Perceived transition readiness among adolescents and young adults with neurofibromatosis type 1 and plexiform neurofibromas: a cross-sectional descriptive study.

OBJECTIVES: Neurofibromatosis type 1 (NF1) is a genetic cancer predisposition syndrome that can impact multiple organ systems and is associated with plexiform neurofibroma tumors, requiring care from birth through adulthood. Adolescents and young adults (AYAs) with NF1 face several barriers to transition from pediatric to adult care. This cross-sectional study aimed to assess transition readiness in this population and to evaluate relationships between specific NF1 symptoms and transition readiness. METHODS: AYAs (aged 16-24) enrolled in existing studies related to NF1 were eligible. AYAs and their parents completed measures of transition readiness (Transition Readiness Assessment Questionnaire version 4 [TRAQ-4]), and AYAs also completed a transition readiness interview (UNC TRxANSITION). RESULTS: Thirty-eight AYAs (mean age = 19.95 ± 2.68 years) participated in the study. Average TRAQ scores indicated that AYAs were still learning Self-Management skills (M = 3.37, SD = 1.08) and Self-Advocacy skills (M = 3.98, SD = 0.67). Older AYAs had higher TRAQ scores for Self-Management (r = 0.70, p < .001) and Self-Advocacy (r = 0.41, p = .011) than younger AYAs. Parents and AYAs had similar TRAQ scores. About one third of AYAs (37.8%, n = 14) expressed uncertainty about how NF1 might affect them in the future. The remaining AYAs mostly expressed concerns regarding tumor growth, pain, or cancer. CONCLUSIONS: In this small study, preliminary findings suggest that AYAs with NF1 express confidence in many areas of transition readiness but continue to require support, particularly with Self-Management skills. Given the gaps in understanding of future health risks, AYAs with NF1 would benefit from early assessment, psychoeducation, and support for transition readiness to adult care.

Neurotoxicity following CD19/CD28ζ CAR T-cells in children and young adults with B-cell malignancies.

BACKGROUND: Neurotoxicity is an established toxicity of CD19 CAR T-cell therapy; however, there is little information on neurotoxicity in children, adolescents, and young adults (CAYA) receiving CD19/CD28ζ CAR T-cells for B-cell malignancies. METHODS: We analyzed neurotoxicity of CD19/CD28ζ CAR T-cells in CAYA treated on a phase I study (NCT01593696). Assessments included daily inpatient monitoring, caregiver-based neuro-symptom checklist (NSC), exploratory neurocognitive assessments, clinically-indicated imaging, CSF analysis, and systematic cytokine profiling, outcomes of which were associated with cytokine release syndrome (CRS) and treatment response postinfusion. Patients with active CNS leukemia were included. RESULTS: Amongst 52 patients treated, 13 patients had active CNS leukemia at infusion. Neurotoxicity was seen in 11/52 (21.2%) patients, with an incidence of 29.7% (11/37) in patients with CRS. Neurotoxicity was associated with the presence and severity of CRS. Those with neurotoxicity had higher levels of peak serum IL-6, IFNγ, and IL-15. Additionally, CNS leukemia was effectively eradicated in most patients with CRS. Pilot neurocognitive testing demonstrated stable-to-improved neurocognitive test scores in most patients, albeit limited by small patient numbers. The NSC enabled caregiver input into the patient experience. CONCLUSIONS: This is the first systematic analysis of neurotoxicity utilizing a CD19/CD28ζ CAR construct in CAYA, including in those with active CNS involvement. The experience demonstrates that the neurotoxicity profile was acceptable and reversible, with evidence of anti-leukemia response and CNS trafficking of CAR T-cells. Additionally, neurocognitive testing, while exploratory, provides an opportunity for future studies to employ systematic evaluations into neurotoxicity assessments and validation is needed in future studies.

Adolescents and young adults with neurofibromatosis type 1: A descriptive study of adaptive functioning.

Neurofibromatosis type 1 (NF1) is a genetic syndrome affecting about 1 in 3500 individuals; many of those affected have plexiform neurofibroma (pNF) tumors and associated symptoms and complications. Furthermore, learning and attention problems, as well as deficits in adaptive functioning, are common, often beginning in early childhood. This study aimed to describe adaptive functioning and to examine relationships between adaptive functioning and cognitive and academic variables and level of independence among adolescents and young adults (AYA) with NF1 and pNF tumors. Fifty-five AYA aged 16-31 years participated in a series of neuropsychological evaluations while parents completed the Vineland Adaptive Behavior Scales (VABS-II) as part of a larger natural history study. Over one-third (35%) of AYA were neither in school nor employed. Mean VABS-II daily living and socialization scores were low average while mean Verbal and Performance IQ scores were average. VABS-II scores were positively correlated with processing speed, executive functioning, and working memory scores. Verbal IQ was the only significant predictor of work/school status. Identification of the correlates and predictors of adaptive functioning and life achievement can help guide healthcare providers with the early identification of risk factors and possible areas for intervention.

Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1.

BACKGROUND AND OBJECTIVES: Neurofibromatosis type 1 (NF1)-associated cognitive impairments carry significant lifelong morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of mitogen-activated protein kinase inhibitor (MEKi) treatment. METHODS: Fifty-nine patients with NF1 aged 5-27 years on an MEKi clinical trial treating plexiform neurofibroma underwent pretreatment and follow-up cognitive assessments over 48 weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were the primary outcomes. Group-level (paired t tests) and individual-level analyses (Reliable Change Index, RCI) were used. RESULTS: Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: t (58) = 3.03, p = 0.004, d = 0.24; 48-week Metacognition Index: t (39) = 2.70, p = 0.01, d = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ2 = 11.95, p = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate (p > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ2 = 8.36, p = 0.004, OR = 4.6, and 48-week χ2 = 9.34, p = 0.004, OR = 5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than nonimpaired patients (24 weeks 46% vs 8%; χ2 = 9.54, p = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ2 = 7.50, p = 0.02, OR = 9.0). DISCUSSION: Our data show no evidence of neurotoxicity in 48 weeks of treatment with an MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.

Sleep disturbance in adults with sickle cell disease: relationships with executive and psychological functioning.

Sleep disturbance is common among children with sickle cell disease (SCD) and is related to neurocognitive difficulties. However, research on sleep disturbances and related variables among adults with SCD is extremely limited. The present study examined the relationship between sleep, executive functioning, and emotional functioning among 62 adults (29 females; M age = 32 years, SD = 7.79) with SCD preparing to undergo a stem cell transplant. Participants were administered a neurocognitive evaluation that included objective and subjective measures of executive functioning, and they completed PROMIS self-report measures of anxiety, depression, and pain intensity. Results showed that about 17% of participants endorsed clinically significant sleep disruptions, while 16.1% and 8% endorsed clinically significant symptoms of anxiety and depression, respectively. Sleep disturbance in these adults was not significantly correlated with objective or subjective measures of executive functioning. Moreover, anxiety, but not depression, was a significant mediator between self-reported sleep difficulties and both objective and subjective measures of executive functioning while controlling for pain intensity. Future research on sleep interventions will be essential for ameliorating the effects of sleep disturbance on executive functioning and anxiety among adults with SCD.

Systematic Evaluation of Neurotoxicity in Children and Young Adults Undergoing CD22 Chimeric Antigen Receptor T-Cell Therapy.

Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.

The Relationship Between Heart Rate Variability, Psychological Flexibility, and Pain in Neurofibromatosis Type 1.

Individuals with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) can experience chronic pain. Previous research has examined the relationship between heart rate variability (HRV) and persistent pain. HRV is an index of autonomic nervous system functioning, and reflects the variability in time elapsed between heartbeats. Patients with chronic pain tend to exhibit lower HRV, which has been associated with poor adaptability, or psychological flexibility, to stress. The aim of the current study was to examine relationships between HRV, psychological flexibility, and pain in a sample of adolescents and young adults (AYAs) with NF1 and PNs. AYA participants (n = 40) 16 to 34 years of age with NF1 completed baseline measures of pain and psychological functioning, and underwent a 5-minute electrocardiogram (ECG). A subset of 20 participants completed follow-up questionnaires and a second ECG 8 weeks later. Spectral analyses of ECGs yielded a measure of high-frequency heart rate variability (HF-HRV). Baseline correlations revealed that lower HF-HRV is related to greater inflexibility and more pain interference, but not pain intensity. Moreover, psychological inflexibility significantly mediated the relationship between HF-HRV and pain interference. Finally, regression models indicated that baseline psychological inflexibility is a significant predictor of HF-HRV at follow-up and, separately, that baseline HF-HRV significantly predicted pain intensity at follow-up. These findings suggest complex mind-body processes in the experience of pain in NF1, which have not been studied previously. Implications for pain-related interventions and future research are discussed.

An Internet support group for parents of children with neurofibromatosis type 1: a qualitative analysis.

Parents of children with neurofibromatosis type 1 (NF1), a rare genetic condition, are at risk for emotional distress. While they may benefit from support groups, they may find it difficult to access support. We conducted an 8-week Internet support group (ISG) with 33 parents (29 mothers, 4 fathers) of children with NF1. Transcripts were evaluated using inductive thematic analysis to determine parental needs and concerns; a process and content theme were identified, with each containing codes and subcodes. In terms of process, parents utilized the ISG to seek out information, share information and experiences, and provide and receive emotional support. Common content codes included medical concerns, psychosocial/cognitive development, and accessing NF1 community resources. These concerns highlight the importance of providing parents with reliable information about their child's condition, providing multidisciplinary support to the children with NF1 and their families, and encouraging involvement in the NF1 community.

Developmental screening in children with CHD: Ages and Stages Questionnaires.

OBJECTIVE: Standardised developmental screening tools are important for the evaluation and management of developmental disorders in children with CHD; however, psychometric properties and clinical utility of screening tools, such as the Ages & Stages Questionnaires, Third Edition (ASQ-3), have not been examined in the CHD population. We hypothesised that the ASQ-3 would be clinically useful for this population. Study design ASQ-3 developmental classifications for 163 children with CHD at 6, 12, 24, and/or 36 months of age were compared with those obtained from concurrent developmental testing with the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: When ASQ-3 screening failure was defined as ⩾1 SD below the normative mean, specificity (⩾81.9%) and negative predictive value (⩾81.0%) were high across ASQ-3 areas. Sensitivity was high for gross motor skills (79.6%), increased with age for communication (35.7-100%), and generally decreased with age for problem solving (73.1-50.0%). When ASQ-3 screening failure was defined as ⩾2 SD below the normative mean, specificity (⩾93.6%) and positive predictive value (⩾74.5%) were generally high across ASQ-3 areas, but sensitivity was low (31.1%) to fair (62.8%). The ASQ-3 showed improved accuracy in predicting delays over clinical risk factors alone. CONCLUSIONS: The ASQ-3 appears to be a clinically useful tool for screening development in children with CHD, although its utility varied on the basis of developmental area and time point. Clinicians are encouraged to refer children scoring ⩾1 SD below the normative mean on any ASQ-3 area for formal developmental evaluation.

Systematic psychosocial screening in a paediatric cardiology clinic: clinical utility of the Pediatric Symptom Checklist 17.

OBJECTIVE: To examine the clinical utility of the Pediatric Symptom Checklist 17 for identifying psychosocial concerns and improving access to psychology services within a paediatric cardiology clinic. METHOD: Parents of 561 children (aged 4-17 years) presenting for follow-up of CHD, acquired heart disease, or arrhythmia completed the Pediatric Symptom Checklist 17 as part of routine care; three items assessing parental (1) concern for learning/development, (2) questions about adjustment to cardiac diagnosis, and (3) interest in discussing concerns with a behavioural healthcare specialist were added to the questionnaire. A psychologist contacted the parents by phone if they indicated interest in speaking with a behavioural healthcare specialist. RESULTS: Percentages of children scoring above clinical cut-offs for externalising (10.5%), attention (8.7%), and total (9.3%) problems were similar to a "normative" primary-care sample, whereas fewer children in this study scored above the cut-off for internalising problems (7.8%; p<0.01). Sociodemographic, but not clinical, characteristics were associated with Pediatric Symptom Checklist 17 scores. 17% of the parents endorsed concerns about learning/development, and 20% endorsed questions about adjustment to diagnosis. History of cardiac surgery was associated with increased concern about learning/development (p<0.01). Only 37% of the parents expressing psychosocial concerns reported interest in speaking with a psychologist. CONCLUSIONS: The Pediatric Symptom Checklist 17 may not be sensitive to specific difficulties experienced by this patient population. A questionnaire with greater focus on learning/development and adjustment to diagnosis may yield improved utility. Psychology integration in clinics serving high-risk cardiac patients may decrease barriers to behavioural healthcare services.

Maternal depressive symptoms and disease care status in youth with type 1 diabetes.

OBJECTIVE: The current study assessed relations among maternal depressive symptoms, poorer youth diabetes adherence, and glycemic control. Specifically, hypothesized mediating links of lowered expectations of parental involvement, less parental monitoring, and more conflict were examined. METHOD: Participants included 225 mothers and their young adolescents, aged 11-14 years (M = 12.73 years, SD = 1.2) diagnosed with T1D. Maternal depressive symptoms and outcome expectancies for maternal involvement were evaluated with self-report questionnaires. Multisource, parent/youth, and multimethod assessment of adherence, parental monitoring, and conflict were evaluated during a baseline assessment from a larger randomized clinical trial. RESULTS: The first hypothesized structural equation model demonstrated a good fit and indicated that more maternal depressive symptoms were directly associated with less parental monitoring and more conflict, which in turn each were associated with poorer adherence and glycemic control. Although higher involvement expectancies were associated with more monitoring and less conflict, they were not associated with other model variables. A second alternative model also fit the data well; poorer youth adherence was associated with more conflict that in turn related to maternal depressive symptoms. CONCLUSIONS: Two models were tested by which maternal depressive symptoms and poorer youth adherence were interrelated via less monitoring and more conflict. Follow-up longitudinal evaluation can best characterize the full extent of these relations.