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

Purpose Cancer cells require a supply of amino acids, particularly essential amino acids such as branched-chain amino acids (BCAAs, i.e., valine, leucine, and isoleucine), to meet the increased nutrient demands of malignant tumors. The cell-autonomous and non-autonomous roles of altered BCAA supply have been implicated in cancer progression. The critical proteins involved in BCAA uptake, transport, metabolism, etc. serve as potential therapeutic biomarkers in human cancers. Here, we summarize the potential anti-tumor mechanism of BCAA by exploring the chain reaction triggered by increased BCAA supply in the tumor. Method A system-wide strategy was employed to provide a generic solution to establish the links between BCAA and cancer based on comprehensive omics, molecular experimentation, and data analysis. Results BCAA over-supplementation (900 mg/kg) significantly inhibited tumor growth and reduced tumor burden, with isoleucine having the most pronounced effect. Surprisingly, isoleucine inhibited tumor growth independently of mTORC1 activation, a classical amino acid sensor. Exploratory transcriptome analysis revealed that Phosphatase and tensin homolog (PTEN) is the critical factor in the anti-tumor effect of isoleucine. By inhibiting PTEN ubiquitination, isoleucine can promote PTEN nuclear import and maintain PTEN nuclear stability. Interestingly, this process was regulated by isoleucine-tRNA ligase, cytoplasmic (IARS), a direct target of isoleucine. We demonstrated the enhanced interaction between IARS and PTEN in the presence of excess isoleucine. At the same time, IARS knockout leads to loss of isoleucine tumor suppressor ability. Conclusion Overall, our results provide insights into the regulation of the IARS-PTEN anti-tumor axis by isoleucine and reveal a unique therapeutic approach based on enhancing cellular isoleucine supply.

OBJECTIVE To delineate the impact of treatment exposures and chronic health conditions on psychological, educational, and social outcomes in adolescent survivors of Wilms tumor. METHODS Parent reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of Wilms tumor and 698 adolescent siblings. Adjusting for race and household income, survivors were compared to siblings on the Behavior Problems Index and educational outcomes. Multivariable modified Poisson regression estimated relative risks (RR) for therapeutic exposures and chronic health conditions (CTCAE 4.03 graded) among survivors, adjusting for sex, race, income, and age at diagnosis. RESULTS Compared to siblings, adolescent survivors of Wilms tumor were more likely to take psychoactive medication (9.4% vs. 5.1%, p < 0.001) and utilize special education services (25.5% vs. 12.6%, p < 0.001) but did not differ significantly in emotional and behavioral problems. Survivors were less likely to be friendless (7.2% vs. 10.1%, p = 0.04) but were more likely to have difficulty getting along with friends (14.5% vs. 7.8%, p < 0.001). Among survivors, use of special education services was associated with abdomen plus chest radiation (RR = 1.98, CI:1.18-3.34). Those with grade 2-4 cardiovascular conditions had higher risk for anxiety/depression (RR = 1.95, CI:1.19-3.19), headstrong behaviors (RR = 1.91, CI:1.26-2.89), and inattention (RR = 1.56, CI:1.02-2.40). CONCLUSIONS Adolescent survivors of Wilms tumor were similar to siblings with respect to mental health concerns overall but were more likely to require special education. Monitoring of psychosocial and academic problems through adolescence is warranted, especially among those treated with radiation to the abdomen plus chest or with cardiac conditions.

Background: To the authors' knowledge, few studies to date have examined long-term neurocognitive outcomes in survivors of childhood soft-tissue sarcoma. Methods: A total of 150 survivors (41% of whom were female with a mean current age of 33 years [SD, 8.9 years] and a time since diagnosis of 24 years [SD, 8.7 years]) and 349 community controls (56% of whom were female with a mean current age of 35 years [SD, 10.2 years]) completed comprehensive neuropsychological testing, echocardiography, electrocardiography, pulmonary function tests, endocrine evaluation, and physical examination. Patient-reported outcomes of health-related quality of life (HRQOL) and social attainment were collected. Survivors were compared with norms and controls on neurocognitive outcomes using general linear models, and on HRQOL and social attainment using modified Poisson models. The impacts of treatment and chronic health conditions on outcomes were examined using multivariable general linear models (effect size was expressed as unstandardized β estimates that reflected the unit of change from a mean of 0 and an SD of 1) and modified Poisson models (effect size expressed as relative risks). Results: Compared with controls and population norms, survivors demonstrated lower performance on measures of verbal reasoning (mean z score, −0.45 [SD, 1.15]; P

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.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.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.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.Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes.

Background: Childhood cancer survivors are at risk for cardiovascular morbidity and mortality that is not fully explained by cancer-directed therapies. We examined the contribution of emotional stress and distress to cardiac health in adult survivors of childhood cancer. Methods: Participants included 3,267 adult survivors enrolled in the St. Jude Lifetime Cohort Study [median (range) 29.9 (18.1–64.5) years of age; 7.7 (0–24.8) years at diagnosis; 48.4% female]. Survivors completed comprehensive medical assessments and standardized measures of depression, anxiety, posttraumatic stress symptoms (PTSS), and perceived stress. Cardiovascular-related conditions included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia, myocardial infarction (severity graded 0–4), and metabolic syndrome (yes/no). Multivariable modified Poisson models examined associations between symptoms of stress/distress and cardiovascular outcomes. Longitudinal associations between stress/distress and new-onset cardiovascular outcomes, defined as a change from grade ≤1 at initial evaluation to grade ≥2 at follow-up (median 3.9 years) were examined in 1,748 participants. Results: In multivariable cross-sectional models, stress/distress was associated with hypertension [risk ratio (RR) = 1.24; 95% confidence interval (CI), 1.07–1.43], dyslipidemia (RR = 1.29; 95% CI, 1.03–1.61), and metabolic syndrome (RR = 1.35; 95% CI, 1.17–1.54) independent of known cardiovascular risk factors. In longitudinal models, stress/distress was associated with new-onset dysrhythmia (RR = 2.87; 95% CI, 1.21–6.78), perceived stress with hypertension (RR = 1.42; 95% CI, 1.04–1.95), and PTSS and anxiety with dyslipidemia (RR = 1.72; 95% CI, 1.13–2.62; RR = 1.54; 95% CI, 1.01–2.35, respectively). Conclusions: Stress/distress is independently associated with adverse cardiovascular outcomes among childhood cancer survivors. Impact: Improving psychological health may serve as a potential intervention target for optimizing cardiac health among childhood cancer survivors.

BACKGROUND: The impact of specific treatment modalities on long-term renal function and blood pressure among adult survivors of Wilms tumor (WT) has not been well-documented. METHODS: Among 40 WT survivors and 35 non-cancer controls, we estimated the glomerular filtration rate (eGFR) using the Chronic Kidney Disease-Epidemiology (CKD-EPI) equations with and without cystatin C, obtained 24-hour ambulatory blood pressure readings, and, among survivors only, measured (99m)Tc diethylenetriamine pentaacetic acid (DTPA) plasma clearance. Survivors were treated with unilateral nephrectomy and non-nephrotoxic chemotherapy. Twenty received whole abdomen radiation therapy (WART) [median –16.5 Gray (Gy)], and 20 received no radiation therapy. Pairwise comparisons between survivors treated with and without WART, and each group to controls were performed using two-sample t-tests. RESULTS: Twenty-six (65%) WT survivors were female and 33 (83%) were non-Hispanic white. GFR estimated with creatinine or creatinine + cystatin C was decreased among irradiated survivors compared to controls. No irradiated or unirradiated participant had an eGFR (creatinine + cystatin C) < 60 ml/min/1.73m(2). The prevalence of hypertension was significantly increased among unirradiated (25%) and irradiated survivors (35%) compared to controls (0%). Of the 24-hour ambulatory blood pressure monitoring parameters evaluated, only mean sleep period diastolic blood pressure load of those who received WART was significantly different from that of controls. CONCLUSIONS: Chronic kidney disease was infrequent in long-term survivors of unilateral non-syndromic WT, whether treated with WART or no radiation. The prevalence of hypertension was increased in both groups compared to controls, emphasizing the need for ongoing monitoring of renal and cardiovascular health.

The development of gastric cancer is frequently related to the overexpression of wild-type p21 proteins, but it is rarely related to mutated Ras proteins. We previously constructed a broad-spectrum anti-p21-Ras single-chain variable fragment antibody (scFv), which was carried by the oncolytic adenovirus KGHV500. Here we explored the antitumor effects of this recombinant oncolytic adenovirus carried by cytokine-induced killer (CIK) cells on human gastric SGC7901 cells that overexpress wild-type Ras. The MTT assay, scratch test, Transwell assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay were performed in vitro to investigate the proliferation, migration, invasiveness, and cell apoptosis rate, respectively, of the human gastric cell line SGC7901 treated with KGHV500 adenovirus. Then, the tumor-targeting ability and systemic safety of KGHV500 adenovirus delivered by CIK cells were explored in vivo. We found that KGHV500 adenovirus could significantly inhibit proliferation, migration, and invasiveness and promote cell apoptosis in SGC7901 cells in vitro. In vivo studies showed that CIK cells could successfully deliver KGHV500 adenovirus to the tumor site; the two vectors synergistically killed tumor cells, and the treatment was relatively safe for normal tissues. In conclusion, this therapeutic strategy of recombinant adenovirus KGHV500 delivered by CIK cells offers a positive prospect for the targeted therapy of Ras-related cancers. Keywords: oncolytic adenovirus, anti-p21-Ras, scFv, CIK cell, gastric cancer, SGC7901

10045 Background: Survivors of childhood cancer have functional limitations and health-related morbidity consistent with an accelerated aging phenotype. We characterized aging using a Deficit Accumulation Index (DAI) which examines the accumulation of multiple aging-related deficits readily available from medical records and self-report. DAI’s are used as surrogates of biologic aging and are validated to predict mortality in adult cancer patients. Methods: We included childhood cancer survivors (N = 3,758, mean age 30 [SD 8], 22 [9] years post diagnosis, 52% male) and community controls (N = 575, mean age 34 [10] 44% male) who completed clinical assessments and questionnaires and who were followed for mortality through December 31st, 2018 (mean follow-up 6.1 [3.1] years). Using the initial SJLIFE clinical assessment, a DAI score was generated as the proportion of deficits out of 44 items related to aging, including chronic conditions (e.g. hearing loss, hypertension), psychosocial and physical function, and activities of daily living. The total score ranged 0 to 1; scores > 0.20 are robust, while moderate and large clinically meaningful differences are 0.02 and 0.06, respectively. Linear regression compared the DAI in survivors and controls with an age*survivor/control interaction and examined treatment associations in survivors. Cox-proportional hazards models estimated risk of death associated with DAI. All models were adjusted for age, sex, and race. Results: Mean [SD] of DAI was 0.17 [0.11] for survivors and 0.10 [0.08] for controls. 32% of survivors had a DAI above the 90th percentile of the control distribution (p < 0.001). After adjustment for covariates, survivors had a statistically and clinically meaningfully higher DAI score than controls (β = 0.072 95%CI 0.062, 0.081; p < 0.001). When plotted against age, the adjusted DAI at the average age of survivors (30 years) was 0.166 (95% CI 0.160,0.171), which corresponded to 60 years of age in controls, suggesting premature aging of 30 years. The mean difference in DAI between survivors and controls increased with age from 0.06 (95% CI 0.04, 0.07) at age 20 to 0.11 (95% CI 0.08, 0.13) at age 60, consistent with an accelerated aging phenotype (p = 0.014). Cranial radiation, abdominal radiation, cyclophosphamide, platinum agents, neurosurgery, and amputation were each associated with a higher DAI (all p≤0.001). Among survivors, a 0.06 increase in DAI was associated with a 41% increased risk of all-cause mortality (HR 1.41 95%CI 1.32, 1.50; p < 0.001). Conclusions: Survivors of childhood cancer experience significant age acceleration that is associated with an increased risk of mortality; longitudinal analyses are underway to validate these findings. Given the ease of estimating a DAI, this may be a feasible method to quickly identify survivors for novel and tailored interventions that can improve health and prevent premature mortality.

PURPOSE: To examine the association between posttraumatic stress symptoms (PTSS), neurocognitive and psychosocial late-effects, health behaviors, and healthcare utilization in long-term survivors of childhood cancer. METHODS: Participants included individuals (N=6844; 52.5% female; mean [SD] age at diagnosis =7.6[5.8], at follow-up =34.9[7.5]) in the Childhood Cancer Survivor Study (CCSS). Follow-up included the Posttraumatic Stress Scale, Brief Symptom Inventory-18, Short-form 36 Health-related quality of life (HRQOL) survey, CCSS Neurocognitive Questionnaire, and questions about sociodemographics, physical health, health behaviors and healthcare utilization. Modified Poisson regression and multinomial logistic regression models examined associations between post-traumatic stress symptoms (PTSS) and neurocognitive, HRQOL, health behavior, and healthcare outcomes when adjusting for sociodemographics, disease, and treatment. RESULTS: Long-term survivors with PTSS (N= 995, 14.5%) reported more impairment in mental (relative risk [RR] 3.42, 95% confidence interval [CI] 3.05–3.85) and physical (RR=2.26, CI= 1.96–2.61) HRQOL. PTSS was also associated with increased impairment in task efficiency (RR=3.09, CI=2.72–3.51), working memory (RR=2.55, CI= 2.30–2.83), organization (RR=2.11, CI= 1.78–2.50) and emotional regulation (RR=3.67, CI=3.30–4.09). Survivors with PTSS were significantly more likely to attend cancer-specific health visits in the past 2-years (OR=1.89, CI=1.50–2.39), and showed greater likelihood of either high frequency (OR= 1.89, CI= 1.50–2.39) or complete lack of (OR=1.63, CI=1.32–2.01) primary care visits compared to survivors without PTSS. CONCLUSIONS: Survivors with PTSS reported significantly more psychosocial and neurocognitive late effects, and were more likely to engage in variable use of healthcare. IMPLICATIONS FOR CANCER SURVIVORS: PTSS is associated with additional challenges for a population vulnerable to adverse late effects. Inclusion of integrative services during follow up visits may benefit functional outcomes.

Objective Sleep disorders are associated with psychological and physical health, although reports in long-term survivors of childhood cancer are limited. We characterized the prevalence and risk factors for behaviors consistent with sleep disorders in survivors and examined longitudinal associations with emotional distress and physical health outcomes. Methods Survivors (n = 1933; median [IQR] age = 35 [30, 41]) and siblings (n = 380; age = 33 [27, 40]) from the Childhood Cancer Survivor Study completed measures of sleep quality, fatigue, and sleepiness. Emotional distress and physical health outcomes were assessed approximately 5 years before and after the sleep survey. Multivariable logistic or modified Poisson regression models examined associations with cancer diagnosis, treatment exposures, and emotional and physical health outcomes. Results Survivors were more likely to report poor sleep efficiency (30.8% vs 24.7%; prevalence ratio [PR] = 1.26; 95% confidence interval, 1.04-1.53), daytime sleepiness (18.7% vs 14.2%; PR = 1.31 [1.01-1.71]), and sleep supplement use (13.5% vs 8.3%; PR = 1.56 [1.09-2.22]) than siblings. Survivors who developed emotional distress were more likely to report poor sleep efficiency (PR = 1.70 [1.40-2.07]), restricted sleep time (PR = 1.35 [1.12-1.62]), fatigue (PR = 2.11 [1.92-2.32]), daytime sleepiness (PR = 2.19 [1.71-2.82]), snoring (PR = 1.85 [1.08-3.16]), and more sleep medication (PR = 2.86 [2.00-4.09]) and supplement use (PR = 1.89[1.33-2.69]). Survivors reporting symptoms of insomnia (PR = 1.46 [1.02-2.08]), fatigue (PR = 1.31 [1.01-1.72]), and using sleep medications (PR = 2.16 [1.13-4.12]) were more likely to develop migraines/headaches. Conclusions Survivors report more sleep difficulties and efforts to manage sleep than siblings. These sleep behaviors are related to worsening or persistently elevated emotional distress and may result in increased risk for migraines. Behavioral interventions targeting sleep may be important for improving health outcomes.

10547 Background: The contribution of emotional distress and stress to cardiac health in adult survivors of childhood cancer has not been reported, despite evidence of causal associations in the general population. Methods: Comprehensive medical assessments and standardized measures of depression, anxiety, post-traumatic stress disorder, and perceived stress were performed on 3,267 survivors in the St. Jude Lifetime Cohort (median[range] 29.9[18.0-64.5] years of age; 7.7[0-24.8] years at diagnosis; 49% female). Physical outcomes included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia (grades 2-4 per the NCI CTCAE criteria), myocardial infarction (grades 3-4), and metabolic syndrome (yes/no). Multivariable generalized linear models examined associations between these outcomes with any distress/stress, adjusted for demographics, cumulative anthracycline dose and thoracic radiation, physical activity, BMI, smoking, and alcohol intake. Unadjusted longitudinal associations between distress/stress and new onset cardiac conditions were examined among survivors who completed repeat medical assessment(s) (n = 1748; median follow-up = 3.9 years). New onset conditions were defined as a change from grade 0-1 at baseline to ≥ grade 2 at follow-up. Results: Survivor reported distress/stress (29% overall) was more prevalent in those with hypertension (28.2% vs 19.5%, P< 0.001), dyslipidemia (16.4% vs. 11.3%, P< 0.001), diabetes (9.4% vs. 6.9%, P= 0.02), and metabolic syndrome (32.2% vs. 23.2%, P< 0.001), but not among dysrhythmia, cardiomyopathy, and myocardial infarction. In separate multivariable models, distress/stress was associated with hypertension (RR = 1.24, 95% CI 1.07-1.43), dyslipidemia (RR = 1.29, 95% CI 1.03-1.61), and metabolic syndrome (RR = 1.35, 95% CI 1.17-1.54). Baseline distress/stress was associated with new onset hypertension (OR = 1.33, 95% CI 0.94-2.01), dyslipidemia (OR = 1.37, 95% CI 0.94-1.87), and dysrhythmia (OR = 2.78, 95% CI 1.12-6.91). Conclusions: Emotional distress/stress is associated with adverse cardiovascular health and may serve as an intervention target for improving cardiac health outcomes among survivors of childhood cancer.

e22525 Background: Many childhood cancer survivors have been exposed to hepatotoxic agents. We assessed longitudinal hepatic injury, using alanine aminotransferase (ALT) elevation, and associated factors in a large cohort of long-term survivors. Methods: We evaluated SJLIFE participants ( > 10 years post-diagnosis, age ≥18 years) who had two or more determinations of ALT (T1 baseline, T2 last evaluation). Elevated ALT was defined as ALT > Upper Limit of Normal (ULN, 30 IU/mL for males and 19 IU/mL for females). Elastic net was used to perform model selection for elevated ALT at T2. Modified Poisson regression was used to identify risk factors for elevated ALT at T2. Results: Serial ALT assessments were available for 1941 survivors (49.6% female, 82.2% non-Hispanic white [NHW]). Their median age at diagnosis and T1 were 7.6 years (interquartile range [IQR] = 3.4-13.5) and 31.7 years (IQR = 26.1-38.1), respectively. Elapsed time from diagnosis to T1, and T1 to T2, were 23.3 years (IQR = 17.8-29.6) and 5.2 years (IQR = 4.4-5.7). ALT was normal at T1 and T2 in 45.7%, and persistently (25.9%) or newly (11.7%) abnormal in 37.6%. Compared to those with normal ALT at T1, those with elevated ALT at T2 were more likely to have NHW race/ethnicity, treatment with busulfan, increasing volume of the liver exposed to 10 Gray (Gy) or more (V10), body mass index (BMI) > 25 kg/m2, hepatitis C, metabolic syndrome, or treatment with atorvastatin, rosuvastatin or simvastatin at T2. History of hematopoietic stem cell transplantation (HSCT), but not busulfan, were additional risk factors included in the models for V15 and V20 (Table). Conclusions: Demographic, treatment, lifestyle, and non-oncologic interventions increase the risk for ALT elevation in survivors. These results may guide future treatment designs and lifestyle interventions. [Table: see text]

Survivors of pediatric brain tumors are at risk for disease and treatment-related cognitive and academic declines.1,2 Medulloblastoma, the most common malignant pediatric brain tumor, commonly occurs in the posterior fossa region and is usually diagnosed before the age of 10 years.3,4 Five-year survival rates for patients with medulloblastoma are 70%–85% with a treatment protocol that includes surgical resection, craniospinal irradiation, and chemotherapy.5 Younger age at diagnosis and higher doses of radiation are associated with worse cognitive and academic outcomes.6–10 Thus, contemporary protocols designed to limit radiation exposure use risk-adapted radiation dosing and a reduced clinical target volume (CTV) for the boost irradiation to the primary tumor site. The current study presents results from one of the first clinical protocols to reduce the CTV to the tumor bed to 1.0 cm for all patients. Clinical treatment-related events also have the potential to impact changes in cognitive and academic outcomes. Hearing loss can occur in patients treated with the platinum-based compound cisplatin because of its ototoxic effects, especially in children.11 Platinum-induced hearing loss is typically bilateral, symmetrical, permanent, and sensorineural in nature.12–14 Hearing loss is also a potential adverse outcome from cranial irradiation, which can damage any auditory structures from the external ear to the higher auditory pathways that are within the radiation fields. Thus, hearing loss can present as conductive, sensorineural, mixed, or retrocochlear in nature.15 Cisplatin is a platinum-based chemotherapy that is effective against medulloblastoma16 and is typically included as an adjuvant in protocol-based treatment that includes surgery and cranial irradiation. Patients receiving combined cranial irradiation and platinum-based chemotherapy experience greater hearing loss compared with patients receiving irradiation alone.17,18 Thus, medulloblastoma patients are at high risk for hearing loss. To date, no study has examined the longitudinal impact of hearing loss on changes in cognitive and academic outcomes in medulloblastoma patients. Posterior fossa syndrome (PFS), considered a consequence of surgery in the posterior fossa region, occurs in up to 29% of medulloblastoma patients.19,20 PFS is variable in presentation but typically includes diminished speech or mutism and is often accompanied by ataxia, hypotonia, emotional lability, and other neurocognitive sequelae.21 Recently, PFS was associated with worse cognitive outcomes at 12-months post diagnosis in medulloblastoma patients.22 Few studies have examined the longitudinal impact of PFS on changes in cognitive and academic outcomes in medulloblastoma patients. The present study aims to estimate changes in intellectual ability and academic outcomes (reading and math) during the 5 years following diagnosis of medulloblastoma. Hearing loss, PFS, age at diagnosis, and disease risk status (high vs average) were included in models that examined changes in cognition associated with treatment-related factors. We hypothesized that children with serious hearing loss (ie, loss serious enough to require hearing aids) would exhibit a steeper decline in intellectual and academic outcomes compared with children without serious hearing loss. Similarly, we postulated that children who developed PFS, compared with children who did not, would exhibit a steeper decline in intellectual and academic outcomes. Finally, as predicted by the literature, we expected that children who were younger at the time of diagnosis and who received more cranial radiation due to high-risk status would exhibit a steeper decline in intellectual and academic outcomes compared with patients older at diagnosis who received less radiation due to average-risk status.

11570 Background: Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols included treatment modifications, which may have ameliorated late health outcomes for rhabdomyosarcoma (RMS) survivors treated in more recent era. Methods: We evaluated chronic health conditions (CHCs) and late mortality ( > 5 years from diagnosis) among survivors treated 1970-1990 (IRSG I-III) and 1991-1999 (IRSG IV), and associations with specific treatments to identify treatment-related factors for adverse outcomes. Associations between treatments and CHCs and mortality were evaluated using Fine and Gray’s proportional hazards method accounting for competing risks. Results: 856 survivors treated 1970-90 (median diagnosis age 5.4 years [0- 20]) and 306 treated 1991-99 (median diagnosis age 5.5 years [0-20]) were included. Significant exposure differences between eras included higher percentage (53% vs. 17%, p < 0.01) receiving ≥ 20gm/m2 cumulative alkylators in 1991-99, but more receiving platinums (13% vs 5%, p < 0.01) and abdomen/ pelvis radiation (29% vs. 23%, p = 0.04) in 1970-90. 20-year cumulative incidence for any (40% vs. 28%, p < 0.01), ≥2 (16% vs. 7%, p < 0.01), and endocrine (8% vs. 2.5%, p < 0.01) grade 3-5 CHCs was higher in 1970-90 compared to 1991-99. The hazard ratio (HR) for any (HR 0.7, 95% Confidence Interval [CI] 0.55-0.9), ≥2 (HR 0.38, 95% CI 0.22-0.66) and endocrine (HR 0.25, 95% CI 0.09-0.67) grade 3-5 CHC was lower for 1991-99 survivors than 1970-90. The effect of era (1991-99 vs 1970-90, HR 0.73; 95% CI 0.59-0.91) on CHC was not attenuated when treatment variables were added to multivariable model. Exposures with increased risk of grade 3-5 CHC included platinums (hearing, HR 2, 95% CI 1.07-3.8), anthracycline ≥250mg/m2 (cardiovascular, HR 2.7, 95% CI 1.2-6) and abdomen/ pelvis radiation (second malignant neoplasms, HR 2.1, 95% CI 1.1-4, gastrointestinal, HR 7.4, 95% CI 3.5-16 and endocrine, HR 2.5, 95% CI 1.4-4.4). Gonadal dysfunction was the most common endocrine CHC. There was no difference in all cause or cause-specific mortality between the two cohorts. Conclusions: RMS survivors from the IRSG IV era are at reduced risk for late onset chronic health conditions compared to previous era.

10048 Background: We assessed renal function in a large, clinically assessed cohort of childhood cancer survivors. Methods: Creatinine and qualitative urine protein was measured in 2753 survivors (>10 years (years) post-diagnosis, age ≥18 years). Renal function was graded per the Kidney Disease International Global Outcomes 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD). Multivariable logistic regression was used to estimate associations between demographics, treatment exposures, and CKD (grades 1-5 and 3-5). Radiation treatment was expressed as percentage of total kidney volume treated with 5 (V5), 10 (V10), 15 (V15) and 20 (V20) Gray. Results: Among 2753 survivors, 48.7% were female and 82.5% non-Hispanic white. Median age at diagnosis - 7.3 years (interquartile range [IQR]=3.3-13.2), median age at evaluation - 31.4 years (IQR=25.8-37.8), and median time from diagnosis to evaluation - 23.2 years (IQR=17.6-29.7). Prevalence of grades 1-5 and 3-5 CKD was 7.4% and 2.1%, respectively (grade 1=113, grade 2=30, grade 3=44, grade 4=5, and grade 5=8). Individual and cumulative aminoglycoside doses and treatment with high-dose methotrexate were not associated with CKD (data not shown). Cumulative number of doses of ambisome/abelcet and of amphotericin B were significant risk factors for grades 1-5 and grades 3-5 CKD in models for V15 and V20 (data not shown). The multivariable results for V10 are shown in the Table. Conclusions: In addition to nephrotoxic antineoplastic and supportive care therapy, race, ethnicity, and body composition contribute to risk of CKD in long-term survivors. These novel results inform late effects reduction strategies for future treatment protocols and identify survivors at highest risk for CKD. [Table: see text]

10566Background: The impact of specific treatment modalities on long-term renal function among adult survivors of Wilms tumor (WT) has not been well-documented. Methods: We clinically evaluated 40 ...

10049 Background: Little is known about psychological and educational problems experienced by adolescent survivors of Wilms tumor (WT), including the impact of treatment exposures and chronic health conditions. Methods: Parent-reports from the Childhood Cancer Survivor Study were analyzed for 666 adolescent survivors of WT (Mean[SD] age at survey = 15.3[1.65] years; age at diagnosis = 2.8[1.77] years) and 698 siblings (15.4[1.66] years). Adjusting for race and household income, survivors were compared to siblings on the Behavior Problem Inventory and educational services. Among survivors, therapeutic exposures and chronic medical conditions (CTCAE 4.03 coding) were examined via multivariable log binomial regression adjusting for sex, race, income and age at diagnosis to calculate adjusted Relative Risk (aRR) and 95% confidence intervals (CI). Results: Compared to siblings, survivors were more likely to use psychoactive medication (9.4 vs. 5.1%, p = .0002) or be in special education for learning problems, inattention, and/or low test scores (19.1 vs. 11.1%, p = .003) but had similar rates of depression/anxiety, headstrong behavior, inattention, social withdrawal, and antisocial behavior (p’s > .05). Survivors who received radiation therapy (RT) to the abdomen (aRR 1.64, CI 1.03-2.61) or abdomen and chest (aRR 1.95, CI 1.16-3.26) were more likely to be in special education for any reason than those without RT. Those with grade 2-4 cardiovascular conditions were more likely to have anxiety/depression (aRR 2.04, CI 1.26-3.30), headstrong behavior (aRR 1.95, CI 1.30-2.93), or inattention (aRR 1.58, CI 1.04-2.42) compared to survivors with grade 0/1 conditions. Survivors were more likely to be in special education if they had problems with antisocial behavior, anxiety/depression, headstrong behavior, inattention or social withdrawal (p’s < .05). Conclusions: Psychological intervention may be needed for adolescent survivors of WT treated with RT to the abdomen or abdomen and chest or with higher grade cardiovascular conditions. These survivors are more likely to experience behavioral and emotional problems, which in turn increases risk for placement in special education.

10567 Background: We assessed hepatic injury (HI) in a large cohort of childhood cancer survivors (CCS). Methods: We measured aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in 2751 SJLIFE CCS ( > 10 years (yrs) post-diagnosis, age ≥18 yrs), and graded using the Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. Multivariable log binomial regression was used to estimate associations between demographic and clinical factors and grades 1–4 ALT and AST. Variables with a p < 0.1 were examined in multivariable models. Results: 1339 (48.7%) CCS were female. 2271 (82.6%) were non-Hispanic white (NHW). Median age at diagnosis - 7.4 yrs, median age at evaluation - 31.4 yrs, and median time from diagnosis to evaluation - 23.2 yrs. 177 (6.4%) had grades 1-4 AST (grade 1 = 164, grade 2 = 9, grade 3 = 4), and 421 (15.3%) had grades 1-4 ALT (grade 1 = 394, grade 2 = 18, grade 3 = 8). The multivariable results are shown in the table below. Conclusions: Male gender, obesity, hepatitis C virus infection, and treatment with busulfan are risk factors for increased AST and ALT. V10 is an additional risk factor for increased ALT. These results may guide future treatment designs and lifestyle interventions. [Table: see text]