Neurocognitive outcome in children with sickle cell disease after myeloimmunoablative conditioning and haploidentical hematopoietic stem cell transplantation: a non-randomized clinical trial.

Background: Due to the risk of cerebral vascular injury, children and adolescents with high-risk sickle cell disease (SCD) experience neurocognitive decline over time. Haploidentical stem cell transplantation (HISCT) from human leukocyte antigen-matched sibling donors may slow or stop progression of neurocognitive changes. Objectives: The study is to determine if HISCT can ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression, determine which specific areas of neurocognitive functioning are particularly vulnerable to SCD, and determine if there are age-related differences in neurocognitive functioning over time. Methods: We performed neurocognitive and neuroimaging in SCD recipients following HISCT. Children and adolescents with high-risk SCD who received parental HISCT utilizing CD34+ enrichment and mononuclear cell (T-cell) addback following myeloimmunoablative conditioning received cognitive evaluations and neuroimaging at three time points: pre-transplant, 1 and 2 years post-transplant. Results: Nineteen participants (13.1 ± 1.2 years [3.3-20.0]) received HISCT. At 2 years post-transplant, neuroimaging and cognitive function were stable. Regarding age-related differences pre-transplantation, older children (≥13 years) had already experienced significant decreases in language functioning (p < 0.023), verbal intelligence quotient (p < 0.05), non-verbal intelligence quotient (p < 0.006), and processing speed (p < 0.05), but normalized post-HISCT in all categories. Conclusion: Thus, HISCT has the potential to ameliorate SCD-associated neurocognitive changes and prevent neurocognitive progression. Further studies are required to determine if neurocognitive performance remains stable beyond 2 years post-HISCT.Clinical trial registration: The study was conducted under an investigator IND (14359) (MSC) and registered at clinicaltrials.gov (NCT01461837).

Are Young Adult Survivors of Pediatric Cancer Being Overlooked? Cognitive Testing Results and Referrals in Child, Adolescent, and Young Adult Survivors.

Treatment gaps in meeting the neuropsychological needs of young adult (YA) cancer survivors can be attributed to several clinical and systemic reasons. Access to neurocognitive care can be increased through the effective integration of neuropsychological monitoring and intervention in survivorship care. In this brief report, we aim to compare the efficacy of a brief neuropsychological screener (DIVERGT) in meeting the assessment and referral needs of pediatric and YA cancer survivors (n = 40) as part of a wellness and survivorship clinic. Participants (n = 40) were patients who presented to a pediatric oncology survivorship clinic over the span of 15 months.

Significant improvement of child physical and emotional functioning after familial haploidentical stem cell transplant.

Allogeneic stem cell transplantation (AlloSCT) represents the only curative therapy for sickle cell disease (SCD). However, limited availability of matched related donors and suboptimal outcomes following AlloSCT with unrelated donors has led to investigation of alternative donors. Among children with high-risk SCD, we evaluated health-related quality of life (HRQoL) impact in the two years following familial haploidentical SCT. HRQoL was collected from parent and child raters, using the Child Health Ratings Inventories Generic measure and haploidentical SCT-specific module. Repeated measures models were fit to assess HRQoL changes over time and by rater. Nineteen children (mean age 12.9 yrs [standard deviation, 5.3]; 63% male) and their parents were included. There were no differences in the 2-yr trajectories of child physical or emotional functioning (EF) by rater. Child physical functioning and EF scores were significantly lower at day +45 than baseline, but scores recovered by day +180. There was significant improvement in EF (p = 0.03) at 2 yrs vs baseline. A similar pattern of scores over time was seen for parent ratings of child's global HRQoL. Despite treatment intensity in the initial months following AlloSCT, patient scores recovered or exceeded baseline scores at two years. This trial is registered at clinicaltrials.gov (NCT01461837).

Stable to improved cardiac and pulmonary function in children with high-risk sickle cell disease following haploidentical stem cell transplantation.

Children with sickle cell disease (SCD) are at high-risk of progressive, chronic pulmonary and cardiac dysfunction. In this prospective multicenter Phase II trial of myeloimmunoablative conditioning followed by haploidentical stem cell transplantation in children with high-risk SCD, 19 patients, 2.0-21.0 years of age, were enrolled with one or more of the following: history of (1) overt stroke; (2) silent stroke; (3) elevated transcranial Doppler velocity; (4) multiple vaso-occlusive crises; and/or (5) two or more acute chest syndromes and received haploidentical transplants from 18 parental donors. Cardiac and pulmonary centralized cores were established. Pulmonary function results were expressed as percent of the median of healthy reference cohorts, matched for age, sex, height and race. At 2 years, pulmonary functions including forced expiratory volume (FEV), FEV1/ forced vital capacity (FVC), total lung capacity (TLC), diffusing capacity of lung for carbon monoxide (DLCO) were stable to improved compared to baseline values. Importantly, specific airway conductance was significantly improved at 2 years (p < 0.004). Left ventricular systolic function (fractional shortening) and tricuspid regurgitant velocity were stable at 2 years. These results demonstrate that haploidentical stem cell transplantation can stabilize or improve cardiopulmonary function in patients with SCD.

A functional magnetic resonance imaging study of left hemisphere language dominance in children.

BACKGROUND: Functional magnetic resonance imaging is a noninvasive method of assessing language dominance in a pediatric population. OBJECTIVE: To determine the pattern of receptive language lateralization in healthy children. DESIGN: We used functional magnetic resonance imaging to assess an auditory language task in 11 children (7 girls, 4 boys; mean age, 8.5 years). Participants alternately rested and listened to descriptors of nouns presented auditorily, naming the object described silently. Asymmetry indices ([(left - right)/(left + right)]) were calculated for a priori-determined regions of interest. RESULTS: The results showed strong activation bilaterally, with greater activation on the left in the superior and middle temporal gyri. Other areas of activation included the cuneus, the left inferior temporal gyrus, the prefrontal area, and the left fusiform and lingual gyri. Regions of interest analysis of individual scans showed additional activation in the left frontal lobe. Asymmetry indices showed strong left lateralization of the inferior frontal gyrus, middle frontal gyrus, and the Wernicke region. CONCLUSIONS: Hemispheric lateralization was clearly demonstrated in 8 children. As in adults, left hemisphere lateralization of receptive language is present at age 8 years.

Developmental aspects of language processing: fMRI of verbal fluency in children and adults.

We examined developmental differences, in location and extent of fMRI language activation maps, between adults and children while performing a semantic fluency task. We studied 29 adults and 16 children with echo planar imaging BOLD fMRI at 1.5 T using covert semantic verbal fluency (generation of words to categories compared to rest) using a block design. Post task testing was administered to assess performance. Individual data were analyzed with an a priori region of interest approach from t maps (t = 4) and asymmetry indices (AI). Group studies were analyzed using SPM 99 (Wellcome, UK; fixed effect, corrected P < 0.0001). We found no significant differences in location or laterality of activation between adults and children for a semantic verbal fluency task. Adults activated more pixels than children in left inferior frontal gyrus and left middle frontal gyrus, but AIs were the similar across ages (r(2) < 0.09). Extent or laterality of activation was not affected by performance (r(2) < 0.15). The brain areas that process semantic verbal fluency are similar in children and adults. The laterality of activation does not change appreciably with age and appears to be strongly lateralized by age 7 years.