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Background: Current staging systems for unresectable or metastatic neuroblastoma do not reliably predict responses to chemotherapy in infants under 1 year of age. Previous studies have indicated that the DNA content, or ploidy, of malignant neuroblasts can discriminate between good and poor responders in this group of patients, but the clinical utility of ploidy assessment has remained in question.Purpose: We tested, in a prospective nonrandomized study, the hypothesis that neuroblast ploidy could be used as the sole guide for treatment selection in infants with unresectable or metastatic tumors and could differentiate between those who would respond to our previous standard regimen and those who would benefit from an immediate switch to another therapy.Methods: One hundred seventy-seven infants were enrolled in this trial. Five of these infants were subsequently excluded (two ineligible, two lacking ploidy information, and one protocol violation); therefore, 172 patients were included in the study. One hundred thirty infants with hyperdiploid tumors (DNA index > 1.0; better prognosis in retrospective studies) were treated with a well-tolerated regimen of cyclophosphamide (150 mg/m2 per day orally or intravenously on days 1-7) and doxorubicin (35 mg/m2 intravenously on day 8). Forty-two infants with diploid tumors (DNA index = 1.0; worse prognosis in retrospective studies) received cisplatin (90 mg/m2 intravenously on day 1) and teniposide (100 mg/ m2 intravenously on day 3) after an initial course of cyclophosphamide plus doxorubicin. Statistical end points were response and long-term survival. In addition, we assessed within each ploidy group (i.e., patients with hyperdiploid tumors and those with diploid tumors) the prognostic significance of NMYC gene copy number, tumor stage, and other variables commonly measured in this disease.Results: Of the 127 assessable infants with hyperdiploid tumors, 115 (91%) had complete responses--85 after receiving five courses of cyclophosphamide plus doxorubicin and 30 after receiving further therapy including cisplatin plus teniposide. The 3-year survival estimate for the entire hyperdiploid group was 94% (95% confidence interval [CI] = 89%-98%). Nineteen (46%) of 41 assessable infants with diploid tumors were complete responders. The overall 3-year survival estimate for this group was 55% (95% CI = 39%-70%). Prognostic factor analysis indicated that NMYC gene amplification and an elevated serum lactate dehydrogenase level were statistically significant markers of higher risk disease within the diploid group (two-sided P values of .005 and .003, respectively). Only NMYC was predictive in the hyperdiploid group (P = .003).Conclusion: Use of a prognostic staging system based on tumor cell ploidy, augmented with the NMYC gene copy number and serum level of lactate dehydrogenase, would very likely improve the treatment of infants with unresectable or metastatic neuroblastoma. Patients with diploid tumors characterized by an amplified NMYC locus represent a particularly unfavorable risk group that may benefit from innovative new therapies. [ABSTRACT FROM AUTHOR]

Behavioral research demonstrates a critical transition in preschooler's mental-state understanding (i.e., theory of mind; ToM), revealed most starkly in performance on tasks about a character's false belief (e.g., about an object's location). Questions remain regarding the neural and cognitive processes differentiating children who pass versus fail behavioral false-belief tasks and the extent to which there is continuity versus change in the ToM neural network. To address these questions, we analyzed event-related spectral power in the electroencephalogram (EEG) to investigate how preschoolers' neural activity during passive viewing of false-belief scenarios related to their explicit behavioral ToM performance. We found that neural activity during passive viewing of false-belief events (6-9 Hz EEG 'alpha' suppression in right temporoparietal [RTP] electrodes) strongly related to children's explicit ToM. However, children's RTP alpha suppression differed depending on their explicit behavioral ToM performance: Children who did better on a broad battery of standard ToM tasks and who passed explicit behavioral false-belief tasks showed greater RTP alpha suppression when the character's belief first became false (during the 'location-change' event); whereas children who did worse on the ToM battery and who failed explicit behavioral false-belief tasks showed greater RTP alpha suppression only later when they could evaluate the character's behavior in the context of prior events (during the 'active-search' event). Findings shed light on what differentiates preschoolers who pass versus fail explicit false-belief tasks and raise questions about how to interpret existing neuroscience data from ToM tasks across infancy to adulthood. RESEARCH HIGHLIGHTS: Preschool children's neural activity (EEG 6-9 Hz suppression in right temporoparietal [RTP] electrodes) during passive-viewing of false-belief events was related to their explicit behavioral theory-of-mind performance. Children who did better on a theory-of-mind (ToM) battery and passed explicit false-belief tasks showed greater RTP alpha suppression when the character's belief first became false. Children who performed worse on the ToM battery and failed explicit false-belief tasks showed greater RTP alpha suppression later when observing the character's search behavior. Findings reveal change in preschoolers' ToM neural correlates and suggest that the presence of RTP activity does not necessarily indicate 'mature' theory of mind., (© 2024 The Author(s). Developmental Science published by John Wiley & Sons Ltd.)

In the first few months of life, infants display intriguing individual differences in how they react to novel stimuli in their environment. Infant "negative reactive" tendencies have been robustly linked to resting brain activity profiles that confer risk for maladaptive socioemotional outcomes. The present study examines whether and how caregiver behavior in early infancy may interact with infant negative reactivity to alter the extent to which such tendencies predict risk-related brain activity profiles. In the present study, 51 mothers (all White; age M = 32 years, SD = 3; 70.8% monthly household income > 3,400 U.S. dollars) and their infants (39.2% female at birth) participated. We measured infant negative reactivity and maternal contingent responsiveness to infant's gaze during mother-infant interactions at age 4 months. At 10-11 months, we assessed infants' resting electroencephalographic (EEG) 6-9 Hz frontal asymmetry (a marker of risk for maladaptive regulatory behaviors and withdrawal), infant fearful withdrawal, and infant empathic behavior. We found that maternal contingent responsiveness to 4-month-old infant's gaze in naturalistic interactions moderated the relation between 4-month infant negative reactivity and 11-month resting EEG asymmetry. Results suggest that maternal contingent responsiveness alters the extent to which early reactive tendencies end up "embedded" in infant brain activity profiles. Exploratory analyses revealed that the interaction between maternal contingent responsiveness and infant reactivity predicting infant resting EEG asymmetry, in turn predicted infants' fearful withdrawal and empathic behaviors also assessed at 10-11 months. Findings demonstrate the critical buffering role of maternal contingent responsive behaviors in reducing potential maladaptive neural and socioemotional outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The ability to accurately decode others' facial expressions is essential for successful social interaction. Previous theories suggest that aspects of parental emotionality-the frequency, persistence and intensity of parents' own emotions-can influence children's emotion perception. Through a combination of mechanisms, parental emotionality may shape how children's brains specialize to respond to emotional expressions, but empirical data are lacking. The present study provides a direct empirical test of the relation between the intensity, persistence and frequency of parents' own emotions and children's neural responses to perceiving emotional expressions. Event-related potentials (ERPs) were recorded as typically developing 3- to 5-year-old children (final Ns = 59 and 50) passively viewed faces expressing different emotional valences (happy, angry and fearful) at full and reduced intensity (100% intense expression and 40% intense expression). We examined relations between parental emotionality and children's mean amplitude ERP N170 and negative central responses. The findings demonstrate a clear relation between parental emotionality and children's neural responses (in the N170 mean amplitude and latency) to emotional expressions and suggest that parents may influence children's emotion-processing neural circuitry., (© The Author(s) 2024. Published by Oxford University Press.)

Substance-use disorders (SUDs) and drug addiction are not only national, but also global health concerns that have worsened during and after the COVID-19 pandemic. Acupuncture augments the endogenous opioid system and, therefore, has a theoretical basis as a treatment for opioid use disorders (OUDs). The basic science of acupuncture, its clinical research in addiction medicine, and decades of success of the National Acupuncture Detoxification Association protocol offer positive findings supporting this protocol's utility for treating SUDs. Considering the mounting opioid/substance-use concerns and deficiencies in SUD treatment availability in the United States, acupuncture can be a safe, feasible treatment option and adjunct in addiction medicine. Furthermore, large governmental agencies are lending support to acupuncture for treating acute and chronic pain, which, in turn, could translate to prevention of SUDs and addictions. This article is a narrative review of the background, the basic science and clinical research, and future direction of acupuncture in addiction medicine., Competing Interests: No financial conflicts of interest exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

Event-related potentials (ERPs) are advantageous for investigating cognitive development. However, their application in infants/children is challenging given children's difficulty in sitting through the multiple trials required in an ERP task. Thus, a large problem in developmental ERP research is high subject exclusion due to too few analyzable trials. Common analytic approaches (that involve averaging trials within subjects and excluding subjects with too few trials, as in ANOVA and linear regression) work around this problem, but do not mitigate it. Moreover, these practices can lead to inaccuracies in measuring neural signals. The greater the subject exclusion, the more problematic inaccuracies can be. We review recent developmental ERP studies to illustrate the prevalence of these issues. Critically, we demonstrate an alternative approach to ERP analysis-linear mixed effects (LME) modeling-which offers unique utility in developmental ERP research. We demonstrate with simulated and real ERP data from preschool children that commonly employed ANOVAs yield biased results that become more biased as subject exclusion increases. In contrast, LME models yield accurate, unbiased results even when subjects have low trial-counts, and are better able to detect real condition differences. We include tutorials and example code to facilitate LME analyses in future ERP research., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Postnatal maternal anxiety is common (estimates as high as 40% prevalence) and is associated with altered mother-infant interactions (e.g., reduced maternal emotional expression and engagement). Neural circuitry supporting infants' face and emotion processing develops in their first year. Thus, early exposure to maternal anxiety may impact infants' developing understanding of emotional displays. We examine whether maternal anxiety is associated with individual differences in typically developing infants' neural responses to emotional faces., Methods: One hundred and forty two mother-infant dyads were assessed when infants were 5, 7, or 12 months old. Infants' electroencephalographic (EEG) data were recorded while passively viewing female happy, fearful, and angry faces. Three event-related potential (ERP) components, each linked to face and emotion processing, were evaluated: NC, N290, and P400. Infant ERP amplitude was related to concurrent maternal-report anxiety assessed with the Spielberger State-Trait Anxiety Inventory (Trait form)., Results: Greater maternal anxiety predicted more negative NC amplitude for happy and fearful faces in left and mid-central scalp regions, beyond covarying influences of maternal depression symptoms, infant negative emotionality, and infant age., Conclusions: Postnatal maternal anxiety is related to infants' neural processing of emotional expressions. Infants of mothers endorsing high trait anxiety may need additional attentional resources to process happy and fearful faces (expressions less likely experienced in mother-infant interactions). Future research should investigate mechanisms underlying this association, given possibilities include experiential, genetic, and prenatal factors., (© 2021 Association for Child and Adolescent Mental Health.)

Motivation influences cognitive control, particularly in childhood and adolescence. Previous work finds that the error-related negativity (ERN), an event-related potential (ERP) linked to cognitive control following errors, is influenced by social motivation. However, it is unclear whether the influences of social motivation on the ERN extend to stimulus-locked neural correlates of cognitive control. This study reexamines how social motivation influences cognitive control in adolescence by exploring motivational influences on two stimulus-locked ERPs; the N2 and P3. Adolescent girls (8-17 years of age) completed a flanker task under two different conditions. In the social condition, girls were led to believe that they were evaluated by a peer during a flanker task. In the nonsocial condition, girls completed a flanker task while evaluated by a computer. Results revealed that all girls exhibited a larger P3 in social as compared to nonsocial contexts, whereas the N2 was not different between contexts. In addition, the largest P3 enhancements were observed among younger girls. These findings suggest that social motivation influences some ERP components related to cognitive control, and such influences change across development. Additionally, findings suggest the importance of including multiple ERPs when interpreting the functional significance of motivation on cognitive control., (© 2021 Wiley Periodicals LLC.)

Children's explicit theory of mind (ToM) understandings change over early childhood. We examined whether there is longitudinal stability in the neurobiological bases of ToM across this time period. A previous study found that source-localized resting EEG alpha attributable to the dorsal medial prefrontal cortex (DMPFC) and right temporoparietal junction (RTPJ) was associated with children's performance on a battery of theory of mind tasks. Here, we investigated a small subset of children (N = 12) in that original study as a preliminary investigation of whether behavioral measures of ToM performance, and/or EEG localized to the DMPFC or RTPJ predicted ToM-specific fMRI responses 3.5 years later. Results showed that preschoolers' behavioral ToM-performance positively predicted later ToM-specific fMRI responses in the DMPFC. Preschoolers' resting EEG attributable to the DMPFC also predicted later ToM-specific fMRI responses in the DMPFC. Given the small sample, results represent a first exploration and require replication. Intriguingly, they suggest that early maturation of the area of the DMPFC related to ToM reasoning is positively linked with its specific recruitment for ToM reasoning later in development, affording implications for characterizing conceptual ToM development, and its underlying neural supports., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Theta oscillations (4-8 Hz) provide an organizing principle of cognitive control, allowing goal-directed behavior. In adults, theta power over medial-frontal cortex (MFC) underlies conflict/error monitoring, whereas theta connectivity between MFC and lateral-frontal regions reflects cognitive control recruitment. However, prior work has not separated theta responses that occur before and immediately after a motor response, nor explained how medial-lateral connectivity drives different kinds of control behaviors. Theta's role during adolescence, a developmental window characterized by a motivation-control mismatch also remains unclear. As social observation is known to influence motivation, this might be a particularly important context for studying adolescent theta dynamics. Here, adolescents performed a flanker task alone or under social observation. Focusing first on the nonsocial context, we parsed cognitive control into dissociable subprocesses, illustrating how theta indexes distinct components of cognitive control working together dynamically to produce goal-directed behavior. We separated theta power immediately before/after motor responses, identifying behavioral links to conflict monitoring and error monitoring, respectively. MFC connectivity was separated before/after responses and behaviorally-linked to reactive and proactive control, respectively. Finally, distinct forms of post-error control were dissociated, based on connectivity with rostral/caudal frontal cortex. Social observation was found to exclusively upregulate theta measures indexing post-response error monitoring and proactive control, as opposed to conflict monitoring and reactive control. Linking adolescent cognitive control to theta oscillations provides a bridge between non-invasive recordings in humans and mechanistic studies of neural oscillations in animal models; links to social observation provide insight into the motivation-control interactions that occur during adolescence., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Although many studies have examined the location and function of the mirror neuron system (MNS) in human adults, we know relatively little about its development. The current study fills this gap by using fMRI to examine for the first time the development of the brain regions implicated in action execution, action observation, and their overlap. We examined age-related differences in brain activation by contrasting a group of children (n = 21) and adults (n = 18). Surfaced-based analyses of action execution and action observation revealed that brain activity for action observation and execution in children is similar to adults, though adults displayed greater activity than children within the right superior parietal lobe during action execution and the occipital lobe during action observation compared to control. Further, within-individual measures of overlapping activation between action observation and execution revealed age-related differences, such that adults, compared to children, displayed more spatial overlap. Moreover, the extent of the overlap in activation across conditions was related to better motor skills and action representation abilities in children. These data indicate that the MNS changes between middle childhood and adulthood. The data also demonstrate the functional significance of the putative MNS to motor skills and action representation during development., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the present study we examined the neural correlates of facial emotion processing in the first year of life using ERP measures and cortical source analysis. EEG data were collected cross-sectionally from 5- (N = 49), 7- (N = 50), and 12-month-old (N = 51) infants while they were viewing images of angry, fearful, and happy faces. The N290 component was found to be larger in amplitude in response to fearful and happy than angry faces in all posterior clusters and showed largest response to fear than the other two emotions only over the right occipital area. The P400 and Nc components were found to be larger in amplitude in response to angry than happy and fearful faces over central and frontal scalp. Cortical source analysis of the N290 component revealed greater cortical activation in the right fusiform face area in response to fearful faces. This effect started to emerge at 5 months and became well established at 7 months, but it disappeared at 12 months. The P400 and Nc components were primarily localized to the PCC/Precuneus where heightened responses to angry faces were observed. The current results suggest the detection of a fearful face in infants' brain can happen shortly (~200-290 ms) after the stimulus onset, and this process may rely on the face network and develop substantially between 5 to 7 months of age. The current findings also suggest the differential processing of angry faces occurred later in the P400/Nc time window, which recruits the PCC/Precuneus and is associated with the allocation of infants' attention., (© 2018 John Wiley & Sons Ltd.)

Infants' pointing is associated with concurrent and later language development. The communicative intention behind the point-i.e., imperative versus declarative-can affect both the nature and strength of these associations, and is therefore a critical factor to consider. Parents' pointing is associated with both infant pointing and infant language; however, less work has examined the intent behind parents' points. We explore relations between parents' and infants' pointing at the level of communicative intention, and examine how pointing relates to concurrent and longitudinal infant language skills. In a sample of 52 mother-infant dyads, we measured mother and infant pointing at infant age 12-months, and infant expressive and receptive language at 12-, 18-, and 24-months. We found that mothers produced points with a variety of intentions, however we did not find relations between mother and infant pointing within the different communicative intentions. Replicating previous research, infant declarative pointing was related both concurrently and longitudinally to their language ability. Mothers' declarative pointing was related to their infants' concurrent language, while their imperative pointing was not. Further, there was an interaction between parent and infant declarative pointing, such that the positive relation between parents' declarative pointing and their infants' concurrent receptive language was present only for those infants who were also producing declarative points themselves. Findings suggest that parents' declarative pointing may support both their infants' early word learning and, perhaps, provides a model for their infant to begin using points as well. This study constitutes an important initial exploration of these relations.

Adolescence is a developmental period characterized by increased social motivation and a heightened concern of peer evaluation. However, little research has examined social influences on neural functioning in adolescence. One psychophysiological measure of motivation, the error-related negativity (ERN), is an ERP following an error. In adults, the ERN is enhanced by contextual factors that influence motivation, such as social observation and evaluation. The current study examined relations among age and neural responses in social contexts in adolescence. Seventy-six adolescent girls (9-17 years old) completed a flanker task under two different conditions. In the social condition, adolescent girls were informed that two other adolescents would be observing and providing feedback about their performance. In the nonsocial condition, adolescent girls completed a flanker task alone and were told feedback was computer generated. Results revealed that younger adolescents exhibited a larger ERN in social contexts than nonsocial contexts. In contrast, there were no differences in the ERN between contexts among older adolescents. In addition, enhancements of the ERN in social contexts among younger adolescents diminished the relation between the ERN and age. These findings suggest that the ERN is sensitive to social contexts in early adolescence, and developmental changes in the ERN may be partially explained by contextual factors that influence motivation., (© 2018 Society for Psychophysiological Research.)

Objective: Behavioral inhibition (BI) is a temperament identified in early childhood that is a risk factor for later social anxiety. However, mechanisms underlying the development of social anxiety remain unclear. To better understand the emergence of social anxiety, longitudinal studies investigating changes at behavioral neural levels are needed., Method: BI was assessed in the laboratory at 2 and 3 years of age (N = 268). Children returned at 12 years, and an electroencephalogram was recorded while children performed a flanker task under 2 conditions: once while believing they were being observed by peers and once while not being observed. This methodology isolated changes in error monitoring (error-related negativity) and behavior (post-error reaction time slowing) as a function of social context. At 12 years, current social anxiety symptoms and lifetime diagnoses of social anxiety were obtained., Results: Childhood BI prospectively predicted social-specific error-related negativity increases and social anxiety symptoms in adolescence; these symptoms directly related to clinical diagnoses. Serial mediation analysis showed that social error-related negativity changes explained relations between BI and social anxiety symptoms (n = 107) and diagnosis (n = 92), but only insofar as social context also led to increased post-error reaction time slowing (a measure of error preoccupation); this model was not significantly related to generalized anxiety., Conclusion: Results extend prior work on socially induced changes in error monitoring and error preoccupation. These measures could index a neurobehavioral mechanism linking BI to adolescent social anxiety symptoms and diagnosis. This mechanism could relate more strongly to social than to generalized anxiety in the peri-adolescent period., (Copyright © 2017 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Many psychological theories posit foundational links between two fundamental constructs: (1) our ability to produce, perceive, and represent action; and (2) our ability to understand the meaning and motivation behind the action (i.e. Theory of Mind; ToM). This position is contentious, however, and long-standing competing theories of social-cognitive development debate roles for basic action-processing in ToM. Developmental research is key to investigating these hypotheses, but whether individual differences in neural and behavioral measures of motor action relate to social-cognitive development is unknown. We examined 3- to 5-year-old children's (N = 26) EEG mu-desynchronization during production of object-directed action, and explored associations between mu-desynchronization and children's behavioral motor skills, behavioral action-representation abilities, and behavioral ToM. For children with high (but not low) mu-desynchronization, motor skill related to action-representation abilities, and action-representation mediated relations between motor skill and ToM. Results demonstrate novel foundational links between action-processing and ToM, suggesting that basic motor action may be a key mechanism for social-cognitive development, thus shedding light on the origins and emergence of higher social cognition., (© 2016 John Wiley & Sons Ltd.)

A fundamental issue in cognitive neuroscience is how the brain encodes others' actions and intentions. In recent years, a potential advance in our knowledge on this issue is the discovery of mirror neurons in the motor cortex of the nonhuman primate. These neurons fire to both execution and observation of specific types of actions. Researchers use this evidence to fuel investigations of a human mirror system, suggesting a common neural code for perceptual and motor processes. Among the methods used for inferring mirror system activity in humans are changes in a particular frequency band in the electroencephalogram (EEG) called the mu rhythm. Mu frequency appears to decrease in amplitude (reflecting cortical activity) during both action execution and action observation. The current meta-analysis reviewed 85 studies (1,707 participants) of mu that infer human mirror system activity. Results demonstrated significant effect sizes for mu during execution (Cohen's d = 0.46, N = 701) as well as observation of action (Cohen's d = 0.31, N = 1,508), confirming a mirroring property in the EEG. A number of moderators were examined to determine the specificity of these effects. We frame these meta-analytic findings within the current discussion about the development and functions of a human mirror system, and conclude that changes in EEG mu activity provide a valid means for the study of human neural mirroring. Suggestions for improving the experimental and methodological approaches in using mu to study the human mirror system are offered., ((c) 2016 APA, all rights reserved).)

Behaviorally, children's explicit theory of mind (ToM) proceeds in a progression of mental-state understandings: developmentally, children demonstrate accurate explicit desire-reasoning before accurate explicit belief-reasoning. Given its robust and cross-cultural nature, we hypothesize this progression may be paced in part by maturation/specialization of the brain. Neuroimaging research demonstrates that the right temporoparietal junction (TPJ) becomes increasingly selective for ToM reasoning as children age, and as their ToM improves. But this research has narrowly focused on beliefs or on undifferentiated mental-states. A recent ERP study in children included a critical contrast to desire-reasoning, and demonstrated that right posterior potentials differentiated belief-reasoning from desire-reasoning. Taken together, the literature suggests that children's desire-belief progression may be paced by specialization of the right TPJ for belief-reasoning specifically, beyond desire-reasoning. In the present study, we tested this hypothesis directly by examining children's belief- and desire-reasoning using functional near-infrared spectroscopy in conjunction with structural magnetic resonance imaging to pinpoint brain activation in the right TPJ. Results showed greatest activation in the right TPJ for belief-reasoning, beyond desire-reasoning, and beyond non-mental reasoning (control). Findings replicate and critically extend prior ERP results, and provide clear evidence for a specific neural mechanism underlying children's progression from understanding desires to understanding beliefs.

Fifty-eight consecutive children with high-risk malignancies were treated with CY, and targeted topotecan followed by autologous hematopoietic cell transplantation (AHCT) in a phase I/II Institutional Review Board-approved study. Twelve participants enrolled in phase I; 5 received dose level 1 of topotecan 3 mg/m(2) per day, with subsequent doses targeted to total systemic exposure of 100±20 ng h/mL and CY 750 mg/m(2) per day. Seven participants received dose level 2. CY dose escalation to 1 g/m(2) per day was considered excessively toxic; one died from irreversible veno-occlusive disease and two experienced reversible hepatotoxicity. These adverse events halted further dose escalation. A total of 46 participants were enrolled in phase II; results are on the 51 participants who received therapy at dose level 1, the maximum tolerated dose. Diagnoses included neuroblastoma (26), sarcoma (9), lymphoma (8), brain tumors (5), Wilms (2) and retinoblastoma (1). Twenty participants (39.3%) were in CR1 at enrollment; median age was 5.1 years. Most common non-hematological grade III-IV toxicity was gastrointestinal (n=37). Neutrophil and platelet engraftment occurred at a median of 15 and 24 days, respectively. Twenty-six (51%) participants remain alive at a median of 6.4 years after AHCT. CY 3.75 g/m(2), and targeted topotecan followed by AHCT are feasible and produce acceptable toxicity in children with high-risk malignancies.

Theory of mind requires belief- and desire-understanding. Event-related brain potential (ERP) research on belief- and desire-reasoning in adults found mid-frontal activations for both desires and beliefs, and selective right-posterior activations only for beliefs. Developmentally, children understand desires before beliefs; thus, a critical question concerns whether neural specialization for belief-reasoning exists in childhood or develops later. Neural activity was recorded as 7- and 8-year-olds (N = 18) performed the same diverse-desires, diverse-beliefs, and physical control tasks used in a previous adult ERP study. Like adults, mid-frontal scalp activations were found for belief- and desire-reasoning. Moreover, analyses using correct trials alone yielded selective right-posterior activations for belief-reasoning. Results suggest developmental links between increasingly accurate understanding of complex mental states and neural specialization supporting this understanding., (© 2012 Blackwell Publishing Ltd.)

Representational theory of mind (RTM) development follows a universal developmental timetable whereby major advances in reasoning about mental representations occur between the ages of 3 and 5 years old. This progression appears to be only absent in the case of specific neurodevelopmental impairments, such as autism. Taken together, this suggests that neuromaturational factors may play a role in RTM development. Recent EEG work has shown that one neuromaturational factor pacing this universal developmental timetable is the functional maturation of medial prefrontal cortex. The neurotransmitter dopamine (DA) is thought to play a crucial role in typical frontal lobe development. Therefore, the goal of the present study was to investigate the role that DA may play in RTM development. Ninety-one 48-62-month olds were given a battery of RTM tasks along with EEG measurement. EEG recordings were analyzed for eyeblinks, a reliable indicator of DA functioning, and we calculated their average eyeblinks per minute (EBR). Regression analyses showed that EBR was associated with RTM after controlling for children's performance on a Stroop-like measure, language ability, gender, and age. These findings provide evidence that DA functioning is associated with RTM in the preschool years, and are discussed with respect to how DA might provide a mechanism that helps to account for both neurobiological and experiential factors that are known to affect the timetable of preschoolers' RTM development., (2010 Elsevier Ltd. All rights reserved.)

Baseline electroencephalogram (EEG) data were collected from twenty-nine 4-year-old children who also completed batteries of representational theory-of-mind (RTM) tasks and executive functioning (EF) tasks. Neural sources of children's EEG alpha (6-9 Hz) were estimated and analyzed to determine whether individual differences in regional EEG alpha activity predicted children's RTM performance, while statistically controlling for children's age and EF skills. Results showed that individual differences in EEG alpha activity localized to the dorsal medial prefrontal cortex (dMPFC) and the right temporal-parietal juncture (rTPJ) were positively associated with children's RTM performance. These findings suggest that the maturation of dMPFC and rTPJ is a critical constituent of preschoolers' explicit theory-of-mind development.

Bone loss is a consequence of exposure to high-dose radiotherapy. While damage to bone vasculature and reduced proliferation of bone-forming osteoblasts has been implicated in this process, the effect of radiation on the number and activity of bone-resorbing osteoclasts has not been characterized. In this study, we exposed mice to a whole-body dose of 2 Gy of X rays to quantify the early effects of radiation on osteoclasts and bone structural properties. Female C57BL/6 mice (13 weeks old) were divided into two groups: irradiated and nonirradiated controls. Animals were killed humanely 3 days after radiation exposure. Analysis of serum chemistry revealed a 14% increase in the concentration of tartrate resistant acid phosphatase (TRAP)-5b, a marker of osteoclast activity, in irradiated mice (P < 0.05). Osteoclast number (+44%; P < 0.05) and osteoclast surface (+213%; P < 0.001) were elevated in TRAP-stained histological sections of tibial metaphyses. No significant change was observed in osteoblast surface or osteocalcin concentration or in trabecular microarchitecture (i.e. bone volume fraction) as measured through microcomputed tomography (P > 0.05). This study provides definitive, quantitative evidence of an early, radiation-induced increase in osteoclast activity and number. Osteoclastic bone resorption may represent a contributor to bone atrophy observed after therapeutic irradiation.

Purpose: The goal of Pediatric Oncology Group 9243 was to improve outcomes for children with intermediate-risk neuroblastoma (NB)., Patients and Methods: Patients were assigned to treatments on the basis of age, tumor MYCN status, and tumor cell ploidy. Children in the less intensive arm A received cyclophosphamide/doxorubicin and surgery. Patients not in complete remission postoperatively were treated with cisplatin/etoposide, cyclophosphamide/doxorubicin, and additional surgery. Patients with less favorable features were assigned to arm B, which consisted of carboplatin, etoposide, ifosfamide, and surgery. Survival rates were determined using an intent-to-treat approach., Results: For arm-A patients, the 6-year event-free survival (EFS) was 86% with an SE of 3%. For arm-B patients, the 6-year EFS was 46% with an SE of 7%. MYCN status was the only statistically significant prognostic variable. Among patients whose tumors were MYCN nonamplified, a trend toward improved EFS was seen in children with hyperdiploid versus diploid tumors. However, many of these children responded well to salvage therapy, and overall survival rates did not differ on the basis of ploidy. Six-year EFS rates for arm B were patients with MYCN nonamplified, hyperdiploid tumors, 86% with an SE of 3%; patients with MYCN nonamplified, diploid tumors, 74% with an SE of 10%; patients with MYCN-amplified, hyperdiploid tumors, 46% with an SE of 15%; and patients with MYCN-amplified, diploid tumors, 22% with an SE of 10%., Conclusion: Outcomes for patients with MYCN-nonamplified, hyperdiploid tumors were excellent. Therapy reductions for these patients merit study. A trend toward less favorable outcomes for patients with MYCN-nonamplified, diploid tumors was observed; more children may need to be evaluated before therapy is reduced for this subgroup. For patients with MYCN-amplified tumors, new strategies are needed.

Hemolytic uremic syndrome (HUS) is an uncommon but potentially life-threatening complication of hematopoietic stem cell transplantation. We retrospectively studied the medical records of 293 children who underwent allogeneic bone marrow transplantation at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of and to identify risk factors for transplant-associated HUS. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation for patients with hematologic malignancies (n = 244); patients with nonmalignant diseases (n = 49) received disease-specific regimens. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. HUS developed in 28 (9.6%) patients at a median of 171 days after transplantation. We identified older donor age (P = .029), use of antithymocyte globulin in the conditioning regimen (P = .008), and recipient CMV seronegativity (P = .011) as being associated with an increased risk of HUS. With a multiple regression analysis, the use of antithymocyte globulin (beta = .86; P = .04) and recipient cytomegalovirus seronegativity (beta = .93; P = .035) remained significant risk factors for the development of HUS.

Hemorrhagic cystitis (HC) is a well-documented adverse event experienced by patients undergoing hematopoietic stem cell transplantation. When severe, HC causes significant morbidity, leads to renal complications, prolongs hospitalization, increases health-care costs, and occasionally contributes to death. We retrospectively studied the medical records of 245 children undergoing an initial allogeneic bone marrow transplantation for malignant disease at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of HC in all patients and to identify the risk factors for HC in this cohort. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. Severe HC developed in 27 patients (11.0%). The median duration of HC was 73 days (range, 5-619 days); 12 patients had ongoing HC at the time of death. In univariate analyses, patients were at increased risk of severe HC if they were male (P =.021) or had received T cell-depleted grafts (P =.017), grafts from unrelated donors (P =.021), a lower total nucleated cell dose (P =.032), or antithymocyte globulin (P =.0446). Multiple regression analysis revealed male sex (beta =.97; P =.027) and unrelated donor graft recipients (beta =.83; P =.039) to be significant factors.

The histiocytoses are rare disorders of antigen-processing phagocytic or antigen-presenting cells. Allogeneic bone marrow transplantation (BMT) can be curative of these disorders. We report a series of five children with Langerhans cell histiocytosis (n=2) or hemophagocytic lymphohistiocytosis (n=3), who received allogeneic BMT with a total body irradiation (TBI)-containing regimen (TBI, cytarabine, and cyclophosphamide) at our institution between 1995 and 2000. One of these patients received busulfan, cyclophosphamide, and etoposide for the first of two BMTs. All grafts except one (a matched sibling-donor graft) were T-cell-depleted grafts from unrelated donors. All received cyclosporine graft-versus-host disease (GvHD) prophylaxis; the recipient of the matched sibling graft also received methotrexate. Three patients engrafted at a median of 24 days after transplantation. The patient who did not receive TBI experienced primary graft failure and recurrent disease. After the TBI-containing conditioning regimen was given, a second transplant engrafted on day +17. One patient with concurrent myelodysplastic syndrome died of toxicity on day +33 without evidence of engraftment. No acute or chronic GvHD was observed. Four patients survive disease-free, a median of 63 months after transplantation, all with Lansky performance scores of 100. We conclude that a conditioning regimen containing TBI but not etoposide is effective in allogeneic BMT for children with histiocytic diseases.

Background: Children with hepatocellular carcinoma (HCC) were treated on a prospective, randomized trial and were then analyzed to determine whether children with the fibrolamellar (FL) histologic variant of HCC have a more favorable presentation, increased surgical resectability, greater response to therapy, and improved outcome compared with children who have typical HCC., Methods: Forty-six patients were enrolled on Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group Study 8945/Children's Cancer Group Study 8881) between August 1989 and December 1992. After undergoing initial surgery or biopsy, children with Stage I HCC (n = 8 patients), Stage III HCC (n = 25 patients), and Stage IV HCC (n = 13 patients) were assigned randomly, regardless of histology, to receive treatment either with cisplatin, vincristine, and fluorouracil (n = 20 patients) or with cisplatin and continuous-infusion doxorubicin (n = 26 patients)., Results: Ten of 46 patients (22%) had the fibrolamellar variant of HCC (FL-HCC). For the entire cohort, the estimated 5-year event free survival (EFS) rate (+/- standard deviation) was 17% +/- 6%. There was no difference in outcome among patients who were treated with either regimen. The 5-year EFS rate for patients with FL-HCC was no different the rate for patients with typical HCC (30% +/- 15% vs. 14% +/- 6%, respectively; P = 0.18), although the median survival was longer in patients with FL-HCC. There was no difference in the number of patients with advanced-stage disease, the incidence of surgical resectability at diagnosis, or the response to treatment between patients with FL-HCC and patients with typical HCC., Conclusions: Children with FL-HCC do not have a favorable prognosis and do not respond any differently to current therapeutic regimens than patients with typical HCC. Children with initially resectable HCC have a good prognosis irrespective of histologic subtype, whereas outcomes are poor uniformly for children with advanced-stage disease. The use of novel chemotherapeutic agents and the incorporation of other treatment modalities are indicated to improve the dismal survival of pediatric patients with all histologic variants of advanced-stage HCC., (Copyright 2003 American Cancer Society.)

In murine models, transgenic chemokine-cytokine tumor vaccines overcome many of the limitations of single-agent immunotherapy by producing the sequence of T-cell attraction followed by proliferation. The safety and immunologic effects of this approach in humans were tested in 21 patients with relapsed or refractory neuroblastoma. They received up to 8 subcutaneous injections of a vaccine combining lymphotactin (Lptn)- and interleukin-2 (IL-2)-secreting allogeneic neuroblastoma cells in a dose-escalating scheme. Severe adverse reactions were limited to reversible panniculitis in 5 patients and bone pain in 1 patient. Injection-site biopsies revealed increased cellularity caused by infiltration of CD4+ and CD8+ lymphocytes, eosinophils, and Langerhans cells. Systemically, the vaccine produced a 2-fold (P =.035) expansion of CD4+ T cells, a 3.5-fold (P =.039) expansion of natural killer (NK) cells, a 2.1-fold (P =.014) expansion of eosinophils, and a 1.6-fold (P =.049) increase in serum IL-5. When restimulated in vitro by the immunizing cell line, T cells collected after vaccination showed a 2.3-fold increase (P =.02) of T-helper (TH2)-type CD3+IL-4+ cells. Supernatant collected from restimulated cells showed increased amounts of IL-4 (11.4-fold; P =.021) and IL-5 (8.7-fold; P =.002). Six patients had significant increases in NK cytolytic activity. Fifteen patients made immunoglobulin G (IgG) antibodies that bound to the immunizing cell line. Measurable tumor responses included complete remission in 2 patients and partial response in 1 patient. Hence, allogeneic tumor cell vaccines combining transgenic Lptn with IL-2 appear to have little toxicity in humans and can induce an antitumor immune response.

Purpose: To assess the effects of the low-osmolar contrast agent iopamidol and antimicrobial drugs on renal function in pediatric, adolescent, and young adult patients who have undergone bone marrow transplantation (BMT)., Materials and Methods: A retrospective review of records of 120 consecutive pediatric patients who underwent allogeneic BMT in 1997 or 1998 was performed. Eighty-nine patients (median age, 8.1 years) fulfilled study eligibility criteria. Cumulative doses of nephrotoxic antimicrobial drugs were recorded, as well as serum creatinine and blood urea nitrogen concentrations from 24 hours before to 72 hours after each administration of iopamidol during a computed tomographic examination performed within 100 days after BMT. Random coefficient models were used to estimate nephrotoxic effects., Results: Mean baseline glomerular filtration rate was 130.2 mL/min/1.73 m(2), and mean baseline creatinine concentration was 0.51 mg/dL (45 micro mol/L). Older age at BMT (P <.001), use of foscarnet (P =.003), and receipt of iopamidol (P =.073) each prompted a rise in serum creatinine concentration. The antiviral drug foscarnet was associated with the largest increase in the creatinine level; the use of iopamidol effected a relatively small rise in creatinine level., Conclusion: Iopamidol nephrotoxicity was negligible in this cohort of pediatric patients who had undergone allogeneic BMT, even in the presence of elevated renal function levels.

A 6-year-old girl with neuroblastoma developed swelling and erythema of her right upper eyelid following administration of an interleukin-2 and lymphotactin gene-modified allogeneic neuroblastoma cell vaccine. Computed tomography demonstrated a cystic lesion in the subperiosteal space. A biopsy of the mass showed necrotic neuroblastoma with minimal associated inflammation. To our knowledge, this case represents the first description of occult orbital metastases in a patient with neuroblastoma detected after administration of an antitumor vaccine.

Purpose: To estimate the disease-response rate, proportion of patients whose tumors can be made resectable, event-free survival (EFS), and toxicity in children with unresectable or metastatic hepatoblastoma (HB) after sequential treatment with the following: (1) carboplatin (CARBO); (2) CARBO, vincristine, and fluorouracil (CARBO-VCR-5-FU); and (3) high-dose cisplatin and etoposide (HDDP-ETOP)., Patients and Methods: Thirty-three assessable patients with stage III (n = 22) and stage IV (n = 11) HB were treated sequentially with one course of CARBO (700 mg/m(2)), followed by three courses of CARBO (700 mg/m(2)), day 0; 5-FU (1,000 mg/m(2)/d), by continuous infusion days 0 to 2; and VCR (1.5 mg/m(2)), days 0, 7, and 14. After that therapy, patients whose tumors were resectable underwent surgery and then received two additional courses of CARBO-VCR-5-FU. Children whose tumors remained unresectable after CARBO-VCR-5-FU or who demonstrated no response or progressive disease during this therapy received two courses of HDDP (40 mg/m(2)/d), days 1 to 5; and ETOP (100 mg/m(2)/d), days 2 to 4., Results: Five-year EFS estimates were 59% +/- 11% for stage III disease (n = 22) and 27% +/- 16% for stage IV disease (n = 11), respectively (P =.037). Twenty-seven (82%) of 33 patients had at least a partial response to chemotherapy; 18 (55%) of 33 responded to CARBO; 24 (80%) of 30 responded to CARBO and CARBO-VCR-5-FU; and nine (75%) of 12 responded to HDDP-ETOP. Surgical resection was achieved in 19 (58%) of 33 patients, including 15 (68%) of 22 stage III patients and four (36%) of 11 stage IV patients. Five-year EFS for patients whose tumors were completely resected was 79% +/- 10%., Conclusion: Patients treated sequentially with CARBO, CARBO-VCR-5-FU, and HDDP-ETOP had response rates and EFS comparable to other therapeutic regimens. This regimen is effective in treating localized, unresectable HB and potentially has less toxicity than other regimens. Novel approaches are needed for patients with metastatic disease.

Purpose: To determine surgical resectability, event-free survival (EFS), and toxicity in children with hepatocellular carcinoma (HCC) randomized to treatment with either cisplatin (CDDP), vincristine, and fluorouracil (regimen A) or CDDP and continuous-infusion doxorubicin (regimen B)., Patients and Methods: Forty-six patients were enrolled onto Pediatric Intergroup Hepatoma Protocol INT-0098 (Pediatric Oncology Group (POG) 8945/Children's Cancer Group (CCG) 8881). After initial surgery or biopsy, children with stage I (n = 8), stage III (n = 25), and stage IV (n = 13) HCC were randomly assigned to receive regimen A (n = 20) or regimen B (n = 26)., Results: For the entire cohort, the 5-year EFS estimate was 19% (SD = 6%). Patients with stage I, III, and IV had 5-year EFS estimates of 88% (SD = 12%), 8% (SD = 5%), and 0%, respectively. Five-year EFS estimates were 20% (SD = 9%) and 19% (SD = 8%) for patients on regimens A and B, respectively (P =.78), with a relative risk of 1.2 (95% confidence interval, 0.60 to 2.3) for regimen B when compared with regimen A. Outcome was similar for either regimen within disease stages. Events occurred before postinduction surgery I in 18 (47%) of 38 patients with stage III or IV disease, and tumor resection was possible in two (10%) of the remaining 20 children with advanced-stage disease after chemotherapy., Conclusion: Children with initially resectable HCC have a good prognosis and may benefit from the use of adjuvant chemotherapy. Outcome was uniformly poor for children with advanced-stage disease treated with either regimen. New therapeutic strategies are needed for the treatment of advanced-stage pediatric HCC.

The degree of histoincompatibility that can be tolerated, and the relative importance of matching at individual HLA class I and class II locus in bone marrow transplantation (BMT) has not been established. We hypothesized that matching for HLA-DR may not be more important than matching for HLA-A or HLA-B in selection of a donor for successful BMT. We retrospectively analyzed the outcomes of 248 consecutive pediatric patients who received allogeneic BMT from related donors (RD, n = 119) or unrelated donors (URD, n = 129). HLA-A and HLA-B were serologically matched, and HLA-DRB1 were identical by DNA typing in 69% of donor-recipient pairs. Most patients (89%) had hematologic malignancies; the rest had aplastic anemia or a congenital disorder. One HLA-A antigen mismatch was associated with a decrease in survival (p = 0.003) and a delay in granulocyte engraftment (p = 0.02) in recipients of RD marrow; as well as a decrease in survival (p = 0.02) and the development of severe acute graft-versus-host disease (GVHD) (p = 0.03) in recipients of URD marrow. One HLA-B antigen mismatch was associated with a decrease in the survival (p = 0.05) and the development of severe GVHD (p = 0.0007) in recipients of RD marrow. One HLA-DRB1 allele mismatch was associated only with a decrease in the survival (p = 0.0003) of recipients of RD marrow. Results of this study suggest that disparity in HLA-A and HLA-B antigens may not be better tolerated than disparity in HLA-DR allele in allogeneic BMT. Further studies are warranted to confirm our results.

To assess the utility of fluorescence in situ hybridization (FISH) for analysis of MYCN gene amplification in neuroblastoma, we compared this assay with Southern blot analysis using tumor specimens collected from 232 patients with presenting characteristics typical of this disease. The FISH technique identified MYCN amplification in 47 cases, compared with 39 by Southern blotting, thus increasing the total number of positive cases by 21%. The major cause of discordancy was a low fraction of tumor cells (< or =30% replacement) in clinical specimens, which prevented an accurate estimate of MYCN copy number by Southern blotting. With FISH, by contrast, it was possible to analyze multiple interphase nuclei of tumor cells, regardless of the proportion of normal peripheral blood, bone marrow, or stromal cells in clinical samples. Thus, FISH could be performed accurately with very small numbers of tumor cells from touch preparations of needle biopsies. Moreover, this procedure allowed us to discern the heterogeneous pattern of MYCN amplification that is characteristic of neuroblastoma. We conclude that FISH improves the detection of MYCN gene amplification in childhood neuroblastomas in a clinical setting, thus facilitating therapeutic decisions based on the presence or absence of this prognostically important biologic marker.

To test whether magnetic resonance angiography can document the evolution of vasculopathy in patients with sickle cell disease, we reviewed records to identify all patients who underwent magnetic resonance angiography from 1993 to 1999. Of 512 angiographies performed, 105 were of sickle cell disease patients, and 24 sickle cell disease patients 7 years of age or older underwent baseline and follow-up examinations. Films were paired by patient, blinded as to examination date and treatment, and quantitatively compared. Four patients who received allogeneic bone marrow transplantation were compared to 7 patients who received other therapy and to 13 untreated patients. Quantitative analysis revealed a 10% increase in the measured diameter of 64 vessels (p = 0.001) following any treatment. Patients who had undergone allogeneic bone marrow transplantation exhibited a 12% increase in the lumen of 22 vessels (p = 0.041), whereas patients treated with chronic transfusion or hydroxyurea exhibited an 8% increase in 42 vessels (p = 0.016). In 2 patients with severe stenosis, the artery normalized after transplantation, and the blood flow rate was reduced in all patients who underwent transplantation. In untreated patients, there was a trend for the size of the arterial lumen to decrease, which is consistent with disease progression. Results suggest that treatment can reverse progression of vasculopathy. Bone marrow transplantation may enable stenoses to heal and can substantially reduce cranial blood velocity, suggesting that allogeneic bone marrow transplantation may prevent infarction or brain damage.

Background: Immunotherapy using cytokine-expressing tumor cells has shown promise as an anticancer strategy. We have recently begun a trial of interleukin-2 (IL-2) gene-modified allogeneic neuroblastoma cells administered in a sequence of eight injections to patients with high-risk neuroblastoma following completion of primary therapy. Six patients to date have completed treatment., Procedure: We examined humoral responses to the immunizing cell line and, when available, to the patients' autologous tumor cells using an in vitro binding assay., Results: Five of six patients developed a rise in antitumor antibodies to the immunizing neuroblastoma cell line following vaccination. Two of these patients had autologous tumor available; both demonstrated a humoral response to these cells as well., Conclusions: Our results demonstrate that vaccination with IL-2-expressing allogeneic tumor cells after intensive primary therapy can elicit a humoral response to the immunizing line. These antibodies are cross-reactive with the patients' own tumor cells in the two cases in which autologous cells were available. This suggests that different patients' tumors may share common antigens that can be exploited in immunotherapy strategies and supports the continued exploration of allogeneic tumor cells as tumor vaccines., (Copyright 2000 Wiley-Liss, Inc.)

Purpose: To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML)., Patients and Methods: Of 77 survivors (median follow-up duration, 16. 7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed., Results: Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z: score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z: score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up., Conclusion: Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.

Ocular manifestations have been attributed to the Epstein-Barr virus (EBV), largely on the basis of seroepidemiologic data. Two patients who developed conjunctival disease as the presenting feature of EBV infection are reported, each confirmed by in situ hybridization of EBV genome in affected tissue biopsy specimens. Recognition of EBV-induced ocular disease as an initial presentation of clinical EBV infection is important to the practitioner because of the ubiquitous nature of this herpesvirus.

Purpose: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children., Patients and Methods: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days., Results: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL)., Conclusion: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.

Background: Chemotherapy, radiotherapy, and surgical decompression with laminectomy are effective therapeutic options in the treatment of cord compression from neuroblastoma (NB). We report the long-term outcome of patients with intraspinal NB treated with or without laminectomy at two large pediatric oncology centers., Procedure: We reviewed the medical records and radiographs of 26 children with intraspinal NB treated at Children's Memorial Hospital in Chicago, Illinois, between 1985 and 1994 or at St. Jude Children's Research Hospital in Memphis, Tennessee, between 1967 and 1992., Results: Twenty-four of the 26 patients are alive and disease-free (follow-up of 2-29 years; median, 10 years 2 months). Fifteen of the 23 patients with neurologic impairment underwent initial laminectomy. Nine of these 15 patients recovered neurologic function, including 3 patients who presented with paraplegia. Eleven of the 15 patients who underwent laminectomy have developed mild to severe spinal deformities. Eight patients with neurologic symptoms consequent to cord compression were treated with initial chemotherapy and/or surgery, but did not undergo laminectomy. Three patients with mild to moderate deficits recovered neurologic function. Four of 11 patients with intraspinal NB who did not undergo laminectomy have mild to severe scoliosis., Conclusions: A low incidence of neurologic recovery was seen in patients with long-standing severe cord compression regardless of treatment modality. For patients with partial neurologic deficits, recovery was seen in most patients following chemotherapy or surgical decompression with laminectomy. A higher incidence of spinal deformities was seen in the patients treated with initial laminectomy.