ community effects of contamination. Biological threshold concentrations derived in this manner are being considered or have already been adopted by some regulatory agencies as a means for deriving sediment guidelines (e.g., Canada's Provincial Sediment Quality Guidelines). In order to test the validity of this method, we constructed several Monte Carlo simulations to illustrate that the methodology used to develop these guidelines is flawed by the effects of sampling and statistical artifacts that emerge from undersampling a lognormal density function. As a case study, this paper will present the screening level concentration method used by the Ontario Ministry of the Environment (Toronto, ON, Canada) and provide the results of several probabilistic exercises highlighting these issues. We present a word of caution on the applicability of methods that rely exclusively on statistical and mathematical relationships between invertebrate data and sediment concentrations to derive sediment quality guidelines.