PNOC015: Repeated convection-enhanced delivery of MTX110 (aqueous panobinostat) in children with newly diagnosed diffuse intrinsic pontine glioma.

BACKGROUND: The objective of this study was to determine the safety, tolerability, and distribution of MTX110 (aqueous panobinostat) delivered by convection-enhanced delivery (CED) in patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who completed focal radiation therapy (RT). METHODS: Patients with DIPG (2-21 years) were enrolled after RT. CED of MTX110 combined with gadoteridol was completed across 7 dose levels (DL) (30-90 µM; volumes ranging from 3 mL to 2 consecutive doses of 6 mL). An accelerated dose escalation design was used. Distribution of infusate was monitored with real-time MR imaging. Repeat CED was performed every 4-8 weeks. Quality-of-life (QoL) assessments were obtained at baseline, every 3 months on therapy, and end of therapy. RESULTS: Between May 2018 and March 2020, 7 patients who received a total of 48 CED infusions, were enrolled (median age 8 years, range 5-21). Three patients experienced dose-limited toxicities. Four grade 3 treatment-related adverse events were observed. Most toxicities were transient new or worsening neurologic function. Median overall survival (OS) was 26.1 months (95% confidence interval: 14.8-not reached). Progression-free survival was 4-14 months (median, 7). Cumulative percentage of tumor coverage for combined CED infusions per patient ranged from 35.6% to 81.0%. Increased CED infusions were negatively associated with self-reported QoL assessments. CONCLUSION: Repeat CED of MTX110 with real-time imaging with gadoteridol is tolerable for patients with DIPG. Median OS of 26.1 months compares favorably with historical data for children with DIPG. The results support further investigation of this strategy in a larger cohort.

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

Success at Scale: Outcomes of Community-Based Neurodevelopment Intervention (CASITA) for Children Ages 6-20 months With Risk of Delay in Lima, Peru.

This study is a randomized controlled trial of a 12-week community-based group parenting intervention ("CASITA") in Lima, Peru. CASITA improved neurodevelopment in a pilot study of 60 Peruvian children and subsequently scaled to 3,000 households throughout the district. The objective of this study was to assess intervention effectiveness when implemented at scale. A total of 347 children ages 6-20 months (52.7% male, 100% identified as "mestizo") at risk for developmental difficulties were randomized to immediate or delayed CASITA. At 3 months after enrollment, the immediate arm showed significantly higher overall development, based on the Extended Ages and Stages Questionnaire and Home Observation for Measurement of the Environment scores (Cohen's ds = .36 and .31, respectively). Programs demonstrably effective at scale could help address children's development risks worldwide.

CASITA: a controlled pilot study of community-based family coaching to stimulate early child development in Lima, Peru.

OBJECTIVE: To determine whether the 3-month, community-based early stimulation coaching and social support intervention 'CASITA', delivered by community health workers, could improve early child development and caregiver-child interaction in a resource-limited district in Lima, Peru. DESIGN: A controlled two-arm proof-of-concept study. SETTING: Six neighbourhood health posts in Carabayllo, a mixed rural/urban district in Lima. Sessions were held in homes and community centres. PARTICIPANTS: Children aged 6-24 months who screened positive for risk of neurodevelopmental delay (using validated developmental delay tool) and poverty (using progress out of poverty tool) were enrolled with their caregivers. Dyads with children born >21 days early were excluded. INTERVENTION: 12-week parenting/support intervention plus nutritional support (n=41) or nutrition alone (n=19). OUTCOME MEASURES: Development and home environment differences and mean changes from baseline to 3 months postintervention were evaluated using age-adjusted z-scores on the Extended Ages and Stages Questionnaire (EASQ) and the Home Observation Measurement of the Environment (HOME) scores, respectively. RESULTS: Development in CASITA improved significantly in all EASQ domains, whereas the control group's z-scores did not improve significantly in any domain. The mean adjusted difference (MAD) in change in EASQ age-adjusted z-scores between the two study arms was 1.39 (95% CI 0.55 to 2.22); Cohen's d effect size of 0.87 (95% CI 0.23 to 1.50). Likewise, intervention significantly improved global HOME scores versus control group (MAD change of 6.33 (95% CI 2.12 to 10.55); Cohen's d of 0.85 (95% CI 0.28 to 1.41)). CONCLUSIONS: An evidence-based early intervention delivered weekly during 3 months by a community health worker significantly improved children's communication, motor and personal/social development in this proof-of-concept study.

Community-Based Needs Assessment of Neurodevelopment, Caregiver, and Home Environment Factors in Young Children Affected by HIV in Lima, Peru.

BACKGROUND: In many resource-poor settings such as Peru, children affected by HIV have a high prevalence of neurodevelopmental delays (NDDs) and remain excluded from adequate treatment. METHODS: Community health workers (CHWs) administered NDD screening instruments to assess child development and associated caregiver and household factors in 14 HIV-affected parent-child dyads. Focus group discussion with caregivers was conducted to explore their needs and behaviors around early child stimulation and to assess their perceptions of the screening experience. RESULTS: Over 70% of the children had abnormal classification in at least 1 (out of 5) developmental domains according to Ages and States Questionnaire-provided cutoff scores. Caregiver depression and stress were associated with abnormal development as were some parenting behavior factors. Knowledge about child development was low. Caregivers felt testing and discussing results with a CHW were very insightful. Reported caregiver behavior differed between caregivers with HIV-infected children and those with uninfected children. CONCLUSION: Taken together, these exploratory quantitative data suggest that parenting behaviors associated with low child development scores may be modifiable and that community-based testing is well received and informative to these HIV-infected caregivers.

Cognitive Functioning and Academic Performance in Elementary School Children with Anxious/Depressed and Withdrawn Symptoms.

RATIONALE: Few studies have evaluated the relationship between depressive symptomatology and neuropsychological performance in children without symptomatic depression. OBJECTIVES: This study determined the relationship between anxious/depressed and withdrawn symptoms and performance on cognitive and academic achievement measures. METHODS: 335 Caucasian and Hispanic children aged 6 to 11 years who participated in the Tucson Children's Assessment of Sleep Apnea (TuCASA) study were administered a comprehensive neuropsychological battery measuring cognitive functioning and academic achievement. Their parents completed the Child Behavior Checklist (CBCL). Correlations between performance on the cognitive and academic achievement measures and two Internalizing scales from the CBCL were calculated. Comparisons were made between a "Clinical" referral group (using a T-score of ≥ 60 from the CBCL scales) and a "Normal" group, as well as between Caucasians and Hispanics. RESULTS: No differences were found between those participants with increased anxious/depressed or withdrawn symptoms on the CBCL and those without increased symptoms with respect to age, gender, ethnicity, or parental education level. However, significant negative correlations were found between these symptoms and general intellectual function, language, visual construction skills, attention, processing speed, executive functioning abilities, aspects of learning and memory, psychomotor speed and coordination, and basic academic skills. CONCLUSIONS: These findings support the hypothesis that depressive symptomatology negatively impacts performance on cognitive and academic achievement measures in school-aged children and these findings are not affected by ethnicity. The findings also reinforce the concept that the presence of anxious/depressed or withdrawn symptoms needs to be considered when evaluating poor neuropsychological performance in children.