Novel and replicated clinical and genetic risk factors for toxicity from high-dose methotrexate in pediatric acute lymphoblastic leukemia.

STUDY OBJECTIVE: Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance. DESIGN: We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m2 of MTX. Measurements We performed germline genotyping to determine genetic ancestry and allele status for 49 single nucleotide polymorphisms (SNPs) identified from the literature as related to MTX disposition. Bayesian hierarchical ordinal regression models for creatinine increase and for prolonged MTX clearance were developed. MAIN RESULTS: Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85%-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance. CONCLUSIONS: These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

Germline Genetic and Treatment-Related Risk Factors for Diabetes Mellitus in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study and St Jude Lifetime Cohorts.

PURPOSE: To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer. METHODS: Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS. RESULTS: There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10-8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10-7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation. CONCLUSION: There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.

Programmed cell death ligand 1 expression in aggressive pediatric non-Hodgkin lymphomas: frequency, genetic mechanisms, and clinical significance.

Programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are immunomodulatory molecules overexpressed in lymphomas and are promising immunotherapy targets for hematologic malignancies. However, studies of PD-1/PD-L1 overexpression and their clinical significance in aggressive pediatric non-Hodgkin lymphomas (NHL) are limited. We assessed PD-1/PD-L1 overexpression using immunohistochemistry in 68 aggressive pediatric NHL: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL, n=8), Burkitt lymphoma (BL, n=27), and large B-cell lymphoma (LBCL) de novo LBCL, n=22 and diffuse LBCL arising as monomorphic post-transplant lymphoproliferative disorder [PTLD-DLBCL], n=11. In LBCL, correlations between PD-L1 overexpression and Epstein-Barr virus (EBV) status, cell of origin, stage, nodal status, overall survival (OS), and event-free survival (EFS) were examined. The genetic mechanisms of PD-L1 overexpression were investigated using targeted next-generation sequencing (NGS) and cytogenetic data. All ALK+ ALCL samples, 50.0% of de novo LBCL (11/22), 72.7% of PTLD-DLBCL (8/11), and no BL overexpressed PD-L1. Overexpressed PD-L1 correlated with EBV positivity (P=0.033) in LBCL and lower EFS in de novo LBCL (P=0.017). NGS of select LBCL revealed distinct somatic mutations and an ultra-hypermutated PTLD-DLBCL. Most cases with 9p24.1 copy gains overexpressed PD-L1 although some cases had no discernible genetic drivers of PD-L1 overexpression. Overexpressed PD-L1 is common in pediatric LBCL, associated with EBV positivity and 9p24.1 gains, and may have prognostic significance in de novo LBCL. Furthermore, diverse molecular mechanisms for PD-L1 overexpression in aggressive pediatric NHL can occur. Thus, additional studies exploring the therapeutic and prognostic significance and molecular mechanisms of PD-L1 overexpression in aggressive pediatric NHL are warranted.

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

An evidence-based, risk-adapted algorithm for antifungal prophylaxis reduces risk for invasive mold infections in children with hematologic malignancies.

BACKGROUND: Children with hematologic malignancies, especially those who receive intensive chemotherapy, are at high risk for invasive mold infections (IMI) that confer substantial mortality. Randomized controlled trials support the use of antifungal prophylaxis with antimold activity as an optimal strategy for risk reduction in this population, but studies outlining the practical application of evidence-based recommendations are lacking. PROCEDURE: We conducted a 15-year, single-institution retrospective review in a diverse cohort of children with hematologic malignancies treated with chemotherapy to determine the incidence of proven or probable IMI diagnosed between 2006 and 2020. Multivariable logistic regression was used to identify host and disease factors associated with IMI risk. We then compared the incidence and type of IMI and related factors before and after 2016 implementation of an evidence-based, risk-adapted antifungal prophylaxis algorithm that broadened coverage to include molds in patients at highest risk for IMI. RESULTS: We identified 61 cases of proven or probable IMI in 1456 patients diagnosed with hematologic malignancies during the study period (4.2%). Implementation of an antifungal prophylaxis algorithm reduced the IMI incidence in this population from 4.8% to 2.9%. Both Hispanic ethnicity and cancer diagnosis prior to 2016 were associated with risk for IMI. CONCLUSION: An evidence-based, risk-adapted approach to antifungal prophylaxis for children with hematologic malignancies is an effective strategy to reduce incidence of IMI.

COVID-19 outcomes in a large pediatric hematology-oncology center in Houston, Texas.

An understanding of the behavior of SARS-CoV-2 in pediatric hematology-oncology patients is essential to the optimal management of these patients during the COVID-19 pandemic. This study describes the characteristics and outcomes of COVID-19 disease in children with cancer or hematologic disorders treated at a large children's hospital. A retrospective cohort study was conducted at Texas Children's Cancer and Hematology Center from January 1, 2020 to September 30, 2020. All patients with a primary hematology-oncology diagnosis and SARS-CoV-2 positivity by reverse transcription polymerase chain reaction were identified. Clinical and laboratory data were obtained from the medical record. Descriptive analyses were performed to evaluate COVID-19-related outcomes and risk factors for severe disease in this population. We identified 109 patients with COVID-19 disease, including 52 hematology, 51 oncology, and 6 HSCT patients; median age was 10.3 years (IQR 4.4-15.9), and 58.7% were male. Seventy-four percent of the patients were managed in the outpatient setting. Patients with sickle cell disease were more likely to require hospitalization. ICU care was needed in 8% (n = 9) of the entire cohort, and mechanical ventilation was required in 6.4% (6 oncology patients, 1 hematology patient). COVID-19 contributed to the deaths of two cancer patients. No deaths occurred in hematology or HSCT patients. In conclusion, the risk of severe COVID-19 complications is slightly higher in pediatric hematology-oncology patients than in the general pediatric population but lower than initially feared. For most asymptomatic patients, primary disease management may continue as planned, but treatment decisions must be individualized.

Novel risk factors for glucarpidase use in pediatric acute lymphoblastic leukemia: Hispanic ethnicity, age, and the ABCC4 gene.

BACKGROUND: Carboxypeptidase G2 (CPDG2 ; glucarpidase) is a rescue drug for patients at risk for kidney injury from high-dose methotrexate (MTX). As there are no strategies for predicting patients who will require CDPG2 , we evaluated the role of demographic, clinical, and genetic factors for CPDG2 use. PROCEDURE: Cases who received CPDG2 and controls who did not were identified by chart review of acute lymphoblastic leukemia (ALL) patients who received MTX doses between 1000 and 5000 mg/m2 between 2010 and 2017. We used multivariable Bayesian logistic regression to evaluate the association of CPDG2 use with demographic and clinical variables and, on a subset of patients, with genetic ancestry and 49 single nucleotide variants previously associated with MTX toxicity. RESULTS: We identified 423 patients who received 1592 doses of MTX. Of the 18 patients who received CPDG2 , 17 (94%) were Hispanic. No patients who received 1000 or 2000 mg/m2 of MTX received CPDG2 . Hispanic ethnicity (odds ratio: 4.68; 95% compatibility interval: 1.63-15.06) and older age (1.87 [1.17-3.17]) were associated with receiving CPDG2 . Of the 177 patients in the genomic cohort, 11 received CPDG2 . Each additional G allele of rs7317112 in ABCC4 increased the odds of requiring CPDG2 (3.10 [1.12-6.75]). Six other loci (NTRK1/rs10908521, TSG1/rs9345389, STT3B/rs1353327, SCLO1B1/rs4149056, GATA3/rs3824662, ARID5B/rs10821936) demonstrated probabilities of association between 88% and 97%. CONCLUSION: We demonstrated that demographic characteristics, including Hispanic ethnicity and age, are associated with CPDG2 use. Additionally, we provide evidence that inherited genetic variation is associated with risk of requiring CPDG2 . If validated in independent populations, this information could be leveraged to develop targeted toxicity prevention strategies for children with ALL.

Neighborhood deprivation index is associated with weight status among long-term survivors of childhood acute lymphoblastic leukemia.

PURPOSE: Area deprivation index (ADI), a measure of neighborhood socioeconomic disadvantage, has been linked to metabolic outcomes in the general population but has received limited attention in survivors of childhood acute lymphoblastic leukemia (ALL), a population with high rates of overweight and obesity. METHODS: We retrospectively reviewed heights and weights of ≥ 5 year survivors of pediatric ALL (diagnosed 1990-2013). Residential addresses were geocoded using ArcGIS to assign quartiles of ADI, a composite of 17 measures of poverty, housing, employment, and education, with higher quartiles reflecting greater deprivation. Odds ratios (OR) and 95% confidence intervals (CI) for the association between ADI quartiles and overweight/obesity or obesity alone were calculated with logistic regression. RESULTS: On average, participants (n = 454, 50.4% male, 45.2% Hispanic) were age 5.5 years at diagnosis and 17.4 years at follow-up. At follow-up, 26.4% were overweight and 24.4% obese. Compared to the lowest ADI quartile, survivors in the highest quartile were more likely to be overweight/obese at follow-up (OR = 2.33, 95% CI: 1.23-4.44) after adjusting for race/ethnicity, sex, age at diagnosis, and age at follow-up. The highest ADI quartile remained significantly associated with obesity (OR = 5.28, 95% CI: 1.79-15.54) after accounting for weight status at diagnosis. CONCLUSIONS: This study provides novel insights into possible social determinants of health inequalities among survivors of childhood ALL by reporting a significant association between neighborhood deprivation and overweight/obesity. IMPLICATIONS FOR CANCER SURVIVORS: Survivors of childhood ALL residing in neighborhood with greater socioeconomic disadvantage may be at increased risk of overweight and obesity and candidates for targeted interventions.

Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL. METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors. RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age. CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.

Defining the Inflammatory Plasma Proteome in Pediatric Hodgkin Lymphoma.

Hodgkin lymphoma (HL) histopathology is characterized by rare malignant Reed-Sternberg cells among an inflammatory infiltrate. We hypothesized that characteristics of inflammation in pediatric HL lesions would be reflected by the levels of inflammatory cytokines or chemokines in pre-therapy plasma of children with HL. The study objectives were to better define the inflammatory pre-therapy plasma proteome and identify plasma biomarkers associated with extent of disease and clinical outcomes in pediatric HL. Pre-therapy plasma samples were obtained from pediatric subjects with newly diagnosed HL and healthy pediatric controls. Plasma concentrations of 135 cytokines/chemokines were measured with the Luminex platform. Associations between protein concentration and disease characteristics were determined using multivariate permutation tests with false discovery control. Fifty-six subjects with HL (mean age: 13 years, range 3-18) and 47 controls were analyzed. The cytokine/chemokine profiles of subjects with HL were distinct from controls, and unique cytokines/chemokines were associated with high-risk disease (IL-10, TNF-α, IFN-γ, IL-8) and slow early response (CCL13, IFN-λ1, IL-8). TNFSF10 was significantly elevated among those who ultimately relapsed and was significantly associated with worse event-free survival. These biomarkers could be incorporated into biologically based risk stratification to optimize outcomes and minimize toxicities in pediatric HL.

Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients.

Allogeneic hematopoietic stem cell transplant (HSCT) for relapsed pediatric non-Hodgkin lymphoma (NHL) is often reserved for patients with certain NHL subtypes or high-risk disease whereas the remainder receive autologous HSCT. Given the aggressive nature of pediatric NHL, we performed allogeneic HSCTs for all patients regardless of disease risk. We report overall survival (OS) and prognostic variables in 36 pediatric patients who underwent allogeneic HSCT between 1998 and 2016. OS at 3 years was 67%. The 3-year OS varied based on NHL subtype: 100% for anaplastic large cell lymphoma (n = 14), 63% for diffuse large B-cell lymphoma (n = 8), 17% for lymphoblastic lymphoma (LL; n = 9) and 80% for other subtypes combined (n = 5). Disease status influenced outcome with 3-year OS of 100% for patients in complete remission (n = 15), 59% with partial remission (PR; n = 17), and 0% with progressive/stable disease (n = 3) (P = .004). Of the 17 patients in PR, all 6 with LL died of relapsed disease, whereas the other 11 attained remission after HSCT and remained disease-free. The cumulative incidence of relapse after HSCT for LL was 78% compared with 15% for all other NHL subtypes combined (P < .0001). Cumulative incidence of nonrelapse mortality (NRM) was low in our cohort at 6%. Hence, allogeneic HSCT is a well-tolerated and useful therapeutic option with low rates of NRM and relapse for all NHL subtypes except LL with active disease at HSCT.

Interactions between visual working memory and visual attention among survivors of pediatric acute lymphoblastic leukemia (ALL) and their healthy peers.

Introduction: There is increasing concern for adverse cognitive late effects among survivors of pediatric acute lymphoblastic leukemia (ALL) given the widespread impact they have on academic achievement, particularly working memory and attention. We assessed performance among survivors and their healthy peers on a dual task paradigm measuring visual working memory (VWM) and visual attention independently and the dynamic relationship between the two. Assessing specific subsets within cognitive domains allows for understanding the distinct nature of cognitive impairments. Method: Participants were 34 survivors of ALL who have been off-treatment and disease free for 7.5 years; and 20 healthy controls, all between the ages of 10 and 18 years. We utilized behavioral single- and dual-task paradigms. In the dual tasks, participants maintained several items in VWM while performing a visual attention task (Eriksen Flanker Task) that required processing of a target stimulus while inhibiting the processing of distractor stimuli. The single tasks involved performing only the VWM task or only the visual attention task. Results: Results revealed survivors of ALL performed significantly worse than their healthy peers on the single visual attention task but not the single VWM task. Of particular interest, group differences were obtained on the dual VWM and visual attention tasks, such that the VWM and attention tasks reciprocally interfered with each other only among survivors and not their healthy peers. Conclusions: Our results highlight a core deficit in visual attention that is exacerbated by VWM demands among survivors of ALL. The implementation of tasks from cognitive neuroscience paradigms may be sensitive to cognitive impairments experienced by cancer survivors. Assessment and intervention practices among survivors of pediatric ALL are discussed.

Weight trends in a multiethnic cohort of pediatric acute lymphoblastic leukemia survivors: A longitudinal analysis.

BACKGROUND: As survival rates for childhood acute lymphoblastic leukemia (ALL) continue to improve, there is growing concern over the chronic health conditions that survivors face. Given that survivors of childhood ALL are at increased risk of cardiovascular complications and obesity, we sought to characterize BMI trends from diagnosis through early survivorship in a multi-ethnic, contemporary cohort of childhood ALL patients and determine if early weight change was predictive of long-term weight status. METHODS: The study population consisted of ALL patients aged 2-15 years at diagnosis who were treated with chemotherapy alone at Texas Children's Hospital. Each patient had BMI z-scores collected at diagnosis, 30-days post-diagnosis, and annually for five years. Linear regression models were estimated to evaluate the association between: 1) BMI z-score change in the first 30 days and BMI z-scores at five-years post-diagnosis; and 2) BMI z-score change in the first year post-diagnosis and BMI z-scores at five-years post-diagnosis. RESULTS: This retrospective cohort study included longitudinal data from 121 eligible patients. The mean BMI z-scores for the population increased significantly (p-value<0.001) from baseline (mean = 0.25) to 30 days post-diagnosis (mean = 1.17) before plateauing after one year post-diagnosis (mean = 0.99). Baseline BMI z-scores were statistically significant predictors to five year BMI z-scores (p <0.001). Independent of baseline BMI z-score and other clinical factors, the BMI z-score at one year post-diagnosis was significantly associated with BMI z-score at five-years post-diagnosis (ß = 0.63, p <0.001), while BMI z-score at 30 days post-diagnosis was not (ß = 0.10, p = 0.23). CONCLUSION: Our results suggest that weight gain within the first year after diagnosis is more strongly associated with long-term BMI than early weight gain (within 30 days). If confirmed, this information may help identify a window of time during therapy when ALL patients would benefit most from weight management directed interventions.

DNA methylation and obesity in survivors of pediatric acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study.

Because survivors of pediatric acute lymphoblastic leukemia (ALL) are more likely to be obese than unaffected contemporaries, we compared DNA methylation profiles between normal-weight and obese survivors at adiposity-associated CpG sites previously-reported by epigenome-wide association studies (EWAS) of body mass index (BMI) in the general population. We selected 96 ALL survivors from the Childhood Cancer Survivor Study: 48 obese and 48 normal weight. The Illumina HumanMethylation450 BeadChip was used to compare DNA methylation at 211 loci identified in EWAS of BMI in the general population. Thirty-nine loci were associated (false discovery rate <0.05) with obesity among survivors who only received chemotherapy (n = 49). No loci were significantly associated with obesity among CRT-exposed survivors (n = 47). Our results suggest that previously identified BMI-DNA methylation loci are associated with obesity in ALL survivors who were spared CRT, while no loci were significantly associated with obesity in survivors who received CRT.

Comparison of height and weight after 12 vs. 18 Gy cranial radiation therapy in pediatric acute lymphoblastic leukemia (ALL) patients.

PURPOSE: To compare the effect of 12 versus 18 Gy cranial radiation therapy (RT) on height and weight indices among pediatric patients with acute lymphoblastic leukemia (ALL). METHODS AND MATERIALS: Records of children with ALL who were 2 to 14 years old at the time of RT and were treated at a single institution between 2000 and 2011 were reviewed. Patients' height, weight, and body mass index were converted into z-scores using the Centers for Disease Control growth charts to normalize the values to number of standard deviations from the mean. These values were measured at the pre-RT clinic visit and subsequent yearly intervals. The z-scores of the growth indices were fitted into a generalizing estimating equations model and analyzed by various clinical factors. RESULTS: A total of 48 patients met the study criteria, including 32 boys and 16 girls. The median age at the time of RT was 7 years (range, 2-14 years). Patients were separated into 2 dose groups: 12 Gy (n = 30) and 18 Gy (n = 18). Median follow-up was 4.9 years (range, 3.0-11.8 years) and 6.0 years (range, 3.1-10.5 years) and the median pre-RT height z-scores were -0.55 (range, -2.2 to 1.4) and -0.85 (range, -3.1 to 0.8) for the 2 groups, respectively (P = .65). Patients who received 18 Gy had a significant difference in change in height compared with those who received 12 Gy, who were able to maintain normal growth during the first 3 years of follow-up. This did not appear to be sex-specific, and there was no difference in change in weight or body mass index. CONCLUSIONS: Compared with 18 Gy, patients with ALL who received 12 Gy of cranial RT had less height impairment in the first 3 years post-RT, but further prospective studies are needed.

Predictors of Suboptimal Follow-up in Pediatric Cancer Survivors.

Attendance to follow-up care after completion of cancer treatment is an understudied area. We examined demographic, clinical, and socioeconomic predictors of follow-up by pediatric cancer patients at a large center in 442 newly diagnosed patients using multivariable logistic regression analyses. Patients who did not return to clinic for at least 1000 days were considered lost to follow-up. Two hundred forty-two (54.8%) patients were lost. In multivariable analyses, the following variables were independent predictors of being lost to follow-up: treatment with surgery alone (odds ratio [OR]=6.7; 95% confidence interval [CI], 3.1-14.9), older age at diagnosis (reference, 0 to 4; ages, 5 to 9: OR=1.8, 95% CI, 1.1-3; ages, 10 to 14: OR=3.3; CI, 1.8-6.1; and ages, 15 and above: OR=4.8; CI, 2.1-11.7), lack of history of stem cell transplantation (OR=2, 95% CI, 1.04-3.7) and lack of insurance (OR=3.4; CI, 1.2-9.2). Hispanic patients had the best follow-up rates (53.7%) compared to whites and blacks (P=0.03). Attendance to long-term follow-up care is suboptimal in childhood cancer survivors. Predictors that were associated with nonattendance can be used to design targeted interventions to improve follow-up care for survivors of pediatric cancer.

Prevalence and Predictors of Overweight and Obesity Among a Multiethnic Population of Pediatric Acute Lymphoblastic Leukemia Survivors: A Cross-Sectional Assessment.

As previous studies of obesity in survivors of pediatric acute lymphoblastic leukemia (ALL) have primarily been conducted among non-Hispanic white survivors or children treated on older protocols, our objective was to describe the prevalence and correlates of overweight status among an ethnically diverse population of pediatric ALL survivors, largely treated with more contemporary therapies. We evaluated the overweight/obesity status of pediatric ALL survivors (n=406) followed in the Texas Children's Cancer Center between 2004 and 2014. Survivors were classified as underweight, normal weight, overweight, or obese on the basis of their body mass index at their most current follow-up visit. Our results showed that Hispanic ethnicity (39% of the subjects) was associated with being overweight (adjusted odds ratio=1.88; 95% confidence interval, 1.13-3.14) or obese (adjusted odds ratio=2.84; 95% confidence interval, 1.59-5.06) at follow-up, even after adjusting for cranial radiotherapy (CRT) exposure. Body mass index z-score at diagnosis was also associated with overweight/obesity at follow-up. In addition, there was a statistically significant interaction between younger age at diagnosis and CRT, indicating that younger age at diagnosis was associated with obesity among patients who received CRT. These findings may help identify pediatric ALL patients that are at increased risk of being overweight or obese after treatment.

Birth Characteristics and Childhood Leukemia Risk: Correlations With Genetic Markers.

Birth characteristics such as birth order, birth weight, birth defects, and Down syndrome showed some of the first risk associations with childhood leukemia. Examinations of correlations between birth characteristics and leukemia risk markers have been limited to birth weight-related genetic polymorphisms. We integrated information on nongenetic and genetic markers by evaluating the relationship of birth characteristics, genetic markers for childhood acute lymphoblastic leukemia (ALL) susceptibility, and ALL risk together. The multiethnic study consisted of cases with childhood ALL (n=161) and healthy controls (n=261). Birth characteristic data were collected through questionnaires, and genotyping was achieved by TaqMan SNP Genotyping Assays. We observed risk associations for birth weight over 4000 g (odds ratios [OR]=1.93; 95% confidence interval [CI], 1.16-3.19), birth length (OR=1.18 per inch; 95% CI, 1.01-1.38), and with gestational age (OR=1.10 per week; 95% CI, 1.00-1.21). Only the HFE tag single-nucleotide polymorphism (SNP) rs9366637 showed an inverse correlation with a birth characteristic, gestational age, with a gene-dosage effect (P=0.005), and in interaction with a transferrin receptor rs3817672 genotype (Pinteraction=0.05). This correlation translated into a strong association for rs9366637 with preterm birth (OR=5.0; 95% CI, 1.19-20.9). Our study provides evidence for the involvement of prenatal events in the development of childhood ALL. The inverse correlation of rs9366637 with gestational age has implications on the design of HFE association studies in birth weight and childhood conditions using full-term newborns as controls.