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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. [ABSTRACT FROM AUTHOR]

Background: Premature aging is a significant concern in adult survivors of childhood cancer as they develop aging-related conditions at a younger age than their peers with no history of childhood cancer. Although modifiable lifestyle factors, such as diet, are postulated to affect aging process, supporting evidence is sparse. Methods: We examined if the consumption of sugar and sugar-sweetened beverages was related to premature aging in 3322 adult survivors of childhood cancer in the St. Jude Lifetime Cohort. Premature aging was assessed using the Deficit Accumulation Index (DAI) that was a ratio of the number of age-related chronic health conditions each survivor had out of 44 conditions total. Multinomial logistic regressions adjusting for confounders were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: There were 46% of childhood cancer survivors consumed SSBs once or more times per day. High intake of sugar, especially sugars added to foods during preparation or processing, and habitual consumption of sugar-sweetened beverage were associated with an increased risk of premature aging. Discussion: Our findings support a need to include strategies to reduce sugar and sugar-sweetened beverages consumption in lifestyle interventions to promote healthy aging in adult survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Patient activation is a very important psychological construct to examine in individuals who have chronic conditions, because it assesses the one's confidence in managing their own health and care. For childhood cancer survivors, continued follow-up is imperative to monitor late effects conditions; yet many do not adhere to surveillance guidelines. Therefore, investigating this construct could highlight risk factors in the population that contribute to low activation. Furthermore, examining the long-term impact of patient activation on psychological health as well as its contribution to health behavior could provide a reasonable target for interventions to enhance health outcomes in survivors. Background: Patient activation describes a willingness to take action to manage health and is associated with health outcomes. The purpose of this study was to characterize patient activation and its association with psychological outcomes and health behaviors in childhood cancer survivors. Methods: Participants were from the St. Jude Lifetime Cohort Study (SJLIFE). Activation levels (1–4, 4 = highest activation) were measured with the Patient Activation Measure (PAM). Psychological outcomes and health behaviors were obtained via self-report. Cognitive function was assessed by trained examiners. ANOVA or chi-squared tests were utilized to assess group-level differences in activation. Multivariable regression models were used to assess associations between PAM scores and outcomes of interest. Results: Among 2708 survivors and 303 controls, more survivors endorsed lower activation levels than the controls (11.3 vs. 4.7% in level 1) and fewer survivors endorsed the highest level of activation than the controls (45.3 vs. 61.5% in level 4). Not endorsing depression (OR: 2.37, 95% CI 1.87–2.99), anxiety (OR: 2.21, 95% CI 1.73–2.83), and somatization symptoms (OR: 1.99, 95% CI 1.59–2.50), general fear (OR: 1.45, 95% CI 1.23–1.71) and body-focused (OR: 2.21, 95% CI 1.83–2.66), cancer-related worry, and physical (OR: 2.57, 95% CI 2.06–3.20) and mental (OR: 2.08, 95% CI 1.72–2.52) HRQOL was associated with higher levels of activation. Lower activation was associated with not meeting physical activity guidelines (OR: 2.07, 95% CI 1.53–2.80). Conclusions: Survivors endorsed lower activation levels than peers. Interventions to improve physical and psychological health outcomes could leverage these results to identify survivors who benefit from support in patient activation. [ABSTRACT FROM AUTHOR]

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/m2 versus none (OR 4.38, CI 1.06–18.08) and etoposide exposure >2036 mg/m2 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. [ABSTRACT FROM AUTHOR]

Background Childhood cancer survivors are at high risk for morbidity and mortality and poor patient-reported outcomes, typically health-related quality of life (HRQOL). However, associations between DNA methylation–based aging biomarkers and HRQOL have not been evaluated. Methods DNA methylation was generated with Infinium EPIC BeadChip on blood-derived DNA (median for age at blood draw = 34.5 years, range = 18.5-66.6 years), and HRQOL was assessed with age at survey (mean = 32.3 years, range = 18.4-64.5 years) from 2206 survivors in the St Jude Lifetime Cohort. DNA methylation–based aging biomarkers, including epigenetic age using multiple clocks (eg, GrimAge) and others (eg, DNAmB2M: beta-2-microglobulin; DNAmADM: adrenomedullin), were derived from the DNAm Age Calculator (https://dnamage.genetics.ucla.edu). HRQOL was assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey to capture 8 domains and physical and mental component summaries. General linear models evaluated associations between HRQOL and epigenetic age acceleration (EAA; eg, EAA_GrimAge) or other age-adjusted DNA methylation–based biomarkers (eg, ageadj_DNAmB2M) after adjusting for age at blood draw, sex, cancer treatments, and DNA methylation–based surrogate for smoking pack-years. All P values were 2-sided. Results Worse HRQOL was associated with greater EAA_GrimAge (physical component summaries: β = -0.18 years, 95% confidence interval [CI] = -0.251 to -0.11 years; P  = 1.85 × 10−5; and 4 individual HRQOL domains), followed by ageadj_DNAmB2M (physical component summaries: β = -0.08 years, 95% CI = -0.124 to -0.037 years; P  = .003; and 3 individual HRQOL domains) and ageadj_DNAmADM (physical component summaries: β = -0.082 years, 95% CI = -0.125 to -0.039 years; P  = .002; and 2 HRQOL domains). EAA_Hannum (Hannum clock) was not associated with any HRQOL. Conclusions Overall and domain-specific measures of HRQOL are associated with DNA methylation measures of biological aging. Future longitudinal studies should test biological aging as a potential mechanism underlying the association between poor HRQOL and increased risk of clinically assessed adverse health outcomes. [ABSTRACT FROM AUTHOR]

Background: Prevalence and risk of poor psychological outcomes following rhabdomyosarcoma (RMS) are not well‐established. Methods: Participants in this cross‐sectional, case‐control study (n = 713 survivors, 42.5% female; mean [SD] age, 30.5 [6.6] years; n = 706 siblings, 57.2% female; mean age, 32.8,[7.9] years) completed measures of neurocognition, emotional distress, and health‐related quality of life (HRQOL). Multivariable logistic regression models identified treatments, health behaviors, and chronic conditions associated with impairment. Results: Relative to siblings, more survivors reported neurocognitive impairment (task efficiency: 21.1% vs. 13.7%, emotional regulation: 16.7% vs. 11.0%, memory: 19.3% vs. 15.1%), elevated emotional distress (somatic distress: 12.9% vs. 4.7%, anxiety: 11.7% vs. 5.9%, depression: 22.8% vs. 16.9%) and poorer HRQOL (physical functioning: 11.1% vs. 2.8%, role functioning due to physical problems: 16.8% vs. 8.2%, pain: 17.5% vs. 10.0%, vitality: 22.3% vs. 13.8%, social functioning: 14.4% vs. 6.8%, emotional functioning: 17.1% vs. 10.6%). Cranial radiation increased risk for impaired task efficiency (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.14–4.63), whereas chest and pelvic radiation predicted increased risk of physical functioning (OR, 2.68; 95% CI, 1.16–6.21 and OR, 3.44; 95% CI, 1.70–6.95, respectively). Smoking was associated with impaired task efficiency (OR, 2.06; 95% CI, 1.14–3.70), memory (OR, 2.23; 95% CI, 1.26–3.95), anxiety (OR, 2.71; 95% CI, 1.36–5.41) and depression (OR, 1.77; 95% CI, 1.01–3.11). Neurologic conditions increased risk of anxiety (OR, 2.30; 95% CI, 1.04–5.10), and hearing conditions increased risk of depression (OR, 1.79; 95% CI, 1.05–3.03). Neurologic and hearing conditions, respectively, were associated with impaired memory (OR, 2.44; 95% CI, 1.20–4.95 and OR, 1.87; 95% CI, 1.05–3.35) and poor health perception (OR, 2.62; 95% CI, 1.62–1.28 and OR, 2.33; 95% CI, 1.34–4.06). Conclusions: RMS survivors are at significant risk for poor psychological outcomes. Advancing therapies for local control, smoking cessation, and managing chronic medical conditions may mitigate poor outcomes following RMS. Research on psychological outcomes following pediatric rhabdomyosarcoma is scarce, limiting the understanding of the prevalence of and risk factors for neurocognitive impairment, emotional distress, and quality of life among survivors. This study showed that rhabdomyosarcoma survivors are at significant risk for poor psychological outcomes, and advancing therapies for local tumor control, smoking cessation, and managing chronic medical conditions may be important for mitigating risk. [ABSTRACT FROM AUTHOR]

Background: Siblings of children with cancer may experience adverse household economic consequences, but their financial outcomes in adulthood are unknown. Methods: A total of 880 siblings (aged 18–64 years) of adult‐aged childhood cancer survivors were surveyed to estimate the prevalence of financial hardship by three established domains (behavioral, material, and psychological). For individual financial hardship items matching the contemporaneous National Health Interview Survey or Behavioral Risk Factor Surveillance System, siblings were compared with the general population by calculating adjusted prevalence odds ratios (ORs) to sample‐weighted responses. Multivariable logistic regression models examined associations between sibling characteristics and each hardship domain and between sibling hardship and survivors' cancer/treatment characteristics. Results: Behavioral, material, and psychological hardship was reported by 24%, 35%, and 28%, respectively. Compared with national survey respondents, siblings were more likely to report worries about medical bills (OR, 1.14; 95% confidence interval [CI], 1.06–1.22), difficulty affording nutritious foods (OR, 1.79; 95% CI, 1.54–2.07), and forgoing needed medical care (OR, 1.38; 95% CI, 1.10–1.73), prescription medications (OR, 2.52; 95% CI, 1.99–3.20), and dental care (OR, 1.34; 95% CI, 1.15–1.57) because of cost. Sibling characteristics associated with reporting financial hardship in one or more domains included female sex, older age, chronic health conditions, lower income, not having health insurance, high out‐of‐pocket medical expenditures, and nonmedical/nonhome debt. No survivor cancer/treatment characteristics were associated with sibling financial hardship. Conclusions: Adult siblings of childhood cancer survivors were more likely to experience financial hardship compared with the general population. Childhood cancer may adversely affect entire households, with potentially lasting implications. Adult siblings of long‐term childhood cancer survivors may experience greater aspects of financial hardship compared with the general population. A childhood cancer diagnosis and treatment may adversely affect entire households, with potentially lasting implications. [ABSTRACT FROM AUTHOR]

Background Sleep problems following childhood cancer treatment may persist into adulthood, exacerbating cancer-related late effects and putting survivors at risk for poor physical and psychosocial functioning. This study examines sleep in long-term survivors and their siblings to identify risk factors and disease correlates. Methods Childhood cancer survivors (≥5 years from diagnosis; n = 12 340; 51.5% female; mean [SD] age = 39.4 [9.6] years) and siblings (n = 2395; 57.1% female; age = 44.6 [10.5] years) participating in the Childhood Cancer Survivor Study completed the Pittsburgh Sleep Quality Index (PSQI). Multivariable Poisson-error generalized estimating equation compared prevalence of binary sleep outcomes between survivors and siblings and evaluated cancer history and chronic health conditions (CHC) for associations with sleep outcomes, adjusting for age (at diagnosis and current), sex, race/ethnicity, and body mass index. Results Survivors were more likely to report clinically elevated composite PSQI scores (>5; 45.1% vs 40.0%, adjusted prevalence ratio [PR] = 1.20, 95% CI = 1.13 to 1.27), symptoms of insomnia (38.8% vs 32.0%, PR = 1.26, 95% CI = 1.18 to 1.35), snoring (18.0% vs 17.4%, PR = 1.11, 95% CI = 1.01 to 1.23), and sleep medication use (13.2% vs 11.5%, PR = 1.28, 95% CI = 1.12 to 1.45) compared with siblings. Within cancer survivors, PSQI scores were similar across diagnoses. Anthracycline exposure (PR = 1.13, 95% CI = 1.03 to 1.25), abdominal radiation (PR = 1.16, 95% CI = 1.04 to 1.29), and increasing CHC burden were associated with elevated PSQI scores (PRs = 1.21-1.48). Conclusions Among survivors, sleep problems were more closely related to CHC than diagnosis or treatment history, although longitudinal research is needed to determine the direction of this association. Frequent sleep-promoting medication use suggests interest in managing sleep problems; behavioral sleep intervention is advised for long-term management. [ABSTRACT FROM AUTHOR]

Cancer survivors are at a high risk for treatment-related late effects, particularly neurocognitive impairment in the attention and executive function domains. These can be compounded in pediatric populations still undergoing neural development, which has increased interest in survivorship studies and neurorehabilitation approaches to mitigate these effects. Cognitive training regimens have shown promise as a therapeutic intervention for improving cognitive function. Therapist-guided and computerized training programs with adaptive paradigms have been successfully implemented in pediatric populations, with positive outcomes on attention and working memory. Another interventional approach is neuromodulation to alter plasticity. Transcranial electrical stimulation can modulate cortical surface activity, and cranial nerve stimulation alters autonomic activity in afferent brainstem pathways. However, they are more systemic in nature and have diffuse spatial targeting. Transcranial focused ultrasound (tFUS) modulation overcomes these limitations with high spatial specificity and the ability to target deeper brain regions. In this review, we discuss the efficacy of tFUS for modulating specific brain regions and its potential utility to augment cognitive training programs as a complementary intervention. [ABSTRACT FROM AUTHOR]

Objective Childhood cancer survivors are at risk for hypogonadism. The impact of hypogonadism on neurocognitive impairment and emotional distress in the non-cancer population has been shown; however, the relationship among the childhood cancer survivor population is unknown. We aimed to evaluate the contribution of hypogonadism to neurocognitive impairment and emotional distress among survivors. Design Cross-sectional study using retrospective cohort. Methods In total, 3628 survivors who completed standard neurocognitive tests (six domains: processing speed, memory, executive function, attention, academics, and global cognition) and self-reported emotional distress were included in our study. Participants were stratified by sex and gonadal status. Outcomes were compared between hypogonadal and eugonadal groups by multivariable analysis, adjusting for established predictors, and mediation analyses to determine the direct/indirect effects of hypogonadism on outcomes. Results The hypogonadal group exhibited a higher prevalence of neurocognitive impairment across domains, but no difference in emotional distress. Hypogonadal females exhibited higher relative risk (1.7, 95% CI, 1.2–2.5) for impaired visual processing speed, compared to eugonadal females after adjusting for cancer-related variables. In mediation models, hypogonadism had a significant direct (P <.01) and indirect (from P <.01) impact on impairment in visual processing speed among females. Males demonstrated direct (P =.03) and indirect (P =.04) impact of hypogonadism on motor processing speed. Conclusion Processing speed may be the most vulnerable neurocognitive domain associated with hypogonadism in survivors, while other domains were mainly impacted by cancer-related variables. Our findings support the need for further evaluation of the impact of sex hormone replacement therapy on neurocognitive function. [ABSTRACT FROM AUTHOR]

Background Germline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENGaging and Activating cancer survivors in Genetic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing. Methods The ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services. Discussion With many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)‐directed therapies. Methods: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS‐treated]; median age [range] = 25.5 years [18–48]; time since diagnosis = 17.7 years [6.8–30.2]) and 8039 without CNS‐directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. Results: Among CNS‐treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In contrast to 50% of non‐CNS‐treated survivors and 60% of siblings, a fourth fully independent class of CNS‐treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70–3.68), seizure (OR = 9.70, 95% CI: 7.37–12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16–3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40–3.88) were associated with non‐independence among CNS‐treated survivors. Non‐independence was associated with emotional distress symptoms. Interpretation: CNS‐treated survivors do not attain full independence comparable to non‐CNS‐treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment‐related neurological sequalae. [ABSTRACT FROM AUTHOR]

Objective: The primary aim of this study was to assess the feasibility of a developmentally tailored neurocognitive assessment in survivors of childhood acute leukemia with Down syndrome (DS‐leukemia). A secondary aim was to compare outcomes in the DS‐leukemia group to a historical comparison group of individuals with DS and no history of childhood cancer. Methods: Survivors of DS‐leukemia (n = 43; 56% male, mean [SD] age at diagnosis = 4.3 [4.5] years; age at evaluation = 15 [7.9] years) completed a neurocognitive assessment battery that included direct measures of attention, executive function, and processing speed, and proxy ratings of attention problems and executive dysfunction. Direct assessment outcomes were compared to a historical comparison cohort of individuals with DS and no history of childhood cancer (DS‐control; n = 117; 56% male, mean [SD] age at evaluation = 12.7 [3.4] years). Results: Rates of valid task completion ranged from 54% to 95%, suggesting feasibility for most direct assessment measures. Compared to the DS‐control group, the DS‐leukemia group had significantly lower completion rates on measures of executive function (p = 0.008) and processing speed (p = 0.018) compared to the DS‐control group. There were no other significant group differences in completion rates. Compared to the DS‐control group, the DS‐leukemia group had significantly more accurate performance on two measures of executive function (p = 0.032; p = 0.005). Compared to the DS‐control group, the DS‐leukemia group had significantly more problems with executive function as identified on proxy ratings (6.5% vs. 32.6%, p = <0.001). Conclusion: Children with Down syndrome (DS) are at increased risk for developing acute leukemia compared to the general population but are systematically excluded from neurocognitive outcome studies among leukemia survivors. This study demonstrated the feasibility of evaluating neurocognitive late effects in leukemia survivors with DS using novel measures appropriate for populations with intellectual developmental disorder. [ABSTRACT FROM AUTHOR]

Background: Survivors of pediatric central nervous system (CNS) tumors are at risk for neurocognitive and social difficulties throughout childhood. This study characterized social cognition (perception and reasoning from social cues) and adjustment in adulthood. Methods: A total of 81 adult survivors of pediatric CNS tumors (51% female; mean [SD] age, 28.0 [5.8] years), were recruited across four groups: (1) no radiation therapy (RT) [n = 21], (2) infratentorial (IT) tumors + focal RT [n = 20], (3) IT tumors + craniospinal irradiation [n = 20], and (4) supratentorial tumors + focal RT [n = 20]. Prevalence of social cognitive and adjustment impairments was compared to test norms. Multivariable models examined clinical and neurocognitive predictors of social cognition and its impact on functional outcomes. Results: Survivors demonstrated elevated risk of severe social cognitive impairments (social perception Morbidity Ratio [95% CI] 5.70 [3.46–9.20]), but self‐reported few social adjustment problems. Survivors of IT tumors treated with craniospinal irradiation performed nearly 1 SD worse than survivors treated without RT on multiple measures of social cognition (e.g., social perception: β = −0.89, p =.004). Impaired executive functioning and nonverbal reasoning were associated with worse social cognitive performance (e.g., social perception: β = −0.75, p <.001; β = –0.84, p <.001, respectively). Better social perception was associated with higher odds of attaining full‐time employment (odds ratio, 1.52 [1.17–1.97]) and at least some college education (odds ratio, 1.39 [1.11–1.74]). Conclusions: Adult survivors of CNS tumors are at elevated risk of severely impaired social cognition, but do not perceive social adjustment difficulties. Better understanding of potential mechanisms underlying social cognitive deficits may inform intervention targets to promote better functional outcomes for at‐risk survivors. Adult survivors of childhood central nervous system tumors are at elevated risk of severely impaired social cognition, but do not perceive social adjustment difficulties. Infratentorial tumor survivors treated with craniospinal radiation demonstrated worse social cognition, which was in turn associated with reduced social attainment. [ABSTRACT FROM AUTHOR]

Background: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap. Methods: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease. Results: Survivors (N = 837; median [range] age, 25 [17–58] years, age diagnosed, 1 [0–21] years) were compared to sibling controls (N = 728; age, 32 [16–43] years). Survivors had higher risk of impaired task efficiency (≤1 year relative risk [RR], 1.48; 95% confidence interval [CI], 1.08–2.03; >1 year RR, 1.58; 95% CI, 1.22–2.06) and emotional regulation (≤1 year RR, 1.51; 95% CI, 1.07–2.12; >1 year RR, 1.44; 95% CI, 1.06–1.95). Impaired task efficiency associated with platinum exposure (≤1 year RR, 1.74; 95% CI, 1.01–2.97), hearing loss (≤1 year RR, 1.95; 95% CI, 1.26–3.00; >1 year RR, 1.56; 95% CI, 1.09–2.24), cardiovascular (≤1 year RR, 1.83; 95% CI, 1.15–2.89; >1 year RR, 1.74; 95% CI, 1.12–2.69), neurologic (≤1 year RR, 2.00; 95% CI, 1.32–3.03; >1 year RR, 2.29; 95% CI, 1.64–3.21), and respiratory (>1 year RR, 2.35; 95% CI, 1.60–3.45) conditions. Survivors ≤1 year; female sex (RR, 1.54; 95% CI, 1.02–2.33), cardiovascular (RR, 1.71; 95% CI, 1.08–2.70) and respiratory (RR, 1.99; 95% CI, 1.14–3.49) conditions associated impaired emotional regulation. Survivors were less likely to be employed full‐time (p <.0001), graduate college (p =.035), and live independently (p <.0001). Conclusions: Neuroblastoma survivors report neurocognitive impairment impacting adult milestones. Identified health conditions and treatment exposures can be targeted to improve outcomes. Plain Language Summary: Survival rates continue to improve in patients with neuroblastoma.There is a lack of information regarding neurocognitive outcomes in neuroblastoma survivors; most studies examined survivors of leukemia or brain tumors.In this study, 837 adult survivors of childhood neuroblastoma were compared to siblings from the Childhood Cancer Survivorship Study.Survivors had a 50% higher risk of impairment with attention/processing speed (task efficiency) and emotional reactivity/frustration tolerance (emotional regulation).Survivors were less likely to reach adult milestones such as living independently.Survivors with chronic health conditions are at a higher risk of impairment.Early identification and aggressive management of chronic conditions may help mitigate the level of impairment. Survivors of neuroblastoma had a 50% higher risk of impaired task efficiency and emotional regulation compared to siblings. Those with chronic health conditions were at higher risk of neurocognitive impairment. [ABSTRACT FROM AUTHOR]

Background Genetic predispositions may modulate risk for developing neurocognitive late effects in childhood acute lymphoblastic leukemia (ALL) survivors. Methods Long-term ALL survivors (n = 212; mean = 14.3 [SD = 4.77] years; 49% female) treated with chemotherapy completed neurocognitive testing and task-based functional neuroimaging. Based on previous work from our team, genetic variants related to the folate pathway, glucocorticoid regulation, drug metabolism, oxidative stress, and attention were included as predictors of neurocognitive performance, using multivariable models adjusted for age, race, and sex. Subsequent analyses evaluated the impact of these variants on task-based functional neuroimaging. Statistical tests were 2-sided. Results Survivors exhibited higher rates of impaired attention (20.8%), motor skills (42.2%), visuo-spatial memory (49.3%-58.3%), processing speed (20.1%), and executive function (24.3%-26.1%) relative to population norms (10%; P  < .001). Genetic variants implicated in attention deficit phenotypes predicted impaired attention span (synaptosome associated protein 25, F (2,172) = 4.07, P  =  .019) and motor skills (monoamine oxidase A, F (2,125) = 5.25, P  =  .007). Visuo-spatial memory and processing speed varied as a function of genetic variants in the folate pathway (methylenetetrahydrofolate reductase [ MTHFRrs1801133 ], F (2,165) = 3.48, P  =  .033; methylenetetrahydrofolate dehydrogenase 1 [ MTHFD1rs2236225 ], F (2,135) = 3.8, P  =  .025; respectively). Executive function performance was modulated by genetic variants in the folate pathway (MTHFD1rs2236225 , F (2,158) = 3.95, P  =  .021; MTHFD1rs1950902 , F (2,154) = 5.55, P  =  .005) and glucocorticoid regulation (vitamin D receptor, F (2,158) = 3.29, P  =  .039; FKBP prolyl isomerase 5, F (2,154) = 5.6, P  =  .005). Additionally, MTHFD1 rs2236225 and FKBP prolyl isomerase 5 were associated with altered brain function during attention and working memory (P  < .05; family wise error corrected). Conclusions Results extend previous findings of genetic risk of neurocognitive impairment following ALL therapy and highlight the importance of examining genetic modulators in relation to neurocognitive deficits. [ABSTRACT FROM AUTHOR]

Purpose: Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS. Methods: Five-year survivors of osteosarcoma (N = 604; median age 37.0 years) and EWS (N = 356; median age 35.0 years) diagnosed at < 21 years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties. Results: Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P = 0.03] and 14.0% [P = 0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P < 0.0001] and 15.2% [P = 0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P = 0.01]). Comorbid impairment (i.e., ≥ 2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P < 0.001]) and EWS survivors (16.3% [P = 0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR = 2.17; 95% CI = 1.21–3.88) and emotional regulation (RR = 1.88; 95% CI = 1.01–3.52), and respiratory conditions were associated with worse organization (RR = 2.60; 95% CI = 1.05–6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR = 1.98; 95% CI = 1.22–3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment. Conclusions: Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time. Implications for Cancer Survivors: Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes. [ABSTRACT FROM AUTHOR]

Background: Treatment‐related late effects can worsen over time among cancer survivors. Such worsening health states may trigger changes in internal standards, values, or conceptualization of quality‐of‐life (QOL). This "response‐shift" phenomenon can jeopardize the validity of QOL assessment, and misrepresent QOL comparisons over time. This study tested response‐shift effects in reporting future‐health concerns among childhood cancer survivors who experienced progression in chronic health conditions (CHCs). Methods: 2310 adult survivors of childhood cancer from St. Jude Lifetime Cohort Study completed a survey and clinical assessment at two or more timepoints. Based on 190 individual CHCs graded for adverse‐event severity, global CHC burden was classified as "progression" or "non‐progression". QOL was assessed using the SF‐36TM eight domains and physical‐ and mental‐component summary scores (PCS, MCS). A single global item measured concerns about future health. Random‐effects models comparing survivors with and without progressive global CHC burden (progressors vs. non‐progressors) evaluated response‐shift effects (recalibration, reprioritization, reconceptualization) in reporting future‐health concerns. Results: Compared with non‐progressors, progressors were more likely to de‐emphasize (or downplay) overall physical and mental health in evaluating future‐health concerns (p‐values<0.05), indicating recalibration response‐shift, and more likely to de‐emphasize physical health earlier rather than later in follow‐up (p‐value<0.05), indicating reprioritization response‐shift. There was evidence for a reconceptualization response‐shift with progressor classification associated with worse‐than‐expected future‐health concerns and physical health, and better‐than‐expected pain and role‐emotional functioning (p‐values<0.05). Conclusion: We identified three types of response‐shift phenomena in reporting concerns about future health among childhood cancer survivors. Survivorship care or research should consider response‐shift effects when interpreting changes in QOL over time. [ABSTRACT FROM AUTHOR]

Background: Adult survivors of childhood cancer have poor adherence to nutrition guidelines and inadequate intake of dietary vitamins D and E, potassium, fiber, magnesium, and calcium. The contribution of vitamin and mineral supplement use to total nutrient intake in this population is unclear. Methods: We examined the prevalence and dose of nutrient intake among 2570 adult survivors of childhood cancer participating in the St. Jude Lifetime Cohort Study, and the association of dietary supplement use with treatment exposures, symptom burden, and quality of life. Results: Nearly 40% of the adult survivors of cancer survivors reported regular use of dietary supplements. Although cancer survivors who used dietary supplements were less likely to have inadequate intake of several nutrients, they were also more likely to have excessive intake (total nutrient intake ≥ tolerable upper intake levels) of folate (15.4% vs. 1.3%), vitamin A (12.2% vs. 0.2%), iron (27.8% vs. 1.2%), zinc (18.6% vs. 1%), and calcium (5.1% vs. 0.9%) compared with survivors who did not use dietary supplements (all p < 0.05). Treatment exposures, symptom burden, and physical functioning were not associated with supplement use, whereas emotional well‐being and vitality were positively associated with supplement use among childhood cancer survivors. Conclusions: Supplement use is associated with both inadequate and excessive intake of specific nutrients, but positively impacts aspects of quality of life among childhood cancer survivors. Adult survivors of childhood cancer who used dietary supplements were less likely to have inadequate intake of several nutrients but were also more likely to have excessive intake of specific nutrients compared with those who did not use dietary supplements. Health care providers need to monitor dietary supplement use among long‐term survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Background: Young adults in the general population are at risk of experiencing loneliness, which has been associated with physical and mental health morbidities. The prevalence and consequences of loneliness in young adult survivors of childhood cancer remain unknown. Methods: A total of 9664 young adult survivors of childhood cancer (median age at diagnosis 10.5 years [interquartile range (IQR), 5–15], 27.1 years at baseline [IQR, 23–32]) and 2221 siblings enrolled in the Childhood Cancer Survivor Study completed a self‐reported survey question assessing loneliness on the Brief Symptom Inventory‐18 at baseline and follow‐up (median follow‐up, 6.6 years). Multivariable models evaluated the prevalence of loneliness at baseline only, follow‐up only, and baseline + follow‐up, and its associations with emotional distress, health behaviors, and chronic conditions at follow‐up. Results: Survivors were more likely than siblings to report loneliness at baseline + follow‐up (prevalence ratio [PR] 2.2; 95% confidence interval [CI], 1.7–3.0) and at follow‐up only (PR, 1.4; 95% CI, 1.1–1.7). Loneliness at baseline + follow‐up was associated with elevated risk of anxiety (relative risk [RR], 9.8; 95% CI, 7.5–12.7), depression (RR, 17.9; 95% CI, 14.1–22.7), and current smoking (odds ratio [OR], 1.7; 95% CI, 1.3–2.3) at follow‐up. Loneliness at follow‐up only was associated with suicidal ideation (RR, 1.5; 95% CI, 1.1–2.1), heavy/risky alcohol consumption (RR, 1.3; 95% CI, 1.1–1.5), and new‐onset grade 2–4 chronic conditions (RR, 1.3; 95% CI, 1.0–1.7). Conclusions: Young adult survivors of childhood cancer have elevated risk of experiencing loneliness, which is associated with future emotional distress, risky health behaviors, and new‐onset chronic conditions. Young adult survivors of childhood cancer are at elevated risk of loneliness compared to siblings. Loneliness is associated with future emotional distress, risky health behaviors, new‐onset chronic health conditions, and future poor quality of life. [ABSTRACT FROM AUTHOR]

Background: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. Questions/purposes: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? Methods: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. Results: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. Conclusion: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. Level of Evidence: Level III, therapeutic study. [ABSTRACT FROM AUTHOR]

Simple Summary: Patient-reported outcome measures (PROMs) are a useful way to assess the subjective experiences of health-related quality of life, functional status, symptoms, and other outcomes in childhood cancer survivors. In survivorship care, PROMs can be used to monitor health status and inform medical decision making. This article provides 10 important considerations for clinicians when they are assessing patient-reported outcomes for childhood cancer survivors. From choosing the right measure to selecting a strategy for clinical response, the purpose of these considerations is to support clinicians in implementing PROMs in their practice while keeping in mind some of the practical barriers and solutions of using PROMs with childhood cancer survivors. We end with an example of a framework for integrating PROMs into the clinical workflow that uses cutting-edge technologies (e.g., mHealth, natural language processing, and machine learning) to minimize interruptions to the clinical workflow and maximize the powerful utility of PROMs in cancer survivorship care. Patient-reported outcome measures (PROMs) are subjective assessments of health status or health-related quality of life. In childhood cancer survivors, PROMs can be used to evaluate the adverse effects of cancer treatment and guide cancer survivorship care. However, there are barriers to integrating PROMs into clinical practice, such as constraints in clinical validity, meaningful interpretation, and technology-enabled administration of the measures. This article discusses these barriers and proposes 10 important considerations for appropriate PROM integration into clinical care for choosing the right measure (considering the purpose of using a PROM, health profile vs. health preference approaches, measurement properties), ensuring survivors complete the PROMs (data collection method, data collection frequency, survivor capacity, self- vs. proxy reports), interpreting the results (scoring methods, clinical meaning and interpretability), and selecting a strategy for clinical response (integration into the clinical workflow). An example framework for integrating novel patient-reported outcome (PRO) data collection into the clinical workflow for childhood cancer survivorship care is also discussed. As we continuously improve the clinical validity of PROMs and address implementation barriers, routine PRO assessment and monitoring in pediatric cancer survivorship offer opportunities to facilitate clinical decision making and improve the quality of survivorship care. [ABSTRACT FROM AUTHOR]

Background: We aimed to characterize premature aging as an accumulation of deficits in survivors of pediatric cancer compared to community controls and examine associations with host/treatment factors, neurocognition, and mortality.Methods: Pediatric cancer survivors (N = 4,000, median age 28.6 [IQR 23-35], 20 [15-27] years post-diagnosis) and community controls (N = 638, median age 32 [25-40]) completed clinical assessments, questionnaires, and were followed for mortality through April 30th, 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/most severe), summed and divided by the total yielding a ratio (higher=more deficits). Scores <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/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 andethnicity.Results: The adjusted mean DAI among survivors at age 30 years was 0.16 corresponding to age 63 in controls (33 years premature aging; β = 0.07 95%CI 0.06-0.08; p<.001). Cranial/abdominal radiation, alkylators, platinum, and neurosurgery were associated with worse DAI (p's≤.001). Higher scores were associated with increased risk of neurocognitive impairment in all domains (p's<.001) and increased risk of death (DAI 0.20-0.35 HR = 2.80, 95%CI 1.97-3.98; DAI ≥0.35 HR = 5.08, 95%CI 3.52-7.34).Conclusion:  Pediatric cancer survivors experience significant premature aging. The DAI may be used to identify survivors at greatest risk of poor health outcomes. [ABSTRACT FROM AUTHOR]

Social epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5'-cytosine-phosphate-guanine-3' (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH–CpG associations (P < 9 × 10−8), 25 of which were validated in survivors of African ancestry (P < 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking–related genes (e.g., CLDND1 and CPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors' health. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs) are used in clinical work and research to capture the subjective experiences of childhood cancer patients and survivors. PROs encompass content domains relevant and important to this population, including health-related quality-of-life (HRQOL), symptoms, and functional status. To inform future efforts in the application of PRO measures, this review describes the existing generic and cancer-specific PRO measures for pediatric cancer populations and summarizes their characteristics, available language translations, content coverage, and measurement properties into tables for clinicians and researchers to reference before choosing a PRO measure that suits their purpose. We have identified often unreported measurement properties that could provide evidence about the clinical utility of the PRO measures. Routine PRO assessment in pediatric cancer care offers opportunities to facilitate clinical decision-making and improve quality of care for these patients. However, we suggest that before implementing PRO measures into research or clinical care, the psychometric properties and content coverage of the PRO measures must be considered to ensure that PRO measures are appropriately assessing the intended construct in childhood cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: Pediatric patients who undergo hematopoietic cell transplant (HCT) are at risk for neurocognitive impairments, which can impact quality of life. Given limited long-term studies, we aimed to characterize the late neurocognitive outcomes in a cohort of pediatric HCT survivors. Methods: Eligible survivors (HCT at age < 21 year and ≥ 1 year post-HCT) completed a 60-question survey of neurocognitive function and quality of life, which included the Childhood Cancer Survivor Study Neurocognitive Questionnaire (CCSS-NCQ) and the Neuro-Quality of Life Cognitive Function Short Form (Neuro-QoL). Analyses of risk factors included univariate comparisons and multivariable logistic regression. Results: Participants (n = 199, 50.3% female, 53.3% acute leukemia, 87.9% allogeneic transplants) were surveyed at median age of 37.8 years (interquartile range [IQR] 28.5–48.8) at survey and median 27.6 years (IQR 17.0–34.0) from transplant. On the CCSS-NCQ, 18.9–32.5% of survivors reported impairments (Z score > 1.28) in task efficiency, memory, emotional regulation, or organization, compared with expected 10% in the general population (all p < 0.01). In contrast, survivors reported average Neuro-QoL (T score 49.6±0.7) compared with population normative value of 50 (p = 0.52). In multivariable regression, impaired Neuro-QoL (T score < 40) was independently associated with hearing issues (OR 4.97, 95% CI 1.96-12.6), history of stroke or seizure (OR 4.46, 95% CI 1.44-13.8), and sleep disturbances (OR 6.95, 95% CI 2.53–19.1). Conclusions: Although long-term survivors of pediatric HCT reported higher rates of impairment in specific neurocognitive domains, cognitive quality of life was perceived as similar to the general population. Subsets of survivors with certain co-morbidities had substantially worse neurocognitive outcomes. Implications for Cancer Survivors: While the long-term impact of pediatric HCT can include neurocognitive deficits, survivors report average cognitive quality of life. [ABSTRACT FROM AUTHOR]

Objective: To characterize the prevalence and predictors of concerns regarding future health and cancer risk among siblings of childhood cancer survivors. Methods: This study reports longitudinal data (baseline and follow-up) from 3969 adult siblings (median age = 29 [range 18–56] years) of long-term survivors of childhood cancer (median time since diagnosis 19.6 [9.6–33.8] years). Self-reported future health and cancer risk concerns (concerned vs not concerned) were assessed. Demographics and health data reported by both the siblings and their matched cancer survivors were examined as risk factors for health concerns using multivariable logistic regression. Results: Percentage of siblings reporting future health and cancer risk concerns, respectively, decreased across decade of survivors' diagnosis: 1970s (73.3%; 63.9%), 1980s (67.2%; 62.6%), and 1990s (45.7%; 52.3%). Risk factors associated with future health concerns included sibling chronic health conditions (grade 2 Odds Ratio [OR]=1.57, 95% CI: 1.12–2.20; grades 3–4 OR=1.86, 95% CI: 1.18–2.94; compared to less than grade 2). Risk factors associated with future cancer concerns included sibling chronic health conditions (grade 2 OR=1.43, 95% CI: 1.05–1.94; grades 3–4 OR=1.64, 95% CI: 1.09–2.47; compared to less than grade 2). Conclusions: Sibling concerns regarding future health and cancer have diminished in recent decades. There are subgroups of siblings that are at-risk for future health and cancer risk concerns. Implications for Cancer Survivors: Routine screening of concerns in at-risk siblings of survivors of childhood cancer may benefit the siblings of cancer survivors. These individuals may benefit from early interventions during diagnosis and treatment of their siblings. [ABSTRACT FROM AUTHOR]

Background Long-term survivors of pediatric acute lymphoblastic leukemia are at elevated risk for neurocognitive deficits and corresponding brain dysfunction. This study examined sex-based differences in functional neuroimaging outcomes in acute lymphoblastic leukemia survivors treated with chemotherapy alone. Methods Functional magnetic resonance imaging (fMRI) and neurocognitive testing were obtained in 123 survivors (46% male; median [min-max] age = 14.2 years [8.3-26.5 years]; time since diagnosis = 7.7 years [5.1-12.5 years]) treated on the St. Jude Total XV treatment protocol. Participants performed the n-back working memory task in a 3 T scanner. Functional neuroimaging data were processed (realigned, slice time corrected, normalized, smoothed) and analyzed using statistical parametric mapping with contrasts for 1-back and 2-back conditions, which reflect varying degrees of working memory and task load. Group-level fMRI contrasts were stratified by sex and adjusted for age and methotrexate exposure. Statistical tests were 2-sided (P  < .05 statistical significance threshold). Results Relative to males, female survivors exhibited less activation (ie, reduced blood oxygen dependent–level signals) in the right parietal operculum, supramarginal gyrus and inferior occipital gyrus, and bilateral superior frontal medial gyrus during increased working memory load (family-wise error–corrected P  = .004 to.008, adjusting for age and methotrexate dose). Female survivors were slower to correctly respond to the 2-back condition than males (P  < .05), though there were no differences in overall accuracy. Performance accuracy was negatively correlated with fMRI activity in female survivors (Pearson's r  = −0.39 to −0.29, P  = .001 to.02), but not in males. Conclusions These results suggest the working memory network is more impaired in female survivors than male survivors, which may contribute to ongoing functional deficits. [ABSTRACT FROM AUTHOR]

Purpose: To examine self-reported (30-day) sleep versus nightly actigraphy-assessed sleep concordance in long-term survivors of childhood cancer. Methods: Four hundred seventy-seven participants enrolled in the St. Jude Lifetime Cohort (53.5% female, median (range) age 34.3 (19.3–61.6) years, 25.4 (10.9–49.3) years from diagnosis) completed the Pittsburgh Sleep Quality Index and ≥ 3 nights of actigraphy. Participants had neurocognitive impairment and/or a self-reported prolonged sleep onset latency (SOL). Self-reported 30-day sleep and nightly actigraphic sleep measures for sleep duration, SOL, and sleep efficiency (SE) were converted into ordinal categories for calculation of weighted kappa coefficients. General linear models estimated associations between measurement concordance and late effects. Results: Agreements between self-reported and actigraphic measures were slight to fair for sleep duration and SOL measures (kw = 0.20 and kw = 0.22, respectively; p < 0.0001) and poor for SE measures (kw = 0.00, p = 0.79). In multivariable models, severe fatigue and poor sleep quality were significantly associated with greater absolute differences between self-reported and actigraphy-assessed sleep durations (B = 26.6 [p < 0.001] and B = 26.8 [p = 0.01], respectively). Survivors with (versus without) memory impairment had a 44-min higher absolute difference in sleep duration (B = 44.4, p < 0.001). Survivors with, versus without, depression and poor sleep quality had higher absolute discrepancies of SOL (B = 24.5 [p = 0.01] and B = 16.4 [p < 0.0001], respectively). Poor sleep quality was associated with a 12% higher absolute difference in SE (B = 12.32, p < 0.0001). Conclusions: Self-reported sleep and actigraphic sleep demonstrated discordance in our sample. Several prevalent late effects were statistically significantly associated with increased measurement discrepancy. Future studies should consider the impacts of late effects on sleep assessment in adult survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

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. Adult survivors of childhood cancer are at risk for poorer cognitive, health‐related quality of life, and social outcomes. Seizure frequency, independently of the underlying etiology, is associated with poorer outcomes in non–brain tumor survivors, and this implies that they may be a more vulnerable population with a lower threshold for impact from seizures of any severity. [ABSTRACT FROM AUTHOR]

Background: Some adult survivors of childhood cancers develop frailty at higher rates than expected based on their chronological age. This study examined the incidence of frailty among survivors at 10 or more years after diagnosis, frailty prevalence 5 years later, and risk factors for becoming frail.Methods: Frailty was measured at study entry and 5 years later. Logistic regression tested the associations of several factors with having frailty at 5 years for all participants and separately by sex and by study entry frailty status. Cox models evaluated the hazard of death associated with entry frailty considering covariates.Results: Cancer survivors (range = 0-22 years at diagnosis, median = 7 years) were ages 18-45 years (median = 30 years) at study entry. Frailty prevalence increased from 6.2% (95% confidence interval [CI] = 5.0% to 7.5%) to 13.6% (95% CI = 11.9% to 15.4%) at 5 years. Risk factors for frailty at follow-up among all survivors included chest radiation 20 Gy or higher (odds ratio [OR] = 1.98, 95% CI = 1.29 to 3.05), cardiac (OR = 1.58, 95% CI = 1.02 to 2.46), and neurological (OR = 2.58, 95% CI = 1.69 to 3.92) conditions; lack of strength training (OR = 1.74, 95% CI = 1.14 to 2.66); sedentary lifestyle (OR = 1.75, 95% CI = 1.18 to 2.59); and frailty at study entry (OR = 11.12, 95% CI = 6.64 to 18.61). The strongest risk factor for death during follow-up was prior frailty (OR = 3.52, 95% CI = 1.95 to 6.32).Conclusions: Prevalent frailty more than doubled at 5 years after study entry among adult childhood cancer survivors. Frailty at entry was the strongest risk factor for death. Because treatment exposures cannot be changed, mitigation of other risk factors for frailty, including lack of strength training and sedentary lifestyle, may decrease risk of adverse health events and improve longevity in survivors. [ABSTRACT FROM AUTHOR]

Background The effect of chemotherapy on brain development in long-term survivors of pediatric acute lymphoblastic leukemia (ALL) was systematically reviewed. Methods A systematic search of Pubmed, Scopus, and PsycINFO databases was conducted to identify articles published between January 2000 and February 2020 that implemented magnetic resonance imaging to assess brain structure and function in pediatric ALL survivors (diagnosed younger than 21 years of age). The review included articles that were published on children diagnosed with ALL between 0 and 21 years of age and treated with chemotherapy-only protocols. Articles meeting the inclusion criteria described survivors on average of 5 years or more from diagnosis and were peer-reviewed articles and original studies. Results The search yielded 1975 articles with 23 articles meeting inclusion criteria. The review revealed that survivors had statistically significant alterations in brain anatomy, most commonly a smaller hippocampus and impaired microstructural white matter integrity in frontal brain regions. Survivors also had impaired brain function including lower brain network efficiency and altered resting state connectivity. Survivors also displayed widespread reductions in brain activation (ie, frontal, temporal, parietal brain regions) during cognitive tasks. Conclusion Although the neurotoxic effects of cancer treatment are reduced in the absence of cranial radiation, survivors treated on chemotherapy-only protocols still display long-term alterations in brain structure and function, which contribute to lifelong neurocognitive late effects. [ABSTRACT FROM AUTHOR]

Background: Neurocognitive impairment and obesity are common adverse sequelae in survivors of childhood acute lymphoblastic leukemia (ALL); however, the association has not been investigated. Methods: Neurocognitive function was evaluated once in survivors of ALL who were at least 8 years old and 5 years from their diagnosis. In a cross‐sectional analysis, the associations with the body mass index (BMI) category and Z score were examined. A longitudinal analysis used the overweight/obesity area under the curve (AUC), which was determined via the trapezoidal rule by a sum of the integrals defined by the BMI Z score at each time point and the time intervals of the BMI measurement. Results: For 210 survivors, the median BMI Z score at diagnosis was 0.17, which increased to 0.54 at the end of induction and to 0.74 at the neurocognitive assessment. In the cross‐sectional analysis, overweight/obese survivors scored significantly lower than others on the measures of executive function (cognitive flexibility, planning, verbal fluency, working memory, and spatial construction; all P <.05), attention (attention span and risk taking; all P <.05), and processing speed (visual motor coordination, visual speed, and motor speed; all P <.05). In the longitudinal analysis, when the treatment period was subdivided into 4 time periods (induction, consolidation, early maintenance, and late maintenance), a greater overweight/obesity AUC during induction therapy was associated with worse cognitive flexibility (P =.01) and slower motor speed (P =.02), which persisted throughout the treatment. Conclusions: Overweight/obesity was significantly associated with neurocognitive impairment during long‐term follow‐up, and this association started early in treatment for ALL. Novel early interventions to provide cognitive training and prevent weight gain are required for patients at risk. In a cohort of 210 children with acute lymphoblastic leukemia (ALL) at a median follow‐up of 7.5 years from diagnosis, overweight/obese survivors score significantly worse than others on measures of neurocognitive performance. This association with overweight/obesity status is already seen during induction therapy, and this suggests that early multidisciplinary interventions should be implemented to prevent obesity and to alleviate adverse neurocognitive sequelae in survivors of ALL. [ABSTRACT FROM AUTHOR]

PURPOSE: Social integration and relationship issues have been understudied among adolescent and young adult (AYA) cancer survivors. This study compared social relationships (social networks, support, and isolation) between AYA cancer survivors and noncancer controls, and identified social integration mechanisms through which the cancer experience influences patient-reported outcomes (PROs). MATERIALS AND METHODS: One hundred two AYA cancer survivors and 102 age, sex, and race-matched noncancer controls from a national Internet panel completed an online survey to identify up to 25 of closest friends and relatives whom they have contacted within the past 2 years. Participants' interpersonal connections were used to create a social network index. The Duke-UNC Functional Social Support Questionnaire, UCLA Loneliness Scale, and PROMIS-29 Profile were used to measure social support, perceived isolation or loneliness, and PROs (physical functioning, pain interference, fatigue, anxiety, and depression domains), respectively. Path analysis tested effects of cancer experience on PROs using serial social relationship variables as mediators. RESULTS: Compared with controls, survivors of lymphoma, leukemia, and solid tumor had better social networks; however, survivors of solid tumor and central nervous system malignancies had higher perceived loneliness (all P values <.05). Cancer experience was directly associated with poor PROs (P values <.05 for all domains except fatigue) and indirectly associated through the social network-support-loneliness pathway (all P values <.05). Survivors with higher loneliness had lower physical functioning and higher pain interference, fatigue, anxiety, and depression versus controls with lower loneliness (all P values <.05). CONCLUSION: Compared with controls, survivors were more socially connected but experienced greater loneliness, which was associated with poorer PROs. Screening social integration issues during follow-up care and providing appropriate interventions are warranted. [ABSTRACT FROM AUTHOR]