Pediatric Cancer Survivors Research Articles

Assessment of Risk Factors for Developing Iron Overload in Patients with Pediatric Cancer and Bone Marrow Transplant Survivors: A Single Center Retrospective Chart Review

Background: Pediatric cancer survivors and those with chronic hematologic disorders are at risk for iron overload secondary to frequent transfusion therapy. As this patient population increases in number due to improvement of therapies, it is essential to identify risk factors associated with the development of iron overload. Classifying these risk factors will help improve screening methods and assist in decreasing side effects from iron overload, such as iron deposition resulting in organ damage. Objective: Assessment of risk factors associated with the development of iron overload in pediatric cancer survivors and those who underwent bone marrow transplant. Methods: Retrospective chart review of patients who completed therapy for pediatric malignancy or underwent bone marrow transplant and were screened for iron overload utilizing magnetic resonance imaging (MRI). Iron overload was defined as T2* liver MRI with iron levels of >5mg/g dry weight. Individuals determined to screen positive for iron overload were evaluated for additional demographic and treatment variables, such as race, age at diagnosis, and total transfused blood volume, to assess for risk factors associated with the development of iron overload. Statistical analyses were performed via univariate and multivariate regression models of the variables collected. Results: We report a large cohort of patients with a mean age of 10.6 years who underwent screening T2* liver MRIs. Of 71 patients who underwent liver MRI screening, 89% met criteria for moderately severe iron overload. Blood volume administered (ml) and Non-White Race were found to be statistically significant in association with higher iron content. Mean iron content was 12.9 mg/g in the Non-White group versus 8.8 mg/g in the White group (p=0.0185). For every 100ml/kg increase in the cumulative blood volume transfused, the predicted iron content increased approximately 1 mg/g (p=0.0227); mean transfused blood volume was 340ml/kg among those who met criteria for iron overload versus 224ml/kg among those who did not (p=0.1858). We did not find any correlation between iron content and age at diagnosis, primary diagnosis, BMI at diagnosis, or gender. Conclusions: Iron overload continues to be a risk for pediatric cancer survivors and those who receive chronic transfusions. Our study revealed a statistically significant correlation between increased amount of blood transfusions and development of iron overload; however, no specific quantity of cumulative transfused blood volume was determined to be the threshold for risk. Our study also revealed a statistically significant correlation between Non-White race and the development of iron overload independent of cumulative transfused blood volume. It is possible there are race-based differences in iron metabolism that result in this increased risk. Further studies regarding specific quantities of blood transfusions, assessing physiologic characteristics of the Non-White patient population, and development of iron overload are needed. These findings indicate the importance of continuing to research the development of iron overload in the pediatric cancer and bone marrow transplant population, as well as provide guidance for understanding the risk each unique patient has for developing this complication.

Abstract 12735: Investigating Cardiac Function After Anthracycline Exposure in Childhood Cancer Survivors With Modifiable Cardiovascular Risk Factors

Introduction: Anthracycline exposure can lead to cardiac dysfunction, which may possibly be worsened by secondary cardiovascular risk factors (CVRFs), such as hypertension, hyperlipidemia, obesity and diabetes. The prognostic impact of CVRFs in childhood cancer survivors is largely unknown. Now with advanced cardiac imaging, it is now possible to identify how CVRFs might influence subclinical cardiac function. Hypothesis: Anthracycline-exposed childhood cancer survivors with CVRFs will demonstrate echocardiogram-based subclinical cardiac dysfunction more frequently than those without. Methods: This is a single-center, retrospective study. Inclusion criteria are: < 18 years old, history of anthracycline-containing chemotherapy and 2 echocardiograms performed. Exclusion criteria are: congenital cardiac disease, subsequent cancer relapse and inadequate imaging quality. Echocardiographic images were analyzed for longitudinal left ventricular strain, left ventricular ejection fraction (LVEF) and myocardial performance index (MPI). Wilcoxon rank-sum test was used to compare measures of cardiac function between patients with at least one CVRF (at time of cancer diagnosis) and patients without. Results: There were 111 patients identified with 49.5% having dysfunction at some point in time. CVRFs were identified in 19 patients with the majority of those being obese (52.6%). At baseline, there was a statistically significant difference in mean strain between those with CVRFs vs those without (-19.4% vs -21.3%). At 1-6 months after chemotherapy completion, LVEF was significantly reduced in those with CVRFs vs those without (48.7% vs 59.7%) as well as mean strain (-15.8% vs -20.0%). At >5 years after chemotherapy, there was a decrease in strain magnitude in those with CVRFs vs those without (-17.7% vs -20.5%) along with abnormal mean MPI (0.57 vs 0.44). Conclusions: Anthracycline-exposed pediatric cancer survivors with CVRFs demonstrate reduced cardiac function at baseline and both at near-and long-term follow-up. Further investigation is warranted to investigate the significance of these reduced echocardiographic measures and CVRFs among childhood cancer survivors to mitigate cardiac morbidity as they age into adulthood.

Circulating IL-17 reduces the risk of cisplatin-induced hearing loss in children: a bidirectional two-sample Mendelian randomization study

Studies have reported that cytokines and their related signaling pathways play a role in inner ear diseases. In clinical practice, approximately 50% of pediatric cancer patients experience irreversible hearing loss after cisplatin treatment. However, currently, there is a lack of systematic research on the causal relationship between circulating cytokines and cisplatin-induced hearing loss in children. Genetic variant data for 41 circulating cytokines were obtained from a meta-analysis of genome-wide association studies (GWAS) among 8293 individuals of Finnish descent. The GWAS data for Cisplatin-induced hearing loss in children were derived from a multicenter cohort of European pediatric cancer patients and survivors (N = 390), including both cases with hearing loss after cisplatin chemotherapy and controls without hearing loss. Multiple methods were employed for bidirectional Mendelian randomization (MR) estimation. Bonferroni correction was applied to adjust the original P-values, followed by a series of sensitivity analyses. In the directional Mendelian randomization (MR) analysis, it was found that IL-17 was significantly associated with a reduced risk of Cisplatin-induced hearing loss in children (OR: 0.18, CI: 0.06–0.48, P < 0.001, FDR = 0.041). In the reverse MR analysis, there were some nominal causal relationships of Cisplatin-induced hearing loss in children with certain cytokines [M-CSF: (OR: 1.04, CI: 1.01–1.08, P = 0.010, FDR = 0.41); IL-2RA: (OR: 1.03, CI: 1.00–1.05, P = 0.044, FDR = 0.447); MIP-1β: (OR: 1.02, CI: 1.00–1.04, P = 0.041, FDR = 0.447)]. leave-one-out analysis demonstrated that only M-CSF exhibited stability. These findings reveal a causal relationship between IL-17 and cisplatin-induced hearing loss in children. Further research is needed to determine the potential protective mechanisms of IL-17 in cisplatin-induced ototoxicity.

Impact of Survivorship Care Plans (SCP) on Mortality in a Contemporary Cohort of Pediatric Patients Diagnosed with a Blood Cancer

Background: The 5-year overall survival for pediatric blood cancer (i.e., leukemia, lymphoma) is greater than 85%. However, blood cancers and their treatment predispose survivors to the risk of late effects and premature mortality. This study examines the association between the receipt of a personalized survivorship care plan (SCP) and mortality among survivors of childhood blood cancer. Methods: This retrospective cohort included survivors who were treated for a newly diagnosed blood cancer at Children's Healthcare of Atlanta (CHOA) between 2002-2016 and in remission for ≥2 years post-treatment (i.e., eligible to be seen in Aflac Cancer Survivor Clinic). Descriptive analyses were conducted to examine SCP receipt and mortality through 12/31/2020 based on linkage to the National Death Index. The cumulative incidence of death was estimated from the time of eligibility for survivor clinic until the date of death, 12/31/2020, or five years (y) post-eligibility date, whichever occurred earlier. A multivariable Cox proportional-hazard model was used, with SCP receipt as a time-dependent variable, to estimate the association between SCP receipt and 5-year mortality, controlling for age at diagnosis, sex, race/ethnicity, and cancer therapy exposure. Results: Among the 1,239 eligible survivors identified, 982 (79.3%) received a SCP at a median time of 0.50 y (IQR: 0.21, 0.84 y) from eligibility for survivor clinic. Recipients of a SCP (vs. non-recipients) were more likely to be female (44.8% vs. 38.1%; p=0.055), non-Hispanic White (56.6% vs. 47.5%; p=0.006), and younger at the initial cancer diagnosis (mean ± SD age: 8.4 ± 5.4 vs. 11.0 ± 5.8 y; p&amp;lt;0.001). Receiving a SCP differed by cancer type: 82.3% of patients diagnosed with acute lymphoid leukemia (ALL), 86.3% of acute myeloid leukemia (AML) patients, and 80.6% of other leukemia patients received a SCP vs. 68.6% of Hodgkin lymphoma patients and 76.1% of non-Hodgkin lymphoma patients (p&amp;lt;0.001). Therapy exposure differed among SCP recipients, with 75.6% receiving chemotherapy alone, 12.9% chemotherapy and radiation therapy, and 11.5% stem cell transplantation (SCT) The unadjusted 5-year survival was not significantly different between survivors who received a SCP and those who did not (98.8% [95% CI: 98.1, 99.6] vs. 96.4% [93.9%, 98.9%], p=0.065). In multivariable analysis, receipt of a SCP was marginally associated with a lower risk of death (adjusted hazard ratio [aHR]: 0.37 [95% CI: 0.14, 1.01], p=0.053; Table 1). Additionally, receipt of SCT (aHR: 9.16 [95% CI: 3.34, 25.1], p&amp;lt;0.001) was associated with a higher risk of death. Conclusions: Early evaluation of our cohort eligible for a survivorship clinic suggests an association between the receipt of a SCP and a higher adjusted 5-year survival in pediatric blood cancer survivors. Receiving an SCT remains an independent risk factor for mortality. Longitudinal follow-up of this cohort allows for the assessment of mortality trajectory and pattern. Capture of healthcare utilization will inform the impact of survivorship care and further define lifetime risk after contemporary treatment.

12 Differential Processing Efficiency Skills in Survivors of Pediatric Primary CNS Cancer and Cancers of non-CNS Origin

Objective:Pediatric cancer and cancer-related treatments may disrupt brain development and place survivors at risk for long term problems with cognitive functions. Processing efficiency has been operationalized as a nuanced cognitive skill that reflects both processing speed (PS) and working memory (WM) abilities and is sensitive to neurobiological disruption. Pediatric cancer survivors are at risk for processing efficiency deficits; however, a thorough characterization of processing efficiency skills across pediatric primary central nervous system (CNS) tumor and non-CNS cancer survivors has not yet been reported.Participants and Methods:Participants were selected from a mixed retrospective clinical database of pediatric cancer survivors (Total n=160; primary CNS tumor n=33; Non-CNS n=127). Univariate analyses were conducted to examine differences in processing efficiency mean scores (t-tests) and percent impairment (scores &gt;1 SD below mean; chi-squared tests) between the total sample and normative sample, and across groups (CNS vs. Non-CNS). Multiple linear regressions were utilized to evaluate the relationships between additional risk factors, including biological sex, age at diagnosis, time since treatment, and socioeconomic status, and processing efficiency outcomes.Results:The total sample obtained lower scores on WM (M=90.83, SD=13.35) and PS (M=88.86, SD=14.38) measures than normative samples (M=100, SD=15), p &lt; 0.001. Greater percentage of pediatric cancer survivors demonstrated impairment across all processing efficiency measures (24.8-38.1%) than normative samples (15.9%), p &lt; 0.001. Regarding group differences, the CNS group obtained lower mean WM (M=84.85, SD =11.77) and PS (M=80, SD=14.18) scores than the Non-CNS group (WM M=92.39, SD=13.32; PS M=91.16, SD=13.56), p &lt; 0.001. Rates of impairment between groups only differed for PS scores, with 63.6% of the CNS group and 31.5% of the non-CNS group demonstrating impairment, p &lt; 0.001. Primary CNS tumor cancer type and male biological sex emerged as the only significant risk factors that predicted processing efficiency skills, with male sex predicting lower scores on PS (ß=8.91 p&lt;.001) and semantic fluency (ß=7.59, p=.007).Conclusions:These findings indicate that both pediatric primary CNS tumor and non-CNS cancer survivors exhibit substantial weaknesses in processing efficiency skills after treatment. While both groups demonstrated deficits compared to normative samples, the CNS group was more susceptible to PS impairments than non-CNS group. A basic initial study of the relationships between risk factors and processing efficiency skills revealed that primary CNS cancer was a predictor of lower performance on working memory and processing speed measures, while male biological sex was a significant risk factor for worse performance on processing speed and semantic fluency measures. Continued focus on the construct of processing efficiency in pediatric cancer survivors is warranted. Applying a standardized approach to assessing and communicating this nuanced cognitive skill could contribute to advancing both clinical practice and outcomes research of pediatric cancer survivors.

5 The Impact of Sex and Associations With Treatment Exposures on Neurocognitive Impairment in Pediatric Cancer Survivors: A report from the Childhood Cancer Survivor Study

Objective:Sexual dimorphism in human brain structure and behavior is influenced by exposure to sex hormones during critical developmental periods. In children, cancer and cancer treatments may alter hormone activity and brain development, impacting neurocognitive functions.Participants and Methods:Five-year survivors of childhood cancer (N=15,560) diagnosed at &lt;21 years from 1970 to 1999, and 3,206 siblings from the Childhood Cancer Survivor Study completed the Neurocognitive Questionnaire (NCQ), a measure of self-reported task efficiency (TE), emotion regulation (ER), Organization, and working memory (WM). We compared rates of cognitive impairment (i.e., NCQ scores &gt;90th percentile) in survivors and same-sex siblings, and sex differences in risk factors for cognitive impairment (i.e., treatment exposures, chronic health conditions (CHCs), cancer diagnosis, age at diagnosis) using modified Poisson regressions.Results:Survivors were more likely to report cognitive impairment than same-sex siblings (Males: TE OR=2.3, p&lt;.001; ER OR=1.7, p=.008; Organization OR=1.5, p=.04; WM OR=2.3, p&lt;.001. Females: TE OR=2.6, p&lt;.001; ER OR=1.9, p&lt;.001; Organization OR=1.5, p=.02; WM OR=2.6, p&lt;.001). Within survivors, females were more likely than males to report impairment in TE (OR=1.2, p=.001), ER (OR=1.5, p&lt;.001), and WM (OR=1.2, p&lt;.001). There were no sex differences in symptom severity in siblings (all ps&gt;.05). Risk factors for cognitive impairment in survivors included cranial radiation dose (TE &lt;20Gy OR=1.5, p=.008, ≥20Gy OR=2.5, p&lt;.001; ER OR=1.5, p&lt;.001; Organization &lt;20 Gy OR=1.4, p&lt;.001; &lt; WM 20 Gy OR=1.8, p&lt;.001, ≥20Gy OR=2.7, p&lt;.001), presence of moderate to severe CHCs (TE 1 CHC OR=1.9, p&lt;.001, &gt;1 CHC OR=3.6, p&lt;.001; ER 1 CHC OR=1.7, p&lt;.001, &gt;1 CHC OR=2.2, p&lt;.001; Organization 1 CHC OR=1.5, p=.001, &gt;1 CHC OR=2.5, p&lt;.001; WM 1 CHC OR=1.8, p&lt;.001, &gt;1 CHC OR=4.1, p&lt;.001). There were sex differences in cognitive impairment risk factors in survivors. In females, cranial radiation dose (&lt;20 Gy TE OR=1.6, p=.02; ≥20Gy TE OR=1.4, p=.01), leukemia diagnosis (TE OR=1.4, p=.02), or diagnosis age between 3-5 years (WM OR=1.4, p=.02) conferred higher risk for cognitive impairment compared to males with the same history. Females diagnosed with Hodgkin’s lymphoma (Organization OR=0.61, p=.05) or non-Hodgkin’s lymphoma (Organization OR=0.55, p=.03) were at lower risk for cognitive impairment compared to males.Conclusions:We found sex-specific differences in rates of, and risk factors for, neurocognitive impairment, suggesting a sex vulnerability. Future studies examining interactions between sex hormones and treatment exposures during brain development will enable tailoring treatments follow-up interventions to ensure that quality of life is maximized.

Impact of survivorship care plans on mortality in a contemporary cohort of childhood cancer survivors.

481 Background: Childhood cancer and its treatment predispose survivors to the risk of late effects, resulting in debilitating and life-threatening diseases. The heterogeneous construction and dissemination of survivorship care plans (SCPs) have raised the question of their ability to improve the quality of cancer survivorship care. This study aims to determine what populations of eligible patients were seen in a pediatric cancer survivor program and received a personalized SCP; and to investigate the association between receiving a SCP and overall mortality. Methods: This retrospective cohort study included patients treated for a newly diagnosed cancer at Children’s Healthcare of Atlanta (CHOA) in 2002-2016 who were ≥2 years post-treatment and in remission (i.e., eligibility to be seen in the Aflac Cancer Survivor Clinic of CHOA). Descriptive analyses were conducted to examine SCP receipt between 01/01/2005 and 12/31/2020 and mortality through 12/31/2020 based on linkage to the National Death Index. A multivariable cox proportional hazard model was used to estimate the association between SCP receipt and mortality, controlling for sex, race/ethnicity, and treatment with chemotherapy and/or radiation therapy. Results: Among 3,394 eligible pediatric cancer survivors, 1,894 (55.8%) received a SCP at a median of 0.7 years (Q1-Q3: 0.3-1.7 years) from eligibility for survivorship clinic. Recipients of a SCP were younger at original diagnosis (mean ± SD age: 7.7 ± 5.6 vs. 9.1 ± 6.0 years), more likely to be diagnosed with leukemia (82.9%) or lymphoma (70.7%) vs. CNS tumor (29.4%) or other solid tumor (35.1%) (p&lt;0.01), and more likely to have received chemotherapy (73.7% vs. 9.0%, p&lt;0.01) or radiation therapy (69.4% vs. 52.0%, p&lt;0.01). Overall, 3.4% of patients were deceased at the end of follow-up (median follow-up from eligibility: 7.0 [Q1-Q3: 4.0-10.8 years]). Receipt of a SCP was associated with an improvement in survival in multivariable model (adjusted hazard ratio: 0.31 [95% CI: 0.31, 0.46]). Conclusions: Overall survival was superior in survivors who received a SCP compared to those who did not. Longitudinal follow-up of this cohort enables us to examine patterns of death and healthcare utilization to delineate the effectiveness of survivorship care, and to further define lifetime risk after contemporary treatment.

22 Resilience and Functional Impairment in Latino Patients with Pediatric Brain Tumor (PBT)

Objective:Children with pediatric brain tumors (PBT) are at increased risk of psychosocial challenges (e.g., emotional distress, social difficulties), which in turn can result in functional impairment, or problems engaging appropriately across settings. These concerns have been shown to be especially pronounced in patients with lower socioeconomic status (SES), which tends to be overrepresented among ethnic minorities, such as Latino populations. On the other hand, resilience (the ability to utilize resources to alleviate stress and overcome adversity) can act as a protective factor against functional impairment. While resilience has been found to be lower among Latino survivors of pediatric cancer, little is known about the potential role of resilience in mitigating functional impairment among Latino patients with PBT. The authors hypothesized poorer resilience and increased functional impairment among Latino patients with PBT compared to normative expectations, in an attempt to explore need for additional support within this population.Participants and Methods:42 Latino patients with PBT ages 2-20 (x=11.08 years, SD=5.24) completed neuropsychological evaluation between 2018 and 2022. The sample was split relatively equally in terms of sex (47.6% male, 52.4% female), tumor location (45.2% infratentorial, 54.8% supratentorial), and household language (47.6% predominantly English, 52.4% predominantly Spanish). Outcome variables included Resiliency and Functional Impairment content scales from the Behavior Assessment Scale for Children – Third Edition: Parent Rating Scales (BASC-3: PRS). Standardized T-scores (x=50; SD=10) were derived using age-appropriate normative data, with higher T-scores indicating better resiliency, yet poorer functional impairment. Median household income for specific neighborhoods was used as a proxy for SES.Results:The sample as a whole did not deviate from age expectations in terms of resiliency [t(41)=-.469, p=.642] or functional impairment [t(38)=.118, p=.907]. However, when separated by household language, participants from English speaking households demonstrated lower resiliency and increased functional impairment as compared to both normative expectations [t(19)=-2.748, p=.006; t(18)=1.882, p=.038, respectively] and participants from Spanish speaking households [t(40)=-3.327, p=.002; t(37)=2.717, p=.010, respectively]. In contrast, participants from Spanish speaking households performed similarly to same-aged peers in terms of both resiliency [t(21)=1.931, p=.067] and functional impairment [t(19)=-1.969, p=.064]. Furthermore, household language predicted both resiliency [F(2, 39)=8.639, p=.0008] and functional impairment [F(2, 36)=6.203, p=.005] above and beyond SES, explaining an additional 29.4% (p=.0002) and 24.3% (p=.002) of the variation in these variables, respectively.Conclusions:Latino patients with PBT from Spanish speaking households had better reported resiliency and lower functional impairment than their counterparts from English speaking households. Given the subjective nature of parent reported outcomes and the importance of appropriately supporting patients and families from underserved populations, the roles of culturally-ingrained protective factors and cultural/linguistic differences in perceiving or articulating distress need further exploration. Future research, including comparison of parent report with objective measurement of impairment, is needed to better understand relationships between home language and these important variables. Additionally, examination of diagnostic and treatment-related factors will be beneficial to determine the best approaches to interventions and resources within this population.

56 Genetic Models for Long-Term Neurocognitive Outcomes in Pediatric Medulloblastoma and Traumatic Brain Injury

Objective:Children who suffer from brain insults (i.e., traumatic brain injury (TBI), chemotherapy and radiation treatment for brain tumors) are susceptible to late-emerging cognitive sequelae. Even with similar neurological risk variables, variability in long-term cognitive outcomes remains an area of investigation for researchers of acquired brain injury. Given the potential for genetic factors to influence response to chemoradiation, researchers have examined associations between germline, inherited, single nucleotide polymorphisms (SNPs), and neurocognitive outcomes for cancer survivors. Children who sustain an uncomplicated mild TBI generally recover without long-term neuropsychological consequences. However, TBI survivors have overlapping mechanism categories with cancer survivors through secondary injury variables that can be influenced by genomic variation (e.g., oxidative stress and neuroinflammation). Furthermore, the study of genomic vulnerability is limited in heterogenous groups of pediatric TBI survivors. This study aims to identify associations between genotype and long-term neurocognitive outcomes for acquired brain injury survivors by utilizing machine learning to uncover pathophysiological similarities and differences between groups.Participants and Methods:Fourteen brain tumor survivors, 139 traumatic brain injury survivors, and 63 healthy, age-matched controls completed the Letter N-back task to obtain performances on core neurocognitive skills (attention, working memory, and processing speed). Ten targeted genotypes were examined across five pathophysiological pathways (neurotransmission, oxidative stress, neuroinflammation, plasticity, growth and repair, and folate metabolism). Data were trained and tested utilizing three regression machine learning models. Mean estimated error and R2 were generated for each neurocognitive outcome. A feature importance score for models with positive variance was generated to determine how predictive a given SNP is for neurocognitive outcomes.Results:Genotype only accounted for a small amount of variance in cognitive outcomes when all clinical groups were combined. The mean absolute error for the best-fitting models from analyses where all groups were combined decreased when groups were examined separately; however, the differences in model R2 values were not significant. The relationship between brain tumor survivors and processing speed performance depended on genotype. Two SNPs had positive feature importance at the interaction level (rs58225473 and rs1801394). These SNPs are located on the CACNB2 and MTR genes and have functional consequences for neurotransmission and folate metabolism. Models of traumatic brain injury survivors did not explain positive variance and could not be examined for feature importance. Additionally, even when removing the only mechanism of action that should not be relevant for TBI survivors (folate metabolism polymorphisms), the TBI models still did not explain positive variance.Conclusions:Findings of the importance of two key SNPs on MTR and CACNB2 genes align with recent systematic reviews, which found associations between these polymorphisms and neuropsychological outcomes in more than one group or cohort of pediatric cancer survivors. Models for TBI survivors were limited by the heterogeneity of the group and ceiling effects on performance. An understanding of genetic vulnerabilities influenced by treatment and injury-related factors in acquired brain injury will inform our understanding of the developing and recovering childhood brain. The current study is an initial contribution to this goal and highlights the utility of machine learning methodology for future studies that examine the influence of genetic heterogeneity in pediatric acquired brain injury.

Loss of humeral immunity in childhood cancer survivors not having undergone hematopoietic stem cell transplantation.

Data are limited and conflicting regarding loss of immunity in childhood cancer survivors who did not undergo hematopoietic stem cell transplantation. The purpose of this retrospective, single center study is to provide further data to help build unifying revaccination guidelines post-chemotherapy in childhood cancer survivors not having undergone hematopoietic stem cell transplantation. This retrospective study included 28 childhood cancer survivors, 14 males and 14 females, whose treatment consisted of at least 3 months of chemotherapy and with confirmation of completing their primary vaccination series prior to therapy. The rate of vaccine titer seropositivity for cancer survivors was compared with the expected general population, based on long-term studies of anti-body persistence. Decreased seropositivity for measles, mumps, rubella, varicella, tetanus, and hepatitis B was found in patients across all categories of malignancy compared with the general population. However, tetanus was not statistically significant. Results were more pronounced for those with hematological malignancies. This study indicates that pediatric cancer survivors, especially those with hematological malignancies, may have greater loss of protective antibodies from primary vaccinations. Further studies are needed to provide guidelines for revaccination of both hematologic malignancies and solid tumor childhood cancer survivors who did not undergo hematopoietic stem cell transplantation.

VersKiK: Study protocol of an observational registry-based study on the current state of follow-up care and adherence to follow-up guidelines after cancer in childhood or adolescence

BackgroundThis article describes the study design of the quantitative part of the VersKiK study, The primary objectives of this study are to examine the occurrence of late effects in survivors of childhood or adolescent cancer (module 1), investigate health-related vulnerabilities and medical service utilization within this survivor group (modules 1 and 3), and assess the alignment between documented follow-up care for cardiological and audiological late effects with guideline recommendations, along with evaluating the extent of adherence among paediatric cancer survivors (module 3). MethodsThis is a non-interventional retrospective observational cohort study. It is based on stochastically linked insurance claims data from approximately 150,000 statutory insured persons with information concerning around 25,000–30,000 cancer survivors recorded in the German Childhood Cancer Register (GCCR). To explore adherence to selected follow-up guidelines, intention to treat treatment data from clinical study groups for particular diagnostic entities will be additionally included. DiscussionThe growing group of survivors after cancer in childhood and adolescence is representing a special population with an increasing demand for life-long healthcare services through relative high probability of late effects. Currently, there is a limited evidence in Germany on utilization of corresponding medical services and adherence to follow-up guidelines. With this study design, we are aiming to address these gaps and, consequently, suggest improvements to existing follow-up guidelines and follow-up care provision in Germany.

Pediatric Cancer Survivors Found to Have Higher Lifetime Risk of MH Disorders

Pediatric Cancer Survivors Found to Have Higher Lifetime Risk of MH Disorders

Where Are the Children? A Thematic Analysis of State, Territory, and Tribal Organization Comprehensive Cancer Control Plans

BackgroundThe Center for Disease Control's Comprehensive Cancer Control Program (CCCP) funds initiatives in fifty states, the District of Columbia, seven U.S. territories, and seven tribal organizations to prevent and control cancer. These initiatives influence policy, care, research, and advocacy for cancer treatment. We performed an analysis of CCCP plans for states, U.S. territories, and tribal organizations to understand the extent of inclusion of pediatric cancer care. MethodsWe conducted a thematic and quantitative analysis of CCCP plans for states, U.S. territories, and tribal organizations. Plans were assessed by two reviewers and scored for discussion of cancer prevention, risk factors, early detection and screening, treatment and innovation, access, barriers to care, and survivorship in childhood cancer. ResultsPlans from fifty states, the District of Columbia, seven territories, seven tribal organizations, and one Pacific Regional (USAPI) plan were reviewed, for a total of sixty-six plans. Up-to-date CCCP plans were available through the CDC or state websites for 74% of states, 57% of territories, and 71% of tribal organizations; older plans were available for all groups without up-to-date CCCP plans. While all plans referenced children, most did so in the context of childhood exposures influencing adult cancer risks (e.g., sun, tobacco, HPV). Few plans contained a section dedicated to childhood cancer (30% states, 14.3% territories, 14.3% tribes). A minority of plans specifically discussed early detection and screening (14% states, 0% territories, 14.3% tribes), treatment and innovation (32% states, 0% territories, 28.6% tribes), access to cancer care (38% states, 28.6% territories, 28.6% tribes), reducing barriers to cancer care (28% states, 42.9% territories, 28.6% tribes), and pediatric cancer survivorship (42% states, 0% territories, 28.6% tribes). ConclusionsPromoting inclusion of pediatric cancer in CCPs will help to standardize pediatric cancer care, eliminate treatment disparities across state lines, and allow for comprehensive understanding of pediatric oncology. Level of EvidenceLevel IV.

Informing the Delivery of Physical Activity Leadership for Pediatric Patients Undergoing Cancer Treatment

ABSTRACT Physical activity (PA) is an important facet in survivorship care. Standardized curriculum which teaches undergraduate student exercise leaders how to implement PA programs for childhood cancer survivors have not been developed. Delivery of PA programs are limited by resources, so utilizing students to lead PA sessions is a potentially cost-effective approach. The purpose of this study was to learn how to optimize mentorship of student PA leaders in pediatric oncology. The aims were to report on the level of guidance provided to the student PA leaders, share student PA leaders’ reflection of their mentorship and the challenges they faced. Student PA leaders designed and delivered a 31-week, virtual PA program to pediatric cancer survivors (5–18-year-olds). Mentors provided feedback on the recorded sessions. PA leaders were interviewed about their perceptions, their experiences and the type of feedback they valued the most. Student PA leaders received the most feedback during the first 2 weeks of the program, suggesting close oversight is needed during this time. Students valued the feedback on improving PA delivery/instruction the most. Students reported feeling anxious prior to sessions, especially when new content would be introduced because they were unsure how the patients would respond to the new activities. Reinforcing that the leaders have the ability to minimize PA barriers and provide support may help to resolve their anxiety of working with this population. Using a similar approach as presented in this paper may be advantageous in the development of high-performing PA leaders.

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Cisplatin triggers oxidative stress, apoptosis and pro-inflammatory responses by inhibiting the SIRT1-mediated Nrf2 pathway in chondrocytes.

Although the height of the proliferating layer that was suppressed in the growth plate has been recognized as an adverse effect of cisplatin in pediatric cancer survivors, the detailed pathological mechanism has not been elucidated. Sirtuin-1 (SIRT1) has been reported as an essential modulator of cartilage homeostasis, but its role in cisplatin-induced damage of chondrocytes remains unclear. In this study, we examined how cisplatin affected the expression of SIRT1 and cell viability. Next, we showed downregulation of SIRT1 after cisplatin treatment resulted in suppression of Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), leading to inhibition of Nrf2 nuclear translocation and subsequently decreased Heme oxygenase-1(HO-1) and NAD(P)H Quinone Dehydrogenase 1(NQO-1) expression. Blockage of the SIRT1/ PGC-1α axis not only increased oxidative stress with lower antioxidant SOD and GSH, but also contributed to mitochondrial dysfunction evidenced by the collapse of membrane potential and repression of mitochondrial DNA copy number and ATP. We also found that Cisplatin up-regulated the p38 phosphorylation, pro-inflammatory events and matrix metalloproteinases (MMPs) in chondrocytes through the SIRT1-modulated antioxidant manner. Collectively, our findings suggest that preservation of SIRT1 in chondrocytes may be a potential target to ameliorate growth plate dysfunction for cisplatin-receiving pediatric cancer survivors.

Systolic myocardial function measured by echocardiographic speckle-tracking and peak oxygen consumption in pediatric childhood cancer survivors-a PACCS study.

Cancer therapy-related cardiotoxicity is a major cause of cardiovascular morbidity in childhood cancer survivors. The aims of this study were to investigate systolic myocardial function and its association to cardiorespiratory fitness in pediatric childhood cancer survivors. In this sub-study of the international study "Physical Activity and fitness in Childhood Cancer Survivors" (PACCS), echocardiographic measures of left ventricular global longitudinal strain (LV-GLS) and right ventricular longitudinal strain (RV-LS) were measured in 128 childhood cancer survivors aged 9-18 years and in 23 age- and sex-matched controls. Cardiorespiratory fitness was measured as peak oxygen consumption achieved on treadmill and correlated to myocardial function. Mean LV-GLS was reduced in the childhood cancer survivors compared to the controls, -19.7% [95% confidence interval (CI) -20.1% to -19.3%] vs. -21.3% (95% CI: -22.2% to -20.3%) (p = 0.004), however, mainly within normal range. Only 13% of the childhood cancer survivors had reduced LV longitudinal strain z-score. Mean RV-LS was similar in the childhood cancer survivors and the controls, -23.2% (95% CI: -23.7% to -22.6%) vs. -23.3% (95% CI: -24.6% to -22.0%) (p = 0.8). In the childhood cancer survivors, lower myocardial function was associated with lower peak oxygen consumption [correlation coefficient (r) = -0.3 for LV-GLS]. Higher doses of anthracyclines (r = 0.5 for LV-GLS and 0.2 for RV-LS) and increasing time after treatment (r = 0.3 for LV-GLS and 0.2 for RV-LS) were associated with lower myocardial function. Left ventricular function, but not right ventricular function, was reduced in pediatric childhood cancer survivors compared to controls, and a lower left ventricular myocardial function was associated with lower peak oxygen consumption. Furthermore, higher anthracycline doses and increasing time after treatment were associated with lower myocardial function, implying that long-term follow-up is important in this population at risk.

Modeling Cardiotoxicity in Pediatric Oncology Patients Using Patient-Specific iPSC-Derived Cardiomyocytes Reveals Downregulation of Cardioprotective microRNAs.

Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.

Making sense of the cancer journey: Pediatric cancer survivors' and their parents' autobiographical memories.

Youth diagnosed with acute lymphoblastic leukemia (ALL) and their caregiver's experience a myriad of challenges in all domains of health that extend beyond treatment. Yet, little is known about how the cancer experience, and recollections associated with the experience, impact survivorship. We explored pediatric ALL survivors' and their caregivers' autobiographical memories of the cancer experience from diagnosis onwards. Survivors of ALL, and one of their caregivers, were recruited through a local clinic. Survivors and their caregivers completed a demographic survey and semi-structured, private, one-on-one interviews. Demographic information were analyzed using descriptive statistics. Interviews were transcribed verbatim and analyzed using reflexive thematic analysis at the level of the individual and dyad. Insights from survivors (N = 19; Mage = 15.3years) and their caregivers (n = 19; Mage = 45.4years) were captured. Analyses generated two themes contingent on role (i.e., survivor or caregiver): (1) It is hard to recall my cancer experience and (2) We did as much as we could to manage our child's cancer experience and two unified themes (present in both survivors and their caregivers): (3) It took a village to get through the cancer experience and (4) The cancer diagnosis and experience has had a lasting impact. Findings highlight the varied and long-lasting ways cancer impacts survivors of pediatric ALL and their caregivers. Survivors had difficultly remembering their experience or felt that information was withheld and were acutely aware of their caregiver's distress. Caregivers were cautious and intentionally limited the information they shared. Survivors desired to be included within, or told about, decisions related to their healthcare and were acutely aware of their caregiver's distress. Efforts should be made to communicate with survivors (from diagnosis onward) openly and to consider strategies to minimize the short- and long-term impacts of pediatric ALL among survivors and their caregivers.

Emotional and behavioral problems of pediatric cancer survivors and their siblings: Concordance of child self-report and parent proxy-report.

Childhood cancer confronts families with major challenges. The study aimed at developing an empirical and multi-perspective understanding of emotional and behavioral problems of cancer survivors diagnosed with leukemia and brain tumors and their siblings. Further, the concordance between child self-report and parent proxy-report was examined. 140 children (72 survivors, 68 siblings) and 309 parents were included in the analysis (respond rate: 34%). Patients, diagnosed with leukemia or brain tumors, and their families were surveyed on average 7.2months after the end of intensive therapy. Outcomes were assessed using the German SDQ. Results were compared with normative samples. Data were analyzed descriptively, and group differences between survivors, siblings, and a norm sample were determined using one-factor ANOVA followed by pairwise comparisons. The concordance between the parents and children was determined by calculating Cohen's kappa coefficient. No differences in the self-report of survivors and their siblings were identified. Both groups reported significantly more emotional problems and more prosocial behavior than the normative sample. Although the interrater reliability between parents and children was mostly significant, low concordances were found for emotional problems, prosocial behavior (survivor/parents), and peer relationship problems (siblings/parents). The findings point out the importance of psychosocial services in regular aftercare. These should not only focus on survivors, but additionally address the siblings' needs. The low concordance between the parents' and the children's perspectives on emotional problems, prosocial behavior, and peer relationship problems suggests the inclusion of both perspectives to allow needs-based support.