Fatigue in children who have recently completed treatment for acute lymphoblastic leukemia: a longitudinal study.

BACKGROUND: This study examined fatigue in patients treated for childhood acute lymphoblastic leukemia (ALL) over a 2-year period (3- to 27-months post-treatment completion), from the perspective of children and parent caregivers, compared to a healthy comparison group. METHODS: Eighty-three patients (4-16 years at enrolment) and their parents, reported on the child's fatigue using the Pediatric Quality of Life Inventory- Multidimensional Fatigue Scale (PedsQL-MFS), at 3- 15- and 27-months post-treatment completion, and 53 healthy children and their parents reported on fatigue across the same timepoints. RESULTS: Parent proxy-reporting showed that parents of ALL patients reported more total fatigue than parents of the comparison group at all time points, with all subscales elevated (general, cognitive, and sleep/rest fatigue). In contrast, patient self-report of fatigue over this period differed from the comparison children for the general fatigue subscale only. Self-reported total fatigue was worse than the comparison group at the 27-month timepoint, with cognitive and sleep/rest fatigue symptoms contributing to this difference. Expected improvements in fatigue over time were not evident in either patient or parent report and no demographic risk factors were identified. Parents and children from both groups reported significantly more fatigue at all time points compared to commonly utilised normative population data. CONCLUSIONS: Patients treated for childhood ALL are impacted by fatigue symptoms in the post-treatment and early survivorship period. These findings highlight that patients in the 2-years following treatment require increased symptom surveillance and may benefit particularly from interventions that target cognitive and sleep/rest fatigue.

Parent perceptions of pediatric oncology care during the COVID-19 pandemic: An Australian study.

BACKGROUND: We examined parents' perceptions of their child's oncology care during a period of significant COVID-19 restrictions in Australia. METHODS: Parents of children, 0-18 years, receiving hospital-based cancer treatment, completed a survey examining their COVID-19 exposure and impact, information and knowledge, and perception of their child's medical care. Recruitment occurred between October and November 2020. RESULTS: Eighty-four parents (95% mothers) completed the survey. Sixty-seven percent of patients were diagnosed pre-COVID-19. The majority of parents (76%) reported negative impacts of COVID-19 on family life, including parenting and emotional well-being despite exposure to COVID-19 cases being very low (4%). Family functioning and parent birthplace were associated with COVID-19 impact and distress. Parents perceived the hospital as a safe place during the pandemic. Very few parents reported delaying presentation to the emergency department (12%). The majority identified no change (69%) or delay (71%) in their child's treatment delivery. Over 90% of parents were confident that COVID-19 did not impact medical decision-making. They felt confident in their COVID-19 knowledge and sought information from trusted sources. Parents reported a positive relationship with their child's care team (93%); however, access to some support services was reduced. CONCLUSION: Understanding patient and family experiences of pediatric oncology care across international contexts during the pandemic is important to inform present and future health care responses. In the Australian context of low infection rates and strict community restrictions, parents perceived their child's oncology care to be relatively unaffected. However, findings indicate that family well-being was impacted, which warrants further investigation.

Behavioral and Emotional Functioning of Children and Adolescents at the End of Treatment for Acute Lymphoblastic Leukemia Compared to Healthy Peers.

This study describes the behavioral and emotional adjustment of 77 children and adolescents 3 months post-treatment for acute lymphoblastic leukemia (ALL), compared to 52 age and sex-matched healthy peers. Parents, teachers, and self-report ratings on the Behavioral Assessment System for Children, Second Edition (BASC-2) were utilized to measure psychological function. While overall mean scores were in the average range for both groups, parents and teachers rated patients higher on behavior symptoms, internalizing problems and adaptive skill difficulties. No significant differences between groups were observed on self-report, and inter-rater correlations were low to moderate. For the ALL group, maternal university completion was associated with elevations on parent report of behavioral problems, while no other factors predicted either parent or teacher report on other scales. Findings indicate that a subset of patients will require specialist psychosocial support to optimise their adjustment following treatment completion.

Parental adjustment following their child's completion of acute lymphoblastic leukemia treatment.

BACKGROUND: Few studies haveexamined parent and family adaptation in the early period following the end of childhood cancer treatment. We examined parent adjustment at the end of their child's treatment for acute lymphoblastic leukemia (ALL). METHODS: Parents of childhood cancer survivors (CCS), who were 3 months post-ALL treatment, and parents of typically developing children completed measures of psychological and family functioning. Parents of CCS also completed distress and posttraumatic stress symptom (PTSS) questionnaires related to their child's cancer experience. RESULTS: One hundred twenty-nine parents were recruited: 77 parents of CCS and 52 comparison parents. Overall mean psychological symptoms of depression, anxiety and stress, and family functioning were within normal limits for both groups. Parents of CCS endorsed higher scores for stress, depression, and family problems; however, mean scores for emotional distress were low for both groups, in particular the comparison group. Parents of CCS endorsed low rates of PTSS. Fifty-one percent of parents of CCS scored above the distress thermometer (DT-P) clinical cutoff (>4), with items elevated across all six DT-P domains. However, most parents did not indicate a wish to speak to a health professional about their symptoms. CONCLUSION: Specialist psychosocial intervention may be indicated for only a subset of parents at the end of treatment. As per psychosocial standards of care, effective screening at this timepoint is warranted. Further examination of appropriate timing of psychosocial information and support services that are tailored to parents' circumstances is needed. eHealth approaches may be appropriate.

Health-related quality of life in paediatric patients up to five years post-treatment completion for acute lymphoblastic leukaemia: a systematic review.

PURPOSE: Despite survival rates greater than 90%, treatment for paediatric acute lymphoblastic leukaemia (ALL) remains challenging for families. The early post-treatment phase is an especially unique time of adjustment. The primary aim of this review was to identify and synthesise research on health-related quality of life (HRQoL) for patients up to five years post-treatment. The secondary aim was to identify if theorised risk/resistance model factors could explain any variance in reported HRQoL. METHODS: We conducted a systematic review using the PRISMA guidelines across five databases: Embase, Medline, Psychinfo, Pubmed, and Cochrane. Only studies examining HRQoL up to five years post-treatment were included. Studies were excluded if they covered periods greater than five years post-treatment or did not differentiate between patients with ALL and other cancers. After assessing the quality of each study sample size, patient characteristics, HRQoL outcomes and HRQoL correlates were extracted and summarised. RESULTS: A total of 14 studies representing 1254 paediatric patients, aged 2-18 years, were found. HRQoL findings were mixed, dependent on time since completion and comparison group. Patient HRQoL was mostly lower compared to normative data, whilst higher compared to healthy control groups, patients on treatment, and patients with other types of cancers. Lower HRQoL was also found to be associated with demographic (age and sex), family dysfunction, and treatment-related factors. CONCLUSIONS: Completing treatment signalled a significant improvement in HRQoL for patients compared to being on treatment. Overall, however, HRQoL was still significantly lower than the population during the early post-treatment period.

The relationship between cognitive and neuroimaging outcomes in children treated for acute lymphoblastic leukemia with chemotherapy only: A systematic review.

Cognitive late-effects have been identified in patients treated with chemotherapy-only protocols for childhood acute lymphoblastic leukemia (ALL), yet the underlying neuropathology is not well understood. This review synthesized recent findings from eight articles investigating the relationship between neurocognitive and neuroimaging outcomes for patients treated for ALL with chemotherapy-only protocols. Reported cognitive domains, imaging methods, and neuroanatomy examined were variable. Despite this, 62.5% (n = 5) of the reviewed studies found a significant relationship between cognitive and imaging outcomes. Greater understanding of the effects of treatment on neuroanatomy and cognitive outcomes is critical for proactively managing ALL cognitive late-effects. Research directions are suggested.

Motor functioning during and following treatment with chemotherapy for pediatric acute lymphoblastic leukemia.

This systematic review evaluated empirical studies examining motor skills in children during and following treatment for acute lymphoblastic leukemia. Most studies indicated that children on-treatment display poorer gross and fine motor abilities than healthy peers, but generally have intact visual-motor integration skills. Studies have reported gross motor difficulties in 5-54% of survivors. There is some limited evidence for long-term fine motor deficits. The evidence for visual-motor integration difficulties in the survivor population is less consistent. Larger studies with a longitudinal design are needed to further specify the onset and timing of motor difficulties and ascertain risk factors.

Feasibility of neurobehavioral screening following diagnosis of pediatric cancer.

BACKGROUND: Neurobehavioral deficits will affect up to 50% of pediatric cancer survivors treated with central nervous system (CNS)-directed therapies. Guidelines suggest assessment of neurobehavioral skills at diagnosis be extended from patients with brain tumors to include all patients requiring CNS-directed therapies. However, comprehensive neuropsychological assessment at diagnosis is difficult to implement and resource intensive. A screening assessment targeted at the neurobehavioral domains known to be impacted by cancer treatments may be more feasible. This study aimed to assess the feasibility of implementing baseline neurobehavioral screening following childhood cancer diagnosis. PROCEDURE: A consecutive sample of 59 recently diagnosed patients requiring CNS-directed therapies, and 49 healthy controls were assessed using a targeted neurobehavioral screen, which included measures of developmental, cognitive, academic, behavioral, and psychosocial functioning. Feasibility was assessed using a formal feasibility framework, with criteria of brevity, simplicity, relevance, acceptability, and value. Neurobehavioral assessment was compared to standard care to determine the quality of information acquired from the screen. RESULTS: Mean time from diagnosis to assessment was 5.17 weeks. Assessments were completed within 1 hour for 87% of patients. Participant and researcher evaluation indicated the screen was acceptable across a range of criteria, with no differences between clinical and control groups. Compared to standard medical record documentation, the screen provided significant additional information on developmental and neurobehavioral status of patients at diagnosis. CONCLUSION: A brief neurobehavioral screen in the early period following cancer diagnosis is feasible and provides valuable baseline data for children at risk of neurobehavioral late-effects of cancer treatments.

Striatal activity during intentional switching depends on pattern stability.

The theoretical framework of coordination dynamics posits complementary neural mechanisms to maintain complex behavioral patterns under circumstances that may render them unstable and to voluntarily switch between behaviors if changing internal or external conditions so demand. A candidate neural structure known to play a role in both the selection and maintenance of intentional behavior is the basal ganglia. Here, we use functional magnetic resonance imaging to explore the role of basal ganglia in intentional switching between bimanual coordination patterns that are known to differ in their stability as a function of movement rate. Key measures of pattern dynamics and switching were used to map behavior onto the associated neural circuitry to determine the relation between specific behavioral variables and activated brain areas. Results show that putamen activity is highly sensitive to pattern stability: greater activity was observed in bilateral putamen when subjects were required to switch from a more to a less stable pattern than vice versa. Since putamen activity correlated with pattern stability both before and during the switching process, its role may be to select desired actions and inhibit competing ones through parametric modulation of the intrinsic dynamics. Though compatible with recent computational models of basal ganglia function, our results further suggest that pattern stability determines how the basal ganglia efficiently and successfully select among response alternatives.

Developmental coordination disorder in geographic cohorts of 8-year-old children born extremely preterm or extremely low birthweight in the 1990s.

AIM: The aim of the study was to examine the prevalence of developmental coordination disorder (DCD) at the age of 8 years in a geographic cohort of extremely preterm or extremely-low-birthweight (EP/ELBW) children and a term-born comparison group, as well as associated academic outcomes, parents' perceptions of motor performance, and changes in prevalence during the 1990s. METHOD: Moderate DCD was defined as a score below the 5th centile on the Movement Assessment Battery for Children in children without cerebral palsy or intellectual impairment. DCD rates were compared in a group of 132 8-year-old children born in 1997 at 22 to 27 weeks' gestation or birthweight of less than 1000 g (49% male, 51% female) and a comparison group of 154 term-born children (55% male, 45% female). The Wechsler Intelligence Scale for Children - 4th edition and the Wide Range Achievement Test - 3rd edition were used to measure academic and cognitive outcomes. Parental perceptions of motor performance were measured using the physical function scale of the Child Health Questionnaire, parent-report form (CHQ PF50). The results for children with and without DCD were then compared. To assess changes in prevalence throughout the 1990s, DCD rates were compared with those found in children from the same region born in 1991 to 92. RESULTS: The mean number of completed weeks of gestation in the EP/ELBW children and in the comparison group of term-born children for whom data were available for analysis was 26.5 (SD 1.9) and 39.2 (SD 1.1) respectively, and the mean birthweight was 830 g (SD 163) and 3511 g (SD 462) respectively. The prevalence of DCD was 16% in the EP/ELBW group and 5% in the comparison group (odds ratio 3.45; 95% confidence interval [CI] 1.47-8.09%). Academic outcomes for reading, spelling, and arithmetic were poorer among children with DCD than among those without DCD (mean difference [95% CI] 10.2 [0.9-19.7; p=0.03], 8.9 [2.2-15.5; p=0.01], and 7.9 [1.4-14.5; p=0.02] respectively). Parental perceptions were poorly predictive of DCD. INTERPRETATION: EP/ELBW children have higher rates of DCD and experience more academic difficulties than term-born children. As parental perceptions are not a reliable screen, clinical assessments of motor skills in this vulnerable population are important.

Brain morphology and information processing at the completion of chemotherapy-only treatment for pediatric acute lymphoblastic leukemia.

Background: Approximately 50% of survivors of childhood acute lymphoblastic leukemia (ALL) demonstrate cognitive impairments. However, the trajectory of change and contributing neuropathology is unclear, limiting our ability to tailor intervention content and timing. This study aimed to explore information processing abilities and brain morphology early post-treatment for pediatric ALL. Procedure: Twenty-one children at the end of ALL treatment and 18 controls underwent neuropsychological assessment. A subset also completed structural magnetic resonance imaging. Results: A principal component analysis generated two cognitive factors: information processing capacity and information processing speed. Compared to control group, the ALL group displayed deficits in capacity, but not speed. No group differences were identified in morphology. No relationship was identified between capacity or speed and morphology. Conclusion: Early cognitive intervention should target information processing abilities using a system-wide approach. Future studies should employ alternative imaging techniques sensitive to white-matter microstructure when exploring pathology underlying information processing deficits.

White Matter Microstructure and Information Processing at the Completion of Chemotherapy-Only Treatment for Pediatric Acute Lymphoblastic Leukemia.

Little is known about white matter microstructure and its role in information processing abilities of children treated for acute lymphoblastic leukemia (ALL) early posttreatment. Twenty-one survivors of ALL and 18 controls (7-16 years) underwent neurocognitive assessment. A subsample underwent diffusion-weighted magnetic resonance imaging. The ALL group performed poorer on measures of processing capacity, and had widespread areas of decreased fractional anisotropy and increased radial diffusivity. Significant group by white matter microstructure interactions was found when predicting processing speed. Findings provide evidence for an atypical brain-behavior relationship early posttreatment for childhood ALL. Replication in a larger sample is required.

Optimized 3D co-registration of ultra-low-field and high-field magnetic resonance images.

The prototypes of ultra-low-field (ULF) MRI scanners developed in recent years represent new, innovative, cost-effective and safer systems, which are suitable to be integrated in multi-modal (Magnetoencephalography and MRI) devices. Integrated ULF-MRI and MEG scanners could represent an ideal solution to obtain functional (MEG) and anatomical (ULF MRI) information in the same environment, without errors that may limit source reconstruction accuracy. However, the low resolution and signal-to-noise ratio (SNR) of ULF images, as well as their limited coverage, do not generally allow for the construction of an accurate individual volume conductor model suitable for MEG localization. Thus, for practical usage, a high-field (HF) MRI image is also acquired, and the HF-MRI images are co-registered to the ULF-MRI ones. We address here this issue through an optimized pipeline (SWIM-Sliding WIndow grouping supporting Mutual information). The co-registration is performed by an affine transformation, the parameters of which are estimated using Normalized Mutual Information as the cost function, and Adaptive Simulated Annealing as the minimization algorithm. The sub-voxel resolution of the ULF images is handled by a sliding-window approach applying multiple grouping strategies to down-sample HF MRI to the ULF-MRI resolution. The pipeline has been tested on phantom and real data from different ULF-MRI devices, and comparison with well-known toolboxes for fMRI analysis has been performed. Our pipeline always outperformed the fMRI toolboxes (FSL and SPM). The HF-ULF MRI co-registration obtained by means of our pipeline could lead to an effective integration of ULF MRI with MEG, with the aim of improving localization accuracy, but also to help exploit ULF MRI in tumor imaging.

Family Functioning and Mood and Anxiety Symptoms in Adolescents Born Extremely Preterm.

OBJECTIVE: To (1) compare adolescent- and parent-perceived family functioning between extremely preterm/extremely low birth weight (<28 wk/<1000 g, EP/ELBW) and normal birth weight (>2499 g, NBW) adolescents and (2) determine whether adolescents' or parents' ratings of family functioning were related to concurrent depression and anxiety symptoms in the adolescent and whether these relationships varied by birth group. METHODS: One hundred ninety-three EP/ELBW and 151 NBW adolescents (aged 15-20 yr) and their parents rated aspects of family functioning on the Family Environment Scale. Adolescents rated current depression and anxiety symptoms on the Center for Epidemiologic Studies Depression Scale-Revised and Beck Anxiety Inventory. Family functioning was compared across the groups using linear regression, and logistic regression was used to assess relationships between family functioning domains and elevated depression and anxiety scores. RESULTS: Compared with NBW controls, EP/ELBW adolescents reported similar levels of family Cohesiveness and Expressiveness, but less Conflict, and more Organization and Control. Parent ratings of family functioning were similar between groups except for higher Control scores in EP/ELBW group parents. Poorer family functioning as rated by adolescents, but not parents, was associated with increased depression/anxiety symptoms. These findings were generally consistent across both the EP/ELBW and control groups. CONCLUSION: EP/ELBW adolescents report generally positive family functioning. While adolescents' perceptions of family functioning are associated with concurrent adolescent mental health, parental perceptions of family functioning may not be indicative of adolescents' mental health. Importantly, EP/ELBW adolescents do not appear to be more vulnerable to anxiety/depression in the context of poorly perceived family functioning than their NBW peers.

Fast Room Temperature Very Low Field-Magnetic Resonance Imaging System Compatible with MagnetoEncephaloGraphy Environment.

In recent years, ultra-low field (ULF)-MRI is being given more and more attention, due to the possibility of integrating ULF-MRI and Magnetoencephalography (MEG) in the same device. Despite the signal-to-noise ratio (SNR) reduction, there are several advantages to operating at ULF, including increased tissue contrast, reduced cost and weight of the scanners, the potential to image patients that are not compatible with clinical scanners, and the opportunity to integrate different imaging modalities. The majority of ULF-MRI systems are based, until now, on magnetic field pulsed techniques for increasing SNR, using SQUID based detectors with Larmor frequencies in the kHz range. Although promising results were recently obtained with such systems, it is an open question whether similar SNR and reduced acquisition time can be achieved with simpler devices. In this work a room-temperature, MEG-compatible very-low field (VLF)-MRI device working in the range of several hundred kHz without sample pre-polarization is presented. This preserves many advantages of ULF-MRI, but for equivalent imaging conditions and SNR we achieve reduced imaging time based on preliminary results using phantoms and ex-vivo rabbits heads.

Executive function in adolescents born <1000 g or <28 weeks: a prospective cohort study.

BACKGROUND AND OBJECTIVES: Extremely preterm (EP; <28 weeks) birth and extremely low birth weight (ELBW; <1000 g) are risk factors for poor cognitive outcomes, including in executive function (EF; higher-order cognitive skills necessary for goal-directed, adaptive functioning and important for academic and behavioral-emotional outcomes). We aimed to (1) extend the limited data on EF in EP/ELBW survivors in adolescence compared with normal birth weight controls, and (2) determine changes in EF between ages 8 and 17 years in both groups. METHODS: Two hundred twenty-eight EP/ELBW and 166 control adolescents (mean age, 17 years) from a prospective geographical cohort were assessed with multiple EF tasks, and parent- and self-ratings of behavioral EF. The Rey Complex Figure and Behavior Rating Inventory of Executive Function parent report were also administered at age 8 years, enabling examination of change in scores between childhood and adolescence. RESULTS: EP/ELBW adolescents performed more poorly than controls in verbal processing speed, attentional control, cognitive flexibility, and goal-setting (effect sizes, -0.7 to -0.2 SD), but not psychomotor reaction time. Group differences were of similar magnitude across tasks. From childhood to late adolescence, EP/ELBW children improved their accuracy of the Rey Complex Figure copy more than controls. According to parents, executive behaviors were largely stable over time in both groups. CONCLUSIONS: Adolescents born EP/ELBW have poorer EF skills across multiple domains than controls. From childhood to late adolescence, different aspects of EF improved, but others did not, underscoring the need for multidomain, longitudinal assessments in this high-risk population.

Visuomotor function in children treated for acute lymphoblastic leukaemia with chemotherapy only.

This study aimed to evaluate visuomotor function in children treated for acute lymphoblastic leukaemia (ALL). The performance of 64 children, 1-7 years post-chemotherapy for ALL, was compared to that of their healthy peers (n = 56) on visuomotor integration (VMI) and motor coordination (MC) tasks. Children posttreatment for ALL displayed significantly reduced VMI, but not MC, performances as compared to controls. Children treated on chemotherapy-only ALL regimes are at heightened risk for visuomotor integration deficits. Monitoring of visuomotor skills and implementation of appropriate interventions targeting higher level visuomotor integration skills should form an important component of any ALL long-term effects program.

School-age outcomes of extremely preterm or extremely low birth weight children.

OBJECTIVE: Research is required to monitor changes in the nature of neurobehavioral deficits in extremely preterm (EP) or extremely low birth weight (ELBW) survivors. This study examines cognitive, academic, and behavioral outcomes at age 8 years for a regional cohort of EP/ELBW children born in 1997. METHODS: The EP/ELBW cohort comprised all live births with a gestational age <28 weeks (EP) or birth weight <1000 g (ELBW) born in the state of Victoria, Australia, in 1997. Of 317 live births, 201 (63.4%) survived to 2 years of age.A term/normal birth weight (T/NBW) cohort was recruited comprising 199 infants with birthweights ≥2500 g or gestational age ≥37 weeks [corrected]. Measures of intellectual ability, educational achievement, and behavior were administered at age 8. RESULTS: Retention was 94% for the EP/ELBW group and 87% for the T/NBW group. The EP/ELBW group performed poorer than the T/NBW group on measures of IQ, educational achievement, and certain behavioral domains, even after adjustment for sociodemographic factors and exclusion of children with neurosensory impairment. The rate of any neurobehavioral impairment was elevated in the EP/ELBW group (71% vs 42%), and one-half of subjects had multiple impairments. The outcomes for those with <750 g birth weight or <26 weeks' gestational age were similar to those with a birth weight of 750 to 999 g or a gestational age of 26 to 27 weeks, respectively. CONCLUSIONS: Despite ongoing improvements in the management of EP/ELBW infants, the rate of neurobehavioral impairment at school-age remains too high relative to controls.