Newly identified chemotherapy-induced peripheral neuropathy in a childhood cancer survivorship clinic.

Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating side effect of pediatric cancer therapy, can be challenging to diagnose. We estimated the prevalence of newly identified and previously diagnosed CIPN in the regional HEROS Childhood Cancer Survivorship Clinic. From 2016 to 2018, 148 survivors (45.3% female, age 17.1 [SD 7.7] years, 81.8% in ongoing routine oncology follow-up) had their initial survivorship evaluation at an average of 7.4 (SD 6.6) years from diagnosis. Fifty-six survivors (37.8%) had CIPN, of these 46 (82.1%) were newly identified. Our findings demonstrate CIPN may be missed in routine oncology care, and new methods are needed to screen for CIPN.

The association of health status and cancer history of young adult survivors of childhood cancer with parental accompaniment to survivorship clinic visits.

PURPOSE: Adult childhood cancer survivors are frequently accompanied by a parent to survivorship clinic. From clinical evaluations among young adult survivors of childhood cancer we aimed to (1) investigate the association between accompaniment and the survivors' health complexity; and (2) determine whether accompaniment is associated with adherence to recommended surveillance tests and follow-up in clinic. METHODS: This was a cross-sectional study of all patients ≥ 18 years old at their first visit to the regional Yale Childhood Cancer Survivorship Clinic from 2003 to 2018. Patients underwent standardized evaluations for medical, neurocognitive, and emotional late effects of therapy; individuals accompanying patients were documented. RESULTS: The 168 patients were a median of 12.0 (range: 0-17.9) years at diagnosis and 22.7 (range: 18.1-39.9) years at evaluation, and 45.8% were accompanied by a parent. In multivariable analyses, 18.0-24.99 years vs. 25.0-39.99 years at visit (OR = 3.43, p = 0.022) and central nervous system (CNS) tumor diagnosis (OR = 6.09 vs. leukemia/lymphoma diagnosis, p = 0.010) were significantly associated with parental accompaniment. Accompaniment was not associated with number and severity of medical late effects, neurocognitive impairment, or emotional distress. Accompaniment was not associated with completed surveillance tests or a clinic follow-up within 2 years. CONCLUSION: Forty-six percent of survivors were accompanied by a parent, and accompaniment was not associated with survivor health status. Accompaniment was not associated with adherence to recommended surveillance tests or clinic follow-up.

Monitoring neurocognitive functioning in childhood cancer survivors: evaluation of CogState computerized assessment and the Behavior Rating Inventory of Executive Function (BRIEF).

BACKGROUND: Many childhood cancer survivors develop neurocognitive impairment, negatively affecting education and psychosocial functioning. Recommended comprehensive neuropsychological testing can be time- and cost- intensive for both institutions and patients and their families. It is important to find quick and easily administered surveillance measures to identify those in need of evaluation. METHODS: We evaluated, individually and in combination, the sensitivity and specificity of the 1) Behavior Rating Inventory of Executive Functioning-Metacognition Index (BRIEF-MCI), and 2) CogState Composite Index (computerized assessment of cognition) in identifying below grade-level performance on state-administered tests of reading and mathematics among childhood cancer survivors. RESULTS: The 45 participants (39% female) were a mean age of 7.1 ± 4.4 years at diagnosis, 14.0 ± 3.0 at evaluation, with a history of leukemia (58%), lymphoma (9%), central nervous system tumors (20%), and other tumors (13%). Impairment on the BRIEF-MCI was associated with low sensitivity (26% reading, 41% mathematics) but stronger specificity (88% reading, 96% mathematics). We found similar associations for the CogState Composite Index with sensitivity of 26% for reading and 29% for mathematics and specificity of 92% for both reading and mathematics. Combining the two measures did not improve sensitivity appreciably (47% reading, 59% mathematics) while reducing specificity (84% reading, 88% mathematics). CONCLUSIONS: While individuals identified from the BRIEF-MCI or CogState Composite would likely benefit from a full neuropsychological evaluation given the strong specificity, use of these measures as screening tools is limited. With poor sensitivity, they do not identify many patients with academic difficulties and in need of a full neuropsychological evaluation. Continued effort is required to find screening measures that have both strong sensitivity and specificity.

The Association Between Motor Skills and Academic Achievement Among Pediatric Survivors of Acute Lymphoblastic Leukemia.

OBJECTIVE: Assess the association between fine motor (FM) and visual-motor integration (VMI) skills and academic achievement in pediatric acute lymphoblastic leukemia (ALL) survivors. METHODS: In this 28-site cross-sectional study of 256 children in first remission, a mean of 8.9 ± 2.2 years after treatment for standard-risk precursor-B ALL, validated measures of FM, VMI, reading, math, and intelligence were administered at mean follow-up age of 12.8 ± 2.5 years. RESULTS: VMI was significantly associated with written math calculation ability (p < .0069) after adjusting for intelligence (p < .0001). VMI was more strongly associated with math in those with lower intelligence (p = .0141). Word decoding was also significantly associated with VMI but with no effect modification by intelligence. FM skills were not associated with either reading or math achievement. CONCLUSION: These findings suggest that VMI is associated with aspects of math and reading achievement in leukemia survivors. These skills may be amenable to intervention.

Prospective, longitudinal assessment of quality of life in children from diagnosis to 3 months off treatment for standard risk acute lymphoblastic leukemia: Results of Children's Oncology Group study AALL0331.

Standard risk acute lymphoblastic leukemia (SR-ALL) has high cure rates, but requires 2-3 years of therapy. We aimed to (i) prospectively evaluate health-related quality of life (HRQOL) during and after SR-ALL therapy, and (ii) identify associated predictors. Parents of 160 SR-ALL patients enrolled on Children's Oncology Group (COG) therapeutic trial AALL0331 at 31 sites completed the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales (physical, emotional and social functioning) and Family Assessment Device-General Functioning (FAD-GF) at 1, 6 and 12 months after diagnosis, and 3 months post-therapy. Mean PedsQL scores in physical, emotional and social functioning were impaired 1 month after diagnosis but steadily improved. Three months post-therapy, impaired physical and social functioning was observed in 27.8 and 25.8% of patients, respectively. In repeated-measures analysis, problematic family functioning predicted emotional (OR = 1.85, 95% CI 1.03-3.34) and social (OR = 1.99, 95% CI 1.21-3.27) impairment. Larger household size was associated with social impairment (OR = 1.21, 95% CI 1.02-1.45). Adverse neurological event(s) during therapy predicted post-therapy physical (OR = 5.17, 95% CI 1.61-16.63) and social (OR = 8.17, 95% CI 1.19-56.16) impairment. HRQOL 1 month after diagnosis was not predictive of HRQOL 3 months after therapy completion. In conclusion, children with SR-ALL experience considerable impairment in HRQOL at the end of induction, but rapidly improve. However, many still experience physical and social impairment 3 months post-therapy, suggesting a role for continued family and physical functioning support. Longer follow-up is needed to determine if post-therapy deficits change over time.

Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis.

Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with 5-year survival rates of ∼90% even after largely eliminating cranial radiation. This meta-analysis assesses the long-term neurocognitive functioning after chemotherapy-only regimens among survivors of childhood ALL. We conducted a systematic review to identify studies that evaluated long-term neurocognitive functioning following treatment of ALL by searching MEDLINE/PubMed, Database of Abstracts of Reviews of Effects, and secondary sources. Studies were included if ALL survivors were in continuous first remission, did not receive any radiation, were at least ≥2 years off therapy or ≥5 years since diagnosis, and were compared with a healthy control group. Weighted mean differences with 95% confidence intervals (CIs) were calculated. Ten nonexperimental studies met all eligibility criteria and included 509 patients and 555 controls. Meta-analysis demonstrated statistically significant moderate impairment across multiple neurocognitive domains evaluated, with intelligence most affected. Significant differences in standard deviation (SD) scores were found for Full Scale intelligence quotient (IQ) (-0.52 SD; 95% CI, -0.68 to -0.37), Verbal IQ (-0.54 SD; 95% CI, -0.69 to -0.40), and Performance IQ (-0.41 SD; 95% CI, -0.56 to -0.27); these SD scores correspond to changes in IQ of 6 to 8 points. Working memory, information processing speed, and fine motor domains were moderately, but statistically significantly, impaired. Meta-analysis of ALL survivors treated without cranial radiation demonstrated significant impairment in IQ and other neurocognitive domains. Patients and their families should be informed about these potential negative effects to encourage surveillance and educational planning. Both preventive and intervention strategies are needed.

Observing behavior and atypically restricted stimulus control.

Restricted stimulus control refers to discrimination learning with atypical limitations in the range of controlling stimuli or stimulus features. In the study reported here, 4 normally capable individuals and 10 individuals with intellectual disabilities (ID) performed two-sample delayed matching to sample. Sample-stimulus observing was recorded with an eye-tracking apparatus. High accuracy scores indicated stimulus control by both sample stimuli for the 4 nondisabled participants and 4 participants with ID, and eye tracking data showed reliable observing of all stimuli. Intermediate accuracy scores indicated restricted stimulus control for the remaining 6 participants. Their eye-tracking data showed that errors were related to failures to observe sample stimuli and relatively brief observing durations. Five of these participants were then given interventions designed to improve observing behavior. For 4 participants, the interventions resulted initially in elimination of observing failures, increased observing durations, and increased accuracy. For 2 of these participants, contingencies sufficient to maintain adequate observing were not always sufficient to maintain high accuracy; subsequent procedure modifications restored it, however. For the 5th participant, initial improvements in observing were not accompanied by improved accuracy, an apparent instance of observing without attending; accuracy improved only after an additional intervention that imposed contingencies on observing behavior. Thus, interventions that control observing behavior seem necessary but may not always be sufficient for the remediation of restricted stimulus control.

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.

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.

The utility of functional magnetic resonance imaging in epilepsy and language.

Functional magnetic resonance imaging (fMRI) is a viable presurgical tool for use with the pediatric epilepsy population as replacement for the intra-carotid sodium amobarbital test (IAT) used to identify hemispheric language dominance. This paper reviews the current imaging research on the identification of language cortex in pediatric epilepsy patients and in normal children. A review of the literature comparing fMRI to the IAT and electrocortical stimulation suggests that fMRI reliably identifies the dominant hemisphere, with pediatric and adult studies producing comparable results. Within-hemisphere localization of eloquent cortex with fMRI is more problematic. Paradigm selection, data analysis techniques, and considerations specific to imaging children are discussed. Utility of fMRI for studying neural plasticity as a result of brain insult (e.g., epilepsy) is also considered.