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Purpose: Although the potential transformative effect of electronic health record (EHR) data on clinical research in adult patient populations has been very extensively discussed, the effect on pediatric oncology research has been limited. Multiple factors contribute to this more limited effect, including the paucity of pediatric cancer cases in commercial EHR-derived cancer data sets and phenotypic case identification challenges in pediatric federated EHR data., Methods: The ExtractEHR software package was initially developed as a tool to improve clinical trial adverse event reporting but has expanded its use cases to include the development of multisite EHR data sets and the support of cancer cohorts. ExtractEHR enables customized, automated data extraction from the EHR that, when implemented across multiple hospitals, can create pediatric cancer EHR data sets to address a very wide range of research questions in pediatric oncology. After ExtractEHR data acquisition, EHR data can be cleaned and graded using CleanEHR and GradeEHR, companion software packages., Results: ExtractEHR has been installed at four leading pediatric institutions: Children's Healthcare of Atlanta, Children's Hospital of Philadelphia, Texas Children's Hospital, and Seattle Children's Hospital., Conclusion: ExtractEHR has supported multiple use cases, including five clinical epidemiology studies, multicenter clinical trials, and cancer cohort assembly. Work is ongoing to develop Fast Health care Interoperability Resources ExtractEHR and implement other sustainability and scalability enhancements.

We develop a Bayesian semiparametric model for the impact of dynamic treatment rules on survival among patients diagnosed with pediatric acute myeloid leukemia (AML). The data consist of a subset of patients enrolled in a phase III clinical trial in which patients move through a sequence of four treatment courses. At each course, they undergo treatment that may or may not include anthracyclines (ACT). While ACT is known to be effective at treating AML, it is also cardiotoxic and can lead to early death for some patients. Our task is to estimate the potential survival probability under hypothetical dynamic ACT treatment strategies, but there are several impediments. First, since ACT is not randomized, its effect on survival is confounded over time. Second, subjects initiate the next course depending on when they recover from the previous course, making timing potentially informative of subsequent treatment and survival. Third, patients may die or drop out before ever completing the full treatment sequence. We develop a generative Bayesian semiparametric model based on Gamma Process priors to address these complexities. At each treatment course, the model captures subjects' transition to subsequent treatment or death in continuous time. G-computation is used to compute a posterior over potential survival probability that is adjusted for time-varying confounding. Using our approach, we estimate the efficacy of hypothetical treatment rules that dynamically modify ACT based on evolving cardiac function., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. [br]For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Disparities in relapse and survival from high-risk neuroblastoma (HRNBL) persist among children from historically marginalized groups even in highly standardized clinical trial settings. Research in other cancers has identified differential treatment toxicity as one potential underlying mechanism. Whether racial and ethnic disparities in treatment-associated toxicity exist in HRNBL is poorly understood., Methods: This is a retrospective study utilizing a previously assembled merged cohort of children with HRNBL on Children's Oncology Group (COG) post-consolidation immunotherapy trials ANBL0032 and ANBL0931 at Pediatric Health Information System (PHIS) centers from 2005 to 2014. Race and ethnicity were categorized to reflect historically marginalized populations as Hispanic, non-Hispanic Black (NHB), non-Hispanic other (NHO), and non-Hispanic White (NHW). Associations between race-ethnicity and intensive care unit (ICU)-level care utilization as a proxy for treatment-associated toxicity were examined with log binomial regression and summarized as risk ratio (RR) and corresponding 95% confidence interval (CI)., Results: The analytic cohort included 370 children. Overall, 88 (23.8%) patients required ICU-level care for a median of 3.0 days (interquartile range [IQR]: 1.0-6.5 days). Hispanic children had nearly three times the risk of ICU-level care (RR 3.1, 95% CI: 2.1-4.5; fully adjusted RR [aRR] 2.5, 95% CI: 1.6-3.7) compared to NHW children and the highest percentage of children requiring cardiovascular-driven ICU-level care., Conclusion: Children of Hispanic ethnicity with HRNBL receiving clinical trial-delivered therapy were more likely to experience ICU-level care compared to NHW children. These data suggest that further investigation of treatment-related toxicity as a modifiable mechanism underlying outcome disparities is warranted., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Targeted cancer drugs (TCDs) have revolutionized oncology but vary in clinical benefit and patient out-of-pocket (OOP) costs. The American Society of Clinical Oncology (ASCO) Value Framework uses survival, toxicity, and symptom palliation data to quantify the net health benefit (NHB) of cancer drugs. We evaluated associations between NHB, uptake, and spending on oral TCDs., Methods: We conducted a retrospective cohort study of patients aged 18-64 years with an incident oral TCD pharmacy claim in 2012-2020 in a nationwide deidentified commercial claims dataset. TCDs were categorized as having high (>60), medium (40-60), and low (<40) NHB scores. We plotted the uptake of TCDs by NHB category and used standard descriptive statistics to evaluate patient OOP and total spending. Generalized linear models evaluated the relationship between spending and TCD NHB, adjusted for cancer indication., Results: We included 8524 patients with incident claims for 8 oral TCDs with 9 first-line indications in advanced melanoma, breast, lung, and pancreatic cancer. Medium- and high-NHB TCDs accounted for most TCD prescriptions. Median OOP spending was $18.78 for the first 28-day TCD supply (interquartile range [IQR] = $0.00-$87.57); 45% of patients paid $0 OOP. Median total spending was $10 118.79 (IQR = $6365.95-$10 600.37) for an incident 28-day TCD supply. Total spending increased $1083.56 for each 10-point increase in NHB score (95% confidence interval = $1050.27 to $1116.84, P < .01 for null hypothesis H0 = $0)., Conclusion: Low-NHB TCDs were prescribed less frequently than medium- and high-NHB TCDs. Total spending on oral TCDs was high and positively associated with NHB. Commercially insured patients were largely shielded from high OOP spending on oral TCDs., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Anthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421., Methods: Subjects received 135 units/m 2 /dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/- 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%-<50%., Results: Twenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m 2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF -3.3% [-7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p  = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF., Discussion: In this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562)., Competing Interests: KL declares: Jazz pharmaceuticals (consulting, advisory board participation); moderate conflict (annual payments $6 k); Abbott Diagnostics (research funding). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that the clinical trial within which these cardiac studies were conducted received drug supply and funding from Jazz Pharmaceuticals. The funder was involved in the review and approval of the clinical trial protocol., (© 2024 Leger, Absalon, Demissei, Smith, Gerbing, Alonzo, Narayan, Hirsch, Pollard, Razzouk, Getz, Aplenc, Kolb, Ky and Cooper.)

Objective: Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML)., Design: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States., Exposure: Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity., Outcome: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey., Result: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction., Conclusions: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Pediatric acute myeloid leukemia (AML) chemotherapy increases the risk of life-threatening complications, including septic shock (SS). An area-based measure of social determinants of health, the social disorganization index (SDI), was hypothesized to be associated with SS and SS-associated death (SS-death)., Methods: Children treated for de novo AML on two Children's Oncology Group trials at institutions contributing to the Pediatric Health Information System (PHIS) database were included. The SDI was calculated via residential zip code data from the US Census Bureau. SS was identified via PHIS resource utilization codes. SS-death was defined as death within 2 weeks of an antecedent SS event. Patients were followed from 7 days after the start of chemotherapy until the first of end of front-line therapy, death, relapse, or removal from study. Multivariable-adjusted Cox regressions estimated hazard ratios (HRs) comparing time to first SS by SDI group., Results: The assembled cohort included 700 patients, with 207 (29.6%) sustaining at least one SS event. There were 233 (33%) in the SDI-5 group (highest disorganization). Adjusted time to incident SS did not statistically significantly differ by SDI (reference, SDI-1; SDI-2: HR, 0.84 [95% confidence interval (CI), 0.51-1.41]; SDI-3: HR, 0.70 [95% CI, 0.42-1.16]; SDI-4: HR, 0.97 [95% CI, 0.61-1.53]; SDI-5: HR, 0.72 [95% CI, 0.45-1.14]). Nine patients (4.4%) with SS experienced SS-death; seven of these patients (78%) were in SDI-4 or SDI-5., Conclusions: In a large, nationally representative cohort of trial-enrolled pediatric patients with AML, there was no significant association between the SDI and time to SS., (© 2023 American Cancer Society.)

Case identification in administrative databases is challenging as diagnosis codes alone are not adequate for case ascertainment. We utilized machine learning (ML) to efficiently identify pediatric patients with newly diagnosed acute lymphoblastic leukemia. We tested nine ML models and validated the best model internally and externally. The optimal model had 97% positive predictive value (PPV) and 99% sensitivity in internal validation; 94% PPV and 82% sensitivity in external validation. Our ML model identified a large cohort of 21,044 patients, demonstrating an efficient approach for cohort assembly and enhancing the usability of administrative data., (© 2024 Wiley Periodicals LLC.)

Background: Despite the widespread implementation of telemedicine, there are limited data regarding its impact on key components of care for patients with incurable or high-risk cancer. For these patients, high-quality care requires detailed conversations regarding treatment priorities (advance care planning) and clinical care to minimize unnecessary acute care (unplanned hospitalizations). Whether telemedicine affects these outcomes relative to in-person clinic visits was examined among patients with cancer at high risk for 6-month mortality., Methods: This retrospective cohort study included adult patients with cancer with any tumor type treated at the University of Pennsylvania who were newly identified between April 1 and December 31, 2020, to be at high risk for 6-month mortality via a validated machine learning algorithm. Separate modified Poisson regressions were used to assess the occurrence of advance care planning and unplanned hospitalizations for telemedicine as compared to in-person visits. Additional analyses were done comparing telemedicine type (video or phone) as compared to in-person clinic visits., Results: The occurrence of advance care planning was similar between telemedicine and in-person visits (6.8% vs. 6.0%; adjusted risk ratio [aRR], 1.25; 95% CI, 0.92-1.69). In regard to telemedicine subtype, patients exposed to video encounters were modestly more likely to have documented advance care planning in comparison to those seen in person (7.5% vs. 6.0%; aRR, 1.48; 95% CI, 1.03-2.11). The 3-month risk for unplanned hospitalization was comparable for telemedicine compared to in-person clinic encounters (21% vs. 18%; aRR, 1.06; 95% CI, 0.81-1.38)., Conclusions: In this study, care delivered by telemedicine, compared to in-person clinic visits, produced comparable rates of advance care planning conversations without increasing hospitalizations, which suggests that vulnerable patients can be managed safely by telemedicine., (© 2023 American Cancer Society.)

We evaluated disparities in disease burden, organ dysfunction, vital signs, and timing of therapy in children newly presenting with acute leukemia. Among 899 patients with acute leukemia diagnosed at two large children's hospitals, a priori lab-based definitions of high disease burden, infection risk, renal dysfunction, and coagulopathy were applied to electronic health record data. Black patients with acute myeloid leukemia had increased prevalence of elevated white blood cell count and uric acid; Black patients with acute lymphoblastic leukemia demonstrated increased prevalence of coagulopathy. Black patients' presentation more frequently included multiple lab abnormalities consistent with advanced physiologic dysfunction. No differences were found in days to therapy initiation., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Pediatric acute myeloid leukemia (AML) therapy is associated with substantial short- and long-term treatment-related cardiotoxicity mainly due to high-dose anthracycline exposure. Early left ventricular systolic dysfunction (LVSD) compromises anthracycline delivery and is associated with inferior event-free and overall survival in de novo pediatric AML. Thus, effective cardioprotective strategies and cardiotoxicity risk predictors are critical to optimize cancer therapy delivery and enable early interventions to prevent progressive LVSD. While dexrazoxane-based cardioprotection reduces short-term cardiotoxicity without compromising cancer survival, liposomal anthracycline formulations have the potential to mitigate cardiotoxicity while improving antitumor efficacy. This overview summarizes the rationale and methodology of cardiac substudies within AAML1831, a randomized Children's Oncology Group Phase 3 study of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in comparison with standard daunorubicin/cytarabine with dexrazoxane in the treatment of de novo pediatric AML., Methods/design: Children (age <22 years) with newly diagnosed AML were enrolled and randomized to CPX-351-containing induction 1 and 2 (Arm A) or standard daunorubicin and dexrazoxane-containing induction (Arm B). Embedded cardiac correlative studies aim to compare the efficacy of this liposomal anthracycline formulation to dexrazoxane for primary prevention of cardiotoxicity by detailed core lab analysis of standardized echocardiograms and serial cardiac biomarkers throughout AML therapy and in follow-up. In addition, AAML1831 will assess the ability of early changes in sensitive echo indices (e.g., global longitudinal strain) and cardiac biomarkers (e.g., troponin and natriuretic peptides) to predict subsequent LVSD. Finally, AAML1831 establishes expert consensus-based strategies in cardiac monitoring and anthracycline dose modification to balance the potentially competing priorities of cardiotoxicity reduction with optimal leukemia therapy., Discussion: This study will inform diagnostic, prognostic, preventative, and treatment strategies regarding cardiotoxicity during pediatric AML therapy. Together, these measures have the potential to improve leukemia-free and overall survival and long-term cardiovascular health in children with AML. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT04293562., Competing Interests: KL, Jazz Pharmaceuticals (consulting, advisory board participation); KL and EC, Abbott Diagnostics (research funding). The reviewer YR declared a shared committee COG with the authors to the handling editor. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Leger, Robison, Narayan, Smith, Tsega, Chung, Daniels, Chen, Englefield, Demissei, Lefebvre, Morrow, Dizon, Gerbing, Pabari, Getz, Aplenc, Pollard, Chow, Tang, Border, Sachdeva, Alonzo, Kolb, Cooper and Ky.)

Purpose: Chemotherapy for pediatric acute myeloid leukemia (AML) is very intensive and many, but not all centers, require extended hospitalization until neutrophil recovery. Child and family preferences, beliefs, and experiences around hospitalization have not been systematically assessed., Patients and Methods: We recruited children with AML and their parents from nine pediatric cancer centers across the United States for a qualitative interview about their experiences of neutropenia management. Interviews were analyzed using a conventional content analysis approach., Results: Of 116 eligible individuals, 86 (74.1%) agreed to participate. Interviews were conducted with 32 children and 54 parents from 57 families. Of these 57 families, 39 were cared for as inpatients and 18 were managed as outpatients. A very high proportion of respondents in both groups reported satisfaction with the discharge management strategy recommended by the treating institution: 86% (57 individuals) of respondents who experienced inpatient management and 85% (17 individuals) of respondents who experienced outpatient management expressed satisfaction. Respondent perceptions associated with satisfaction related to safety (access to emergency interventions, infection risk, close monitoring) and psychosocial concerns (family separation, low morale, social support). Respondents believed it could not be assumed that all children would have the same experience due to varied life circumstances., Conclusion: Children with AML and their parents express a very high degree of satisfaction with the discharge strategy recommended by their treating institution. Respondents saw a nuanced tradeoff between patient safety and psychosocial concerns that was mediated by a child's life circumstances., (© 2023 Wiley Periodicals LLC.)

Importance: Cardiovascular (CV) disease is a substantial cause of morbidity and mortality in cancer due to shared risk factors and exposure to potentially cardiotoxic cancer therapy. However, our understanding of CV risk in patients with head and neck squamous cell carcinoma (HNSCC) is limited., Objective: To define CV risk profiles, incident stroke, myocardial infarction (MI), and mortality in patients with HNSCC., Design, Setting, and Participants: This retrospective, population-based cohort study included 35 897 US veterans with newly diagnosed HNSCC from January 1, 2000, to December 31, 2020. Data were analyzed from May 2022 to January 2023., Exposures: Demographic, cancer-specific, and treatment characteristics., Main Outcomes: Prevalence of CV risk factors, medication use, and control at HNSCC diagnosis; cumulative incidence of stroke and MI; and all-cause death., Results: Of 35 857 US veterans with HNSCC (median [IQR] age, 63 [58-69] years; 176 [0.5%] American Indian or Alaska Native, 57 [0.2%] Asian, 5321 [16.6%] Black, 207 [0.6%] Native Hawaiian or Other Pacific Islander, and 26 277 [82.0%] White individuals), there were high rates of former or current smoking (16 341 [83%]), hypertension (24 023 [67%]), diabetes (7988 [22%]), and hyperlipidemia (18 421 [51%]). Although most patients were taking risk-lowering medications, 15 941 (47%) had at least 1 uncontrolled CV risk factor. Black race was associated with increased risk of having uncontrolled CV risk factor(s) (relative risk, 1.06; 95% CI, 1.03-1.09), and patients with larynx cancer had higher rates of prevalent and uncontrolled risk factors compared with other cancer subsites. Considering death as a competing risk, the 10-year cumulative incidence of stroke and MI was 12.5% and 8.3%, respectively. In cause-specific hazards models, hypertension, diabetes, carotid artery stenosis, coronary artery disease, and presence of uncontrolled CV risk factor(s) were significantly associated with stroke and MI. In extended Cox models, incident stroke and MI were associated with a 47% (95% CI, 41%-54%) and 71% (95% CI, 63%-81%) increased risk of all-cause death, respectively., Conclusion: The results of this cohort study suggest that in HNSCC, the burden of suboptimally controlled CV risk factors and incident risk of stroke and MI are substantial. Modifiable CV risk factors are associated with risk of adverse CV events, and these events are associated with a higher risk of death. These findings identify populations at risk and potentially underscore the importance of modifiable CV risk factor control and motivate strategies to reduce CV risk in HNSCC survivorship care.

Beckwith-Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context., (© 2023 Wiley Periodicals LLC.)

Children living in poverty experience excessive relapse and death from newly diagnosed acute lymphoblastic leukemia (ALL). The influence of household poverty and neighborhood social determinants on outcomes from chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (r/r) leukemia is poorly described. We identified patients with r/r CD19+ ALL/lymphoblastic lymphoma treated on CD19-directed CAR T-cell clinical trials or with commercial tisagenlecleucel from 2012 to 2020. Socioeconomic status (SES) was proxied at the household level, with poverty exposure defined as Medicaid-only insurance. Low-neighborhood opportunity was defined by the Childhood Opportunity Index. Among 206 patients aged 1 to 29, 35.9% were exposed to household poverty, and 24.9% had low-neighborhood opportunity. Patients unexposed to household poverty or low-opportunity neighborhoods were more likely to receive CAR T-cell therapy with a high disease burden (>25%), a disease characteristic associated with inferior outcomes, as compared with less advantaged patients (38% vs 30%; 37% vs 26%). Complete remission (CR) rate was 93%, with no significant differences by household poverty (P = .334) or neighborhood opportunity (P = .504). In multivariate analysis, patients from low-opportunity neighborhoods experienced an increased hazard of relapse as compared with others (P = .006; adjusted hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.3-4.1). There was no difference in hazard of death (P = .545; adjusted HR, 1.2; 95% CI, 0.6-2.4). Among children who successfully receive CAR T-cell therapy, CR and overall survival are equitable regardless of proxied SES and neighborhood opportunity. Children from more advantaged households and neighborhoods receive CAR T-cell therapy with a higher disease burden. Investigation of multicenter outcomes and access disparities outside of clinical trial settings is warranted., (© 2023 by The American Society of Hematology.)

Background: Bloodstream infections (BSIs) are a frequent cause of morbidity in patients with acute myeloid leukemia (AML), due in part to the presence of central venous access devices (CVADs) required to deliver therapy., Objective: To determine the differential risk of bacterial BSI during neutropenia by CVAD type in pediatric patients with AML., Methods: We performed a secondary analysis in a cohort of 560 pediatric patients (1,828 chemotherapy courses) receiving frontline AML chemotherapy at 17 US centers. The exposure was CVAD type at course start: tunneled externalized catheter (TEC), peripherally inserted central catheter (PICC), or totally implanted catheter (TIC). The primary outcome was course-specific incident bacterial BSI; secondary outcomes included mucosal barrier injury (MBI)-BSI and non-MBI BSI. Poisson regression was used to compute adjusted rate ratios comparing BSI occurrence during neutropenia by line type, controlling for demographic, clinical, and hospital-level characteristics., Results: The rate of BSI did not differ by CVAD type: 11 BSIs per 1,000 neutropenic days for TECs, 13.7 for PICCs, and 10.7 for TICs. After adjustment, there was no statistically significant association between CVAD type and BSI: PICC incident rate ratio [IRR] = 1.00 (95% confidence interval [CI], 0.75-1.32) and TIC IRR = 0.83 (95% CI, 0.49-1.41) compared to TEC. When MBI and non-MBI were examined separately, results were similar., Conclusions: In this large, multicenter cohort of pediatric AML patients, we found no difference in the rate of BSI during neutropenia by CVAD type. This may be due to a risk-profile for BSI that is unique to AML patients.

Background: An adequate absolute lymphocyte count (ALC) is an essential first step in autologous chimeric antigen receptor (CAR) T-cell manufacturing. For patients with acute myelogenous leukemia (AML), the intensity of chemotherapy received may affect adequate ALC recovery required for CAR T-cell production. We sought to analyze ALC following each course of upfront therapy as one metric for CAR T-cell manufacturing feasibility in children and young adults with AML., Procedure: ALC data were collected from an observational study of patients with newly diagnosed AML between the ages of 1 month and 21 years who received treatment between the years of 2006 and 2018 at one of three hospitals in the Leukemia Electronic Abstraction of Records Network (LEARN) consortium., Results: Among 193 patients with sufficient ALC data for analysis, the median ALC following induction 1 was 1715 cells/μl (interquartile range: 1166-2388), with successive decreases in ALC with each subsequent course. Similarly, the proportion of patients achieving an ALC >400 cells/μl decreased following each course, ranging from 98.4% (190/193) after course 1 to 66.7% (22/33) for patients who received a fifth course of therapy., Conclusions: There is a successive decline of ALC recovery with subsequent courses of chemotherapy. Despite this decline, ALC values are likely sufficient to consider apheresis prior to the initiation of each course of upfront therapy for the majority of newly diagnosed pediatric AML patients, thereby providing a window of opportunity for T-cell collection for those patients identified at high risk of relapse or with refractory disease., (© 2022 Wiley Periodicals LLC.)

Cardio-oncology research studies often require consideration of potential competing risks, as the occurrence of other events (eg, cancer-related death) may preclude the primary event of interest (eg, cardiovascular outcome). However, the decision to conduct competing risks analysis is not always straightforward, and even when deemed necessary, misconceptions exist about the appropriate choice of analytical methods to address the competing risks. R researchers are encouraged to consider competing risks at the study design stage and are provided provide an assessment tool to guide decisions on analytical approach on the basis of study objectives. The existing statistical methods for competing risks analysis, including cumulative incidence estimations and regression modeling are also reviewed. Cardio-oncology-specific examples are used to illustrate these concepts and highlight potential pitfalls and misinterpretations. R code is also provided for these analyses., Competing Interests: Dr Getz has received support for research effort from a National Heart, Lung, and Blood Institute career development grant (5K01HL143153). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Adverse events are often misreported in clinical trials, leading to an incomplete understanding of toxicities. We aimed to test automated laboratory adverse event ascertainment and grading (via the ExtractEHR automated package) to assess its scalability and define adverse event rates for children with acute myeloid leukaemia and acute lymphoblastic leukaemia., Methods: For this retrospective cohort study from the Children's Oncology Group (COG), we included patients aged 0-22 years treated for acute myeloid leukaemia or acute lymphoblastic leukaemia at Children's Healthcare of Atlanta (Atlanta, GA, USA) from Jan 1, 2010, to Nov 1, 2018, at the Children's Hospital of Philadelphia (Philadelphia, PA, USA) from Jan 1, 2011, to Dec 31, 2014, and at the Texas Children's Hospital (Houston, TX, USA) from Jan 1, 2011, to Dec 31, 2014. The ExtractEHR automated package acquired, cleaned, and graded laboratory data as per Common Terminology Criteria for Adverse Events (CTCAE) version 5 for 22 commonly evaluated grade 3-4 adverse events (fatal events were not evaluated) with numerically based CTCAE definitions. Descriptive statistics tabulated adverse event frequencies. Adverse events ascertained by ExtractEHR were compared to manually reported adverse events for patients enrolled in two COG trials (AAML1031, NCT01371981; AALL0932, NCT02883049). Analyses were restricted to protocol-defined chemotherapy courses (induction I, induction II, intensification I, intensification II, and intensification III for acute myeloid leukaemia; induction, consolidation, interim maintenance, delayed intensification, and maintenance for acute lymphoblastic leukaemia)., Findings: Laboratory adverse event data from 1077 patients (583 from Children's Healthcare of Atlanta, 200 from the Children's Hospital of Philadelphia, and 294 from the Texas Children's Hospital) who underwent 4611 courses (549 for acute myeloid leukaemia and 4062 for acute lymphoblastic leukaemia) were extracted, processed, and graded. Of the 166 patients with acute myeloid leukaemia, 86 (52%) were female, 80 (48%) were male, 96 (58%) were White, and 132 (80%) were non-Hispanic. Of the 911 patients with acute lymphoblastic leukaemia, 406 (45%) were female, 505 (55%) were male, 596 (65%) were White, and 641 (70%) were non-Hispanic. Patients with acute myeloid leukaemia had the most adverse events during induction I and intensification II. Hypokalaemia (one [17%] of six to 75 [48%] of 156 courses) and alanine aminotransferase (ALT) increased (13 [10%] of 134 to 27 [17%] of 156 courses) were the most prevalent non-haematological adverse events in patients with acute myeloid leukaemia, as identified by ExtractEHR. Patients with acute lymphoblastic leukaemia had the greatest number of adverse events during induction and maintenance (eight adverse events with prevalence ≥10%; induction and maintenance: anaemia, platelet count decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, ALT increased, and hypocalcaemia; induction: hypokalaemia; maintenance: aspartate aminotransferase [AST] increased and blood bilirubin increased), as identified by ExtractEHR. 187 (85%) of 220 total comparisons in 22 adverse events in four AAML1031 and six AALL0923 courses were substantially higher with ExtractEHR than COG-reported adverse event rates for adverse events with a prevalence of at least 2%., Interpretation: ExtractEHR is scalable and accurately defines laboratory adverse event rates for paediatric acute leukaemia; moreover, ExtractEHR seems to detect higher rates of laboratory adverse events than those reported in COG trials. These rates can be used for comparisons between therapies and to counsel patients treated on or off trials about the risks of chemotherapy. ExtractEHR-based adverse event ascertainment can improve reporting of laboratory adverse events in clinical trials., Funding: US National Institutes of Health, St Baldrick's Foundation, and Alex's Lemonade Stand Foundation., Competing Interests: Declaration of interests SMC and PCA disclose relationships with the Children's Oncology Group as group and study chairs. MHD received funding from Alex's Lemonade Stand Foundation for this study and funding from Epic Systems. BTF and DSH have received funding from Pfizer and Merck. BTF has also received funding from Astellas. MMG, TPM, and PCA have received research funding from the National Institutes of Health and National Cancer Institute. KDG has received research funding from the US National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute. MMG's institution has a grant to receive funding from the Cancer Prevention Research Institute of Texas, Hyundai Hope on Wheels, the American Society of Clinical Oncology, Children's Cancer Cause, and the American Society of Clinical Investigation. DSH has received funding from Incyte, Eli Lilly, E R Squibb & Sons, Jazz Pharmaceuticals, Bayer, and AstraZeneca. PCA is currently employed by Sanofi. RWG has leadership roles on the board of the American Academy of Pediatrics and the American Board of Pediatrics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure., Methods: We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse., Results: Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment., Conclusion: Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Cardiovascular events are an important cause of morbidity in patients with oropharyngeal squamous cell carcinoma (OPSCC). Radiation and chemotherapy have been associated with increased risk of stroke; up-front surgery allows the opportunity for (chemo)radiotherapy de-escalation., Objective: To evaluate whether up-front surgery was associated with decreased stroke risk compared to nonsurgical treatment for OPSCC., Design, Setting, and Participants: This cohort study was conducted at the US Veterans Health Administration and examined US veterans diagnosed with nonmetastatic OPSCC from 2000 to 2020. Data cutoff was September 17, 2021, and data analysis was performed from October 2021 to February 2022., Exposures: Up-front surgical treatment or definitive (chemo)radiotherapy as captured in cancer registry., Main Outcomes and Measures: Cumulative incidence of stroke, accounting for death as a competing risk; and association between up-front surgery and stroke risk. After generating propensity scores for the probability of receiving surgical treatment and using inverse probability weighting (IPW) to construct balanced pseudo-populations, Cox regression was used to estimate a cause-specific hazard ratio (csHR) of stroke associated with surgical vs nonsurgical treatment., Results: Of 10 436 patients, median (IQR) age was 61 (56-67) years; 10 329 (99%) were male; 1319 (13%) were Black, and 7823 (75%) were White; 2717 received up-front surgery, and 7719 received nonsurgical therapy with definitive (chemo)radiotherapy. The 10-year cumulative incidence of stroke was 12.5% (95% CI, 11.8%-13.3%) and death was 57.3% (95% CI, 56.2%-58.4%). Surgical patients who also received (chemo)radiotherapy had shorter radiation and chemotherapy courses than nonsurgical patients. After propensity score and IPW, the csHR of stroke for surgical treatment was 0.77 (95% CI, 0.66-0.91). This association was consistent across subgroups defined by age and baseline cardiovascular risk factors., Conclusions and Relevance: In this cohort study, up-front surgical treatment was associated with a 23% reduced risk of stroke compared with definitive (chemo)radiotherapy. These findings present an important additional risk-benefit consideration to factor into treatment decisions and patient counseling and should motivate future studies to examine cardiovascular events in this high-risk population.

Background: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL., Procedure: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors., Results: We identified 126 eligible patients, of whom 63% were documented as White, non-Hispanic, 28% as non-White, non-Hispanic, and 9% as Hispanic. Twenty-eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78-0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47-8.36)., Conclusions: Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children., (© 2021 Wiley Periodicals LLC.)

Background: Timely targeted treatment initiation can be challenging because additional biomarker testing is needed for eligibility. The authors hypothesized that timely targeted treatment improves survival relative to nontimely initiation in metastatic HER2+ gastroesophageal adenocarcinoma (GEA)., Methods: The authors performed a retrospective cohort study of metastatic HER2+ GEA treated with first-line (1L) systemic therapy from January 2011 to December 2017 using a nationwide electronic health record-derived deidentified database. Timely targeted treatment-trastuzumab initiation within 14 days after starting 1L chemotherapy-was assessed as a time-varying exposure. Nontimely targeted treatment included patients who initiated trastuzumab after 14 days or who lacked documentation of receiving trastuzumab. Extended Cox regressions compared overall survival (OS) and progression-free survival (PFS) between timely and nontimely groups., Results: A total of 320 patients were included; 59.1% received timely trastuzumab. Relative to nontimely initiation, timely trastuzumab was associated with significantly higher OS (2-year OS, 32.1% vs 15.3%; adjusted hazard ratio [HR], 0.67; 95% CI, 0.51-0.88) and PFS (2-year PFS, 9.2% vs 3.7%; adjusted HR, 0.71; 95% CI, 0.55-0.93). Results remained similar in sensitivity analyses 1) using alternative "timeliness" definitions up to 70 days after starting 1L chemotherapy, 2) comparing any trastuzumab, regardless of timing of initiation, to no trastuzumab, and 3) excluding patients lacking documentation of receiving trastuzumab., Conclusions: Improved survival was observed among metastatic HER2+ GEA patients treated with trastuzumab versus those who were not, regardless of timing of initiation. Although these results reassure clinicians that modest targeted treatment delays may not be detrimental to outcomes, efforts should still ensure that all metastatic HER2+ GEA patients receive trastuzumab., (© 2022 American Cancer Society.)

The relationship between center-specific variation in indication for pediatric heart transplantation and short-term outcomes after heart transplantation is not well described. We used merged patient- and hospital-level data from the United Network for Organ Sharing and the Pediatric Health Information Systems to analyze outcomes according to transplant indication for a cohort of children (≤ 21 years old) who underwent heart transplantation between 2004 and 2015. Outcomes included 30-day mortality, transplant hospital admission mortality, and hospital length of stay, with multivariable adjustment performed according to patient and center characteristics. The merged cohort reflected 2169 heart transplants at 20 U.S. centers. The median number of transplants annually at each center was 11.6, but ranged from 3.5 to 22.6 transplants/year. Congenital heart disease was the indication in the plurality of cases (49.2%), with cardiomyopathy (46%) and myocarditis (4.8%) accounting for the remainder. There was significant center-to-center variability in congenital heart disease as the principal indication, ranging from 15% to 66% (P < 0.0001). After adjustment, neither center volume nor proportion of indications for transplantation were associated with 30-day or transplant hospital admission mortality. In this large, merged pediatric cohort, variation was observed at center level in annual transplant volume and prevalence of indications for heart transplantation. Despite this variability, center volume and proportion of indications represented at a given center did not appear to impact short-term outcomes., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Both short and long interpregnancy intervals (IPIs) have been associated with adverse birth outcomes. We undertook a multistate study to describe the prevalence of selected birth defects by IPI., Methods: We obtained data from nine population-based state birth defects registries for singleton live births in 2000-2009 among mothers with a previous live birth identified through birth certificates. IPI was calculated as the difference between prior birthdate and start of the current pregnancy (conception date). We estimated prevalence of selected defects per 10,000 live births and prevalence ratios (PRs) with 95% confidence intervals (CIs) overall and stratified by maternal age at previous birth and race/ethnicity. Primary analyses focused on short IPI < 6 months and long IPI ≥ 60 months compared to 18-23 months (referent). Sensitivity analyses limited to active-surveillance states and those with<10% missing IPI., Results: Among 5,147,962 eligible births, 6.3% had short IPI while 19.8% had long IPI. Compared to referent, prevalence with short IPI was elevated for gastroschisis (3.7, CI: 3.0-4.5 vs. 2.0, CI: 1.6-2.4) and with both short and long IPI for tetralogy of Fallot (short: 3.4, 2.8-4.2 long: 3.8, 3.4-4.3 vs. 2.7, 2.3-3.2) and cleft lip ± palate (short: 9.9, 8.8-11.2 long: 9.2, 8.5-9.8 vs. 8.4, 7.6-9.2). Stratified analyses identified additional associations, including elevated prevalence of anencephaly with short IPI in younger mothers and limb defects with long IPI in those ages 25-34 at prior birth. Sensitivity analyses showed similar results., Conclusion: In this population-based study, we observed increased prevalence of several birth defects with short and long IPI., (© 2021 Wiley Periodicals LLC.)

Background: The optimal number of chemotherapy courses for low-risk (LR) pediatric acute myeloid leukemia (AML) is not known., Objective: To compare outcomes for four (21.6 g/m 2 cytarabine) versus five (45.6 g/m 2 cytarabine) chemotherapy courses for LR-AML using data from Children's Oncology Group (COG) AAML0531 and AAML1031., Methods: We compared relapse risk (RR), disease-free survival (DFS), and overall survival (OS), and the differential impact in LR subgroups for patients receiving four versus five chemotherapy courses. Cox (OS and DFS) and risk (RR) regressions were used to estimate hazard ratios (HR) to compare outcomes., Results: A total of 923 LR-AML patients were included; 21% received five courses. Overall, LR-AML patients who received four courses had higher RR (40.9% vs. 31.4%; HR = 1.40, 95% confidence interval [CI]: 1.06-1.85), and worse DFS (56.0% vs. 67.0%; HR = 1.45, 95% CI: 1.10-1.91). There was a similar decrement in OS though it was not statistically significant (77.0% vs. 83.5%; HR = 1.45, 95% CI: 0.97-2.17). Stratified analyses revealed the detrimental effects of cytarabine dose de-escalation to be most pronounced in the LR-AML subgroup with uninformative cytogenetic/molecular features who were minimal residual disease (MRD) negative after the first induction course (EOI1). The absolute decrease in DFS with four courses for patients with favorable cytogenetic/molecular features and positive MRD was similar to that observed for patients with uninformative cytogenetic/molecular features and negative MRD at EOI1, though not statistically significant., Conclusions: Our results support de-escalation of cytarabine exposure through the elimination of a fifth chemotherapy course only for LR-AML patients who have both favorable cytogenetic/molecular features and negative MRD after the first induction cycle., (© 2021 Wiley Periodicals LLC.)

Anthracycline chemotherapy remains an integral component of modern pediatric acute myeloid leukemia (AML) regimens and is often delivered at high doses to maximize cancer survival. Unfortunately, high-dose anthracyclines are associated with a significant risk of cardiotoxicity, which may result in early and/or long-term left ventricular systolic dysfunction and heart failure. Moreover, the development of cardiotoxicity during pediatric AML therapy is associated with lower event-free and overall survival, which may be partially attributable to incomplete anthracycline delivery. A combined strategy of primary cardioprotection and close cardiac monitoring can maximize chemotherapy delivery while reducing the toxicity of intensive AML therapy. Primary cardioprotection using dexrazoxane reduces short-term cardiotoxicity without compromising cancer survival. Liposomal anthracycline formulations, which are under active investigation, have the potential to mitigate cardiotoxicity while also improving antitumor efficacy. Primary cardioprotective strategies may reduce but not eliminate the risk of cardiotoxicity; therefore, close cardiac monitoring is also needed. Standard cardiac monitoring consists of serial echocardiographic assessments for left ventricular ejection fraction decline. Global longitudinal strain has prognostic utility in cancer therapy-related cardiotoxicity and may be used as an adjunct assessment. Additional cardioprotective measures should be considered in response to significant cardiotoxicity; these include cardiac remodeling medications to support cardiac recovery and anthracycline dose interruption and/or regimen modifications. However, the withholding of anthracyclines should be limited to avoid compromising cancer survival. A careful approach to cardioprotection during AML therapy is critical to maximize the efficacy of leukemia treatment while minimizing the short- and long-term risks of cardiotoxicity., (Copyright © 2021 by The American Society of Hematology.)

Background: High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531., Methods: Patients on AAML0531 received cytarabine (1600 mg/m 2 )/daunorubicin (150 mg/m 2 )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48 mg/m 2 )/cytarabine (8000 mg/m 2 ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE., Results: MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p = .87; measurable residual disease [MRD]+: 57% vs. 46%, p = .34); or intensification I response (CR: 79% vs. 94%, p = .27; MRD+: 27% vs. 20%, p = 1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p = .63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p = .66). MA was associated with slower neutrophil recovery (median 34 vs. 27 days, p = .007) and platelet recovery (median 29 vs. 24.5 days, p = .04) and longer hospital stay (32 vs. 28 days, p = .01) during induction II., Conclusion: Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593)., (© 2021 Wiley Periodicals LLC.)

Beckwith-Wiedemann Spectrum (BWSp) is the most common epigenetic childhood cancer predisposition disorder. BWSp is caused by (epi)genetic changes affecting the BWS critical region on chromosome 11p15. Clinically, BWSp represents complex molecular and phenotypic heterogeneity resulting in a range of presentations from Classic BWS to milder features. The previously reported tumor risk based on Classic BWS cohorts is 8-10% and routine tumor screening has been recommended. This work investigated the tumor risk and correlation with phenotype within a cohort of patients from Classic BWS to BWSp using a mixed-methods approach to explore phenotype and epigenotype profiles associated with tumor development through statistical analyses with post-hoc retrospective case series review. We demonstrated that tumor risk across BWSp differs from Classic BWS and that certain phenotypic features are associated with specific epigenetic causes; nephromegaly and/or hyperinsulinism appear associated with cancer in some patients. We also demonstrated that prenatal and perinatal factors that are not currently part of the BWSp classification may factor into tumor risk. Additionally, blood testing results are not necessarily synonymous with tissue testing results. Together, it appears that the current understanding from Classic BWS of (epi)genetics and phenotype correlations with tumors is not represented in the BWSp. Further study is needed in this complex population.

Importance: Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management., Objective: To evaluate outpatient vs inpatient neutropenia management for pediatric AML., Design, Setting, and Participants: This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020., Exposures: Discharge to outpatient vs inpatient neutropenia management., Main Outcomes and Measures: The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome., Results: Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management., Conclusions and Relevance: This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.

Purpose: Despite evidence-based guidelines recommending early palliative care, it remains unclear how to identify and refer oncology patients, particularly in settings with constrained access to palliative care. We hypothesize that patient-reported outcome (PRO) data can be used to characterize patients with palliative care needs. To determine if PRO data can identify latent phenotypes that characterize indications for specialty palliative care referral., Methods: We conducted a retrospective study of self-reported symptoms on the Edmonton Symptom Assessment System collected from solid tumor oncology patients (n = 745) referred to outpatient palliative care. Data were collected as part of routine clinical care from October 2012 to March 2018 at eight community and academic sites. We applied latent profile analysis to identify PRO phenotypes and examined the association of phenotypes with clinical and demographic characteristics using multinomial logistic regression., Results: We identified four PRO phenotypes: (1) Low Symptoms (n = 295, 39.6%), (2) Moderate Pain/Fatigue + Mood (n = 180, 24.2%), (3) Moderate Pain/Fatigue + Appetite + Dyspnea (n = 201, 27.0%), and (4) High Symptoms (n = 69, 9.3%). In a secondary analysis of 421 patients, we found that two brief items assessing social and existential needs aligned with higher severity symptom and psychological distress phenotypes., Conclusion: Oncology patients referred to outpatient palliative care in a real-world setting can be differentiated into clinically meaningful phenotypes using brief, routinely collected PRO measures. Latent modeling provides a mechanism to use patient-reported data on a population level to identify distinct subgroups of patients with unmet palliative needs., Competing Interests: Tara L. KaufmannConsulting or Advisory Role: PotentiaMetrics Samuel U. TakvorianStock and Other Ownership Interests: Gilead Sciences, Merck, Portola Pharmaceuticals, Bluebird Bio, Johnson & Johnson, Novartis, PfizerConsulting or Advisory Role: Health Advances, Novartis, Boehringer Ingelheim, NovocureResearch Funding: Pfizer, AstraZeneca, Lilly, Trizell Arif H. KamalEmployment: Prepped Health, Acclivity Health, Votive HealthLeadership: Prepped Health, Acclivity Health, Votive HealthStock and Other Ownership Interests: Acclivity HealthConsulting or Advisory Role: Medtronic, Huron Therapeutics, New Century Health, Compassus, AstraZeneca, Janssen Oncology, United Health GroupTravel, Accommodations, Expenses: Janssen Oncology Angela DeMicheleConsulting or Advisory Role: Context Therapeutics, PfizerResearch Funding: Pfizer, Genentech, Calithera Biosciences, Menarini/Silicon BiosystemsNo other potential conflicts of interest were reported.

Purpose: CD19-targeted chimeric antigen receptor (CAR)-modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed., Methods: We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19., Results: Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts., Conclusion: HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy., Competing Interests: David M. BarrettTravel, Accommodations, Expenses: Therakos David T. TeacheyConsulting or Advisory Role: SobiResearch Funding: Novartis, Beam Therapeutics, NeoImmuneTech Colleen CallahanConsulting or Advisory Role: NovartisSpeakers' Bureau: Peerview Susan R. RheingoldEmployment: OptiNoseStock and Other Ownership Interests: OptiNoseConsulting or Advisory Role: PfizerResearch Funding: Pfizer Richard AplencExpert Testimony: Vorys Pamela A. ShawPatents, Royalties, Other Intellectual Property: I am part of a patent owned by UPenn and currently licensed to Novartis for an algorithm that predicts severe cytokine release syndrome for the CART 19 therapy. I receive 10% of the licensing fees Edward PequignotPatents, Royalties, Other Intellectual Property: As part of Penn's role in the FDA-approval of CAR-T therapy, and for my part as an employee of Penn involved in their research in CAR-T, I have received royalties of approximately $300 in US dollars over the past 2 years Jennifer L. BrogdonEmployment: Novartis Institutes for BioMedical ResearchStock and Other Ownership Interests: Novartis Institutes for BioMedical Research Donald L. SiegelResearch Funding: Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: A patent, owned by the Trustees of the University of Pennsylvania, on which I am listed as an inventor is licensed to Alexion Pharmaceuticals. I receive royalties as stipulated in the University of Pennsylvania Faculty HandbookExpert Testimony: Regeneron Megan M. DavisLeadership: Cellares CorporationConsulting or Advisory Role: Tmunity Therapeutics IncResearch Funding: Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: Novartis Institutes for Biomedical Research—royalties and milestones for patents/knowhow, Tmunity Therapeutics—royalties andmilestones from patents/knowhow Simon F. LaceyConsulting or Advisory Role: Gilead SciencesResearch Funding: Tmunity Therapeutics Inc, Cabaletta Bio, Novartis Institutes for BioMedical ResearchPatents, Royalties, Other Intellectual Property: Patents and IP related to CTL019 (Kymriah) assigned by the University of Pennsylvania to Novartis Elizabeth O. HexnerConsulting or Advisory Role: Blueprint Medicines, ABIM Subspecialty BoardResearch Funding: Blueprint Medicines, Tmunity Therapeutics Inc Gerald B. WertheimEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Bruce L. LevineStock and Other Ownership Interests: Tmunity Therapeutics IncHonoraria: Novartis, TerumoConsulting or Advisory Role: Avectas, Ori Biotech, Vycellix, Immuneel Therapeutics, In8bio, Patheon/ThermoFisher Viral Vector ServicesResearch Funding: Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: Intellectual property and patents in the field of cell and gene therapyTravel, Accommodations, Expenses: Avectas, Terumo Carl H. JuneLeadership: AC ImmuneStock and Other Ownership Interests: Celldex, Tmunity Therapeutics Inc, Cabaletta Bio, Carisma Therapeutics, DeCART Therapeutics, Bluesphere Bio, Cellares, ZIOPHARM Oncology, Decheng Capital, Posieda Therapeutics, VerismaHonoraria: PfizerConsulting or Advisory Role: Celldex, Viracta Therapeutics, Cabaletta Bio, Carisma Therapeutics, Kiadis Pharma, WIRB-Copernicus Group, Janssen OncologyResearch Funding: Novartis, Tmunity Therapeutics IncPatents, Royalties, Other Intellectual Property: IP licensed to Novartis; Royalties paid to University of Pennsylvania, Office of Naval Research; IP and patent royalties, IP licensed to Tmunity Stephan A. GruppConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Janssen, Cellular Biomedicine Group, TCR2 Therapeutics, Humanigen, Roche, Adaptimmune, Alimera Sciences, Cabaletta Bio, CRISPR Therapeutics/VertexResearch Funding: Novartis, Kite/Gilead, Servier, Jazz Pharmaceuticals, VertexPatents, Royalties, Other Intellectual Property: UPenn Toxicity management patentExpert Testimony: Juno Therapeutics Shannon L. MaudeConsulting or Advisory Role: Novartis, Wugen IncResearch Funding: NovartisTravel, Accommodations, Expenses: Novartis, Kite, a Gilead company, Wugen IncNo other potential conflicts of interest were reported.

Introduction: Our objectives were to design and validate methods to identify relapse and hematopoietic stem cell transplantation (HSCT) in children with acute lymphoblastic leukemia (ALL) using administrative data representing hospitalizations at US pediatric institutions., Methods: We developed daily billing and ICD-9 code definitions to identify relapses and HSCTs within a cohort of children with newly diagnosed ALL between January 1, 2004, and December 31, 2013, previously assembled from the Pediatric Health Information System (PHIS) database. Chart review for children with ALL at the Children's Hospital of Philadelphia (CHOP) and Texas Children's Hospital (TCH) was performed to establish relapse and HSCT gold standards for sensitivity and positive predictive value (PPV) calculations. We estimated incidences of relapse and HSCT in the PHIS ALL cohort., Results: We identified 362 CHOP and 314 TCH ALL patients in PHIS and established true positives by chart review. Sensitivity and PPV for identifying both relapse and HSCT in PHIS were > 90% at both hospitals. Five-year relapse incidence in the 10 150-patient PHIS cohort was 10.3% (95% CI 9.8%-10.9%) with 7.1% (6.6%-7.6%) of children underwent HSCTs. Patients in higher-risk demographic groups had higher relapse and HSCT rates. Our analysis also identified differences in incidences of relapse and HSCT by race, ethnicity, and insurance status., Conclusions: Administrative data can be used to identify relapse and HSCT accurately in children with ALL whether they occur on- or off-therapy, in contrast with published approaches. This method has wide potential applicability for estimating these incidences in pediatric ALL, including patients not enrolled on clinical trials., (© 2020 Wiley Periodicals LLC.)

Background: Anti human epidermal growth factor receptor 2 (anti-HER2) therapy with trastuzumab improves overall survival in patients with advanced, HER2-positive gastroesophageal adenocarcinoma (GEA) and is now incorporated into national guidelines. However, little is known about adherence to and determinants of timely HER2 testing and trastuzumab initiation in routine practice., Methods: The authors performed a cross-sectional study of patients who had advanced GEA diagnosed between January 2011 and June 2019 in a nationwide electronic health record-derived database. The annual prevalences of both timely HER2 testing (defined within 21 days after advanced diagnosis) and timely trastuzumab initiation (defined within 14 days after a positive HER2 result) were calculated. Log-binomial regressions estimated adjusted prevalence ratios comparing timely HER2 testing and trastuzumab initiation by patient and tumor characteristics., Results: In total, the cohort included 6032 patients with advanced GEA of whom 1007 were HER2-positive. Between 2011 and 2019, timely HER2 testing increased from 22.4% to 44.5%, whereas timely trastuzumab initiation remained stable at 16.3%. No appreciable differences in timely testing or trastuzumab initiation were noted by age, sex, race, or insurance status. Compared with patients who had metastatic disease at diagnosis, patients who had early stage GEA who did not undergo surgery were less likely to receive timely HER2 testing and trastuzumab initiation (testing prevalence ratio, 0.69; 95% CI, 0.64-0.75; treatment prevalence ratio, 0.32; 95% CI, 0.18-0.56), as were patients with early stage disease who subsequently developed a distant recurrence (testing prevalence ratio, 0.56; 95% CI, 0.47-0.65; treatment prevalence ratio, 0.61; 95% CI, 0.24-1.55)., Conclusions: In patients with advanced GEA, guideline-recommended HER2 testing and anti-HER2 therapy remain underused. Uptake may improve with universal HER2 testing regardless of stage., (© 2021 American Cancer Society.)

Background: Treatment of infants with acute leukemia remains challenging, especially for acute lymphocytic leukemia (ALL). Infants have shown markedly higher rates of induction mortality compared with noninfants. There are limited data on presentation acuity and supportive care utilization in this age group., Methods: In retrospective analyses of patients treated for new onset ALL or acute myeloid leukemia (AML) at pediatric hospitals contributing to the Pediatric Health Information System, we compared presentation acuity, induction mortality, and resource utilization in infants relative to noninfants less than 10 years at diagnosis., Results: Analyses included 10 359 children with ALL (405 infants, 9954 noninfants) and 871 AML (189 infants, 682 noninfants). Infants were more likely to present with multisystem organ failure compared to noninfants for both ALL (12% and 1%, PR = 10.8, 95% CI: 7.4, 15.7) and AML (6% vs. 3%; PR = 2.0, 95% CI: 1.0, 3.7). Infants with ALL had higher induction mortality compared to noninfants, even after accounting for differences in anthracycline exposure and presentation acuity (2.7% vs. 0.5%, HR = 2.1, 95% CI: 1.0, 4.8). Conversely, infants and noninfants with AML had similar rates of induction mortality (3.2% vs. 2.1%, HR = 1.2, 95% CI: 0.3, 3.9), which were comparable to rates among infants with ALL. Infants with ALL and AML had greater requirements for blood products, diuretics, supplemental oxygen, and ventilation during induction relative to noninfants., Conclusions: Infants with leukemia present with higher acuity compared with noninfants. Induction mortality and supportive care requirements for infants with ALL were similar to all children with AML, and significantly higher than those for noninfants with ALL., (© 2021 Wiley Periodicals LLC.)

Misclassification is a pervasive problem in assessing relations between exposures and outcomes. While some attention has been paid to the impact of dependence in measurement error between exposures and outcomes, there is little awareness of the potential impact of dependent error between exposures and covariates, despite the fact that this latter dependency may occur much more frequently, for example, when both are assessed by questionnaire. We explored the impact of nondifferential dependent exposure-confounder misclassification bias by simulating a dichotomous exposure (E), disease (D) and covariate (C) with varying degrees of non-differential dependent misclassification between C and E. We demonstrate that under plausible scenarios, an adjusted association can be a poorer estimate of the true association than the crude. Correlated errors in the measurement of covariate and exposure distort the covariate-exposure, covariate-outcome and exposure-outcome associations creating observed associations that can be greater than, less than, or in the opposite direction of the true associations. Under these circumstances adjusted associations may not be bounded by the crude association and true effect, as would be expected with nondifferential independent confounder misclassification. The degree and direction of distortion depends on the amount of dependent error, prevalence of covariate and exposure, and magnitude of true effect., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Research suggests short interpregnancy intervals increase risks for adverse perinatal outcomes, including some birth defects. A hypothesized cause is nutritional depletion, including folic acid (FA)., Objectives: We evaluated associations between short interpregnancy intervals, alone and in combination with FA intake, and the occurrence of select malformations., Methods: Data were from the National Birth Defects Prevention Study (US case-control, 1997-2011). Participants included multiparous women whose prior pregnancy resulted in live birth. Cases included 8 noncardiac and 6 cardiac defect groups (n = 3219); controls were nonmalformed live-borns (n = 2508). We categorized interpregnancy interval (<6, 6-11, 12-17, and 18-23 mo) and periconceptional FA intake [no FA supplement use and dietary folate equivalents (DFE) <400 µg/d, no FA supplement use and DFE ≥400 µg/d, or any FA supplement use]. We controlled for age, race/ethnicity, income, pregnancy intention, and study center. ORs <0.8 or >1.2 were considered to represent potentially meaningful associations., Results: ORs for <6 compared with 18-23 mo were >1.2 for 4/8 noncardiac and 3/6 cardiac malformations. Among participants with any FA supplement use, ORs comparing <6 with 6-23 mo were <1.2 for most defects. Conversely, most ORs were >1.2 for <6 mo + no FA supplement use and DFE <400 µg/d compared with 6-23 mo + any FA supplement use. Magnitude and precision varied by defect., Conclusions: Short interpregnancy intervals were associated with a trend of higher risks for several defects, notably in the absence of FA supplement use. To our knowledge, our study is the first to provide preliminary empirical support that these etiologies may be related to shorter interpregnancy intervals and possible nutritional deficiencies. Because FA intake is highly correlated with other nutrients, and because our estimates were generally imprecise, more research with larger sample sizes is needed to better understand the role of FA compared with other nutrients in each defect-specific etiology., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: Whether social determinants of health are associated with survival in the context of pediatric oncology-targeted immunotherapy trials is not known. We examined the association between poverty and event-free survival (EFS) and overall survival (OS) for children with high-risk neuroblastoma treated in targeted immunotherapy trials., Methods: We conducted a retrospective cohort study of 371 children with high-risk neuroblastoma treated with GD2-targeted immunotherapy in the Children's Oncology Group trial ANBL0032 or ANBL0931 at a Pediatric Health Information System center from 2005 to 2014. Neighborhood poverty exposure was characterized a priori as living in a zip code with a median household income within the lowest quartile for the cohort. Household poverty exposure was characterized a priori as sole coverage by public insurance. Post hoc analyses examined the joint effect of neighborhood and household poverty using a common reference. All statistical tests were 2-sided., Results: In multivariable Cox regressions adjusted for disease and treatment factors, household poverty-exposed children experienced statistically significantly inferior EFS (hazard ratio [HR] = 1.90, 95% confidence interval [CI] = 1.28 to 2.82, P = .001) and OS (HR = 2.79, 95% CI = 1.63 to 4.79, P < .001) compared with unexposed children. Neighborhood poverty was not independently associated with EFS or OS. In post hoc analyses exploring the joint effect of neighborhood and household poverty, children with dual-poverty exposure (neighborhood poverty and household poverty) experienced statistically significantly inferior EFS (HR = 2.21, 95% CI = 1.48 to 3.30, P < .001) and OS (HR = 3.70, 95% CI = 2.08 to 6.59, P < .001) compared with the unexposed group., Conclusions: Poverty is independently associated with increased risk of relapse and death among neuroblastoma patients treated with targeted immunotherapy. Incorporation of social and environmental factors in future trials as health-care delivery intervention targets may increase the benefit of targeted therapies., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Variation in the gastrointestinal (GI) microbiota after hematopoietic cell transplantation (HCT) has been associated with acute graft-versus-host disease (aGVHD). Because antibiotics induce dysbiosis, we examined the association of broad-spectrum antibiotics with subsequent aGVHD risk in pediatric patients undergoing HCT for acute leukemia. We performed a retrospective analysis in a dataset merged from 2 sources: (1) the Center for International Blood and Marrow Transplant Research, an observational transplantation registry, and (2) the Pediatric Health Information Services, an administrative database from freestanding children's hospitals. We captured exposure to 3 classes of antibiotics used for empiric treatment of febrile neutropenia: (1) broad-spectrum cephalosporins, (2) antipseudomonal penicillins, and (3) carbapenems. The primary outcome was grade II-IV aGVHD; secondary outcomes were grade III-IV aGVHD and lower GI GVHD. The adjusted logistic regression model (full cohort) and time-to-event analysis (subcohort) included transplantation characteristics, GVHD risk factors, and adjunctive antibiotic exposures as covariates. The full cohort included 2550 patients at 36 centers; the subcohort included 1174 patients. In adjusted models, carbapenems were associated with an increased risk of grade II-IV aGVHD in the full cohort (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.02 to 1.51) and subcohort (sub hazard ratio [HR], 1.31; 95% CI, 0.99 to 1.72), as well as with an increased risk of grade III-IV aGVHD (subHR, 1.77; 95% CI, 1.25 to 2.52). Early carbapenem exposure (before day 0) especially impacted aGVHD risk. For antipseudomonal penicillins, the associations with aGVHD were in the direction of increased risk but were not statistically significant. There was no identified association between broad-spectrum cephalosporins and aGVHD. Carbapenems, more than other broad-spectrum antibiotics, should be used judiciously in pediatric HCT recipients to minimize aGVHD risk. Further research is needed to clarify the mechanism underlying this association.

Purpose: To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens., Patients and Methods: This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure., Results: A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% v 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% v 45.1%; P = .534) and OS (65.0% v 61.9%; P = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% v 12.7%; P = .068)., Conclusion: Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.

Background: There is limited evidence regarding the impact of cardiology involvement in the care of cancer patients., Objectives: We evaluated the impact of cardiology involvement on guideline-adherent cardiovascular monitoring and risk factor management in breast cancer patients treated with trastuzumab., Methods: In a single-center retrospective cohort study, we evaluated electronic health records from 1,047 breast cancer patients receiving trastuzumab between January 2009 and July 2018. A visit to a cardiology provider beginning from the 3 months prior to cancer therapy initiation until the last contact date defined cardiology involvement. Guideline-adherent monitoring, defined by echocardiography assessment within the 4 months prior to trastuzumab initiation and follow-up echocardiography at least every 4 months during therapy, was compared in patients with and without cardiology involvement prior to treatment initiation. Multivariable associations between cardiology involvement and time-varying risk factors blood pressure (BP) and body mass index (BMI) were assessed using generalized estimating equations., Results: Cardiology involvement occurred in 293 (28%) patients. A higher proportion of patients with cardiology involvement prior to trastuzumab initiation had guideline-adherent monitoring (76.4% versus 60.1%, p=0.007). Cardiology involvement was associated with an average 1.5mmHg (95% CI -2.9,-0.1, p=0.035) lower systolic BP; which was more pronounced in those with hypertension (-2.7mmHg (95% CI -4.6,-0.7, p=0.007)). Cardiology involvement was associated with a lower BMI in patients with baseline BMI≥25 kg/m 2 (mean difference; -0.5 (95% CI -1.0,-0.1, p=0.027))., Conclusions: Cardiology involvement in breast cancer patients treated with trastuzumab is associated with greater adherence to cardiovascular monitoring and modest improvements in risk factor control., Competing Interests: Disclosures: All authors report no relevant conflict of interest.

Background We examined the longitudinal associations between changes in cardiovascular biomarkers and cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer treated with cardotoxic cancer therapy. Methods and Results Repeated measures of high-sensitivity cardiac troponin T (hs-cTnT), NT-proBNP (N-terminal pro-B-type natriuretic peptide), myeloperoxidase, placental growth factor, and growth differentiation factor 15 were assessed longitudinally in a prospective cohort of 323 patients treated with anthracyclines and/or trastuzumab followed over a maximum of 3.7 years with serial echocardiograms. CTRCD was defined as a ≥10% decline in left ventricular ejection fraction to a value <50%. Associations between changes in biomarkers and left ventricular ejection fraction were evaluated in repeated-measures linear regression models. Cox regression models assessed the associations between biomarkers and CTRCD. Early increases in all biomarkers occurred with anthracycline-based regimens. hs-cTnT levels >14 ng/L at anthracycline completion were associated with a 2-fold increased CTRCD risk (hazard ratio, 2.01; 95% CI, 1.00-4.06). There was a modest association between changes in NT-proBNP and left ventricular ejection fraction in the overall cohort; this was most pronounced with sequential anthracycline and trastuzumab (1.1% left ventricular ejection fraction decline [95% CI, -1.8 to -0.4] with each NT-proBNP doubling). Increases in NT-proBNP were also associated with CTRCD (hazard ratio per doubling, 1.56; 95% CI, 1.32-1.84). Increases in myeloperoxidase were associated with CTRCD in patients who received sequential anthracycline and trastuzumab (hazard ratio per doubling, 1.28; 95% CI, 1.04-1.58). Conclusions Cardiovascular biomarkers may play an important role in CTRCD risk prediction in patients with breast cancer who receive cardiotoxic cancer therapy, particularly in those treated with sequential anthracycline and trastuzumab therapy. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT01173341.

Equal access to clinical trial enrollment is important to ensure that findings are generalizable to the broader population. This study aimed to evaluate disparities in enrollment on pediatric oncology clinical trials. We assessed the relationship between patient characteristics and enrollment on COG trial AAML1031 in a cohort of pediatric patients with AML in the Pediatric Health Information System. The associations of enrollment with outcomes were evaluated. Non-Hispanic Black patients, infants, and patients from zip codes with a lower proportion of poverty were less likely to enroll (30% vs. 61%, p  = .004; 34% vs. 58%, p  = .003; 46% vs. 58%, p  = .02). On-therapy mortality was similar among enrolled and nonenrolled patients (7.3% vs. 8.9%, p  = .47). Differences in early mortality were more pronounced among nonenrolled patients compared to enrolled patients (3.0% vs. 0.5%, p  = .03). Understanding the etiology of these disparities will inform strategies to ensure balanced access to clinical trials across patient populations.

Background: Adverse events (AEs) on Children's Oncology Group (COG) trials are reported manually by clinical research assistants (CRAs). The Common Terminology Criteria for Adverse Events (CTCAE) was developed to provide standardized definitions for identifying and grading AEs. The CTCAE has expanded significantly over its five versions, but the impact of CTCAE definitional changes has not been examined., Procedure: This study compared AE number and ascertainment among the first four CTCAE versions using a case vignette. Each CTCAE version was used to create a list of AEs and grades by two separate CRAs., Results: The CTCAE expanded from 9 categories and 49 AEs in v1.0 to 26 categories and 790 AEs in v4.0. CRAs independently selected different approaches to AE ascertainment-comprehensive and parsimonious. The number of AEs identified in the parsimonious approach was stable with 10-14 in each CTC version. The comprehensive approach identified 9, 20, 29, and 37 AEs in CTC versions 1.0, 2.0, 3.0, and 4.0, respectively. Only approximately 65% of AEs were conclusively graded in versions 2.0 to 4.0 using the comprehensive approach., Conclusions: CTCAE has increased in complexity. Although this increased complexity allows for more granular AE reporting, these data demonstrate potential unintended negative consequences of increasing CTC AE complexity, including the risk of varying approaches to AE capture. A comprehensive evaluation of CTC AE definitions and CRA reporting practices across COG institutions and AEs are needed to improve the accuracy and efficiency of AE reporting., (© 2019 Wiley Periodicals, Inc.)

Background: Black patients with acute myeloid leukemia (AML) are more likely to present with high acuity and consequently experience higher rates of induction mortality than white patients. Given the consistently identified racial disparities in overall survival (OS) among patients with AML, we aimed to evaluate whether there were sustained on-therapy racial differences in inpatient mortality, intensive care unit (ICU) requirements, or supportive care beyond initial induction., Procedure: Within a retrospective cohort of 1239 children diagnosed with AML between 2004 and 2014 in the Pediatric Health Information System (PHIS) database who survived their initial course of induction chemotherapy, we compared on-therapy inpatient mortality, ICU-level care requirements, treatment course duration, cumulative length of hospital stay (LOS), and resource utilization after induction I by race., Results: Over the period from the start of induction II through completion of frontline chemotherapy, there were no significant differences in mortality (adjusted odds ratios [OR], 1.01; 95% confidence intervals [CI], 0.41-2.48), ICU-level care requirements (adjusted OR, 0.93; 95% CI, 0.69-1.26), LOS (adjusted mean difference, 3.2 days; 95% CI, -2.3-9.6), or supportive care resource utilization for black patients relative to white patients. Course-specific analyses also demonstrated no differences by race., Conclusion: Although black patients have higher acuity at presentation and higher induction mortality, such disparities do not persist over subsequent frontline chemotherapy treatment. This finding allows interventions aimed at reducing disparities to be directed at presentation and induction., (© 2018 Wiley Periodicals, Inc.)