Neurocognitive outcomes and functional independence in adult survivors of childhood medulloblastoma diagnosed over three decades.

BACKGROUND: Treatment of childhood medulloblastoma has evolved to reduce neurotoxicity while improving survival. However, the impact of evolving therapies on late neurocognitive outcomes and adult functional independence remains unknown. METHODS: Adult survivors of childhood medulloblastoma (n=505; median[minimum-maximum] age, 29[18-46] years) and sibling controls (n=727; 32[18-58] years) from the Childhood Cancer Survivor Study completed surveys assessing neurocognitive problems and chronic health conditions (CHCs). Treatment exposures were categorized as historical (craniospinal irradiation [CSI]≥30 Gy, no chemotherapy), standard-risk (CSI>0 to <30 Gy +chemotherapy) and high-risk (CSI≥30 Gy +chemotherapy) therapy. Latent class analysis identified patterns of functional independence using employment, independent living, assistance with routine/personal care needs, driver's license, marital/partner status. Multivariable models estimated risk of neurocognitive impairment in survivors versus siblings and by treatment exposure group, and associations between neurocognitive impairment, CHCs, and functional independence. RESULTS: Survivors in each treatment exposure group had 4- to 5-fold elevated risk of impaired memory and task efficiency compared to siblings. Contemporary risk-based therapies did not confer lower risk compared to historical therapy. Survivors treated in the 1990s had higher risk of memory impairment (relative risk [RR] 2.24, 95% confidence interval [CI] 1.39-3.60) compared to survivors treated in the 1970s. Sensorimotor, hearing problems and seizures were associated with 33%-34%, 25-26% and 21%-42% elevated risk of task efficiency and memory impairment, respectively. Treatment-related CHCs and neurocognitive impairment were associated with non-independence. CONCLUSIONS: Despite treatment changes, long-term survivors of childhood medulloblastoma remain at risk for neurocognitive impairment, which was associated with CHCs. Neurocognitive surveillance after contemporary regimens is imperative.

Characterization of chronic pain, pain interference, and daily pain experiences in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

ABSTRACT: Although survivors of childhood cancer are at an increased risk, little is known about the prevalence of chronic pain, associated interference, and daily pain experiences. Survivors (N = 233; mean age = 40.8 years, range 22-64 years; mean time since diagnosis = 32.7 years) from the Childhood Cancer Survivor Study completed pain and psychosocial measures. Survivors with chronic pain completed 2-week, daily measures assessing pain and psychological symptoms using mHealth-based ecological momentary assessment. Multivariable-modified Poisson and linear regression models estimated prevalence ratio estimates (PR) and mean effects with 95% confidence intervals (CI) for associations of key risk factors with chronic pain and pain interference, respectively. Multilevel mixed models examined outcomes of daily pain and pain interference with prior day symptoms. Ninety-six survivors (41%) reported chronic pain, of whom 23 (24%) had severe interference. Chronic pain was associated with previous intravenous methotrexate treatment (PR = 1.6, 95% CI 1.1-2.3), respiratory (PR = 1.8, 95% CI 1.2-2.5), gastrointestinal (PR = 1.6, 95% CI 11.0-2.3), and neurological (PR = 1.5, 95% CI 1.0-2.1) chronic health conditions, unemployment (PR = 1.4, 95% CI 1.0-1.9) and clinically significant depression and anxiety (PR = 2.9, 95% CI 2.0-4.2), as well as a diagnosis of childhood Ewing sarcoma or osteosarcoma (PR = 1.9, 95% CI 1.0-3.5). Higher pain interference was associated with cardiovascular and neurological conditions, unemployment and clinical levels of depression and/or anxiety, and fear of cancer recurrence. For male, but not female survivors, low sleep quality, elevated anxiety, and elevated depression predicted high pain intensity and interference the next day. A substantial proportion of childhood cancer survivors experience chronic pain and significant associated interference. Chronic pain should be routinely evaluated, and interventions are needed.

Using Neurocognitive Phenotypes to Inform Interventions for Adult Survivors of Childhood Cancer.

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 2,958 (74.1%) eligible survivors, who were ≥5 years post-diagnosis and >18 years old, 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/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 [95%CI] 11.41-35.63) including cerebrovascular disease (OR = 14.5, 95%CI = 5.47-38.44) and cerebrovascular accident (OR = 14.7, 95%CI = 7.50-26.40). Modifiable risk factors, like quitting smoking reduced risk for global impairment (OR = 0.21, 95%CI 0.06-0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95%CI 2.86-7.21), attention impairment (OR 2.01, 95%CI 1.41-2.87), processing speed/executive function impairment (OR 1.90, 95%CI 1.46-2.48), and memory impairment (OR 2.09, 95%CI 1.54-2.82). 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.

Cerebellar Mutism Syndrome and Dentato-Thalamo-Cortical Tract Disruption in Diffusion Tractography Following Surgery for Medulloblastoma.

Background Cerebellar mutism syndrome (CMS), a complication following medulloblastoma surgery, has been linked to dentato-thalamo-cortical tract (DTCT) injury; the association of the degree of DTCT injury with severity of CMS-related symptoms has not been investigated. Purpose To investigate the association between severity of CMS-related symptoms and degree and patterns of DTCT injury with use of diffusion tensor imaging (DTI), and if laterality of injury influences neurologic symptoms. Materials and Methods This retrospective case-control study used prospectively collected clinical and DTI data on patients with medulloblastoma enrolled in a clinical trial (between July 2016 and February 2020) and healthy controls (between April and November 2017), matched with the age range of the participants with medulloblastoma. CMS was divided into types 1 (CMS1) and 2 (CMS2). Multivariable logistic regression was used to investigate the relationship between CMS likelihood and DTCT injury. Results Overall, 82 participants with medulloblastoma (mean age, 11.0 years ± 5.2 [SD]; 53 male) and 35 healthy controls (mean age, 18.0 years ± 3.06; 18 female) were included. In participants with medulloblastoma, DTCT was absent bilaterally (AB), absent on the right side (AR), absent on the left side (AL), or present bilaterally (PB), while it was PB in all healthy controls. Odds of having CMS were associated with higher degree of DTCT damage (AB, odds ratio = 272.7 [95% CI: 269.68, 275.75; P < .001]; AR, odds ratio = 14.40 [95% CI: 2.84, 101.48; P < .001]; and AL, odds ratio = 8.55 [95% CI: 1.15, 74.14; P < .001). Left (coefficient = -0.07, χ2 = 12.4, P < .001) and right (coefficient = -0.15, χ2 = 33.82, P < .001) DTCT volumes were negatively associated with the odds of CMS. More participants with medulloblastoma with AB showed CMS1; unilateral DTCT absence prevailed in CMS2. Lower DTCT volumes correlated with more severe ataxia. Unilateral DTCT injury caused ipsilateral dysmetria; AB caused symmetric dysmetria. PB indicated better neurologic outcome. Conclusion The severity of CMS-associated mutism, ataxia, and dysmetria was associated with DTCT damage severity. DTCT damage patterns differed between CMS1 and CMS2. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dorigatti Soldatelli and Ertl-Wagner in this issue.

Adverse Childhood Experiences, Resilience, and Cardiovascular Disease in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: The impact of Adverse Childhood Experiences (ACEs: e.g., abuse, neglect and/or household dysfunction experienced before age 18) and resilience on risk for cardiovascular disease (CVD) has not previously been investigated in adult survivors of childhood cancer. METHODS: We conducted a nested case-control study among long-term, adult-aged survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS). Self-report questionnaires ascertained ACEs and resilience, and scores were compared between cases with serious/life-threatening CVD and controls without CVD matched on demographic and cardiotoxic treatment factors. RESULTS: Among 95 cases and 261 controls, the mean ACE score was 1.4 for both groups; 53.4% of survivors endorsed ≥1 ACE. There was no association between ACEs or resilience and CVD in adjusted models. CONCLUSIONS: ACEs and resilience do not appear to contribute to CVD risk for adult survivors of childhood cancer with cardiotoxic treatment exposures. IMPACT: Although not associated with CVD in this population, ACEs are associated with serious health issues in other populations. Therefore, future studies could investigate effects of ACEs on other health outcomes affecting childhood cancer survivors.

Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study.

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

Hypogonadism and neurocognitive outcomes among childhood cancer survivors.

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.

Health-related quality of life and DNA methylation-based aging biomarkers among survivors of childhood cancer.

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: ß = -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: ß = -0.08 years, 95% CI = -0.124 to -0.037 years; P = .003; and 3 individual HRQOL domains) and ageadj_DNAmADM (physical component summaries: ß = -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.

Severe Sepsis During Treatment for Childhood Leukemia and Sequelae Among Adult Survivors.

Importance: Children undergoing treatment for leukemia are at increased risk of severe sepsis, a dysregulated immune response to infection leading to acute organ dysfunction. As cancer survivors, they face a high burden of long-term adverse effects. The association between sepsis during anticancer therapy and long-term organ dysfunction in adult survivors of childhood cancer has not been examined. Objective: To determine whether severe sepsis during therapy for leukemia in childhood is associated with subsequent chronic health conditions in adult survivors. Design, Setting, and Participants: This cohort study included 644 adult survivors of childhood leukemia who were diagnosed between January 1, 1985, and July 19, 2010, and participated in the St Jude Lifetime Cohort Study. Participants were excluded if they received hematopoietic cell transplant or had relapsed leukemia. Data collection ended June 30, 2017. Data were analyzed from July 1, 2020, to January 5, 2024. Exposures: Severe sepsis episodes, defined according to consensus criteria as septic shock, acute respiratory distress syndrome, or multiorgan dysfunction associated with infection occurring during anticancer therapy, were abstracted by medical record review for all participants. Main Outcomes and Measures: Common Terminology Criteria for Adverse Events-defined chronic health condition outcomes were independently abstracted. Associations between sepsis and cumulative incidence of chronic health conditions (eg, cardiovascular, pulmonary, kidney, neurological, and neurocognitive outcomes) were compared by adjusted hazard ratios from Cox proportional hazards logistic regression. Inverse propensity score weighting was used to adjust for potential confounders, including age, year of diagnosis, and leukemia type. Results: The study sample consisted of 644 adult survivors of pediatric leukemia (329 women [51.1%] and 315 men [48.9%]; including 56 with a history of acute myeloid leukemia and 585 with a history of acute lymphoblastic leukemia) who were most recently evaluated at a median age of 24.7 (IQR, 21.2-28.3) years at a median time after leukemia diagnosis of 17.3 (IQR, 13.7-21.9) years. Severe sepsis during treatment of acute childhood leukemia occurred in 46 participants (7.1%). Participants who experienced severe sepsis during treatment were more likely to develop moderate to severe neurocognitive impairment (29 of 46 [63.0%] vs 310 of 598 [51.8%]; adjusted hazard ratio, 1.86 [95% CI, 1.61-2.16]; P < .001) significantly affecting attention, executive function, memory and visuospatial domains. Sepsis was not associated with long-term risk of cardiovascular, pulmonary, kidney, or neurological chronic health conditions. Conclusions and Relevance: In this cohort study of long-term outcomes in survivors of pediatric leukemia, severe sepsis during anticancer therapy for leukemia was associated with a selectively increased risk for development of serious neurocognitive sequelae. Efforts to reduce the effects of anticancer therapy on long-term function and quality of life in survivors might include prevention of severe sepsis during therapy and early detection or amelioration of neurocognitive deficits in survivors of sepsis.

Mechanisms of sleep disturbances in long-term cancer survivors: a childhood cancer survivor study report.

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.

Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma.

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 (ß = 0.06), sensorimotor (ß = 0.06), and endocrine (ß = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each ß = 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.

Psychological Outcomes in Adolescent and Young Adult Cancer Survivors.

The diagnosis of cancer during adolescent and young adulthood (AYA) may alter the development and psychological trajectory of survivors across their lifespan. The current review focuses broadly on emotional health, social functioning, health behaviors, and cancer-related cognitive impairment (CRCI) among AYA survivors. Overall, AYA survivors appear to be at elevated risk of emotional distress symptoms, mood and anxiety disorders, suicide, and mental health care service utilization compared with individuals without a cancer history. Difficulties with social relationships and reduced achievement of expected social outcomes including educational attainment and employment have been reported. Despite risk for health-related morbidities, including subsequent neoplasms, many AYA survivors do not engage in health behaviors at the recommended levels for physical activity, diet, or tobacco and alcohol use. Although CRCI has not been comprehensively characterized in this population, subgroups of AYA survivors appear to be at risk for experiencing CRCI, including survivors of central nervous system tumors, Hodgkin lymphoma, testicular, and breast cancer. Across each considered domain of psychological functioning, intervention efforts have largely focused on acceptability and feasibility with an increasing focus on e/mHealth approaches. Future research should include multiphase studies, including randomized controlled trials designed to evaluate intervention efficacy and effectiveness. It is imperative that psychological interventions consider the unique needs of AYA survivors by developmental stage and across multiple levels of influence (patient, support system, institution, and health care system).

Neurologic morbidity and functional independence in adult survivors of childhood cancer.

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.

Association of hearing loss with patient-reported functional outcomes in adult survivors of childhood cancer.

BACKGROUND: Hearing loss is prevalent following ototoxic therapy for childhood cancer. Associations between hearing loss, self-perceived hearing handicap, and functional outcomes have not been examined in survivors. METHODS: Adult survivors treated with platinum or head and neck radiotherapy with hearing loss were recruited. A total of 237 survivors (median age at survey = 37.0 years [range = 30.0-45.0 years]; median = 29.1 years [range = 22.4-35.0 years] since diagnosis; median = 4.0 years [range = 2.9-7.7 years] from last audiogram to survey) completed the Hearing Handicap Inventory for Adults and questionnaires on social and emotional functioning and hearing aid use. Hearing loss severity was defined according to Chang criteria. Multivariable logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between hearing loss, hearing handicap, functional outcomes, and hearing aid use with adjustment for sex, race, age at hearing loss diagnosis, and age at survey. RESULTS: Two-thirds of survivors had severe hearing loss, which was associated with increased likelihood of hearing handicap (mild-moderate handicap: OR = 2.72, 95% CI = 1.35 to 5.47; severe handicap: OR = 5.99, 95% CI = 2.72 to 13.18). Survivors with severe hearing handicap had an increased likelihood of social isolation (OR = 8.76, 95% CI = 3.62 to 21.20), depression (OR = 9.11, 95% CI = 3.46 to 24.02), anxiety (OR = 17.57, 95% CI = 3.77 to 81.84), reduced personal income (OR = 2.82, 95% CI = 1.46 to 5.43), and less than full-time employment (OR = 2.47, 95% CI = 1.30 to 4.70). Survivors who did not use a recommended hearing aid were twice as likely to have less than full-time employment (OR = 2.26, 95% CI = 1.10 to 4.61) and reduced personal income (OR = 2.24, 95% CI = 1.08 to 4.63) compared with survivors who wore a hearing aid. CONCLUSION: Self-perceived hearing handicap beyond measured hearing loss is associated with reduced functional outcomes. Assessment of hearing handicap may facilitate targeted interventions in adult survivors with hearing loss.

Deficit Accumulation Index and Biological Markers of Aging in Survivors of Childhood Cancer.

Importance: Survivors of childhood cancer experience premature aging compared with community controls. The deficit accumulation index (DAI) uses readily available clinical data to measure physiological age in survivors; however, little data exist on how well deficit accumulation represents underlying biological aging among survivors of cancer. Objective: To examine the associations between the DAI and epigenetic age acceleration (EAA) and mean leukocyte telomere length (LTL). Design, Setting, and Participants: This cross-sectional study analyzed data from the St Jude Lifetime Cohort, an assessment of survivors of childhood cancer who were treated at St Jude Children's Research Hospital in Memphis, Tennessee. Data were collected between 2007 and 2016, assayed between 2014 and 2019, and analyzed between 2022 and 2023. Participants were adult survivors who were diagnosed between 1962 and 2012 and who survived 5 years or more from time of diagnosis. The analyses were restricted to survivors with European ancestry, as there were too few survivors with non-European ancestry. Exposures: The DAI included 44 aging-related items, such as chronic health conditions and functional, psychosocial, and mental well-being. Item responses were summed and divided by the total number of items, resulting in a ratio ranging from 0 to 1. These DAI results were categorized based on reported associations with hospitalization and mortality: low, defined as a DAI less than 0.2; medium, defined as a DAI of 0.2 to less than 0.35; and high, defined as a DAI of 0.35 or higher. Main Outcomes and Measures: Genome-wide DNA methylation was generated from peripheral blood mononuclear cell-derived DNA. The EAA was calculated as the residuals from regressing the Levine epigenetic age on chronological age. The mean LTL was estimated using whole-genome sequencing data. Results: This study included 2101 survivors of childhood cancer (1122 males [53.4%]; mean [SD] age, 33.9 [9.1] years; median [IQR] time since diagnosis, 25.1 [18.7-31.9] years) with European ancestry. Compared with survivors in the low DAI group, those in the high DAI group experienced 3.7 more years of EAA (ß = 3.66; 95% CI, 2.47-4.85; P < .001), whereas those in the medium DAI group experienced 1.8 more years of EAA (ß = 1.77; 95% CI, 0.84-2.69; P < .001), independent of treatment exposures. The EAA and DAI association was consistent across 3 common diagnoses (acute lymphoblastic leukemia, Hodgkin lymphoma, and central nervous system tumors) and across chronological age groups. For example, among acute lymphoblastic leukemia survivors, those in the medium DAI group (ß = 2.27; 95% CI, 0.78-3.76; P = .001) experienced greater EAA vs those in the low DAI group. Similarly, among survivors younger than 30 years, the high DAI group experienced 4.9 more years of EAA vs the low DAI group (ß = 4.95; 95% CI, 2.14-7.75; P < .001). There were no associations between mean LTL residual and the DAI. Conclusions and Relevance: This cross-sectional study of survivors of childhood cancer showed that the DAI was associated with EAA, suggesting an underlying biological process to the accumulation of deficits. Both the DAI and EAA were effective at identifying aging phenotypes, and either may be used to measure aging and response to interventions targeting aging pathways.

Interventions with Social Integration Components Addressing Psychosocial Outcomes of Young- and Middle-Aged Adult Cancer Individuals: A Systematic Review.

BACKGROUND: The majority of adult cancer patients/survivors encounter social challenges (e.g., obtaining social support, maintaining social relationships, feelings of social isolation). This systematic review summarizes intervention studies addressing social integration or social connectedness issues among young- and middle-aged cancer patients/survivors. METHODS: We searched the PubMed, CINAHL, and Web of Science databases (January 2000-May 2021) to identify intervention studies that addressed social integration, social connectedness, social support, and social isolation for cancer patients/survivors in young- and middle-aged adulthood (18-64.9 years) through a randomized controlled trial (RCT). We categorized the interventions as technology-based, non-technology-based, and mixed-type (technology- and non-technology-based). RESULTS: A total of 28 studies were identified. These interventions demonstrated improved social outcomes (e.g., increased social support, decreased loneliness), increased awareness of available cancer-related resources, and better patient-reported outcomes among patients/survivors versus controls. Specifically, the use of internet-based discussion sessions was associated with improved social cohesion and social support. Receiving social support from peers through networking sites was associated with improved physical activity. Additionally, implementing mixed-type interventions led to better social support from peer survivors, less fear of social interactions, and improved social connectedness. CONCLUSIONS: Using existing technology- and/or non-technology-based platforms to facilitate social connectedness among cancer patients/survivors in young- or middle-aged adulthood can help them cope with stressful life circumstances and improve quality-of-life. Further interventions targeting social integration (e.g., social network interventions) are needed to improve the complex social integration challenges experienced by cancer patients and survivors.

Design and methods of a randomized telehealth-based intervention to improve fitness in survivors of childhood cancer with exercise intolerance.

BACKGROUND: Exercise intolerance among childhood cancer survivors substantially increases risk for early mortality, reduced cognitive function, poor quality of life, emotional distress, and sub-optimal participation in social roles. Fortunately, exercise intolerance is modifiable, even among individuals with impaired cardiopulmonary and neuromuscular health. This study aims to evaluate the impact of tailored exercise intervention remotely supervised by fitness professionals in survivors with exercise intolerance. Telehealth-based delivery of the intervention aims to enhance uptake by removing the burden of travel and allowing participants to gain confidence with exercise and physical activity at home. METHODS: This is an ongoing single-blind, two-arm, prospective, clinical trial that will randomize 160 participants 1:1 to intervention (n = 80) and attention control (n = 80) groups. The intervention group receives an individually tailored exercise prescription based on results from baseline assessments performed remotely via a Health Insurance Portability and Accountability Act-compliant virtual platform and personal preferences for aerobic exercise. Each prescription includes aerobic and strengthening components designed to progress gradually to 150-300-min of moderate aerobic activity and twice weekly strengthening exercises over 20-weeks. The first two weeks are supervised for 6 sessions, tapering to twice/week for weeks 3-4, once/week for weeks 5-8, every other week for weeks 9-16 and once midway between weeks 17-20. The schedule is modifiable depending on participant need, adherence, and response to exercise. Each session is approximately one hour. CONCLUSION: This study tests the efficacy of an individually prescribed, virtually supervised exercise intervention on exercise intolerant childhood cancer survivors. CLINICALTRIALS: gov registration: NCT04714840.

Social cognition and adjustment in adult survivors of pediatric central nervous system tumors.

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: ß = -0.89, p = .004). Impaired executive functioning and nonverbal reasoning were associated with worse social cognitive performance (e.g., social perception: ß = -0.75, p < .001; ß = -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.

Neurocognitive outcomes in adult survivors of neuroblastoma: A report from the Childhood Cancer Survivor Study.

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.

Determinants of health-related quality-of-life in adult survivors of childhood cancer: integrating personal and societal values through a health utility approach.

Background: Childhood cancer survivors are at elevated risk for poor health-related quality-of-life (HRQOL). Identification of potentially modifiable risk factors associated with HRQOL is needed to inform survivorship care. Methods: Participants included 4294 adult childhood cancer survivors from the St. Jude Lifetime Cohort Study who completed a survey and clinical assessment at entry into the survivorship cohort (baseline) and follow-up (median interval: 4.3 years) between 2007 and 2019. The SF-6D compared utility-based HRQOL of survivors to an independent sample from the U.S. Medical Expenditures Panel Survey. Chronic health conditions (CHCs) were graded using modified Common Terminology Criteria for Adverse Events. General linear models examined cross-sectional and temporal associations of HRQOL with CHC burden (total and by organ-system), adjusting for potential risk factors. Findings: Survivors reported poorer HRQOL compared to the general population (effect size [d] = -0.343). In cross-sectional analyses at baseline, significant non-demographic risk factors included higher total CHC burden (driven by more severe cardiovascular [d = -0.119, p = 0.002], endocrine [d = -0.112, p = 0.001], gastrointestinal [d = -0.226, p < 0.001], immunologic [d = -0.168, p = 0.035], neurologic [d = -0.388, p < 0.001], pulmonary [d = -0.132, p = 0.003] CHCs), public (d = -0.503, p < 0.001) or no health insurance (d = -0.123, p = 0.007), current smoking (d = -0.270, p < 0.001), being physically inactive (d = -0.129, p < 0.001), ever using illicit drugs (d = -0.235, p < 0.001), and worse diet quality (d = -0.004, p = 0.016). In temporal analyses, poorer utility-based HRQOL at follow-up was associated with risk factors at baseline, including higher total CHC burden (driven by cardiovascular [d = -0.152, p = 0.002], endocrine [d = -0.092, p = 0.047], musculoskeletal [d = -0.160, p = 0.016], neurologic [d = -0.318, p < 0.001] CHCs), public (d = -0.415, p < 0.001) or no health insurance (d = -0.161, p = 0.007), current smoking (d = -0.218, p = 0.001), and ever using illicit drugs (d = -0.217, p < 0.001). Interpretation: Adult survivors report worse utility-based HRQOL than the general population, and potentially modifiable risk factors were associated with HRQOL. Interventions to prevent the early onset of CHCs, promote healthy lifestyle, and ensure access to health insurance in the early survivorship stage may provide opportunities to improve HRQOL. Funding: The research reported in this manuscript was supported by the U.S. National Cancer Institute under award numbers U01CA195547 (Hudson/Ness), R01CA238368 (Huang/Baker), R01CA258193 (Huang/Yasui), R01CA270157 (Bhakta/Yasui), and T32CA225590 (Krull). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.