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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 2958 (74.1%) eligible survivors, who were at least 5 years postdiagnosis and aged older than 18 years, 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 and 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 [CI] = 11.41 to 35.63) including cerebrovascular disease (OR = 14.5, 95% CI = 5.47 to 38.44) and cerebrovascular accident (OR = 14.7, 95% CI = 7.50 to 26.40). Modifiable risk factors, such as quitting smoking, reduced risk for global impairment (OR = 0.21, 95% CI = 0.06 to 0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95% CI = 2.86 to 7.21), attention impairment (OR = 2.01, 95% CI = 1.41 to 2.87), processing speed and executive function impairment (OR = 1.90, 95% CI = 1.46 to 2.48), and memory impairment (OR = 2.09, 95% CI = 1.54 to 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., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Survivors of childhood central nervous system (CNS) tumors can develop motor and sensory impairment from their cancer and treatment history. We estimated the prevalence of motor and sensory impairment in survivors compared with controls through clinical assessment and identified associated treatment exposures and functional, quality of life (QOL), and social outcomes., Methods: Survivors of childhood CNS tumors from the St. Jude Lifetime Cohort (n = 378, median [range] age 24.0 [18.0-53.0] years, 43.4% female) ≥5 years from diagnosis and controls (n = 445, median [range] age 34.0 [18.0-70.0] years, 55.7% female) completed in-person evaluation for motor and sensory impairment using the modified Total Neuropathy Score. Impairment was graded by modified Common Terminology Criteria for Adverse Events. Multivariable models estimated associations between grade ≥2 motor/sensory impairment, individual/treatment characteristics, and secondary outcomes (function by Physical Performance Test, fitness by physiologic cost index, QOL by Medical Outcomes Survey Short Form-36 physical/mental summary scores, social attainment)., Results: Grade ≥2 motor or sensory impairment was more prevalent in survivors (24.1%, 95% Confidence Interval [CI] 19.8%-29.4%) than controls (2.9%, CI 1.4-4.5%). Among survivors, in multivariable models, motor impairment was associated with vinca exposure <15 mg/m 2 versus none (OR 4.38, CI 1.06-18.08) and etoposide exposure >2036 mg/m 2 versus none (OR 12.61, CI 2.19-72.72). Sensory impairment was associated with older age at diagnosis (OR 1.09, CI 1.01-1.16) and craniospinal irradiation versus none (OR 4.39, CI 1.68-11.50). There were lower odds of motor/sensory impairment in survivors treated in the year 2000 or later versus before 1990 (Motor: OR 0.29, CI 0.10-0.84, Sensory: OR 0.35, CI 0.13-0.96). Motor impairment was associated with impaired physical QOL (OR 2.64, CI 1.22-5.72)., Conclusions: In survivors of childhood CNS tumors, motor and sensory impairment is prevalent by clinical assessment, especially after exposure to etoposide, vinca, or craniospinal radiation. Treating motor impairment may improve survivors' QOL., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Hodgkin lymphoma (HL) survivors experience neurocognitive impairment despite receiving no central nervous system-directed therapy, though little is known about the underlying mechanisms., Experimental Design: HL survivors (n = 197) and age-, sex- and race/ethnicity frequency-matched community controls (n = 199) underwent standardized neurocognitive testing, and serum collection. Luminex multiplex or ELISA assays measured markers of inflammation and oxidative stress. Linear regression models compared biomarker concentrations between survivors and controls and with neurocognitive outcomes, adjusting for age, sex, race, body mass index, anti-inflammatory medication, and recent infections., Results: HL survivors [mean (SD) current age 36 (8) years, 22 (8) years after diagnosis] demonstrated higher concentrations of interleukin-6 (IL6), high-sensitivity c-reactive protein (hs-CRP), oxidized low-density lipoprotein, and glutathione peroxidase (GPx), compared with controls (P's < 0.001). Among survivors, higher concentrations of IL6 were associated with worse visuomotor processing speed (P = 0.046). hs-CRP ≥3 mg/L was associated with worse attention, processing speed, memory, and executive function (P's < 0.05). Higher concentrations of malondialdehyde were associated with worse focused attention and visual processing speed (P's < 0.05). Homocysteine was associated with worse short-term recall (P = 0.008). None of these associations were statistically significant among controls. Among survivors, hs-CRP partially mediated associations between cardiovascular or endocrine conditions and visual processing speed, whereas IL6 partially mediated associations between pulmonary conditions and visuomotor processing speed., Conclusions: Neurocognitive function in long-term survivors of HL appears to be associated with inflammation and oxidative stress, both representing potential targets for future intervention trials., (©2024 American Association for Cancer Research.)

Importance: Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood., Objective: To determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments., Design, Setting, and Participants: Participants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was available. This study examined the prevalence of new-onset neurocognitive impairment between baseline (23.4 years after diagnosis) and follow-up (35.0 years after diagnosis). The analysis was performed from January 2021 to May 2022., Exposures: Cancer treatment exposures were abstracted from medical records. Chronic health conditions were graded using Common Terminology Criteria for Adverse Events version 4.03., Main Outcomes and Measures: The primary outcome was new-onset (present at follow-up, but not present at baseline) neurocognitive impairment (defined as a score in the worst 10% of the sibling cohort). Impairment was assessed using the Childhood Cancer Survivor Study Neurocognitive questionnaire. Relative risks (RRs) and 95% CIs were used to estimate associations of neurocognitive impairment with treatment and health behaviors and conditions using generalized linear models., Results: The cohort comprised 2375 survivors (mean [SD] age at evaluation, 31.8 [7.5] years; 1298 women [54.6%]) of childhood cancer, including acute lymphoblastic leukemia (ALL; 1316 participants), central nervous system (CNS) tumors (488 participants), and Hodgkin lymphoma (HL; 571 participants). A total of 232 siblings (mean [SD] age at evaluation, 34.2 [8.4] years; 134 women [57.8%]) were included. Compared with siblings, a higher proportion of survivors with no impairment in memory at baseline had new-onset memory impairment at follow-up: siblings proportion, 7.8% (95% CI, 4.3%-11.4%); ALL survivors treated with chemotherapy only, 14.0% (95% CI, 10.7%-17.4%); ALL survivors treated with cranial radiation (CRT), 25.8% (95% CI, 22.6%-29.0%); CNS tumor survivors, 34.7% (95% CI, 30.0%-39.5%); and HL survivors, 16.6% (95% CI, 13.4%-19.8%). New-onset memory impairment was associated with CRT in CNS tumor survivors (RR, 1.97; 95% CI, 1.33-2.90) and alkylator chemotherapy greater than or equal to 8000 mg/m2 in ALL survivors treated without CRT (RR, 2.80; 95% CI, 1.28-6.12). Neurologic conditions mediated the impact of CRT on new-onset memory impairment in CNS survivors. Smoking, low educational attainment, and low physical activity were associated with elevated risk for new-onset memory impairment., Conclusions and Relevance: These findings suggest that adult survivors of childhood cancer are at elevated risk for late-onset memory impairment related to modifiable risk factors identified early in survivorship.

Background: The objective of this study was to determine the impact of seizure-related factors on neurocognitive, health-related quality of life (HRQOL), and social outcomes in survivors of childhood cancer., Methods: Survivors of childhood cancer treated at St. Jude Children's Hospital (n = 2022; 48.3% female; median age, 31.5 years; median time since diagnosis, 23.6 years) completed neurocognitive testing and questionnaires. The presence, severity, resolution, and treatment history of seizures were abstracted from medical records. Adjusting for the age at diagnosis, sex, and prior cancer therapy, multivariable models examined the impact of seizures on neurocognitive and HRQOL outcomes. Mediation analyses were conducted for social outcomes., Results: Seizures were identified in 232 survivors (11.5%; 29.9% of survivors with central nervous system [CNS] tumors and 9.0% of those without CNS tumors). In CNS tumor survivors, seizures were associated with poorer executive function and processing speed (P < .02); in non-CNS tumor survivors, seizures were associated with worse function in every domain (P < .05). Among non-CNS survivors, seizure severity was associated with worse processing speed (P = .023), and resolution was associated with better executive function (P = .028) and attention (P = .044). In CNS survivors, seizure resolution was associated with improved attention (P = .047) and memory (P < .02). Mediation analysis revealed that the impact of seizures on social outcomes was mediated by neurocognitive function., Conclusions: Seizures in cancer survivors adversely affect long-term functional and psychosocial outcomes independently of cancer therapy. The resolution of seizure occurrence is associated with better outcomes. Seizure severity is associated with poorer outcomes and should be a focus of clinical management and patient education., (© 2021 American Cancer Society.)

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. β 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: β = 55.54; SE = 25.55; P = .03; right cerebellum: β = 52.57; SE = 25.50; P = .04) and poorer dominant-hand motor processing speed (ie, grooved pegboard performance) (left cerebellum: β = 82.71; SE = 31.04; P = .009; right cerebellum: β = 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 (β = -0.154; SE = 0.063; P = .02), as was increased dexamethasone exposure (β = -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.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences., (© 2019 Wiley Periodicals, Inc.)

Background: Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for both treatment-related exercise intolerance and neurocognitive deficits. This analysis aimed to identify the association between exercise intolerance and neurocognitive impairments in ALL survivors., Methods: Cardiopulmonary exercise testing, results from a 2-hour standardized neuropsychological assessment, and self-report questionnaires were obtained for 341 adult survivors of childhood ALL and 288 controls. Multivariable modeling was used to test associations between oxygen uptake at 85% estimated heart rate (rpkVO 2 ) and neuropsychological test and self-reported questionnaire domains, adjusted for sex, age at diagnosis, cranial radiation, anthracycline, and methotrexate exposure and tobacco smoking status., Results: Compared with controls, survivors had worse rpkVO 2 and performance on verbal intelligence, focused attention, verbal fluency, working memory, dominant/nondominant motor speed, visual-motor speed, memory span, and reading and math measures (all P < .001). In adjusted models, exercise intolerance was associated with decreases in performance of verbal ability, focused attention, verbal fluency, working memory, dominant motor speed, nondominant motor speed, visual-motor speed, memory span, reading academics, and math academics in survivors., Conclusion: This study demonstrates an association between exercise intolerance and neurocognitive outcomes. Research is needed to determine whether interventions that improve exercise tolerance impact neurocognitive function in ALL survivors., (© 2019 American Cancer Society.)

Cranial radiation therapy is associated with white matter-specific brain injury, cortical volume loss, mineralization, microangiopathy and neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia. In this retrospective cross-sectional analysis, neurocognitive testing and 3 T brain MRI's were obtained in 101 survivors treated with cranial radiation. Small focal intracerebral hemorrhages only visible on exquisitely sensitive MRI sequences were identified and localized using susceptibility weighted imaging. Modified Poisson regression was used to assess the effect of cranial radiation on cumulative number and location of microbleeds in each brain region, and multiple linear regression was used to evaluate microbleeds on neurocognitive outcomes, adjusting for age at diagnosis and sex. At least one microbleed was present in 85% of survivors, occurring more frequently in frontal lobes. Radiation dose of 24 Gy conveyed a 5-fold greater risk (95% CI 2.57-10.32) of having multiple microbleeds compared to a dose of 18 Gy. No significant difference was found in neurocognitive scores with either the absence or presence of microbleeds or their location. Greater prevalence of microbleeds in our study compared to prior reports is likely related to longer time since treatment, better sensitivity of SWI for detection of microbleeds and the use of a 3 T MRI platform.

Background: The impact of growth hormone deficiency (GHD) on neurocognitive function is poorly understood in survivors of childhood acute lymphoblastic leukemia (ALL). This study examined the contribution of GHD to functional outcomes while adjusting for cranial radiation therapy (CRT)., Methods: Adult survivors of ALL (N = 571; 49% female; mean age, 37.4 years; age range, 19.4-62.2 years) completed neurocognitive tests and self-reported neurocognitive symptoms, emotional distress, and quality of life. GHD was defined as a previous diagnosis of GHD or a plasma insulin-like growth factor1 level less than -2.0 standard deviations for sex and age at the time of neurocognitive testing. Hypothyroidism, hypogonadism, sex, age at diagnosis, CRT dose, and intrathecal and high-dose intravenous methotrexate were included as covariates in multivariable linear regression models., Results: Of the 571 survivors, 298 (52%) had GHD, and those with GHD received higher doses of CRT (P = .002). Survivors who had GHD, irrespective of prior growth hormone treatment, demonstrated poorer vocabulary (z-score, -0.84 vs -0.61; P = .02), processing speed (z-score, -0.49 vs -0.30; P = .04), cognitive flexibility (z-score, -1.37 vs -0.94; P = .01), and verbal fluency (z-score, -0.74 vs -0.44; P = .001), and they self-reported more neurocognitive problems and poorer quality of life compared with survivors who did not have GHD. Multivariable and mediation models revealed that GHD was associated with small effects on quality of life (general health, P = .01; vitality, P = .01; mental health, P = .01); and CRT dose accounted for the lower neurocognitive outcomes., Conclusions: Adult survivors of childhood ALL who receive CRT are at risk for GHD, although poor neurocognitive outcomes are determined by CRT dose and not by the presence of GHD., (© 2019 American Cancer Society.)

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.