Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

Genetic susceptibility to cognitive decline following craniospinal irradiation for pediatric central nervous system tumors.

BACKGROUND: Survivors of pediatric central nervous system (CNS) tumors treated with craniospinal irradiation (CSI) exhibit long-term cognitive difficulties. Goals of this study were to evaluate longitudinal effects of candidate and novel genetic variants on cognitive decline following CSI. METHODS: Intelligence quotient (IQ), working memory (WM), and processing speed (PS) were longitudinally collected from patients treated with CSI (n = 241). Genotype-by-time interactions were evaluated using mixed-effects linear regression to identify common variants (minor allele frequency > 1%) associated with cognitive performance change. Novel variants associated with cognitive decline (P < 5 × 10-5) in individuals of European ancestry (n = 163) were considered replicated if they demonstrated consistent genotype-by-time interactions (P < .05) in individuals of non-European ancestries (n = 78) and achieved genome-wide statistical significance (P < 5 × 10-8) in a meta-analysis across ancestry groups. RESULTS: Participants were mostly males (65%) diagnosed with embryonal tumors (98%) at a median age of 8.3 years. Overall, 1150 neurocognitive evaluations were obtained (median = 5, range: 2-10 per participant). One of the five loci previously associated with cognitive outcomes in pediatric CNS tumors survivors demonstrated significant time-dependent IQ declines (PPARA rs6008197, P = .004). Two variants associated with IQ in the general population were associated with declines in IQ after Bonferroni correction (rs9348721, P = 1.7 × 10-5; rs31771, P = 7.8 × 10-4). In genome-wide analyses, we identified novel loci associated with accelerated declines in IQ (rs116595313, meta-P = 9.4 × 10-9), WM (rs17774009, meta-P = 4.2 × 10-9), and PS (rs77467524, meta-P = 1.5 × 10-8; rs17630683, meta-P = 2.0 × 10-8; rs73249323, meta-P = 3.1 × 10-8). CONCLUSIONS: Inherited genetic variants involved in baseline cognitive functioning and novel susceptibility loci jointly influence the degree of treatment-associated cognitive decline in pediatric CNS tumor survivors.

Cognitive Sparing in Proton versus Photon Radiotherapy for Pediatric Brain Tumor Is Associated with White Matter Integrity: An Exploratory Study.

Radiotherapy for pediatric brain tumors is associated with reduced white matter structural integrity and neurocognitive decline. Superior cognitive outcomes have been reported following proton radiotherapy (PRT) compared to photon radiotherapy (XRT), presumably due to improved sparing of normal brain tissue. This exploratory study examined the relationship between white matter change and late cognitive effects in pediatric brain tumor survivors treated with XRT versus PRT. Pediatric brain tumor survivors treated with XRT (n = 10) or PRT (n = 12) underwent neuropsychological testing and diffusion weighted imaging >7 years post-radiotherapy. A healthy comparison group (n = 23) was also recruited. Participants completed age-appropriate measures of intellectual functioning, visual-motor integration, and motor coordination. Tractography was conducted using automated fiber quantification (AFQ). Fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) were extracted from 12 tracts of interest. Overall, both white matter integrity (FA) and neuropsychological performance were lower in XRT patients while PRT patients were similar to healthy control participants with respect to both FA and cognitive functioning. These findings support improved long-term outcomes in PRT versus XRT. This exploratory study is the first to directly support for white matter integrity as a mechanism of cognitive sparing in PRT.

Patient-reported neurocognitive function in adult survivors of childhood and adolescent osteosarcoma and Ewing sarcoma.

PURPOSE: Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS. METHODS: Five-year survivors of osteosarcoma (N = 604; median age 37.0 years) and EWS (N = 356; median age 35.0 years) diagnosed at < 21 years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties. RESULTS: Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P = 0.03] and 14.0% [P = 0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P < 0.0001] and 15.2% [P = 0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P = 0.01]). Comorbid impairment (i.e., ≥ 2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P < 0.001]) and EWS survivors (16.3% [P = 0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR = 2.17; 95% CI = 1.21-3.88) and emotional regulation (RR = 1.88; 95% CI = 1.01-3.52), and respiratory conditions were associated with worse organization (RR = 2.60; 95% CI = 1.05-6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR = 1.98; 95% CI = 1.22-3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment. CONCLUSIONS: Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time. IMPLICATIONS FOR CANCER SURVIVORS: Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes.

Pediatric rhabdomyosarcoma incidence and survival in the United States: An assessment of 5656 cases, 2001-2017.

BACKGROUND: While rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, past epidemiology studies of this malignancy used data that covered <30% of the US population. Therefore, we evaluated RMS incidence using data from U.S. Cancer Statistics (USCS) and survival trends using the National Program of Cancer Registries (NPCR), which covers 100% and 94% of the U.S. population, respectively. METHODS: Incidence and survival were assessed for pediatric patients diagnosed with RMS during 2003-2017 and 2001-2016, respectively. Both demographic and clinical variables were evaluated. Age-adjusted incidence rates, average annual percent change (AAPC), and 5-year relative survival (RS) were calculated, all with corresponding 95% confidence intervals (CIs). Cox regression models were used to evaluate the impact of demographic and clinical variables on survival. RESULTS: We identified 5656 primary RMS cases in USCS during 2003-2017. The age-adjusted incidence rate was 4.58 per 1 million (95% CI: 4.46-4.70) with an AAPC of 0.3% (95% CI: -0.7 to 1.2%). In NPCR, 5-year RS for all cases was 68.0% (95% CI: 66.6-69.3%). In multivariable analyses, non-Hispanic (NH) Black cases had worse survival compared with NH White cases (hazard ratio [HR] = 1.16, 95% CI: 1.01-1.33). CONCLUSION: The incidence and survival rates were stable in the largest and most comprehensive population-based analysis for pediatric RMS cases in the U.S. Additionally, we observed a survival disparity among NH Black cases. Findings from this study could inform interventions to address disparities, risk stratification strategies, and clinical trial design.

Scoliosis in Children Treated With Photon Craniospinal Irradiation for Medulloblastoma.

PURPOSE: Scoliosis is a well-recognized complication after abdominal radiation therapy but not reported frequently after craniospinal irradiation (CSI). We examined the incidence and risk factors for scoliosis after CSI in long-term survivors with medulloblastoma. METHODS AND MATERIALS: The records of patients with medulloblastoma seen at one institution from 1996 to 2006 were analyzed for the use of CSI and development of scoliosis as documented on physical examination and spinal imaging. RESULTS: We identified 35 children with medulloblastoma who were ≤12 years of age at time of CSI with a median 14.3 years (range, 5.8-19.3 years) of follow-up. Twenty-seven (77.1%) were male, and median age at CSI was 6.8 years (range, 2.8-12 years). The cumulative incidence of scoliosis at 15 years was 34.6%. The median time to develop scoliosis was 7.1 years (range, 5-11.7 years) after CSI. Treatment with high dose CSI (34.2-40 Gy) and presence of hemiplegia or hemiparesis were found to be risk factors for development of scoliosis. CONCLUSIONS: Scoliosis is an underreported complication of photon craniospinal irradiation.

A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants.

Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

SOD2 genetic variant associated with treatment-related ototoxicity in cisplatin-treated pediatric medulloblastoma.

Manganese superoxide dismutase (MnSOD), encoded by the SOD2 gene, is involved in the detoxification of superoxide anion. Superoxide is likely a source of oxidative stress in the cochlea following treatment with platinum agents and radiation. Therefore, we examined SOD2 variants in association with ototoxicity among cisplatin-treated childhood medulloblastoma patients. Blood samples were obtained from 71 eligible patients treated for pediatric medulloblastoma at Texas Children's Cancer Center (1987-2010). Ototoxicity was defined as requiring the use of a hearing aid sometime after the initiation of therapy. DNA was genotyped on the Illumina HumanOmni-1 Quad BeadChip. A linkage disequilibrium (LD)-based single-nucleotide polymorphism (SNP) selection strategy was used to identify a minimal set of informative variants. Associations between SNPs and ototoxicity were assessed using logistic regression. Of the 71 eligible patients, 26 (37%) suffered from cisplatin-related ototoxicity. Study participants were primarily male (73%) and non-Hispanic white (42%). Five SOD2 variants (rs7855, rs5746151, rs5746136, rs2758331, and rs4880) identified by the LD-based selection strategy were genotyped. After correcting for multiple comparisons, the C-allele of the rs4880 variant was significantly associated with ototoxicity (odds ratio = 3.06, 95% confidence interval: 1.30-7.20) in adjusted models. The rs4880 T > C substitution results in a Val > Ala amino acid change at position 16 of the MnSOD mitochondrial targeting sequence. The Ala variant, which has been associated with increased MnSOD activity, was associated with hearing damage in this study. Platinum-based therapies increase the expression of MnSOD, which may result in an abundance of hydrogen peroxide, a reactive oxygen species. Therefore, oxidative stress may be an important mechanism in therapy-related cochlear damage.

Do longer formula feeding and later introduction of solids increase risk for pediatric acute lymphoblastic leukemia?

Milk formula feeding can elevate insulin-like growth factor-1 levels, possibly impacting leukemogenesis. The intent of the current study is to examine the associations between infant feeding practices and age at introduction of solids on risk of childhood acute lymphoblastic leukemia (ALL). Incident cases of infant and childhood (aged ≤14 years) ALL (n = 142) were enrolled in a case-control study. Cases were frequency matched on age, sex, race, and ethnicity to two sets of controls (n = 284 total). Multivariable logistic regression was used to determine the association between infant feeding practices and age at the introduction of solids and the odds ratio of ALL. In adjusted multivariable analyses, each additional month of formula feeding was associated with a 1.17 (1.09-1.25) odds ratio; each additional month of age at introduction of solids was associated with a 1.18 (1.07-1.30) odds ratio. In this study, longer duration of formula feeding and later age at the introduction of solid foods were independently associated with increased risk of ALL. Additional studies are needed to address the factors influencing duration of formula feeding and delayed introduction of solids. The results support the potential role of energy balance in early life as a contributor to risk for pediatric acute lymphoblastic leukemia.

Glutathione S-transferase P1 single nucleotide polymorphism predicts permanent ototoxicity in children with medulloblastoma.

BACKGROUND: Glutathione S-transferase (GST) enzymes are involved in detoxifying chemotherapy and clearing reactive oxygen species formed by radiation. We explored the relationship between the host GSTP1 105 A > G polymorphism (rs1695), tumor GSTpi protein expression, and clinical outcomes in pediatric medulloblastoma. We hypothesized that the GSTP1 105 G-allele and increased tumor GSTpi expression would be associated with lower progression-free survival and fewer adverse events. PROCEDURE: The study included 106 medulloblastoma/primitive neuroectodermal tumor (PNET) patients seen at Texas Children's Cancer Center. Genotyping was performed using an Illumina HumanOmni1-Quad BeadChip and GSTpi expression was assessed using immunohistochemistry. We used the Kaplan-Meier method for survival analyses and logistic regression for toxicity comparisons. RESULTS: Patients with a GSTP1 105 AG/GG genotype (vs. AA) or who had received high dose craniospinal radiation (≥34 Gy vs. <26 Gy) had a greater risk of requiring hearing aids than their counterparts (OR 4.0, 95% CI 1.2-13.6, and OR 3.1, 95% CI 1.1-8.8, respectively, n = 69). Additionally, there was a statistically significant interaction between these variables. Compared with the lowest risk group (GSTP1 105 AA-low dose radiation), patients with a GSTP1 105 AG/GG genotype who received high dose radiation were 8.4 times more likely to require hearing aids (95% CI 1.4-49.9, p-trend = 0.005, n = 69). When adjusted for age, cumulative cisplatin dose, and amifostine use, the association remained. CONCLUSIONS: The GSTP1 105 G-allele is associated with permanent ototoxicity in pediatric medulloblastoma/PNET and strongly interacts with radiation dose. Patients with this allele should be considered for clinical trials employing radiation dose modifications and cytoprotectant strategies.

Flow cytometry and fluorescence in situ hybridization to detect residual neuroblastoma cells in bone marrow.

BACKGROUND: In patients with neuroblastoma morphological assessment of BM for residual NB cells is not precise, particularly when the number of tumor cells is small. PROCEDURE: To develop a sensitive and rapid method of detecting NB cells in BM, we assessed the efficiency of flow cytometry (FCM) using markers CD9, CD56, and CD45. The percent of CD9+/CD56+/CD45- (NB phenotype) cells was determined by FCM in 41 samples (16 patients) at various time points. For confirmation fluorescence in situ hybridization (FISH) for 17q gain was performed. RESULTS: Nineteen of the 22 (86%) samples that were negative by morphology were positive by FCM (>0.006% CD9+/CD56+/CD45- cells). The longest time to complete the FCM study was 3 hr. In six FISH experiments the sorted CD9+/CD56+/CD45- population had a higher percentage of cells with 17q gain (11.5-95%) compared to a CD56-/CD45+ internal control population (2-8%). CONCLUSIONS: Our preliminary results suggest that FCM determination of the percent of CD9+/CD56+/CD45- cells is an effective method of rapidly detecting NB cells in BM.

Synovial sarcoma of childhood and adolescence: a multicenter, multivariate analysis of outcome.

PURPOSE: To identify prognostic factors related to outcome in 219 children and adolescents with synovial sarcoma. PATIENTS AND METHODS: We combined the experiences of the four following research groups: Cooperative Weichteilsarkomastudie Group, Germany (n = 95); St. Jude Children's Research Hospital, Memphis, TN (n = 49); Istituto Nazionale dei Tumori, Milan, Italy (n = 33); and The University of Texas M.D. Anderson Cancer Center, Houston, TX (n = 42). Kaplan-Meier and Cox proportional hazard analyses were performed. RESULTS: The median age at diagnosis was 13 years (range, 1 to 20 years), and the median follow-up was 6.6 years (range, 0.5 to 30.7 years). The estimated 5-year overall survival and event-free survival rates for the entire group were 80% +/- 3% (SE) and 72% +/- 3%, respectively. A previously unreported interaction between tumor size and invasiveness was observed that statistically significantly related to outcome. In multivarible analysis, patients with T1B and T2B disease (hazard ratio [HR] = 5.6, 95% confidence interval (CI), 1.9 to 16.2; and HR = 5.9, 95% CI, 2.1 to 16.4, respectively) or Intergroup Rhabdomyosarcoma Study (IRS) Clinical Group III and IV disease (HR = 2.7, 95% CI, 1.2 to 6.5; and HR = 14.1, 95% CI, 4.3 to 31.3, respectively) had poor overall survival. Treatment with radiotherapy was related to improved overall survival (HR = 0.4; 95% CI, 0.2 to 0.7). In IRS Group III patients, objective response to chemotherapy (18 of 30, 60%) correlated with improved survival. CONCLUSION: Clinical group, tumor size, and invasiveness are important prognostic factors. Multicenter randomized clinical trials are needed to determine both the effect of chemotherapy on survival and the necessity of local radiotherapy in patients with completely resected tumors.

Birth weight, ethnicity, and occurrence of cancer in children: a population-based, incident case-control study in the State of Texas, USA.

OBJECTIVE: To investigate the relationship between birth weight and risk of early age childhood cancer and whether racial differences in birth weight distribution could explain differences in the incidence of cancer in white, Hispanic, and black children. METHODS: We compared birth weights of 268 children younger than five years old and diagnosed with cancer in the State of Texas in 1995 to the birth weights of 2680 randomly selected, age-matched population-based controls. Birth weight, sex, race/ethnicity, maternal age, smoking status, parity, and gestational age information was ascertained from the birth certificates. Logistic regression analyses were performed to evaluate the association between high birth weight (>4,000 g) and occurrence of childhood cancer. RESULTS: Increased odds ratios (OR) were found for "total cancer cases" (OR 1.4, 95% CI 0.9-2.1), "leukemia cases" (OR 1.7, 95% CI 0.9-3.0) and "acute lymphoblastic leukemia (ALL) cases" (OR 2.2, 95% CI 1.2-4.1). Increased ORs in the former two groups were shown to be due to ALL cases. Including the race/ethnicity variable in the regression model did not affect the ORs. CONCLUSION: Compared to newborns who weighed between 2500 and 4000 g at birth, children who weighed >4,000 g had an increased risk of developing childhood ALL during the first five years of life. Birth weight differences does not explain the sequence of childhood cancer incidence by race/ethnicity.