Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

Airborne Lead Exposure and Childhood Cognition: The Environmental Influences on Child Health Outcomes (ECHO) Cohort (2003-2022).

Objectives. To examine whether a previously reported association between airborne lead exposure and children's cognitive function replicates across a geographically diverse sample of the United States. Methods. Residential addresses of children (< 5 years) were spatially joined to the Risk-Screening Environmental Indicators model of relative airborne lead toxicity. Cognitive outcomes for children younger than 8 years were available for 1629 children with IQ data and 1476 with measures of executive function (EF; inhibitory control, cognitive flexibility). We used generalized linear models using generalized estimating equations to examine the associations of lead, scaled by interquartile range (IQR), accounting for individual- and area-level confounders. Results. An IQR increase in airborne lead was associated with a 0.74-point lower mean IQ score (b = -0.74; 95% confidence interval = -1.00, -0.48). The association between lead and EF was nonlinear and was modeled with a knot at the 97.5th percentile of lead in our sample. Lead was significantly associated with lower mean inhibitory control but not with cognitive flexibility. This effect was stronger among males for both IQ and inhibitory control. Conclusions. Early-life exposure to airborne lead is associated with lower cognitive functioning. (Am J Public Health. 2024;114(3):309-318. https://doi.org/10.2105/AJPH.2023.307519).

The effect of hair type and texture on electroencephalography and event-related potential data quality.

Research utilizing event-related potential (ERP) methods is generally biased with regard to sample representativeness. Among the myriad of factors that contribute to sample bias are researchers' assumptions about the extent to which racial differences in hair texture, volume, and style impact electrode placement, and subsequently, study eligibility. The current study examines these impacts using data collected from n = 213 individuals ages 17-19 years, and offers guidance on collection of ERP data across the full spectrum of hair types. Individual differences were quantified for hair texture using a visual scale, and for hair volume by measuring the amount of gel used in cap preparation. Electroencephalography data quality was assessed with multiple metrics at the preprocessing, post-processing, and variable generation stages. Results indicate that hair volume is associated with small, but systematic differences in signal quality and signal amplitude. Such differences are highly problematic as they could be misattributed to cognitive differences among groups. However, inclusion of gel volume as a covariate to account for individual differences in hair volume significantly reduced, and in most cases eliminated, group differences. We discuss strategies for overcoming real and perceived technical barriers for researchers seeking to achieve greater inclusivity and representativeness in ERP research.

Dynamic regulatory processes among child welfare parents: Temporal associations between physiology and parenting behavior.

This study examined how temporal associations between parents' physiological and behavioral responses may reflect underlying regulatory difficulties in at-risk parenting. Time-series data of cardiac indices (second-by-second estimates of inter-beat intervals - IBI, and respiratory sinus arrhythmia - RSA) and parenting behaviors were obtained from 204 child welfare-involved parents (88% mothers, Mage = 32.32 years) during child-led play with their 3- to 7-year-old children (45.1% female; Mage = 4.76 years). Known risk factors for maltreatment, including parents' negative social cognitions, mental health symptoms, and inhibitory control problems, were examined as moderators of intra-individual physiology-behavior associations. Results of ordinary differential equations suggested increases in parents' cardiac arousal at moments when they showed positive parenting behaviors. In turn, higher arousal was associated with momentary decreases in both positive and negative parenting behaviors. Individual differences in these dynamic processes were identified in association with parental risk factors. In contrast, no sample-wide RSA-behavior associations were evident, but a pattern of increased positive parenting at moments of parasympathetic withdrawal emerged among parents showing more total positive parenting behaviors. This study illustrated an innovative and ecologically-valid approach to examining regulatory patterns that may shape parenting in real-time and identified mechanisms that should be addressed in interventions.

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials. METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods. RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2 ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35). CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.

A dynamic systems account of parental self-regulation processes in the context of challenging child behavior.

To advance the understanding of how parental self-regulation contributes to their role in supporting children's development, this study proposes a model of the dynamic processes involved in parental self-regulation. Based on time-series data from 157 mothers and their 30- to 60-month-old children (49.7% female; 96% White; data collected June 2017-December 2019 in central Pennsylvania, U.S.) during a challenging wait task, the model was tested by examining the temporal relations among challenging child behavior, maternal physiology, and maternal responsiveness. Results were consistent with the hypothesized dynamic negative feedback processes and revealed their associations with the overall quality of parenting behaviors and experiences. Findings elucidate how parents adapt to competing external (attending to child) and internal (restoring parents' equilibrium) demands during parenting challenges.

The reliability of visual ERP components in children across the first year of school.

Event-related potentials (ERPs) are increasingly used as neurophysiological markers of perceptual and cognitive processes conveying risk for psychopathology. However, little is known about the reliability of ERP components during childhood, a time of substantial brain maturation. In the present study, we examine the early visual ERP components (P1, N170, VPP), frequently examined as indicators of attentional bias, for 110 children at kindergarten (T1) and first grade (T2). Children performed a Go/Nogo task at both time points, with exact stimuli changed to reduce habituation. All components showed increases in absolute amplitude and the P1 and VPP also showed decreases in latency. Retest reliability across time was good to very good for amplitude measures (Pearson rs ranging from .54 for N170 to .69 for P1) and low to very good for latencies (rs from .34 for P1 to .60 for N170), despite the change in visual stimuli. Although there was some evidence of moderation by sex, early visual ERP components appear to be a reliable measure of individual differences in attention processing in middle childhood. This has implications for the use of early visual ERP components as trait-like markers for individual differences in perceptual processes in developmental research.

Conducting Event-Related Potential (ERP) Research with Young Children: A Review of Components, Special Considerations and Recommendations for Research on Cognition and Emotion.

There has been an unprecedented increase in the number of research studies employing event-related potential (ERP) techniques to examine dynamic and rapidly-occurring neural processes with children during the preschool and early childhood years. Despite this, there has been little discussion of the methodological and procedural differences that exist for studies of young children versus older children and adults. That is, reviewers, editors, and consumers of this work often expect developmental studies to simply apply adult techniques and procedures to younger samples. Procedurally, this creates unrealistic expectations for research paradigms, data collection, and data reduction and analyses. Scientifically, this leads to inappropriate measures and methods that hinder drawing conclusions and advancing theory. Based on ERP work with preschoolers and young children from 10 laboratories across North America, we present a summary of the most common ERP components under study in the area of emotion and cognition in young children along with 13 realistic expectations for data collection and loss, laboratory procedures and paradigms, data processing, ERP averaging, and typical challenges for conducting this type of work. This work is intended to supplement previous guidelines for work with adults and offer insights to aid researchers, reviewers, and editors in the design and evaluation of developmental research using ERPs. Here we make recommendations for researchers who plan to conduct or who are conducting ERP studies in children between ages 2 and 12, focusing on studies of toddlers and preschoolers. Recommendations are based on both data and our cumulative experience and include guidelines for laboratory setup, equipment and recording settings, task design, and data processing.

When you go low, I go high: Negative coordination of physiological synchrony among parents and children.

The parent-child relationship is an important context for children's emotional development. The current study assessed 43 parent-child dyads while watching a positive film clip and a negative film clip, in order to examine whether partner's physiological reactivity demonstrated dyadic synchrony, and whether this was associated with children's prosocial empathy. Respiratory sinus arrhythmia was measured in both caretakers and children (ages 9-14) and a continuous time series was estimated in order to maximize temporal resolution of physiological dynamics. Dyads varied in both the magnitude and direction of synchrony, with correlation coefficients ranging from moderately negative; r = -.44 (increases in one partner correspond to decreases in the other), to moderately positive; r = .55 (increases in one partner correspond to increases in the other). For both conditions, negative synchrony was correlated with higher child-reported empathy. For the negative mood condition, this effect was moderated by caretaker's emotional acceptance such that positive synchrony was associated with lower levels of empathy among dyads in which caretaker emotional acceptance was lower. These results suggest that positive physiological synchrony during a negative mood condition may not be adaptive for children when their caretaker lacks the skills to appropriately socialize their child's emotional development.

Magnitude and Chronicity of Environmental Smoke Exposure Across Infancy and Early Childhood in a Sample of Low-Income Children.

INTRODUCTION: Infants and young children may be at an increased risk for second- and thirdhand exposure to tobacco smoke because of increased respiration rate and exposure to surface residue. However, relatively fewer studies have examined biomarkers of exposure (cotinine) in children under age 4 years. This study examines the magnitude and chronicity of exposure across early childhood among children from low-income families in order to better characterize contextual risk factors associated with exposure. METHODS: A total of 1292 families were recruited in six nonurban counties of Pennsylvania and North Carolina. Cotinine was assayed from infant saliva at 6, 15, 24, and 48 months of age (N = 1218), and categorized as low (≤0.45 ng/mL), moderate (0.46-12 ng/mL), or high (≥12 ng/mL) at each time point. Categories were highly correlated across time. Latent class analysis was used to summarize patterns of exposure categories across time. RESULTS: Magnitude of exposure in this sample was high, with approximately 12% of infants registering cotinine values at least 12 ng/mL, consistent with active smoking in adults. Greater exposure was associated with lower income, less education, more residential instability, and more instability in adult occupants in the home, whereas time spent in center-based day care was associated with lower exposure. CONCLUSIONS: Young children from low-income, nonurban communities appear to bear a higher burden of secondhand smoke exposure than previous studies have reported. Results contribute to understanding populations at greater risk, as well as specific, potentially malleable, environmental factors that may be examined as direct contributors to exposure. IMPLICATIONS: Results suggest that infants from low-income, nonurban families have higher risk for environmental smoke exposure than data from nationally representative samples. Predictors of exposure offer insights into specific factors that may be targeted for risk reduction efforts, specifically conditions of children's physical space. In addition to considering the increases in risk when an adult smoker lives in a child's home, families should also attend to the possible risk embedded within the home itself, such as residual smoke from previous occupants. For high-risk children, day care appears to mitigate the magnitude of exposure by providing extended time in a smoke-free environment.

The association between perinatal hypoxia exposure and externalizing symptoms and children's decision making in conditions of uncertainty is moderated by DRD2 genotype.

Variants of the DRD2 Taq1A polymorphism, which have been shown to result in functional differences in dopamine D2 receptors (D2R), have been linked to various externalizing outcomes in adults. However, the neurobiological processes that contribute to these associations are not well understood. The current study investigates gene × environment effects on teacher-rated externalizing behaviors and probabilistic decision making in a sample of 333 children (age 9) enrolled in an ongoing longitudinal study. Findings indicate that externalizing behaviors increased as a function of hypoxic exposure only among individuals carrying the A1 (A1+) allele. Results also indicate that willingness to pursue reward under conditions of maximum uncertainty (50% probability) decreased as a function of hypoxic exposure only among A1- individuals. Among A1 carriers, no association between probability decision making and hypoxic exposure emerged. These findings suggest that hypoxia could influence neural development through different biological pathways depending on D2 receptor genotype, and provide insight into the development of individual differences in behavior and decision making.

Quantifying respiratory sinus arrhythmia: Effects of misspecifying breathing frequencies across development.

Low resting respiratory sinus arrhythmia (RSA), and to a lesser extent excessive RSA reactivity to emotion evocation, are observed in many psychiatric disorders characterized by emotion dysregulation, including syndromes spanning the internalizing and externalizing spectra, and other conditions such as nonsuicidal self-injury. Nevertheless, some inconsistencies exist. For example, null outcomes in studies of RSA-emotion dysregulation relations are sometimes observed among younger participants. Such findings may derive from use of age inappropriate frequency bands in calculating RSA. We combine data from five published samples (N = 559) spanning ages 4 to 17 years, and reanalyze RSA data using age-appropriate respiratory frequencies. Misspecifying respiratory frequencies results in overestimates of resting RSA and underestimates of RSA reactivity, particularly among young children. Underestimates of developmental shifts in RSA and RSA reactivity from preschool to adolescence were also observed. Although correlational analyses revealed weak negative associations between resting RSA and aggression, those with clinical levels of externalizing exhibited lower resting RSA than their peers. No associations between RSA reactivity and externalizing were observed. Results confirm that age-corrected frequency bands should be used when estimating RSA, and that literature-wide overestimates of resting RSA, underestimates of RSA reactivity, and underestimates of developmental shifts in RSA and RSA reactivity may exist.

Clinical trial enrollment of adolescents and young adults with sarcoma.

More than half of all sarcomas occur in adolescents and young adults (AYAs) aged 15 to 39 years. After the publication of the AYA series in the April 1, 2016 issue of Cancer, several leaders in the field of sarcoma across disciplines gathered to discuss the status of sarcoma clinical research in AYAs. They determined that a focused effort to include the underrepresented and understudied AYA population in current and future sarcoma clinical trials is overdue. Trial enrichment for AYA-aged sarcoma patients will produce more meaningful results that better represent the disease's biology, epidemiology, and treatment environment. To address the current deficit, this commentary outlines changes believed to be necessary to expediently achieve an increase in the enrollment of AYAs in sarcoma clinical trials. Cancer 2017;123:3434-40. © 2017 American Cancer Society.

Lifestyle behavior interventions delivered using technology in childhood, adolescent, and young adult cancer survivors: A systematic review.

Childhood, adolescent, and young adult cancer survivors demonstrate increased cardio-metabolic risk factors, which are amenable to lifestyle changes. The use of technology to impact lifestyle change expands previously limited intervention access, yet little is known about its use. We summarized lifestyle interventions for survivors delivered using technology, finding six studies, primarily targeting physical activity. Study samples were small and durations ranged from 5 to 16 weeks and outcomes modest. Participants were older, white, survivors of leukemia or brain tumors, and the majority received Web-based interventions. Study quality was moderate. Few technology-based interventions have been developed, suggesting an area of opportunity for survivors.

Recurrent Osteosarcoma Presenting as an Isolated Bone Marrow Relapse.

Osteosarcoma (OS) is a malignant bone tumor which is found primarily in adolescents, with the distal femur as the most common location. OS with a jaw primary is present in only about 10% of cases and the risk of recurrence is considered to be decreased in the jaw versus other primary locations. We present a unique case of a patient with localized OS of the jaw with an isolated recurrence in her bone marrow almost 5 years after completion of initial treatment.

Alternative Donor Hematopoietic Cell Transplantation Conditioned With Myeloablative Busulfan, Fludarabine, and Melphalan is Well Tolerated and Effective Against High-risk Myeloid Malignancies.

Busulfan, fludarabine, and melphalan as hematopoietic cell transplant conditioning, was used in 6 patients aged 1 to 19 years with very high-risk myeloid malignancies. This dose regimen had an acceptable toxicity profile resulting in complete donor engraftment even following transplantation of small 2/6 antigen disparate umbilical cord blood grafts. It provided excellent disease control as all patients had high-risk features in terms of cytogenetics, therapy-related leukemia, and/or significant measurable disease before transplant. All patients remain in remission, without acute or chronic graft-versus-host disease with a median follow-up of 24 months. A larger study is indicated to confirm the efficacy and safety of this regimen.

The dynamics of internalizing and externalizing comorbidity across the early school years.

High rates of comorbidity are observed between internalizing and externalizing problems, yet the developmental dynamics of comorbid symptom presentations are not yet well understood. This study explored the developmental course of latent profiles of internalizing and externalizing symptoms across kindergarten, first grade, and second grade. The sample consisted of 336 children from an urban, low-income community, selected based on relatively high (61%) or low (39%) aggressive/oppositional behavior problems at school entry (64% male; 70% African American, 20% Hispanic). Teachers reported on children's symptoms in each year. An exploratory latent profile analysis of children's scores on aggression/oppositionality, hyperactivity/inattention, anxiety, and social withdrawal symptom factors revealed four latent symptom profiles: comorbid (48% of the sample in each year), internalizing (19%-23%), externalizing (21%-22%), and well-adjusted (7%-11%). The developmental course of these symptom profiles was examined using a latent transition analysis, which revealed remarkably high continuity in the comorbid symptom profile (89% from one year to the next) and moderately high continuity in both the internalizing and externalizing profiles (80% and 71%, respectively). Internalizing children had a 20% probability of remitting to the well-adjusted profile by the following year, whereas externalizing children had a 25% probability of transitioning to the comorbid profile. These results are consistent with the hypothesis that a common vulnerability factor contributes to developmentally stable internalizing-externalizing comorbidity, while also suggesting that some children with externalizing symptoms are at risk for subsequently accumulating internalizing symptoms.

Utility of bone marrow aspiration and biopsy in initial staging of Ewing sarcoma.

BACKGROUND: The current standard of care for initial staging of pediatric Ewing sarcoma (EWS) patients is to obtain a bilateral bone marrow aspiration and biopsy (BMAB). The incidence of bone marrow (BM) disease in patients deemed non-metastatic by conventional and metabolic imaging and the concordance of BM positivity with other clinical characteristics are not well established. PROCEDURE: This study is a multi-institutional retrospective review of newly diagnosed EWS patients less than 40 years of age with initial staging that included imaging and BMAB. RESULTS: A total of 116 patients were eligible with 85 patients considered non-metastatic and 31 considered metastatic by imaging. None of the 85 patients with non-metastatic disease were BMAB positive (0%; 95% CI: 0-4.2%); 13 of the 31 patients with metastases were BMAB positive (41.9%; 95% CI: 24.5-60.9%). Primary tumor size was significantly higher in patients with metastases (P = 0.017). Bone metastasis by imaging had high correlation with BMAB positivity (P = 0.0002). In addition, the number of bony metastatic sites was significantly higher in patients with a positive BMAB as compared to those with a negative BMAB (median 3.5 and 0.0, respectively; P < 0.001). CONCLUSIONS: BMAB may not be required for initial staging of pediatric and young adult EWS patients deemed non-metastatic by imaging. In patients with metastatic disease, there is a high correlation of BM involvement with multiple bone metastases.

Implications of ongoing neural development for the measurement of the error-related negativity in childhood.

Event-related potentials (ERPs) have been proposed as biomarkers capable of reflecting individual differences in neural processing not necessarily detectable at the behavioral level. However, the role of ERPs in developmental research could be hampered by current methodological approaches to quantification. ERPs are extracted as an average waveform over many trials; however, actual amplitudes would be misrepresented by an average if there was high trial-to-trial variability in signal latency. Low signal temporal consistency is thought to be a characteristic of immature neural systems, although consistency is not routinely measured in ERP research. The present study examined the differential contributions of signal strength and temporal consistency across trials in the error-related negativity (ERN) in 6-year-old children, as well as the developmental changes that occur in these measures. The 234 children were assessed annually in kindergarten, 1st, and 2nd grade. At all assessments signal strength and temporal consistency were highly correlated with the average ERN amplitude, and were not correlated with each other. Consistent with previous findings, ERN deflections in the averaged waveform increased with age. This was found to be a function of developmental increases in signal temporal consistency, whereas signal strength showed a significant decline across this time period. In addition, average ERN amplitudes showed low-to-moderate stability across the three assessments whereas signal strength was highly stable. In contrast, signal temporal consistency did not evidence rank-order stability across these ages. Signal strength appears to reflect a stable individual trait whereas developmental changes in temporal consistency may be experientially influenced.

Children's parasympathetic reactivity to specific emotions moderates response to intervention for early-onset aggression.

Following theories that individual differences in respiratory sinus arrhythmia (RSA) denote differential sensitivity to environmental influences, this study examines whether differences in RSA reactivity to specific emotional challenges predict differential response to intervention. We present data from a randomized clinical trial of a targeted intervention for early onset aggression. In collaboration with a high-risk urban school district, 207 kindergarten children (73% African American, 66% male), identified by their teachers as having high levels of aggressive and disruptive behavior, were recruited. All children received a universal social-emotional curriculum. One hundred children were randomly assigned to an additional intervention consisting of weekly peer-based social skills training. Complete RSA data were available for 139 of the children. Teacher-reported externalizing symptoms and emotion regulation in 1st grade (post intervention) were examined controlling for baseline levels. First-grade peer nominations of aggressive behavior, controlling for baseline nominations, were also examined as outcomes. No effect of resting RSA was found. However, greater reactivity to anger was associated with higher externalizing symptoms and lower emotion regulation skills in 1st grade relative to low reactive children. Lower reactivity to fear was associated with greater improvement over time, an effect that was enhanced in the targeted intervention condition. Results suggest that measures of affective reactivity may provide insight into children's capacity to benefit from different types of interventions.