Neurocognitive Outcomes In Survivors Research Articles

The association of environmental factors with neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia (ALL).

To investigate the association of environmental factors, rehabilitation services during therapy and socioeconomic status (SES - insurance type), with neurocognitive outcomes at the end of therapy for survivors of childhood acute lymphoblastic leukemia (ALL). Survivors (n = 236) treated on the St. Jude Total Therapy Study 16 completed end of therapy testing with performance measures (IQ, attention, processing speed, fine motor skills, academics) and caregiver ratings (attention, executive function, adaptive skills). Environmental factors were abstracted from the medical record. Distribution of sex (47.3% female, p = 0.399), treatment arm (45.5% low risk, 54.5% standard/high risk p = 0.929), insurance type (47.7% private, 52.3% public/none, p = 0.117), and mean age at diagnosis (7.7 vs. 6.8years, p = 0.143) were similar for groups with (n = 110; 46.6%) and without (n = 126; 53.6%) rehabilitation services during therapy. Compared to those without rehabilitation, the rehabilitation group (n = 110; 46.4%) had more caregiver reported problems with attention (Z = -0.28 vs. 0.43, p = 0.022), executive function (Z = -0.50 vs. -0.08, p = 0.003), and adaptive skills (Z = -0.41 vs.-0.13, p = 0.031). Among the rehabilitation group, there was no difference in outcomes by insurance status. Among those without rehabilitation, those with public insurance had worse neurocognitive outcomes than those with private insurance in IQ (Z = -0.04 vs. -0.45, p = 0.0115), processing speed (Z = -0.10 vs. -0.75, p = 0.0030), reading (Z = 0.18 vs. -0.59, p < 0.0001), and math (Z = -0.04 vs. -0.50, p = 0.0021). Participation in rehabilitation services during early intensive therapy is associated with end of therapy caregiver-reported neurocognitive outcomes in daily life.

Improved Neurocognitive Outcomes with Contemporary Treatments in Survivors of Early Adolescent and Young Adult Hematologic Malignancies from the Childhood Cancer Survivor Study

Background: Neurocognitive impairments in survivors of hematologic malignancies diagnosed specifically during adolescence and early young adulthood (eAYA survivors) are not well described, despite use of intensive neurotoxic therapies. We evaluated how recent shifts in therapeutic approaches have impacted neurocognitive outcomes in survivors diagnosed during eAYA compared to younger survivors and sibling controls. Methods: We identified 1213 eAYA (diagnosed at 15-21 years) and 4538 pediatric (diagnosed at &amp;lt;15 years) survivors of acute lymphoblastic lymphoma (ALL; n= 301 v. 3274), acute myeloid leukemia (AML; n= 77 v. 424), and Hodgkin lymphoma (HL; n= 835 v. 840) as well as 1014 siblings from the Childhood Cancer Survivor Study (&amp;gt;5 year survivors diagnosed 1970-1999) who completed the Neurocognitive Questionnaire ( Table 1). Impairment was defined as a score in worst 10% of the sibling cohort in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. Survivors were stratified into groups reflective of diagnosis, treatment era, and intensity: HL-chest RT ≥35Gy = HL with chest radiation ≥35Gy (High-risk disease, older regimens); HL-chest RT &amp;lt;35Gy = HL with chest radiation &amp;lt;35Gy (Intermediate risk disease, contemporary regimens); HL-salvage = HL with salvage therapy (High-risk disease, higher intensity regimens), ALL-CRT = ALL with use of cranial radiation (CRT) (Older regimens), ALL-no CRT = ALL without use of CRT (Contemporary regimens), ALL-salvage = ALL with salvage therapy (High-risk disease, higher intensity regimens), AML-chemo = AML with chemotherapy only (Lower risk disease), AML-SCT = AML with history of stem cell transplant (Higher risk disease). The prevalence of neurocognitive impairment compared to siblings was estimated using generalized-estimating-equation logistic regression accounting for potential within-family correlation. Health status and health behaviors were examined as risk factors for neurocognitive impairment. Adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI) are reported. Results: Prevalence of any neurocognitive impairment in the eAYA, pediatric, and sibling groups was 30.8%, 37.7%, and 25.4%, respectively. Prevalence was similar for eAYAs and pediatric survivors of HL (31.0% v. 29.6%, p=0.54) and AML (36.4% v. 40.6%, p=0.49), while lower in eAYA ALL survivors (28.2% v. 38.7%, p&amp;lt;0.01). Compared to siblings, eAYA HL survivors who received salvage therapy were more likely to have impaired Org (OR 2.5, 95% CI 1.2-5.1) and Mem (OR 2.7, 95% CI 1.3-5.8), while those who received high-dose chest RT experienced more Mem impairment (OR 2.0, 95% CI 1.2-3.4) ( Table 2). Compared to siblings, Mem was the most commonly affected domain in eAYA ALL survivors who received CRT (OR 4.0, 95% CI 2.0-7.9); this was not observed in the non-CRT or salvage groups. In a separate analysis of treatment exposures, anthracycline ≥120mg/m 2 uniquely increased prevalence of ER in eAYA ALL survivors (OR 4.7, 95% CI 1.7-12.9). Compared to siblings, survivors of eAYA AML who underwent SCT had higher odds of Mem impairment (OR 5.3, 95% CI 1.9-14.7). In a direct comparison with pediatric AML survivors, eAYA AML survivors were also more likely to have impaired Mem (OR 2.6, 95% CI 1.1-6.2) (data not shown). Being physically active (OR range 0.3-0.7), a never-smoker (OR range 0.5-0.6), and insured (OR range 0.4-0.5) were protective across all domains in eAYA-cancer survivors. Conclusions: Survivors of hematologic cancers diagnosed during eAYA are susceptible to neurocognitive impairment at rates similar to those diagnosed at younger ages for HL and AML but at reduced rates for survivors of ALL. Memory was the most affected domain in eAYA survivors. Contemporary regimens utilizing intermediate-dose (&amp;lt;35Gy) chest RT for HL or omission of cranial RT for ALL attenuated the extent of risk. Future studies should focus on characterizing outcomes across the entire AYA age spectrum.

Genetic predictors of neurocognitive outcomes in survivors of pediatric brain tumors

BackgroundNeurocognitive deficits are common in pediatric brain tumor survivors. The use of single nucleotide polymorphism (SNP) analysis in DNA repair genes may identify children treated with radiation therapy for brain tumors at increased risk for treatment toxicity and adverse neurocognitive outcomes.MaterialsThe Human 660W-Quad v1.0 DNA BeadChip analysis (Illumina) was used to evaluate 1048 SNPs from 59 DNA repair genes in 46 subjects. IQ testing was measured by the Wechsler Intelligence Scale for Children. Linear regression was used to identify the 10 SNPs with the strongest association with IQ scores while adjusting for radiation type.ResultsThe low vs high IQ patient cohorts were well matched for time from first treatment to most recent IQ, first treatment age, sex, and treatments received. 5 SNPs on 3 different genes (CYP29, XRCC1, and BRCA1) and on 3 different chromosomes (10, 19, and 17) had the strongest association with most recent IQ score that was not modified by radiation type. Furthermore, 5 SNPs on 4 different genes (WRN, NR3C1, ERCC4, RAD51L1) on 4 different chromosomes (8, 5, 16, 14) had the strongest association with change in IQ independent of radiation type, first IQ, and years between IQ measures.ConclusionsSNPs offer the potential to predict adverse neurocognitive outcomes in pediatric brain tumor survivors. Our results require validation in a larger patient cohort. Improving the ability to identify children at risk of treatment related neurocognitive deficits could allow for better treatment stratification and early cognitive interventions.

The Impact of Intensified CNS-Directed Therapy on Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia Treated Without Cranial Irradiation.

Findings from St Jude Total Therapy Study 16 (Total 16) showed early intensification of triple intrathecal therapy (ITT) improved CNS disease control for children with newly diagnosed acute lymphoblastic leukemia (ALL) at the greatest risk of CNS relapse. We examined the impact of this treatment on end-of-therapy neurocognitive outcomes. Between 2007 and 2017, 400 (83.5%) of 479 eligible patients treated with Total 16 risk-directed chemotherapy completed protocol-directed neurocognitive testing at the end of therapy. Intensified ITT was defined as ≥ 21 cumulative doses for patients with low-risk ALL (n = 70/194) and ≥ 27 doses for those with standard-to-high risk ALL (n = 81/206). Compared with age-normative expectations, the overall group had significantly lower estimated intelligence quotient (P < .0001), attention (P = .0051), working memory (P = .0001), processing speed (P = .0002), fine motor speed (P = .0001), and math (P = .0087). Caregiver ratings of patient functioning showed elevated risk for problems in attention (P = .0173), executive function (P = .0001), and adaptive skills (P = .0001). Among the low-risk treatment group, there were no significant differences between patients treated with or without intensified ITT (all P's >.10). Among patients with standard-to-high risk ALL, those treated with intensified ITT had poorer working memory (P = .0328) and fine motor speed (P = .0403), and elevated ratings of inattention (P = .0189) and executive dysfunction (P = .0245). In the standard-to-high risk group, females treated with intensified ITT had lower working memory scores. Public insurance status was associated with worse neurocognitive outcomes in both treatment groups. Standard-to-high risk patients treated with intensified ITT are at moderately increased risk for neurocognitive problems. The findings suggest a threshold effect for ITT exposure, which can inform the design of future clinical trials and approaches to neurocognitive monitoring and intervention.

Neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia: Experience from a tertiary care center in India.

Data of neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL) is scarce from low middle-income countries (LMICs), and is influenced by biological and cultural variations. The objective of this study was to assess the prevalence and spectrum of neurocognitive deficits in a cohort of survivors from India. Seventy survivors of childhood ALL were evaluated for neurocognitive deficits by the Indian adaptation of Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IVINDIA ). The prevalence of neurocognitive deficits was calculated based on the full-scale intelligence quotient (FSIQ), and scores in discrete domains like verbal comprehension, perceptual reasoning, working memory, and processing speed were calculated and compared to demographics, treatment, and sociocultural factors. The mean (SD) current age and time since diagnosis was 10.5 (±3.2) years and 5 (±2.8) years, respectively. The mean FSIQ was 86.1 ± 20.5, with significant neurocognitive deficit (FSIQ <90) being prevalent in 50% (95% CI: 38%-62%) of the cohort. The proportion of survivors with deficits in individual domains of verbal comprehension, perceptual reasoning, working memory, and processing speed were 49%, 50%, 47%, and 44%, respectively. The odds of having neurocognitive deficits were higher when a child belonged to lower socioeconomic strata (OR 5.7, p=.004), parents with lower education attainment (OR 4.3, p=.041), and whose birth order was higher (OR 20.1, p=.005). Age at diagnosis/assessment, chemotherapy received, or dose of radiotherapy did not have a direct impact on neurocognition. Rates of neurocognitive deficits are higher in survivors in LMICs, with socioeconomic variables contributing more than the direct neurotoxic effects of treatment.

Routine Neuroimaging: Understanding Brain Injury in Pediatric Extracorporeal Membrane Oxygenation.

This project aims to describe brain injuries on routine neuroimaging in a large single-center neonatal and pediatric cohort supported by extracorporeal membrane oxygenation. The study also aims to examine the association of these injuries with neurocognitive outcomes in survivors and identify laboratory findings associated with neurologic injury. Retrospective observational single-center cohort study. Tertiary care PICU. Pediatric patients with noncardiac indications for extracorporeal membrane oxygenation supported by venoarterial or venovenous extracorporeal membrane oxygenation, with on-extracorporeal membrane oxygenation brain CT or postextracorporeal membrane oxygenation brain CT/MRI. Extracorporeal membrane oxygenation support. Occurrence of brain injury on CT and MRI was reviewed; injuries were scored. Clinical and laboratory results associated with injury were identified. Survivor neurocognitive outcomes were obtained using the Pediatric Overall Performance Category scale and Pediatric Cerebral Performance Category scale. Of 132 imaged patients, 98 (74%) had radiological evidence of brain injury. Mean injury score was 6.5 (± 3.8). Head ultrasounds and clinician suspicion performed poorly in suspecting the presence of injury. Of 104 respondents to neurodevelopmental assessments, 61 (59%) had normal scores; 12.5%, 17%, and 11.5% had mild, moderate, or severe disability. A neuroimaging score greater than 10 was associated with an unfavorable outcome on the Pediatric Cerebral Performance Category (odds ratio, 3.4; p < 0.01) and Pediatric Overall Performance Category (odds ratio, 1.7; p < 0.05). Ischemic injury correlated with worse neurodevelopmental outcome. Preextracorporeal membrane oxygenation lactate, Vasoactive-Inotropic Scores, transaminitis, elevated bilirubin and creatinine levels, and thrombocytopenia were associated with injury occurrence. Brain injury is frequent in extracorporeal membrane oxygenation patients, although the majority of survivors have favorable neurocognitive outcomes. More research is needed in order to understand the etiology of such injuries. Head ultrasound and clinician suspicion are not sensitive in detecting extracorporeal membrane oxygenation-related brain injuries. Protocolizing postextracorporeal membrane oxygenation imaging with brain MRI allows the identification of injuries and provision of timely neurocognitive intervention.

Neurocognitive outcomes in survivors of early adolescent and young adult (eAYA) hematologic cancers from the Childhood Cancer Survivor Study (CCSS).

10029 Background: Neurocognitive impairment in eAYA hematologic cancer survivors has not been well described, despite intensive neurotoxic therapies. We examined prevalence and risk for such impairment in hematologic cancer survivors diagnosed during eAYA compared to a younger age. Methods: We identified 1,213 eAYA (diagnosed at 15-21 years; median [range] follow-up age 40 [30-54]) and 4,538 childhood (diagnosed at &lt;15 years; median age 30 [17-48]) survivors of ALL (n= 301 vs 3274), AML (n= 77 vs 424), and Hodgkin lymphoma (HL; n= 835 vs 840) from the CCSS (diagnosed 1970-1999) who completed the Neurocognitive Questionnaire. Impairment was defined as a score &gt;90% of normative data in task efficiency (TE), organization (Org), memory (Mem), and emotional regulation (ER) domains. 1,014 age-matched siblings were controls. Treatment by diagnosis group, chronic health conditions, health status and health behaviors were examined as risk factors for neurocognitive impairment using multivariable logistic regression. Adjusted odds ratios (ORs) and corresponding 95% CI are reported. Results: Prevalence of neurocognitive impairment (≥1 impaired domain) was similar for eAYAs and childhood survivors of HL (31.0% vs 29.6%, p=0.54) and AML (36.4% vs 40.3%, p=0.51), although eAYA AML survivors were more likely to have impaired Mem (OR=2.3, 95% CI 1.0-5.4). eAYA ALL survivors were less likely to have neurocognitive impairment than childhood ALL survivors (28.2% vs 38.5%, p&lt;.001) due to lower risk for impaired TE (OR=0.7, 95% CI 0.4-1.0) and Org (OR=0.5, 95% CI 0.4-0.9). No factors, including cranial radiation (RT), explained the rate differences. Treatment by diagnosis group (including cranial RT in ALL, chest RT in HL, and salvage therapy use) was not consistently associated with neurocognitive impairment in eAYA survivors. However, anthracycline dose ≥120mg/m2 was a risk factor for impaired ER (OR=6.0, 95% CI 2.0-17.9) only in eAYA ALL survivors. Presence of a neurologic health condition was associated with impairment in all 4 domains in eAYA (ORs ranged 1.7-2.9) and childhood cancer survivors (ORs ranged 1.9-5.3). eAYA survivors with a respiratory condition were more likely to have impaired TE (OR=2.1, 95% CI 1.2-3.8). Being in good general health was associated with less impairment across all 4 domains for eAYA (ORs ranged 0.2-0.4) and childhood survivors (ORs ranged 0.3-0.5). eAYA survivors who never smoked were less likely to have impaired ER (OR=0.4, 95% CI 0.2-0.6) than those who smoke. Conclusions: Survivors of hematologic cancers diagnosed during eAYA are susceptible to neurocognitive impairment at rates similar to those diagnosed at younger ages. Having comorbidities and being in fair/poor general health are risk factors for impairment. Higher anthracycline exposure in ALL survivors diagnosed during eAYA was the only therapy associated with impairment rates.

Association of Hearing Impairment With Neurocognition in Survivors of Childhood Cancer

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. To assess the association of HI with neurocognitive function and the factors in HI that mediate neurocognitive outcomes in survivors of childhood cancer. 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. 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. 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. 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.

Anesthesia Exposure during Therapy Predicts Neurocognitive Outcomes in Survivors of Childhood Medulloblastoma

To examine the contribution of anesthesia exposure during treatment for childhood medulloblastoma to neurocognitive outcomes 3years after tumor diagnosis. In this retrospective study, anesthesia data were abstracted from medical records for 111 patients treated with risk-adapted protocol therapy at St Jude Children's Research Hospital. Neurocognitive testing data were obtained for 90.9% of patients. For the 101 patients (62.4% male) who completed testing, mean age at diagnosis was 10.1years, and 74.3% were staged to have average-risk disease. Anesthesia exposure during treatment ranged from 1 to 52 events (mean=19.9); mean cumulative duration per patient was 21.1hours (range 0.7-59.7). Compared with normative expectations (16%), the group had a significantly greater frequency of at-risk scores (<1 SD) on measures of intelligence (28.7%), attention (35.2%), working memory (26.6%), processing speed (46.7%), and reading (25.8%). Including anesthesia exposure duration to linear regression models accounting for age at diagnosis, treatment intensity, and baseline IQ significantly increased the predicted variance for intelligence (r2=0.59), attention (r2=0.29), working memory (r2=0.31), processing speed (r2=0.44), and reading (r2=0.25; all P values <.001). In survivors of childhood medulloblastoma, a neurodevelopmentally vulnerable population, greater exposure to anesthesia significantly and independently predicts deficits in neurocognitive and academic functioning. When feasible, anesthesia exposure during treatment should be reduced.

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

To the authors' knowledge, few studies to date have examined long-term neurocognitive outcomes in survivors of childhood soft-tissue sarcoma. A total of 150 survivors (41% of whom were female with a mean current age of 33years [SD, 8.9years] and a time since diagnosis of 24years [SD, 8.7years]) and 349 community controls (56% of whom were female with a mean current age of 35years [SD, 10.2years]) 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). 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 100mg/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. Long-term survivors of soft-tissue sarcoma are at risk of neurocognitive problems and poor HRQOL associated with anthracycline treatment and chronic health conditions.

Dexamethasone and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia

Dexamethasone and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia

Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma

Host genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology, are limited. Here, we evaluated variation in host genome of long-term survivors of medulloblastoma and its association with neurocognitive outcome. Whole-genome sequencing was conducted on peripheral blood of long-term survivors of pediatric medulloblastoma who also completed neuropsychological testing. Cognitively impaired and less impaired survivors did not differ in exposure to chemoradiation therapy or age at treatment. Unsupervised consensus clustering yielded two distinct variant clusters that were significantly associated with neurocognitive outcome. Interestingly, 34 of the 36 significant variants were found in noncoding DNA regions with unknown regulatory function. A separate unsupervised cluster analysis of variants within DNA repair genes identified discrete variant groups that were not associated with neurocognitive outcome, suggesting that variations in genes corresponding to a single functional group may be insufficient to predict long-term outcome alone. These findings are supportive of the presence of a genetic diathesis for treatment-related neurocognitive morbidity in medulloblastoma that may be driven by variation in noncoding regulatory elements.

Use of extracorporeal membrane oxygenation and associated outcomes in children hospitalized for sepsis in the United States: A large population-based study.

ObjectiveThe American College of Critical Care Medicine recommends that children with persistent fluid, catecholamine, and hormone-resistant septic shock be considered for extracorporeal membrane oxygenation (ECMO) support. Current national estimates of ECMO use in hospitalized children with sepsis are unknown. We sought to examine the use of ECMO in these children and to examine the overall outcomes such as in-hospital mortality, length of stay (LOS), and hospitalization charges (HC).MethodsA retrospective analysis of the National Inpatient Sample, which approximates a 20% stratified sample of all discharges from United States community hospitals, was performed. All children (≤ 17 years) who were hospitalized for sepsis between 2012 and 2014 were included. The associations between ECMO and outcomes were examined by multivariable linear and logistic regression models.ResultsA total of 62,310 children were included in the study. The mean age was 4.2 years. ECMO was provided to 415 of the children (0.67% of the cohort with sepsis). Comparative outcomes of sepsis in children who received ECMO versus those who did not included in-hospital mortality rate (41% vs 2.8%), mean HC ($749,370 vs $90,568) and mean LOS (28.8 vs 9.1 days). After adjusting for confounding factors, children receiving ECMO had higher odds of mortality (OR 11.15, 95% CI 6.57–18.92, p < 0.001), longer LOS (6.6 days longer, p = 0.0004), and higher HC ($510,523 higher, p < 0.0001).ConclusionsUse of ECMO in children with sepsis is associated with considerable resource utilization but has 59% survival to discharge. Further studies are needed to examine the post discharge and neurocognitive outcomes in survivors.

The Impact of Persistent Leukoencephalopathy on Brain White Matter Microstructure in Long-Term Survivors of Acute Lymphoblastic Leukemia Treated with Chemotherapy Only.

Survivors of acute lymphoblastic leukemia are at risk for neurocognitive deficits and leukoencephalopathy. We performed a longitudinal assessment of leukoencephalopathy and its associations with long-term brain microstructural white matter integrity and neurocognitive outcomes in survivors of childhood acute lymphoblastic leukemia treated on a modern chemotherapy-only protocol. One hundred seventy-three survivors of acute lymphoblastic leukemia (49% female), treated on a chemotherapy-only protocol, underwent brain MR imaging during active therapy and repeat imaging and neurocognitive testing at follow-up (median, 13.5 years of age; interquartile range, 10.7-17.6 years; median time since diagnosis, 7.5 years; interquartile range, 6.3-9.1 years). Persistence of leukoencephalopathy was examined in relation to demographic and treatment data and to brain DTI in major fiber tracts and neurocognitive testing at follow-up. Leukoencephalopathy was found in 52 of 173 long-term survivors (30.0%) and persisted in 41 of 52 (78.8%) who developed it during therapy. DTI parameters were associated with leukoencephalopathy in multiple brain regions, including the corona radiata (fractional anisotropy, P = .001; mean diffusivity, P < .001), superior longitudinal fasciculi (fractional anisotropy, P = .02; mean diffusivity, P < .001), and superior fronto-occipital fasciculi (fractional anisotropy, P = .006; mean diffusivity, P < .001). Mean diffusivity was associated with neurocognitive impairment including in the genu of the corpus callosum (P = .04), corona radiata (P = .02), and superior fronto-occipital fasciculi (P = .02). Leukoencephalopathy during active therapy and neurocognitive impairment at long-term follow-up are associated with microstructural white matter integrity. DTI may be more sensitive than standard MR imaging for detection of clinically consequential white matter abnormalities in childhood acute lymphoblastic leukemia survivors treated with chemotherapy and in children undergoing treatment.

Neurocognitive outcome in survivors of childhood acute lymphoblastic leukemia: experience at a tertiary care hospital in Korea.

This study was conducted to investigate long-term neurocognitive outcomes and to determine associated risk factors in a cohort of Korean survivors of childhood acute lymphoblastic leukemia (ALL). Forty-two survivors of ALL were compared with 42 healthy controls on measures of a neurocognitive test battery. We analysed potential risk factors (cranial irradiation, sex, age at diagnosis, elapsed time from diagnosis, and ALL risk group) on neurocognitive outcomes. ALL patients had lower, but non-significant full-scale intelligence quotient (FSIQ, 107.2±12.2 vs. 111.7±10.2), verbal intelligence quotient (VIQ, 107.7±13.6 vs. 112.2±11.4), and performance intelligence quotient (PIQ, 106.3±14.2 vs. 110.1±10.7) scores than healthy controls. However, patients treated with cranial irradiation performed significantly lower on FSIQ (102.2±8.1), VIQ (103.3±11.7), and PIQ (101.4±13.2) compared to non-irradiated patients and healthy controls. ALL patients also had poor attention, concentration, and executive functions. Among ALL survivors, cranial irradiation was a risk factor for poor FSIQ, being male was a risk factor for poor PIQ, and younger age was a risk factor for poor attention. Therefore, the delayed cognitive effects of ALL treatment and its impact on quality of life require continuing monitoring and management.

Editorial on the role of "Genetic mediators of neurocognitive outcome in survivors of childhood acute lymphoblastic leukemia".

With current chemotherapy regimen favorable event free survival rates can be achieved for children and adolescents with acute lymphoblastic leukemia (ALL). Besides others, neurocognitive late effects come more and more into the focus of attention. Especially, as first reports indicate that the omission of cranial irradiation (CRT) did not solve the problem of neurocognitive deficits. The report by Krull and colleagues analyzed the association of neurocognitive outcome and a large set of potentially predisspoing polymorphisms. The authors identified significant associations between specific polymorphisms and neurocognitive outcome. However, the consequences of such testing need to be discussed carefully.

Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome. Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity. Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01). These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.

Neurocognitive outcome in survivors of pediatric cancer

There are more than 11 million survivors of pediatric cancers living in the US. The largest proportion had leukemia and the group most severely impacted by their cancer and their therapies are the survivors of central nervous system (CNS) tumors. This review describes the neurocognitive outcome for these groups and outlines work aimed at understanding the pathophysiology of and approach to ameliorating neurocognitive dysfunction. The impact of chemotherapy on children treated for leukemia without radiation has been elucidated and the differential impact of different radiation fields and doses among children with CNS malignancies has been described. Newer imaging techniques may predict damage earlier and animal models of chemotherapy-induced neurotoxicity may prove valuable in designing less toxic therapies or finding protective agents. Cognitive training programs, notably computerized programs that can be accessed at home, may be part of successful programs for minimizing neurotoxicity. This review seeks to describe the neurocognitive consequences of cancer and its therapy among pediatric patients treated for leukemia or a CNS tumor. The consequences of therapy with and without cranial radiation are described and information on potentially valuable animal models and imaging techniques are presented. The impact of host pharmacogenomics is outlined.

Corticosteriods, Neurocognition and Stress In Adult Survivors of Childhood Leukemia

AbstractAbstract 738While recent research has demonstrated comparable neurocognitive outcomes in survivors of childhood leukemia (ALL) treated with different types of corticosteroids during induction therapy, the long-term impact of prolonged corticosteroid therapy has not been investigated. We compared neurocognitive and physiologic outcomes in 37 adult survivors of childhood leukemia who were treated with only chemotherapy (i.e., no cranial radiation therapy) on one of two standard therapy protocols (21 treated with 20 g/m2 HD-IV methotrexate and repeated cycles of prednisone for two years; 16 treated with either 20 or 24 g/m2 HD-IV methotrexate and repeated cycles of dexamethasone for two years). Patients underwent neurocognitive evaluations, physical exams, and laboratory tests after overnight fasting. Morning cortisol was assessed at baseline and 12 h after 1 mg dexamethasone (standard dexamethasone suppression test). Groups were similar for male:female ratio (p=0.73), current age (p=0.90), and cumulative HD-IV methotrexate exposure (p=0.68). No differences were detected in final adult height (p=0.85), body mass index (p=0.43), HDL (p=0.86) or LDL (p=0.99) cholesterol, heart rate (p=0.49), triglycerides (p=0.59), serum glucose (p=0.84), insulin (p=0.63), HgA1C (p=0.62), free T4 (p=0.78), IGF-I (p=0.77), or basal morning cortisol (p=0.72). Survivors treated with dexamethasone displayed significantly higher systolic blood pressure compared to the prednisone exposure group (mean=128.5 ± SD 11.71 vs. 117.7±13.78; p=0.02), and a trend for higher diastolic BP (mean=75.1±9.33 vs. 68.7±10.55; p=0.08). Survivors originally treated with dexamethasone displayed significantly less suppression of cortisol following the dexamethasone suppression test (mean 3.82±6.41 μg/dL) compared to those originally treated with prednisone (0.94 ± 0.75 μg/dL; p=0.05). The dexamethasone group demonstrated significantly lower performance on multiple measures neurocognitive function (Tables 1), including mathematical problem solving (p=0.002), semantic verbal memory (p=0.006) and cognitive flexibility (p=0.02). They also reported more difficulty with emotional regulation (p=0.04). These results suggest that adult survivors of childhood leukemia treated with dexamethasone are at increased risk for neurocognitive impairment and poor emotional regulation. These problems may occur in the presence of symptoms of physical stress. Surprisingly, these survivors appear to display persistent late signs of increased reactivity within the hypothalamic-pituitary-adrenal axis. Disclosures:No relevant conflicts of interest to declare.

Neurocognitive Outcomes in Survivors of Childhood Cancer

s To review issues associated with neurocognitive outcome in survivors of pediatric cancer. Recommendations are made for future research directions. A large body of literature pertaining to neurocognitive outcome in cancer survivors was reviewed. Brain development and methodological issues that provide challenges to conducting meaningful research in cancer outcomes also are discussed. Neurotoxic agents used in some cancer therapies produce permanent neurocognitive sequelae, especially in very young children. The state of neurocognitive research for pediatric cancer survivors needs to move beyond empirical studies of neurocognitive sequelae to research that will identify individual patients at risk for neurocognitive morbidity.