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 ALL (N=70, 50% males, mean[SD] age 14.3[4.7] years; 7.4[1.9] years post-diagnosis) completed neurocognitive testing, behavioral ratings, and reported sleep quality and fatigue symptoms at ≥5 years post-diagnosis. Serum was collected concurrently and assayed for interleukin 1-Beta and 6 (IL-1β, IL-6), tumor necrosis factor alpha (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’s<0.05 adjusted for multiple comparison). In female survivors, fatigue was associated with poor executive function (r=0.41; P=0.02), processing speed (r=0.56; P<0.001) and attention (r=0.36 to 0.55; P’s<0.05). Female survivors with frequent nighttime awakening displayed more inattention (P=0.01), hyperactivity (P=0.03), and aggression (P=0.01). Worse executive function, processing speed and behavioral symptoms were observed in female survivors with higher IL-6, IL-1β and hsCRP (P’s<0.05). Male survivors with high TNF-α demonstrated worse organization (P=0.03), but no significant associations between neurocognitive outcomes and sleep/fatigue measures were observed. Conclusion Neurocognitive function in female survivors appears more susceptible to the effects of sleep disturbance and fatigue. Systemic inflammation may play a role in neurocognitive impairment and behavioral symptoms.

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.

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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-oflife/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. Cancer 2021;127:35-44.

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 β 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 (β = −0.14 z scores; P = .04), reading (β = −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: β = −0.63 z score [P = 0.02]; and hearing impairment: β = −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.