Childhood Neurotoxicity and Brain Resilience to Adverse Events during Adulthood.

OBJECTIVE: This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). METHODS: Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age-adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life-threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS-directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. RESULTS: CNS-treated survivors performed worse than non-CNS-treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose-response association between severity/burden score and global neurocognitive impairment, but only among CNS-treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42-3.53; very high OR = 4.07, 95% CI = 2.30-7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS-treated but not non-CNS-treated survivors who were impacted by neurologic conditions. INTERPRETATION: Reduced cognitive/brain reserve associated with CNS-directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534-545.

Pain in long-term survivors of childhood cancer: A systematic review of the current state of knowledge and a call to action from the Children's Oncology Group.

Survivors of childhood cancer may be at risk of experiencing pain, and a systematic review would advance our understanding of pain in this population. The objective of this study was to describe: 1) the prevalence of pain in survivors of childhood cancer, 2) methods of pain measurement, 3) associations between pain and biopsychosocial factors, and 4) recommendations for future research. Data sources for the study were articles published from January 1990 to August 2019 identified in the PubMed, PsycINFO, EMBASE, and Web of Science data bases. Eligible studies included: 1) original research, 2) quantitative assessments of pain, 3) articles published in English, 4) cancers diagnosed between birth and age 21 years, 5) survivors at 5 years from diagnosis and/or at 2 years after therapy completion, and 6) a sample size >20. Seventy-three articles were included in the final review. Risk of bias was considered using the Cochrane risk of bias tool. The quality of evidence was evaluated according to Grading of Recommendations Assessment Development and Evaluation (GRADE) criteria. Common measures of pain were items created by the authors for the purpose of the study (45.2%) or health-related quality-of-life/health status questionnaires (42.5%). Pain was present in from 4.3% to 75% of survivors across studies. Three studies investigated chronic pain according the definition in the International Classification of Diseases. The findings indicated that survivors of childhood cancer are at higher risk of experiencing pain compared with controls. Fatigue was consistently associated with pain, females reported more pain than males, and other factors related to pain will require stronger evidence. Theoretically grounded, multidimensional measurements of pain are absent from the literature.

Neurocognitive and psychosocial outcomes in adult survivors of childhood soft-tissue sarcoma: A report from the St. Jude Lifetime Cohort.

BACKGROUND: To the authors' knowledge, few studies to date have examined long-term neurocognitive outcomes in survivors of childhood soft-tissue sarcoma. METHODS: A total of 150 survivors (41% of whom were female with a mean current age of 33 years [SD, 8.9 years] and a time since diagnosis of 24 years [SD, 8.7 years]) and 349 community controls (56% of whom were female with a mean current age of 35 years [SD, 10.2 years]) completed comprehensive neuropsychological testing, echocardiography, electrocardiography, pulmonary function tests, endocrine evaluation, and physical examination. Patient-reported outcomes of health-related quality of life (HRQOL) and social attainment were collected. Survivors were compared with norms and controls on neurocognitive outcomes using general linear models, and on HRQOL and social attainment using modified Poisson models. The impacts of treatment and chronic health conditions on outcomes were examined using multivariable general linear models (effect size was expressed as unstandardized ß estimates that reflected the unit of change from a mean of 0 and an SD of 1) and modified Poisson models (effect size expressed as relative risks). RESULTS: Compared with controls and population norms, survivors demonstrated lower performance on measures of verbal reasoning (mean z score, -0.45 [SD, 1.15]; P < .001) mathematics (mean z score, -0.63 [SD, 1.07]; P < .001), and long-term memory (mean z score, -0.37 [SD, 1.14]; P < .001). Cumulative anthracycline exposure (per 100 mg/m2 ) was found to be associated with poorer verbal reasoning (ß = -0.14 z scores; P = .04), reading (ß = -0.09 z score; P = .04), and patient-reported vitality (relative risk, 1.32; 95% CI, 1.09-1.59). Neurologic and neurosensory chronic conditions were associated with poorer mathematics (neurologic conditions: ß = -0.63 z score [P = 0.02]; and hearing impairment: ß = -0.75 z scores [P < 0.01]). Better cognitive performance was associated with higher social attainment. CONCLUSIONS: Long-term survivors of soft-tissue sarcoma are at risk of neurocognitive problems and poor HRQOL associated with anthracycline treatment and chronic health conditions.

Behavioral symptoms and psychiatric disorders in child and adolescent long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.

BACKGROUND: Prevalence of emotional, behavioral, and psychiatric outcomes in child and adolescent survivors of childhood acute lymphoblastic leukemia treated on a chemotherapy-only protocol were not well defined. METHODS: Self- and parent-reported emotional and behavioral symptoms were assessed for 161 survivors of childhood acute lymphoblastic leukemia (51.0% female; mean [SD] age 12.1[2.6] years; 7.5[1.6] years post-diagnosis). Age- and sex-adjusted scores were calculated for standardized measures and compared with 90th percentile of norms. Frequencies of survivor psychiatric disorders from structured diagnostic interviews with parents were compared with the general population. Parent emotional distress and post-traumatic stress symptoms were assessed. Associations between child symptoms/disorders and parent distress were examined with log-binomial models, adjusting for highest parent education. RESULTS: Compared with population expectations (10%), more survivors self-reported symptoms of inattention (27.9; 95% CI, 21.0%-35.7%), hyperactivity/impulsivity (26.0%; CI, 19.2%-33.6%), and oppositional-defiant behavior (20.1%; CI, 14.1%-27.3%). Parents reported survivors with more symptoms of inattention (23.6%; CI, 17.2%-31.0%), higher frequencies of obsessive-compulsive disorder (10.3% vs 2%) and oppositional defiant disorder (16.0% vs 9.5%), but not attention-deficit/hyperactivity disorder (7.1% vs 7.8%) or generalized anxiety disorder (3.2% vs 4.1%), compared with national norms. Parent-report of child anxiety disorders was associated with parent self-reported emotional distress but not survivor self-report of anxiety. CONCLUSION: A significant minority of survivors have long-term psychiatric morbidity, multi-informant assessment is important to understand these symptom profiles and to inform selection of appropriate interventions. Interventions targeting inattention and oppositional behavior in children and emotional distress in parents are warranted in families with survivors who display behavioral problems.

Chronic hepatitis C virus infection and neurocognitive function in adult survivors of childhood cancer.

BACKGROUND: Cancer survivors transfused with blood products before reliable screening for hepatitis C virus (HCV) are at risk for infection. This study examined the impact of HCV on neurocognitive function and health-related quality of life (HRQOL) among adult survivors of childhood cancer. METHODS: Neurocognitive testing was conducted for 836 adult survivors of childhood cancer (mean age, 35 years [standard deviation, 7.4 years]; time since diagnosis, 29 years [standard deviation, 6.2 years]) who received blood products before universal HCV screening. No differences were observed between confirmed HCV-seropositive survivors (n = 79) and HCV-seronegative survivors (n = 757) in the primary diagnosis or neurotoxic therapies. Multivariate regression models were used to compare functional outcomes between seropositive and seronegative survivors. RESULTS: Compared with seronegative survivors, seropositive survivors demonstrated lower performance on measures of attention (P < .001), processing speed (P = .008), long-term verbal memory (P = .01), and executive function (P = .001). After adjustments for sex, age at diagnosis, and treatment exposures, seropositive survivors had a higher prevalence of impairment in processing speed (prevalence ratio [PR], 1.3; 95% confidence interval [CI], 1.1-1.6) and executive functioning (PR, 1.3; 95% CI, 1.1-1.6). Differences were not associated with the treatment of HCV or the presence of liver cirrhosis. Seropositive survivors reported worse general HRQOL (PR, 1.6; 95% CI, 1.2-2.1), which was associated with the presence of liver cirrhosis (P = .001). CONCLUSIONS: Survivors of childhood cancer with a history of HCV infection are at risk for neurocognitive impairment and reduced HRQOL beyond the known risks associated with neurotoxic cancer therapies. Cancer 2017;123:4498-505. © 2017 American Cancer Society.

Impact of sleep, fatigue, and systemic inflammation on neurocognitive and behavioral outcomes in long-term survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive impairment, which may be associated with fatigue, sleep problems, systemic inflammation, and oxidative stress. We examined these associations among survivors of childhood ALL treated with chemotherapy only. METHODS: Survivors of childhood ALL (male, n = 35 and female, n = 35; mean age, 14.3 years [standard deviation, 4.7 years] and mean years from diagnosis, 7.4 years [standard deviation, 1.9 years]) completed neurocognitive testing, behavioral ratings, and reported sleep quality and fatigue symptoms 5 years after diagnosis. Serum was collected concurrently and assayed for interleukin (IL)-1ß and IL-6, tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hsCRP), malondialdehyde, myeloperoxidase, and oxidized low-density lipoprotein. General linear modeling was used to assess associations among biomarkers and functional outcomes, adjusting for age and stratified by sex. RESULTS: Survivors performed worse than population norms on executive function and processing speed and reported more behavioral problems (P < .05 adjusted for multiple comparison). In female survivors, fatigue was associated with poor executive function (r = 0.41; P = .02), processing speed (r = 0.56; P < .001), and attention (r = 0.36-0.55; P < .05). Female survivors with frequent nighttime awakening displayed more inattention (P = .01), hyperactivity (P = .03), and aggression (P = .01). Worse executive function, processing speed, and behavioral symptoms were observed in female survivors with higher levels of IL-6, IL-1ß, and hsCRP (P < .05). Male survivors with high levels of TNF-α demonstrated worse organization (P = .03), but no significant associations between neurocognitive outcomes and sleep/fatigue measures were observed. CONCLUSION: Neurocognitive function in female survivors of childhood ALL appears more susceptible to the effects of sleep disturbance and fatigue. Systemic inflammation may play a role in neurocognitive impairment and behavioral symptoms. Cancer 2017;123:3410-9. © 2017 American Cancer Society.

Using Neurocognitive Phenotypes to Inform Interventions for Adult Survivors of Childhood Cancer.

BACKGROUND: Neurocognitive impairments are sequelae of childhood cancer treatment, however little guidance is given to clinicians on common phenotypes of impairment, or modifiable risk factors that could lead to personalized interventions in survivorship. METHODS: Standardized clinical testing of neurocognitive function was conducted in 2,958 (74.1%) eligible survivors, who were ≥5 years post-diagnosis and >18 years old, and 477 community controls. Impairment was examined across 20 measures and phenotypes were determined by latent class analysis. Multinomial logistic regression was used to estimate risk for phenotype, predicted by cancer diagnosis and treatment exposures, chronic health conditions, and lifestyle, adjusted for sex and age. Associations between phenotypes and social attainment were examined. RESULTS: Five neurocognitive phenotypes were identified in survivors (global impairment 3.7%, impaired attention 5.0%, memory impairment 7.2%, processing speed/executive function impairment 9.3%, no impairment 74.8%). Risk of global impairment was associated with severe chronic health condition burden (odds ratio [OR]=20.17, 95% confidence interval [95%CI] 11.41-35.63) including cerebrovascular disease (OR = 14.5, 95%CI = 5.47-38.44) and cerebrovascular accident (OR = 14.7, 95%CI = 7.50-26.40). Modifiable risk factors, like quitting smoking reduced risk for global impairment (OR = 0.21, 95%CI 0.06-0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95%CI 2.86-7.21), attention impairment (OR 2.01, 95%CI 1.41-2.87), processing speed/executive function impairment (OR 1.90, 95%CI 1.46-2.48), and memory impairment (OR 2.09, 95%CI 1.54-2.82). CONCLUSIONS: Results support the clinical utility of neurocognitive phenotyping to develop risk profiles and personalized clinical interventions, such as preventing cerebrovascular disease in anthracycline treated survivors by preventing hypercholesterolemia, smoking, and sedentary lifestyle, to reduce the risk for global impairment.

Physiologic Frailty and Neurocognitive Decline Among Young-Adult Childhood Cancer Survivors: A Prospective Study From the St Jude Lifetime Cohort.

PURPOSE: Eight percent of young-adult childhood cancer survivors meet criteria for frailty, an aging phenotype associated with poor health. In the elderly general population, frailty is associated with neurocognitive decline; this association has not been examined in adult survivors of childhood cancer. METHODS: Childhood cancer survivors 18-45 years old (≥ 10 years from diagnosis) were clinically evaluated for prefrailty or frailty (respectively defined as ≥ 2 or ≥ 3 of: muscle wasting, muscle weakness, low energy expenditure, slow walking speed, and exhaustion [Fried criteria]) and completed neuropsychologic assessments at enrollment (January 2008-June 2013) and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS-directed therapy (cranial radiation, intrathecal chemotherapy, and neurosurgery), and baseline neurocognitive performance. RESULTS: Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrollment. Frail survivors declined an average of 0.54 standard deviation (95% CI, -0.93 to -0.15) in short-term verbal recall, whereas nonfrail survivors did not decline (ß = .22; difference of ßs = -.76; 95% CI, -1.19 to -0.33). Frail survivors declined more than nonfrail survivors on visual-motor processing speed (ß = -.40; 95% CI, -0.67 to -0.12), cognitive flexibility (ß = -.62; 95% CI, -1.02 to -0.22), and verbal fluency (ß = -.23; 95% CI, -0.41 to -0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail ß = -.35; 95% CI, -0.53 to -0.17; frail ß = -.48; 95% CI, -0.83 to -0.12) compared with nonfrail survivors. CONCLUSION: Over approximately 5 years, prefrail and frail young-adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Interventions that have global impact, designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.

Insomnia and Neurocognitive Functioning in Adult Survivors of Childhood Cancer.

BACKGROUND: In noncancer populations, insomnia is known to affect neurocognitive processes. Although the prevalence of insomnia appears to be elevated in survivors of childhood cancer, relatively little is known about its association with neurocognitive performance in this at-risk population. METHODS: A total of 911 survivors (51.9% female; mean [SD] age, 34 [9.0] years; time since diagnosis, 26 [9.1] years) completed direct assessments of attention, memory, processing speed, and executive functioning and self-reported symptoms of sleep (Pittsburgh Sleep Quality Index), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), and daytime sleepiness (Epworth Sleepiness Scale). Sex-stratified general linear models were used to examine associations between insomnia and neurocognitive performance, with adjustment for treatment exposures and chronic health conditions. All statistical tests were two-sided. RESULTS: Insomnia was reported by 22.1% of females and 12.3% of males (P < .001). After adjustment for neurotoxic treatment exposures, insomnia (vs healthy sleepers with no daytime fatigue or sleepiness) was associated with worse neurocognitive performance in the domains of verbal reasoning, memory, attention, executive function, and processing speed (verbal reasoning: males ß = -0.34, P = .04, females ß = -0.57, P < .001; long-term memory: males ß = -0.60, P < .001, females ß = -0.36, P = .02; sustained attention: males ß = -0.85, P < .001, females ß = -0.42, P = .006; cognitive flexibility: males ß = -0.70, P = .002, females ß = -0.40, P = .02). Self-reported sleep disturbance without daytime fatigue or sleepiness or daytime fatigue or sleepiness alone were not consistently associated with poorer neurocognitive performance. CONCLUSIONS: Insomnia was highly prevalent and contributed to the neurocognitive burden experienced by adult survivors of childhood cancer. Treatment of insomnia may improve neurocognitive problems in survivors.

Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer.

Importance: Despite advancements in cancer therapy and supportive care, childhood cancer survivors remain at risk for chronic morbidities associated with disease and treatment, such as hearing impairment (HI) and neurocognitive deficits. This study, to our knowledge, is the first to objectively measure hearing and neurocognitive function in a large cohort of long-term survivors of childhood cancer stratified by treatment exposures. Objective: To assess the association of HI with neurocognitive function and the factors in HI that mediate neurocognitive outcomes in survivors of childhood cancer. Design, Setting, and Participants: Data analyzed in this cross-sectional study were collected for the period April 25, 2007, to June 30, 2017, from participants in the St. Jude Lifetime Cohort Study (SJLIFE), an ongoing study that quantifies the long-term health outcomes of survivors of childhood cancer. Participants included those treated at St. Jude Children's Research Hospital (Memphis, Tennessee) for childhood cancer who survived 5 or more years after their original diagnosis and who were eligible for audiologic and neurocognitive testing. Hearing outcomes were coded using the Chang Ototoxicity Grading Scale. Data analysis was performed from March 22, 2019, to March 5, 2020. Main Outcomes and Measures: Hearing and neurocognitive function. Survivors were grouped by hearing sensitivity (normal hearing [Chang grade 0], mild HI [Chang grades 1a, 1b, and 2a], or severe HI [Chang grade ≥2b]) and stratified by treatment exposure (platinum-only exposure group [treated with cisplatin and/or carboplatin chemotherapy], cochlear radiotherapy [RT] exposure group [treated with cochlear RT with or without platinum-based chemotherapy], or no exposure group [no platinum-based chemotherapy or cochlear RT]). Multivariable log-binomial models were adjusted for age at diagnosis, time since diagnosis, sex, and relevant treatment exposures. Results: A total of 1520 survivors of childhood cancer were analyzed, among whom 814 were male survivors (53.6%), the median (interquartile range [IQR]) age was 29.4 (7.4-64.7) years, and the median (IQR) time since diagnosis was 20.4 (6.1-53.8) years. Prevalence and risk of severe HI among survivors were higher in survivors in the platinum-only (n = 107 [34.9%]; relative risk [RR], 1.68 [95% CI, 1.20-2.37]) or cochlear RT (n = 181 [38.3%]; RR, 2.69 [95% CI, 2.02-3.57) exposure group compared with those in the no exposure group (n = 65 [8.8%]). Severe HI was associated with deficits in verbal reasoning skills (no exposure group RR, 1.11 [95% CI, 0.50-2.43]; platinum-only exposure group RR, 1.93 [95% CI, 1.21-3.08]; cochlear RT exposure group RR, 2.00 [95% CI, 1.46-2.75]), verbal fluency (no exposure group RR, 1.86 [95% CI, 1.19-2.91]; platinum-only exposure group RR, 1.83 [95% CI, 1.24-2.71]; cochlear RT exposure group RR, 1.45 [95% CI, 1.09-1.94]), visuomotor speed (no exposure group RR, 1.87 [95% CI, 1.07-3.25]; platinum-only exposure group RR, 3.10 [95% CI, 1.92-4.99]; cochlear RT exposure group RR, 1.40 [95% CI, 1.11-1.78]), and mathematics skills (no exposure group RR, 1.90 [95% CI, 1.18-3.04]; platinum-only exposure group RR, 1.63 [95% CI, 1.05-2.53]; cochlear RT exposure group RR, 1.58 [95% CI, 1.15-2.18]), compared with survivors with normal hearing or with mild HI. Conclusions and Relevance: Results of this study suggest that severe HI in childhood cancer survivors is associated with neurocognitive deficits independent of the neurotoxic treatment received. Early screening and intervention for HI may facilitate the development and maintenance of neurocognitive function and identify individuals at risk for impairment.

Connectivity of the Cerebello-Thalamo-Cortical Pathway in Survivors of Childhood Leukemia Treated With Chemotherapy Only.

Importance: Treatment with contemporary chemotherapy-only protocols is associated with risk for neurocognitive impairment among survivors of childhood acute lymphoblastic leukemia (ALL). Objective: To determine whether concurrent use of methotrexate and glucocorticoids is associated with interference with the antioxidant system of the brain and damage and disruption of glucocorticoid-sensitive regions of the cerebello-thalamo-cortical network. Design, Setting, and Participants: This cross-sectional study was conducted from December 2016 to July 2019 in a single pediatric cancer tertiary care center. Participants included survivors of childhood ALL who were more than 5 years from cancer diagnosis, age 8 years or older, and treated on an institutional chemotherapy-only protocol. Age-matched community members were recruited as a control group. Data were analyzed from August 2017 to August 2020. Exposure: ALL treatment using chemotherapy-only protocols. Main Outcomes and Measures: This study compared brain volumes between survivors and individuals in a community control group and examined associations among survivors of methotrexate and dexamethasone exposure with neurocognitive outcomes. Functional and effective connectivity measures were compared between survivors with and without cognitive impairment. The Rey-Osterrieth complex figure test, a neurocognitive evaluation in which individuals are asked to copy a figure and then draw the figure from memory, was scored according to published guidelines and transformed into age-adjusted z scores based on nationally representative reference data and used to measure organization and planning deficits. ß values for neurocognitive tests represented the amount of change in cerebellar volume or chemotherapy exposure associated with 1 SD change in neurocognitive outcome by z score (mm3/1 SD in z score for cerebellum, mm3/[g×hr/L] for dexamethasone and methotrexate AUC, and mm3/intrathecal count for total intrathecal count). Results: Among 302 eligible individuals, 218 (72%) participated in the study and 176 (58%) had usable magnetic resonance imaging (MRI) results. Among these, 89 (51%) were female participants and the mean (range) age was 6.8 (1-18) years at diagnosis and 14.5 (8-27) years at evaluation. Of 100 community individuals recruited as the control group, 82 had usable MRI results; among these, 35 (43%) were female individuals and the mean (range) age was 13.8 (8-26) years at evaluation. There was no significant difference in total brain volume between survivors and individuals in the control group. Survivors of both sexes showed decreased mean (SD) cerebellar volumes compared with the control population (female: 70 568 [6465] mm3 vs 75 134 [6780] mm3; P < .001; male: 77 335 [6210] mm3 vs 79 020 [7420] mm3; P < .001). In female survivors, decreased cerebellar volume was associated with worse performance in Rey-Osterrieth complex figure test (left cerebellum: ß = 55.54; SE = 25.55; P = .03; right cerebellum: ß = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: ß = 82.71; SE = 31.04; P = .009; right cerebellum: ß = 91.06; SE = 30.72; P = .004). In female survivors, increased number of intrathecal treatments (ie, number of separate injections) was also associated with Worse Rey-Osterrieth test performance (ß = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (ß = -0.0014; SE = 0.0005; P = .01). Executive dysfunction was correlated with increased global efficiency between smaller brain regions (Pearson r = -0.24; P = .01) compared with individuals without dysfunction. Anatomical connectivity showed differences between impaired and nonimpaired survivors. Analysis of variance of effective-connectivity weights identified a significant interaction association (F = 3.99; P = .02) among the direction and strength of connectivity between the cerebellum and DLPFC, female sex, and executive dysfunction. Finally, no effective connectivity was found between the precuneus and DLPFC in female survivors with executive dysfunction. Conclusions and Relevance: These findings suggest that dexamethasone exposure was associated with smaller cerebello-thalamo-cortical regions in survivors of ALL and that disruption of effective connectivity was associated with impairment of executive function in female survivors.

Social attainment in survivors of pediatric central nervous system tumors: a systematic review and meta-analysis from the Children's Oncology Group.

PURPOSE: Improved therapies for pediatric central nervous system (CNS) tumors have increased survival rates; however, many survivors experience significant long-term functional limitations. Survivors of pediatric CNS tumors can experience deficits in social attainment. The aim of this review was to systematically amalgamate findings pertaining to social attainment (i.e., educational attainment, marriage, employment outcomes) in survivors of pediatric CNS tumors. METHODS: PubMed (web-based), PsycINFO (EBSCO), EMBASE (Ovid), and Web of Science (Thomson Reuters) were used to identify articles published between January 2011 and September 2018. Eligible studies reported outcomes for survivors of pediatric CNS tumors diagnosed before age 21 years and > 5 years from diagnosis and/or > 2 years off therapy. All data were independently abstracted by two reviewers. Random-effects meta-analyses were performed using Review Manager 5.0. RESULTS: The search yielded 7021 unique publications. Forty-six were included in the current review. Meta-analyses revealed survivors of CNS tumors were significantly more likely to have completed compulsory education only (OR = 1.87, 95% CI = 1.66, 2.12, p < 0.00001), less likely to be married (OR = 4.70, 95% CI = 3.89, 5.68, p < 0.00001), and more likely to be unemployed (OR = 2.84, 95% CI = 2.62, 3.08, p < 0.00001) compared to non-cancer controls. Cranial radiation therapy, neurocognitive deficits, and younger age at diagnosis were associated with poorer outcomes. Hearing loss and bilateral blindness were also related to poorer outcomes. Sex did not impact social attainment outcomes. CONCLUSIONS: Survivors of pediatric CNS tumors are at elevated risk for poor attainment of key adult social outcomes. IMPLICATIONS FOR CANCER SURVIVORS: There is a critical need to develop interventions to support survivors in becoming independent and productive adults.

Neurocognitive outcomes in long-term survivors of Wilms tumor: a report from the St. Jude Lifetime Cohort.

PURPOSE: To examine prevalence and predictors of neurocognitive outcomes, social attainment, emotional distress, and health-related quality of life (HRQOL) in long-term survivors of pediatric Wilms tumor (WT). METHODS: One hundred fifty-eight WT survivors (59% female; mean [SD] age 33 [9.1] years; time since diagnosis 29 [9.1] years) and 354 community controls (55.6% female; 35 [10.2] years) completed comprehensive neuropsychological testing and physical examination, including echocardiography/electrocardiography, pulmonary function tests, and endocrine evaluation. Self-report of emotional distress, HRQOL, and social attainment were collected. Impairment was defined in relation to both controls and normative data. Generalized linear models were developed to examine impact of treatment and chronic health conditions on outcomes. RESULTS: WT survivors performed poorer than norms and controls in 6 of 16 cognitive variables and 1 of 8 HRQOL variables, with scores ranging from - 0.64 (mathematics) to - 0.21 (verbal fluency) standard deviations below expectations. Compared to controls, WT survivors were less likely to graduate college (odds ratio 2.23, 95% confidence interval 1.46-3.41) and had more moderate to severe neurologic conditions (18.4% vs 8.2%, p < 0.001), which were associated with poor memory (ß = - 0.90, p < 0.001), attention (ß = - 1.02, p < 0.001), and HRQOL general health (ß = - 0.80, p = 0.0015). Treatment variables and cardiopulmonary morbidity (higher in survivors) were not associated with outcomes. CONCLUSIONS: Survivors of WT demonstrate impairment in neurocognitive function and have lower social attainment during adulthood, with poorer neurocognitive function associated with neurologic morbidity. IMPLICATIONS FOR CANCER SURVIVORS: Survivors of WT should be offered neurocognitive evaluations and rehabilitation. Neurologic conditions should be routinely assessed, and appropriate support offered to reduce risk for functional limitations.

Association Between Anesthesia Exposure and Neurocognitive and Neuroimaging Outcomes in Long-term Survivors of Childhood Acute Lymphoblastic Leukemia.

IMPORTANCE: Limited studies have reported associations between anesthesia and neurocognitive and neuroimaging outcomes, particularly in pediatric patients who undergo multiple exposures to anesthesia as part of chronic disease management. OBJECTIVE: To investigate whether general anesthesia is associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of 212 survivors of childhood acute lymphoblastic leukemia who received treatment between July 7, 2000, and November 3, 2010, and follow-up at a mean (SD) of 7.7 (1.7) years post diagnosis, was conducted at an academic medical center. Of 301 survivors who were alive and eligible for participation, 217 individuals (72.1%) agreed to participate in long-term follow-up. Data analysis was performed from August 23, 2017, to May 3, 2018. EXPOSURES: For 5699 anesthesia procedures, data on duration and cumulative doses of all anesthetics, sedatives, analgesics, anxiolytics, and neuromuscular blockers were abstracted, along with cumulative doses of high-dose intravenous methotrexate and number of triple intrathecal chemotherapy treatments. MAIN OUTCOMES AND MEASURES: Neurocognitive measures of attention, processing speed, executive function, and intelligence were examined. Brain volumes, cortical thickness, and diffusion tensor imaging of the whole brain, corpus callosum, frontal lobes, and parietal lobes were evaluated. RESULTS: Of the 217 study participants, 212 were included in both neurocognitive and brain imaging analysis. Of these, 105 were female (49.5%); mean (SD) age at diagnosis was 14.36 (4.79) years; time since diagnosis was 7.7 (1.7) years. Adjusting for chemotherapy doses and age at diagnosis, neurocognitive impairment was associated with higher propofol cumulative dose (relative risk [RR], 1.40 per 100 mg/kg; 95% CI, 1.11-1.75), flurane exposure (RR, 1.10 per exposure; 95% CI, 1.01-1.21), and longer anesthesia duration (RR, 1.03 per cumulative hour; 95% CI, 1.00-1.06). Slower processing speed was associated with higher propofol dose (estimate [est], -0.30; P = .04), greater number of exposures to fluranes (est, -0.14; P = .01), and longer anesthesia duration (est, -0.04; P = .003). Higher corpus callosum white matter diffusivity was associated with dose of propofol (est, 2.55; P = .01) and duration of anesthesia (est, 2.40; P = .02). Processing speed was significantly correlated with corpus callosum diffusivity (r = -0.26, P < .001). CONCLUSIONS AND RELEVANCE: Higher cumulative anesthesia exposure and duration may be associated with neurocognitive impairment and neuroimaging abnormalities in long-term survivors of childhood acute lymphoblastic leukemia, beyond the known outcomes associated with neurotoxic chemotherapies. Anesthesia exposures should be limited in pediatric populations with chronic health conditions who undergo multiple medical procedures.

Association between dehydroepiandrosterone-sulfate and attention in long-term survivors of childhood acute lymphoblastic leukemia treated with only chemotherapy.

Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive impairment, as well as compromised hypothalamic-pituitary-adrenal (HPA) function. Dehydroepiandrosterone-sulfate (DHEAS) is an adrenal androgen commonly used as a marker of HPA function. In the general population, a low level of DHEAS has been associated with poorer cognition. At ≥2years post-treatment, we examined the association of DHEAS with attention outcomes in 35 male and 34 female long-term survivors of childhood ALL (mean[standard deviation] age at evaluation 14.5[4.7] years; 7.5[1.9] years post-diagnosis) who were treated with only chemotherapy and without prophylactic cranial irradiation. Male survivors with low-normal levels of DHEAS had worse performance than male survivors with high levels of DHEAS on multiple measures of attention (all P's<0.05). However, association between DHEAS and attention measures were not found in female survivors. Our results suggest that survivors of ALL who suffer from partial but persistent adrenal insufficiency may be at risk for neurocognitive deficits. This finding should be validated in a larger prospective study, with attention to sex differences in the potential impact of adrenal insufficiency on neurocognitive outcomes.

Clinical assessment of organizational strategy: An examination of healthy adults.

During the assessment of patients with cognitive difficulties, clinicians often examine strategic processing, particularly the ability to use organization-based strategies to efficiently complete various tasks. Several commonly used neuropsychological tasks are currently thought to provide measures of organizational strategic processing, but empirical evidence for the construct validity of these strategic measures is needed before interpreting them as measuring the same underlying ability. This is particularly important for the assessment of organizational strategic processing because the measures span cognitive domains (e.g., memory strategy, language strategy) as well as types of organization. In the present study, 200 adults were administered cognitive tasks commonly used in clinical practice to assess organizational strategic processing. Factor analysis was used to examine whether these measures of organizational strategic processing, which involved different cognitive domains and types of organization, could be operationalized as measuring a unitary construct. A very good-fitting model of the data demonstrated no significant shared variance among any of the strategic variables from different tasks (root mean square error of approximation < .0001, standardized root-mean-square residual = .045, comparative fit index = 1.000). These findings suggest that organizational strategic processing is highly specific to the demands and goals of individual tasks even when tasks share commonalities such as involving the same cognitive domain. In the design of neuropsychological batteries involving the assessment of organizational strategic processing, it is recommended that various strategic measures across cognitive domains and types of organizational processing are selected as guided by each patient's individual cognitive difficulties.

Association between lesion location and language function in adult glioma using voxel-based lesion-symptom mapping.

BACKGROUND: Management of language difficulties is an important aspect of clinical care for glioma patients, and accurately identifying the possible language deficits in patients based on lesion location would be beneficial to clinicians. To that end, we examined the relationship between lesion presence and language performance on tests of receptive language and expressive language using a highly specific voxel-based lesion-symptom mapping (VLSM) approach in glioma patients. METHODS: 98 adults with primary glioma, who were pre-surgical candidates, were administered seven neurocognitive tests within the domains of receptive language and expressive language. The association between language performance and lesion presence was examined using VLSM. Statistical parametric maps were created for each test, and composite maps for both receptive language and expressive language were created to display the significant voxels common to all tests within these language domains. RESULTS: We identified clusters of voxels with a significant relationship between lesion presence and language performance. All tasks were associated with several white matter pathways. The receptive language tasks were additionally all associated with regions primarily within the lateral temporal lobe and medial temporal lobe. In contrast, the expressive language tasks shared little overlap, despite each task being independently associated with large anatomic areas. CONCLUSIONS: Our findings identify the key anatomic structures involved in language functioning in adult glioma patients using an innovative lesion analysis technique and suggest that expressive language abilities may be more task-dependent and distributed than receptive language abilities.

Executive strategic processing during verbal fluency performance in children with phenylketonuria.

In the current study, we examined a specific aspect of executive abilities, strategic processing, in 32 children with early-treated phenylketonuria (PKU) and 41 typically-developing control children. To do so, clustering and switching were assessed during semantic (animal, food/drink) and phonemic (S, F) fluency tasks. Specifically, number of words generated, number of subcategory clusters, number of words in subcategory clusters, and number of switches between subcategories were analyzed to provide a refined analysis of strategic processing. Compared with controls, children with PKU generated significantly fewer words and made significantly fewer switches between subcategories in the food/drink trial and the phonemic fluency condition. Number of switches was associated with number of words generated in these tasks. In addition, a significant interaction between age and group in number of switches for the food/drink trial reflected a greater increase in number of switches for the control than PKU group as a function of increasing age. These results suggest impairment in frontally-mediated aspects of strategic processing in children with early-treated PKU and indicate that strategic processing should be evaluated carefully as these children age.

Animated toys versus video reinforcement in 16-24-month-old children in a clinical setting.

PURPOSE: To compare the clinical efficacy of visual reinforcement audiometry (VRA) with animated toy animal reinforcement (AVRA) to the efficacy of VRA with video reinforcement (VVRA) in children age 16 to 24 months in a fast-paced medical practice. METHOD: The 145 participants (age 16 to 24 months) were referred by either their primary care physician or an otolaryngology practitioner (physician or nurse practitioner) for audiologic assessment. Children were assigned in a counterbalanced manner to either the AVRA or VVRA group. RESULTS: Significantly more threshold estimates were obtained with AVRA (M = 5.52) than with VVRA (M = 3.47). There were no significant differences in performance based on age, hearing status, or gender. CONCLUSIONS: Number and relative strength of the visual reinforcers used are posited as the main reasons for the disparate outcomes. Clinical practices that test large numbers of children with VRA would be well-served to have both AVRA and VVRA available to meet the needs of individual patients.