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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: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown., Methods: Adult survivors of childhood medulloblastoma (n=505; median[minimum-maximum] age, 29[18-46] years) and sibling controls (n=727; 32[18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI]≥30 Gy, no chemotherapy), standard-risk (CSI>0 to <30 Gy +chemotherapy) and high-risk (CSI≥30 Gy +chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, marital/partner status. Multivariable models estimated risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence., Results: Survivors in each treatment exposure group had 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval [CI] 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems and seizures were associated with 33%-34%, 25-26% and 21%-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with non-independence., Conclusions: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown., Methods: Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided., Results: Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory., Conclusion: Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: We aimed to characterize premature aging as an accumulation of deficits in survivors of pediatric cancer compared with community controls and examine associations with host and treatment factors, neurocognition, and mortality., Methods: Pediatric cancer survivors (n = 4000, median age = 28.6, interquartile range [IQR] = 23-35 years; 20 years postdiagnosis: IQR = 15-27), and community participants without a history of cancer serving as controls (n = 638, median age = 32, IQR = 25-40 years) completed clinical assessments and questionnaires and were followed for mortality through April 30, 2020 (mean [SD] follow-up = 7.0 [3.4] years). A deficit accumulation index (DAI) score was calculated from 44 aging-related items including self-reported daily function, psychosocial symptoms, and health conditions. Items were weighted from 0 (absent) to 1 (present and/or most severe), summed and divided by the total yielding a ratio (higher = more deficits). Scores less than 0.20 are robust, and 0.06 is a clinically meaningful difference. Linear regression compared the DAI in survivors and controls with an age*survivor or control interaction. Logistic regression and Cox-proportional hazards estimated the risk of neurocognitive impairment and death. Models were minimally adjusted for age, sex, and race and ethnicity., Results: The adjusted mean DAI among survivors at age 30 years was 0.16 corresponding to age 63 years in controls (33 years premature aging; β = 0.07, 95% confidence interval [CI] = 0.06 to 0.08; P < .001). Cranial and abdominal radiation, alkylators, platinum, and neurosurgery were associated with worse DAI (P ≤ .001). Higher scores were associated with increased risk of neurocognitive impairment in all domains (P < .001) and increased risk of death (DAI = 0.20-0.35, hazard ratio = 2.80, 95% CI = 1.97 to 3.98; DAI ≥ 0.35, hazard ratio = 5.08, 95% CI = 3.52 to 7.34)., Conclusion: Pediatric cancer survivors experience clinically significant premature aging. The DAI may be used to identify survivors at greatest risk of poor health outcomes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This study estimates the prevalence and identifies predictors of psychoactive medication use in adolescent survivors of childhood cancer (aged 12-18 years) and its associations with functional outcomes at young adulthood (aged 18-28 years)., Methods: This retrospective cohort study includes 5665 adolescent survivors of childhood cancer at no less than 5 years postdiagnosis (53.8% male, median age = 15 years, interquartile range [IQR] = 13-16 years) and 921 adolescent sibling controls. Parent-reported psychoactive medication use during adolescence was collected at baseline. After a median of 8 years, functional outcomes and social attainment were self-reported during adulthood (n = 3114, median age = 22 years, IQR = 20-24 years). Multivariable log-binomial models evaluated associations among risk factors, medication use, and adult outcomes., Results: Higher prevalence of psychoactive medication use was reported in survivors compared with siblings (18.3% vs 6.6%; 2-sided P < .001), with trends for increasing antidepressant and stimulant use in recent treatment eras. After adjusting for cancer treatment and baseline cognitive problems, psychoactive medication use during adolescence was associated with impaired task efficiency (relative risk [RR] = 1.20, 95% confidence interval [CI] = 1.01 to 1.43) and memory (RR = 1.27, 95% CI = 1.05 to 1.52) during adulthood. Survivors who reported continued use of medications from adolescence to adulthood demonstrated poorer emotional regulation (RR = 1.68, 95% CI = 1.24 to 2.27) and organization (RR = 1.82, 95% CI = 1.28 to 2.59) compared with nonusers. Adolescent opioid use was associated with somatization symptoms (RR = 1.72, 95% CI = 1.09 to 2.73) during adulthood, after adjusting for cancer treatment and baseline behavioral problems. They were also more likely to not complete college (RR = 1.21, 95% CI = 1.04 to 1.41) or work full-time (RR = 1.60, 95% CI = 1.23 to 2.08) compared with nonusers., Conclusion: Use of psychoactive medication is more prevalent among adolescent survivors compared with siblings and does not normalize adult outcomes, as evidenced by poorer functional outcomes during young adulthood., (© The Author(s) 2020. Published by Oxford University Press.)

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 β = -0.34, P  = .04, females β = -0.57, P  < .001; long-term memory: males β = -0.60, P  < .001, females β = -0.36, P  = .02; sustained attention: males β = -0.85, P  < .001, females β = -0.42, P  = .006; cognitive flexibility: males β = -0.70, P  =   .002, females β = -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., (© The Author(s) 2020. Published by Oxford University Press.)

Background: Financial hardship among survivors of pediatric cancer has been understudied. We investigated determinants and consequences of financial hardship among adult survivors of childhood cancer., Methods: Financial hardship, determinants, and consequences were examined in 2811 long-term survivors (mean age at evaluation = 31.8 years, years postdiagnosis = 23.6) through the baseline survey and clinical evaluation. Financial hardship was measured by material, psychological, and coping/behavioral domains. Outcomes included health and life insurance affordability, retirement planning, symptoms, and health-related quality of life (HRQOL). Odds ratios (ORs) estimated associations of determinants with financial hardship. Odds ratios and regression coefficients estimated associations of hardship with symptom prevalence and HRQOL, respectively. All statistical tests were two-sided., Results: Among participants, 22.4% (95% confidence interval [CI] = 20.8% to 24.0%), 51.1% (95% CI = 49.2% to 52.9%), and 33.0% (95% CI = 31.1% to 34.6%) reported material, psychological, and coping/behavioral hardship, respectively. Risk factors across hardship domains included annual household income of $39 999 or less vs $80 000 or more (material OR = 3.04, 95% CI = 2.08 to 4.46, psychological OR = 3.64, 95% CI = 2.76 to 4.80, and coping/behavioral OR = 4.95, 95% CI = 3.57 to 6.86) and below high school attainment vs college graduate or above (material OR = 2.22, 95% CI = 1.45 to 3.42, psychological OR = 1.75, 95% CI = 1.18 to 2.62, and coping/behavioral OR = 2.05, 95% CI = 1.38 to 3.06). Myocardial infarction, peripheral neuropathy, subsequent neoplasm, seizure, stroke, reproductive disorders, amputation, and upper gastrointestinal disease were associated with higher material hardship (all P < .05). Hardship across three domains was associated with somatization, anxiety and depression (all P < .001), suicidal ideation (all P < .05), and difficulty in retirement planning (all P < .001). Survivors with hardship had statistically significantly lower HRQOL (all P < .001), sensation abnormality (all P < .001), and pulmonary (all P < .05) and cardiac (all P < .05) symptoms., Conclusions: A substantial proportion of adult survivors of childhood cancer experienced financial hardship. Vulnerable sociodemographic status and late effects were associated with hardship. Survivors with financial hardship had an increased risk of symptom prevalence and impaired HRQOL., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Neurocognitive impairment in survivors of childhood cancer may be associated with direct neurotoxicity, as well as indirect effects of systemic health complications. We evaluated associations among treatment exposures, chronic health conditions, and neurocognitive outcomes in adult survivors of childhood cancer., Methods: Participants included 5507 adult survivors of childhood cancer (47.1% male; mean [SD] age = 31.8 [7.6] years at evaluation; 23.1 [4.5] years postdiagnosis) in the Childhood Cancer Survivor Study who completed a self-report measure of neurocognitive function. Cardiac, pulmonary, and endocrine chronic health conditions were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Structural equation modeling was used to examine a priori hypothesized causal pathways among cancer treatment, subsequent chronic health conditions, and neurocognitive outcomes. Multivariable models were used to estimate relative risk for associations of treatments and chronic conditions on neurocognitive function. All statistical tests were two-sided., Results: One-third of survivors with a grade 2 or higher chronic condition reported impairments in task efficiency and memory. In addition to direct effects of cranial radiation, path analyses and multivariable models demonstrated direct effects of cardiopulmonary (β = 0.10, P = .002; relative risk [RR] = 1.27, 95% confidence interval [CI] = 1.12 to 1.44) and endocrine (β = 0.07, P = .04; RR = 1.14, 95% CI = 1.02 to 1.28) conditions on impaired task efficiency. We identified similar effects of cardiopulmonary condition on memory (P = .01) and emotional regulation (P = .01). Thoracic radiation was associated with impaired task efficiency (P = .01) and emotional regulation (P = .01) through endocrine morbidity., Conclusions: Non-neurotoxic exposures, such as thoracic radiation, can adversely impact survivors' neurocognitive function through chronic conditions. Management of chronic diseases may mitigate neurocognitive outcomes among aging survivors of childhood cancer.

Study Question: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology?, Summary Answer: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology., What Is Known Already: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology., Study Design, Size, Duration: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013., Participants/materials, Setting, Methods: The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI., Main Results and the Role of Chance: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia., Limitations, Reasons for Caution: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia., Wider Implications of the Findings: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL., Study Funding/competing Interest(s): This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Background: Multimodal therapy has improved survival for some childhood CNS tumors. However, whether risk for subsequent neoplasms (SNs) also increases is unknown. We report the cumulative incidence of, and risk factors for, SNs after a childhood primary CNS tumor and determine whether treatment that combines radiation therapy (RT) with chemotherapy increases risk for SNs., Methods: Analyses included 2779 patients with a primary CNS tumor treated at St Jude Children's Research Hospital between 1985 and 2012. Cumulative incidence and standardized incidence ratios (SIRs) were estimated for SNs confirmed by pathology report. Cumulative incidence among the 237 five-year medulloblastoma survivors treated with multimodal therapy (RT + chemotherapy) was compared with a historical cohort of 139 five-year survivors treated with RT but no chemotherapy in the Childhood Cancer Survivor Study., Results: Eighty-one survivors had 97 SNs. The cumulative incidence of first SN was 3.0% (95% CI: 2.3%-3.9%) at 10 years, and 6.0% (95% CI: 4.6%-7.7%) at 20 years from diagnosis. Risks were highest for subsequent glioma, all grades (SIR = 57.2; 95% CI: 36.2-85.8) and acute myeloid leukemia (SIR = 31.8; 95% CI: 10.2-74.1). Compared with RT alone, RT + chemotherapy did not increase risk for SNs (hazard ratio: 0.64; 95% CI: 0.38-1.06). Among five-year survivors of medulloblastoma treated with multimodal therapy, cumulative incidence of SN was 12.0% (95% CI: 6.4%-19.5%) at 20 years, no different than survivors treated with RT alone (11.3%, P = .44)., Conclusion: The cumulative incidence of SNs continues to increase with time from treatment with no obvious plateau, but the risk does not appear to be higher after exposure to multimodal therapy compared with RT alone. Continued follow-up of survivors as they age is essential., (© The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood., Methods: We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score >1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging., Results: Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P < .001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P < .001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P < .001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose-response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT)., Conclusions: Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.

Long-term morbidity for children with low-grade glioma (LGG) requires exposure-specific characterization. Overall survival (OS) and progression-free survival (PFS) were estimated for 361 children diagnosed with LGG between 1985 and 2007 at a single institution. Five-year survivors (n = 240) received risk-based clinical assessment. Cumulative incidence of late effects 15 years from diagnosis were estimated. Risk factors for adverse health were identified using Fine and Gray's approach to Cox's proportional hazards model, accounting for death as a competing risk. OS at 15 years was 86% (95% confidence interval [CI] 82%-90%), and PFS was 55% (95% CI 51%-58%). Among the 240 5-year survivors, the 5-, 10-, and 15-year cumulative incidence of adverse outcomes included blindness: 10%, 13%, and 18%, respectively; hearing loss: 8%, 14%, and 22%; obesity/overweight: 18%, 35%, and 53%; hyperinsulinism: 1%, 5%, and 24%; growth hormone deficiency: 13%, 27%, and 29%;thyroid hormone deficiency: 16%, 28%, and 33%; and adrenocorticotropic hormone (ACTH) deficiency: 12%, 22%, and 26%. Multivariable models demonstrated radiation therapy to be a significant independent predictor of hearing loss, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Diencephalic location was a statistically significant independent risk factor for blindness, growth hormone deficiency, abnormal thyroid function, and ACTH deficiency. Among the 182 5-year survivors assessed for intellectual function, 34% had an intelligence quotient (IQ) below average (<85), associated with younger age at diagnosis, epilepsy, and shunt placement. Survivors of childhood LGG experience substantial long-term adverse effects that continue to increase well beyond the 5-year survival time point.