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Retinoblastoma (RB) is the most common intraocular pediatric malignancy. Advancements in intra-arterial chemotherapy (IAC) for treatment of RB have resulted in dramatic improvement in eye salvage rates. Data regarding IAC outcomes and associated hematologic toxicities are limited. The objective of this retrospective study was to analyze baseline characteristics, efficacy, and hematologic complications associated with IAC treatment in children with RB at a single international referral institution. Ninety-five sessions of IAC were performed in 28 patients. Mean age at RB diagnosis was 12.5 months (SD, 9.2 mo). Fourteen patients had bilateral RB. IAC agents included melphalan, carboplatin, and topotecan. The most common regimens were triple-agent IAC and single-agent melphalan (66.3% and 15.8%, respectively). Median number of IAC sessions was 3 (mean: 3.39, range: 1 to 9). Eye salvage rate was 83.7% with an overall survival rate of 100% at a median follow-up of 29 months (mean: 29.8 mo, range: 1 to 63 mo). A total of 26 patients (92.9%) experienced at least 1 hematologic toxicity during their treatment course Prevalence of neutropenia, anemia, and thrombocytopenia were 89.3%, 85.7%, and 25%, respectively. While IAC is effective in salvaging most eyes with advanced intraocular RB, over half of patients experienced clinically significant neutropenia and anemia. Clinicians should be vigilant in monitoring patients for IAC-related complications.

Background: Lung cancer, the most common cause of cancer-related death in adults, has not been well studied as a subsequent malignant neoplasm (SMN) in childhood cancer survivors. We assessed prevalence, risk factors, and outcomes for lung SMN in the Childhood Cancer Survivor Study (CCSS) cohort. Methods: Among 25,654 5-year survivors diagnosed with childhood cancer ( Results: Forty-two survivors developed a lung SMN [SIR, 4.0; 95% confidence interval (CI), 2.9–5.4] with a cumulative incidence of 0.16% at 30 years from diagnosis (95% CI, 0.09%–0.23%). In a treatment model, chest radiation doses of 10–30 Gy (HR, 3.4; 95% CI, 1.05–11.0), >30–40 Gy (HR, 4.6; 95% CI, 1.5–14.3), and >40 Gy (HR, 9.1; 95% CI, 3.1–27.0) were associated with lung SMN, with a monotone dose trend (Ptrend < 0.001). Survivors of Hodgkin lymphoma (SIR, 9.3; 95% CI, 6.2–13.4) and bone cancer (SIR, 4.4; 95% CI, 1.8–9.1) were at greatest risk for lung SMN. Conclusions: Survivors of childhood cancer are at increased risk for lung cancer compared with the general population. Greatest risk was observed among survivors who received chest radiotherapy or with primary diagnoses of Hodgkin lymphoma or bone cancer. Impact: This study describes the largest number of observed lung cancers in childhood cancer survivors and elucidates need for further study in this aging and growing population.

Background Obesity is a risk factor for many adulthood cancers, but its role in childhood, adolescent, and young adult (AYA) cancer is unknown. Childhood and AYA acute lymphoblastic leukemia (ALL) incidence and obesity prevalence have shown concurrent increases. We sought to identify whether obesity may be a risk factor for childhood and AYA ALL. Methods Characteristics from individuals with ALL, aged 2‐30 years, diagnosed 2004‐2017 and treated on Children's Oncology Group (COG) protocols with available pre‐treatment anthropometric data (N = 4726) were compared to National Health and Nutrition Examination Survey controls (COG AALL17D2). Body mass index (BMI) was defined using standard CDC definitions. Multivariate conditional logistic regression assessed associations between BMI and ALL with additional analyses stratified by sex and race/ethnicity. Results Among cases (72% high‐risk (HR) B‐ALL, 28% T‐ALL), 5% had underweight, 58% normal weight, 17% overweight, and 20% obesity. Underweight (OR 2.11, 95% CI 1.56‐2.85) and obesity (OR 1.32, 95% CI 1.15‐1.53) were associated with B‐ALL diagnosis. Specifically, obesity was associated with B‐ALL among males (OR 1.57, 95% CI 1.30‐1.91) and Hispanic children (OR 1.78, 95% CI 1.39‐2.29). Obesity was also associated with central nervous system (CNS) involvement. Conclusion Pre‐treatment obesity is associated with HR B‐ALL among males and Hispanics, as well as with CNS involvement, suggesting common physiology between obesity and leukemogenesis. An association between underweight and ALL was confirmed, likely due to cancer‐associated wasting. These results have important public health implications for obesity prevention and treatment in children and adolescents to reduce cancer risk., Deviations in body mass index (underweight and obesity) at the time of diagnosis were significantly associated with a diagnosis of pediatric high‐risk (HR) B‐cell acute lymphoblastic leukemia (B‐ALL) compared to normal weight. Specifically, obesity was associated with HR B‐ALL in males and Hispanics. Obesity was also significantly associated with ALL central nervous system (CNS) involvement.

Childhood cancer is the leading cause of nonaccidental death in children and adolescents. Over the past 50 years, development of novel therapies and improvements in supportive care have led to improvements in long-term survival rates. However, there remains great morbidity associated with cancer treatment among childhood cancer survivors, and the outcomes for patients who relapse remain poor. The introduction of precision medicine, an approach that uses the understanding of genetic and biochemical profiles of a disease (as enabled by next-generation sequencing) to tailor treatment to a patient, has quickly started to change the diagnostic and therapeutic landscape of pediatric oncology. With its use, a better understanding of tumor biology, improved classification systems for various cancers, and genetically and molecularly targeted therapeutic strategies have been developed. We review the implementation of precision medicine in pediatric oncology and its effect on diagnosis, management, and treatment of pediatric cancers. [ Pediatr Ann . 2022;51(1):e8–e14.]

Background Pediatric cancer incidence has steadily increased concurrent with rising adult obesity, but associations between maternal obesity and associated comorbidities and pediatric cancer risk remain understudied. We aimed to quantitatively characterize associations of pediatric cancer risk with maternal prepregnancy body mass index (BMI), gestational weight gain, and maternal diabetes. Methods We performed a comprehensive and systematic literature search in Ovid and EMBASE from their inception to March 15, 2021. Eligible studies reported risk estimates and sample sizes and provided sufficient description of outcome and exposure ascertainment. Random effects models were used to estimate pooled effects. Results Thirty-four studies were included in the analysis. Prepregnancy BMI was positively associated with leukemia risk in offspring (odds ratio [OR] per 5-unit BMI increase =1.07, 95% confidence intervals [CI] = 1.04 to 1.11; I2 = 0.0%). Any maternal diabetes was positively associated with acute lymphoblastic leukemia risk (OR = 1.46, 95% CI = 1.28 to 1.67; I2 = 0.0%), even after restricting to birthweight-adjusted analyses (OR = 1.74, 95% CI = 1.29 to 2.34; I2 = 0.0%), and inversely associated with risk of central nervous system tumors (OR = 0.73, 95% CI = 0.55 to 0.97; I2 = 0.0%). Pregestational diabetes (OR = 1.57, 95% CI = 1.11 to 2.24; I2 = 26.8%) and gestational diabetes (OR = 1.40, 95% CI = 1.12 to 1.75; I2 = 0.0%) were also positively associated with acute lymphoblastic leukemia risk. No statistically significant associations were observed for gestational weight gain. Conclusions Maternal obesity and diabetes may be etiologically linked to pediatric cancer, particularly leukemia and central nervous system tumors. Our findings support weight management and glycemic control as important components of maternal and offspring health. Further validation is warranted.

Introduction: Pediatric cancer incidence has steadily increased concurrent with the rise in adult obesity, however, associations between maternal obesity and associated comorbidities and pediatric cancer risk remain understudied. Methods: A comprehensive and systematic literature search in PubMed and EMBASE databases from their inception to March 15th, 2021. Eligible studies reported risk estimates, sample sizes, and provided sufficient description of outcome and exposure ascertainment. Studies were excluded if not complete, published, peer-reviewed studies, or if provided incompatible exposure data. Data quality was assessed according to Newcastle-Ottawa Scale (NOS) guidelines and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Random-effects models were used to estimate pooled effects. Results: Thirty-four studies were included, covering 3,404,747 subjects and 14,706 pediatric cancer cases for pre-pregnancy BMI; 14,748,772 subjects and 44,628 pediatric cancer patients for maternal diabetes; and 2,124,647 participants and 15,915 pediatric cancer cases for gestational weight gain. Pre-pregnancy BMI was significantly associated with leukemia risk in offspring (OR per 5-unit BMI increase =1.07 [95% CI = 1.04-1.11] I2 = 0.0%). Any maternal diabetes was positively associated with acute lymphoblastic leukemia risk (OR=1.46 [95% CI = 1.28-1.67] I2 = 0.0%), even after restricting to birthweight-adjusted analyses (OR [95% CI] = 1.74 [1.29-2.34] I2 = 0.0%), and inversely associated with risk of central nervous system tumors (OR=0.73 [95% CI = 0.55-0.97] I2 = 0.0%). Pre-gestational diabetes (OR=1.57 [95% CI = 1.11-2.24] I2 = 26.8%) and gestational diabetes (OR=1.40 [95% CI = 1.12-1.75] I2 = 0.0%) were also significantly associated with acute lymphoblastic leukemia risk. No significant associations were observed for gestational weight gain and pediatric cancer risk. Conclusions: Maternal obesity and diabetes may be etiologically linked to pediatric cancer, particularly leukemia and central nervous system tumors. Our findings support appropriate weight management and glycemic control as important components of maternal care and offspring health. Further validation studies are warranted. Citation Format: Andrew R. Marley, Allison Domingues, Taumoha Ghosh, Lucie M. Turcotte, Logan G. Spector. Maternal body mass index, diabetes, and gestational weight gain and risk for pediatric cancer in offspring: A systematic review and meta-analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3652.

10551 Background: Lung cancer has been reported as a subsequent neoplasm (SN) in childhood cancer survivors. We aimed to assess the prevalence of and risk factors for lung cancer in the CCSS. Methods: Among 25,654 five-year survivors participating in the CCSS, lung cancer was self-reported and then confirmed by pathologic record review. Cancer treatment exposures were evaluated including chemotherapy and chest radiation by field size (none, small, large) and in a dose group (0-10 Gy, 10-30 Gy, 30-40 Gy, and > 40 Gy). Standardized incidence ratios (SIR) were calculated using rates from the Surveillance, Epidemiology, and End Results program. Hazard ratios (HR) were estimated for demographic and treatment variables using Cox proportional-hazards models. Results: Forty-two survivors developed subsequent malignant lung cancer (SIR 4.0, 95% CI 2.9-5.4), including 25 carcinomas, 7 mesotheliomas and 10 others. Two additional benign neoplasms were also identified. The cumulative incidence of lung SNs was 0.18% at 30 years (95% CI 0.10-0.25). Median time from primary diagnosis was 28 years (range 11-46); median age at diagnosis was 45 years of age (range 15-65). A multivariable model, including all covariates with a p-value < 0.2 in univariate analysis, showed significant associations between lung cancer and older age at diagnosis (HR 10.5, 95% CI 1.4-76.4, for 15-21 years vs. 0-4 years), as well as with primary diagnoses (relative to leukemia, HR 8.7, 95% CI 1.1-66.0, for Hodgkin lymphoma; HR 20.7, 95% CI 1.3-331.0 for neuroblastoma; and HR 21.4, 95% CI 2.3-202.7, for bone cancer). In a treatment model, maximum chest radiation dose (HR 4.1, 95% CI 1.4-11.7, for 30-40 Gy; and HR 8.1, 95% CI 3.0-22.2, for > 40 Gy, relative to 0-10Gy), but not sex, smoking status, or chemotherapy exposures, was associated with lung cancer. Notably, six survivors who developed lung cancer received no radiation and of these, five had a primary bone cancer. At the end of follow-up, 65.9% of survivors with lung cancer were deceased vs. 14.1% of survivors without lung cancer ( p < 0.001). Conclusions: Survivors of childhood cancer are at increased risk for developing lung cancer associated with exposure to high doses of chest radiotherapy. To our knowledge, this is the first study to describe associations with neuroblastoma and bone cancer. Future studies to understand additional treatment-related risk factors beyond chest radiotherapy dose are needed.

Introduction: Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer. Historical studies have found an association between ALL incidence with higher socioeconomic status (SES), though newer findings are contradictory for this association. Nevertheless, it has been well established that inferior outcomes in pediatric ALL are associated with lower SES. We sought to identify if specific ALL disease characteristics at diagnosis are associated with SES to determine if underlying biology plays a role in the known association between inferior outcomes and lower SES. Methods: Demographic and disease characteristics from children and young adults (aged 2-30 years) diagnosed with ALL 2004-2017 and treated on Children's Oncology Group (COG) frontline treatment protocols (N=4,726, AALL17D2) were matched 1:1 (by age, sex, race, and sampling year) and compared to National Health and Nutrition Examination Survey (NHANES) controls. SES for cases was defined using census data to determine the percent of population in a ZIP code living at or below the federal poverty threshold. SES for controls was defined by the individual's poverty income ratio. Chi-square testing and multivariate logistic regressions were performed, adjusting for sex, race/ethnicity, and age, to assess associations between SES and ALL, as well as specific risk-stratifying ALL disease characteristics, including cytogenetics and central nervous disease (CNS) involvement. Results: ALL patients (72% B-ALL, 28% T-ALL) were more likely to be male (62%), 58% were non-Hispanic white, 9% non-Hispanic black and 24% identified as Hispanic. By chi-square analysis, a difference in SES was identified between cases and controls (p Conclusions: To our knowledge, this is the first study to assess associations between SES and ALL disease characteristics that have known prognostic implications in disease outcome. We found that poor prognostic features of ALL including CNS involvement at diagnosis (regardless of sex and race) and presence of MLL rearrangement specifically in non-Hispanic white males, were both associated with low SES. In contrast, favorable prognostic features of ALL were associated with high SES, such as the presence of trisomy of chromosomes 4 and 10, and among Hispanic males the presence of an ETV6-RUNX1 translocation. Our study also replicated the association between ALL diagnosis and high SES, which has been a controversial finding. Nonetheless, our findings suggest that there may be biological factors that play a role in the known association between inferior ALL outcomes and low SES. Further studies to better elucidate this potential biologic role are needed as there may be important implications for future treatment options that could improve outcomes for children with ALL who have low SES, as well as improve disparate outcomes currently seen in ALL treatment. Disclosures No relevant conflicts of interest to declare.

Introduction: Increases in the incidence of both obesity (a risk factor for many adulthood cancers) and acute lymphoblastic leukemia (ALL) in childhood have been observed over the past three decades, thus we sought to identify whether obesity may be an unrecognized risk factor for childhood ALL. Methods: Demographics, anthropometrics and disease characteristics from children and young adults (aged 1-30 years) diagnosed with ALL between 2004-2017 and treated on Children’s Oncology Group (COG) frontline treatment protocols with available pre-treatment anthropometric data (n=4775, AALL17D2) were compared to National Health and Nutrition Examination Survey (NHANES) controls (n=30,107). Individuals were classified as underweight, normal weight, overweight, or obese, per standard CDC age- and sex-based pediatric and adult definitions for body mass index (BMI). Multivariate logistic regressions were performed, adjusting for sex, race/ethnicity, age, socioeconomic status and obesity status, to assess associations between BMI classification and ALL. Additional models were performed stratifying by ALL disease characteristics. Results: ALL patients (72% B-ALL, 28% T-ALL) were more likely to be male (62%), 58% were non-Hispanic white, 9% non-Hispanic black and 24% identified as Hispanic. Among ALL patients, 5% were underweight, 58% normal weight, 17% overweight and 20% obese. Using normal weight as reference, BMI above normal weight classification was associated with ALL diagnosis (overweight, OR=1.10, 95% CI 1.00-1.20, p=0.046; obese, OR=1.15, 95% CI 1.05-1.25, p=0.002), as was underweight (OR=1.74, 95% CI 1.48-2.03, p= Conclusions: This is the first study, to our knowledge, to show that pre-treatment overweight or obesity is associated with ALL, specifically among males and B-cell immunophenotype. Furthermore, ALL CNS involvement was associated with obesity. This study also confirmed the known association between underweight and ALL. Although the associations between BMI status and newly diagnosed ALL may be secondary to detrimental physiologic effects of ALL (i.e. underweight at time of diagnosis), they also suggest a role for inflammation, environmental exposures, or other genetic susceptibility in ALL pathogenesis. Further analyses are needed to elucidate whether other ALL disease characteristics, such as cytogenetics, may be associated with pre-treatment childhood BMI. Citation Format: Taumoha Ghosh, Michaela Richardson, Justin Ryder, Logan Spector, Lucie Turcotte. Obesity as a risk factor for pediatric acute lymphoblastic leukemia: A report from the Children's Oncology Group [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3118.

Background: Asthma is a common comorbid condition in patients with sickle cell disease. It has been well reported that patients with sickle cell and asthma have increased risk of morbidity and mortality, especially in regards to acute chest syndrome. Limited research, however, has been done to establish the role of asthma in vaso-occlusive crisis. Prior work by this group assessed the hypothesis that patients with sickle cell disease and comorbid asthma have increased severity and frequency of vaso-occlusive crisis secondary to increased impairment in oxygen exchange and associated sickling. A positive association was identified, providing groundwork for additional study. Objectives: This study was designed to further identify and risk-stratify patients at increased likelihood of vaso-occlusive complications that would benefit from respiratory-driven interventions. This was proposed through more extensive evaluation of the association between a diagnosis of comorbid asthma and frequency and severity of sickle cell vaso-occlusive crisis in addition to other potential indicators of risk, including passive smoke exposure and pulmonary function testing results. Design/Method: Following development and updating of a comprehensive institutional database, patients were identified with sickle cell disease and comorbid asthma ages 6 to 12 years of age. An additional subset of patients was identified as phenotypic and age-matched controls. Rates of emergency department visits and hospitalizations, frequency of vaso-occlusive crises, association with respiratory symptoms, smoke exposure status, pulmonary function test results, and use of asthma controller medications were retrospectively analyzed over a 5-year period. Data collection and interpretation were accompanied by review of existing literature. Results: Patients with sickle cell disease and comorbid asthma had a statistically significant greater number of presentations for pain over the study period in addition to presentations for acute chest and respiratory symptoms. Analysis of symptom chronology did not show a definitive relationship between onset of respiratory symptoms and subsequent development of pain symptoms. Smoke exposure status was evaluated as a possible compounding factor. A statistically significant association between use of asthma controller medication and patients presenting with pain was identified (p Conclusion: Asthma management may have a role in the treatment of sickle cell vaso-occlusive crisis as evidenced by more frequent pain presentations in patients with asthma as well as a correlation in those patients on controller therapy. Results of pulmonary function testing indicated that not all patients met criteria for an objective diagnosis of asthma, suggesting that there may be a different etiology for these patients' lung impairment. Despite this, pulmonary function testing may still provide insight into disease progression. Further study of the use of asthma management as adjuvant therapy for sickle cell patients is in progress with the intent to improve pain management and decrease hospital encounters and hospital length of stay. Disclosures No relevant conflicts of interest to declare.

OBJECTIVE—Regulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells—a need forming the basis for these studies. RESEARCH DESIGN AND METHODS—Tregs from recent-onset type 1 diabetic patients and healthy control subjects were isolated by fluorescence-activated cell sorting and compared for their capacity to expand in vitro in response to anti-CD3–anti-CD28–coated microbeads and IL-2. Expanded cells were examined for suppressive function, lineage markers and FOXP3, and cytokine production. RESULTS—Both CD4+CD127lo/− and CD4+CD127lo/−CD25+ T-cells could be expanded and used as Tregs. However, expansion of CD4+CD127lo/− cells required the addition of rapamycin to maintain lineage purity. In contrast, expansion of CD4+CD127lo/−CD25+ T-cells, especially the CD45RA+ subset, resulted in high yield, functional Tregs that maintained higher FOXP3 expression in the absence of rapamycin. Tregs from type 1 diabetic patients and control subjects expanded similarly and were equally capable of suppressing T-cell proliferation. Regulatory cytokines were produced by Tregs after culture; however, a portion of FOXP3+ cells were capable of producing interferon (IFN)-γ after reactivation. IFN-γ production was observed from both CD45RO+ and CD45RA+ Treg populations. CONCLUSIONS—The results support the feasibility of isolating Tregs for in vitro expansion. Based on expansion capacity, FOXP3 stability, and functional properties, the CD4+CD127lo/−CD25+ T-cells represent a viable cell population for cellular therapy in this autoimmune disease.