Chintagumpala, Murali

Abstract Background Cranial radiotherapy (RT) is associated with risk for cognitive and adaptive dysfunction. Proton RT (PRT) is a technique hypothesized to spare cognition by reducing exposure to nontarget brain tissue. However, little is known regarding functional outcomes in survivors of pediatric brain tumor (BT) treated with PRT. The present study examined the relationship between cognitive and adaptive outcomes in pediatric BT survivors post‐PRT. Methods Survivors treated with either focal (n = 33) or craniospinal irradiation (CSI; n = 37) PRT completed neurocognitive evaluations approximately 5 years post‐treatment. Results of intelligence testing and ratings of adaptive functioning are reported. Mediation models examined the relationship among radiation field, cognition, and adaptive functioning. Results The PRT CSI group demonstrated worse cognitive outcomes than the PRT Focal group across each cognitive index (Cohen's d = 0.56–0.70). Parent ratings of adaptive functioning were also worse in the PRT CSI group than the PRT Focal group (Global Adaptive Composite, d = 0.53; conceptual skills, d = 0.67). Cognitive performance fully mediated the relationship between radiation field and adaptive outcomes, while controlling for group differences in tumor histology and RT dose. Conclusions Focal PRT survivors demonstrated generally positive outcomes with weaknesses in processing speed and aspects of adaptive functioning. CSI exposure was associated with more consistently poor cognitive and adaptive outcomes. The increased risk for adaptive dysfunction in the PRT CSI group appeared due to the effects of CSI on cognition. Efforts to reduce the volume of tissue exposure to RT remain important.

AbstractPurpose/Objective(s)Bladder and prostate are unfavorable sites for rhabdomyosarcoma (B/P‐RMS), and represent a challenging location for radiotherapy.Materials/MethodsNineteen patients with B/P‐RMS were enrolled on a prospective registry protocol (2008‐2017) and treated with chemotherapy, proton beam therapy (PBT), and surgical resection (n = 8; 42%). Emphasis was given to treatment technique, disease‐related outcomes, and toxicity associated with PBT.ResultsThe majority of patients had bladder RMS (74%) of embryonal histology (95%), Group III (68%), and intermediate‐risk disease by Children's Oncology Group (COG) risk stratification (89%). Seven patients (37%) had primary tumors >5 cm in size. All patients were treated according to COG protocols. With a median follow‐up of 66.2 months, 5‐year overall survival (OS) and progression‐free survival (PFS) were 76%. Four patients (21%) experienced disease relapse, all presenting with local failure. The 5‐year local control (LC) rate was 76%. Tumor size predicted LC, with 5‐year LC for patients with >5 cm tumors being 43% versus 100% for those with ≤5 cm tumors (P = .006). Univariate analysis demonstrated an effect of tumor size on OS (tumor >5 cm, hazard ratio [HR] 17.7, P = .049) and PFS (HR 17.7, P = .049). Acute grade 2 toxicity was observed in two patients (11%, transient proctitis). Late grade 2+ toxicity was observed in three patients (16%; n = 1 grade 2 skeletal deformity; n = 3 transient grade 2 urinary incontinence; one patient experienced both).ConclusionsPBT for B/P‐RMS affords promising disease‐related outcomes with an acceptable toxicity profile. Higher local failure rates were observed for larger tumors, supporting dose‐escalation components of ongoing RMS clinical trials.

10571 Background: Pediatric medulloblastoma patients exposed to craniospinal radiation (CSI) are at high risk of developing endocrinopathies, including hypothyroidism. We sought to evaluate the role of genetic variation on hypothyroidism susceptibility among survivors of pediatric medullobastoma. Methods: Records from 61 medulloblastoma survivors treated at Texas Children’s Hospital between 1997 and 2013 were reviewed. All patients completed baseline and yearly follow-up thyroid assessments. Genome-wide genotyping was performed on Illumina HumanOmni1 and HumanOmni2.5 BeadChip single nucleotide polymorphism (SNP) arrays. Following standard quality control measures and exclusion of rare variants (minor allele frequency [MAF] < 5%), 572,562 autosomal SNPs were included in our analyses. The association between each SNP and hypothyroidism was tested using Fisher’s exact test and logistic regression, assuming additive allelic effects. Results: A total of 25 patients (41%) developed hypothyroidism with median follow-up of 8.3 years from diagnosis (range: 1.8-17.2 years). Primary hypothyroidism was identified in 9 (36%) cases, while the remaining 16 (64%) developed central hypothyroidism. Hypothyroidism was detected in 13 of 40 (33%) individuals exposed to < 30 Gy CSI and 12 of 21 (57%) individuals exposed to ≥30 Gy CSI (p = 0.06). Genome-wide association analysis identified several risk loci, including 3 variants associated with hypothyroidism (p-value < 1x10-5) at chromosome 2q11.2 ( NPAS2 gene). The top overall SNP (MAF = 27.5%, p-value = 6.5x10-7) remained strongly associated with hypothyroidism after accounting for possible confounders, including CSI dose, CSI type (proton/photon), age, sex, and genetic ancestry. Conclusions: Our findings suggest susceptibility to treatment-related hypothyroidism is strongly influenced by common genetic variation in NPAS2. The NPAS2 gene, a central component of the circadian rhythm network, is a transcriptional activator and regulator of DNA damage response and DNA repair genes.

Abstract Purpose To determine the impact of surgery and/or radiation therapy on distant metastatic sites (DMS) in children with stage IV rhabdomyosarcoma (RMS). Methods A retrospective chart review was conducted on all patients with stage IV RMS at Texas Children's Hospital from 1992 to 2012. Data analyzed included age, gender, primary site, histologic subtype, number and sites of metastases, treatment including local therapy to DMS, and Oberlin score. Results The 5‐year progression‐free survival (PFS) and overall survival (OS) rates were 20% and 25%. The 5‐year PFS in patients receiving local therapy to all DMS (n = 16) and to less than all DMS (n = 19) was 31.3% versus 0% ( P = 0.002), whereas the 5‐year OS was 37.3% versus 0% ( P < 0.001), respectively. The 5‐year PFS in patients with isolated lung metastasis versus other types of metastasis was 29% versus 7% ( P = n.s.), whereas the 5‐year OS was 43% versus 10% ( P = 0.01). The 5‐year pulmonary local control was improved by the use of whole lung irradiation (WLI; 56% vs. 10%, P = 0.03). Conclusions Local treatment to all metastatic sites was associated with improved PFS and OS at 5 years. The use of WLI improved pulmonary control in patients with lung metastasis. We recommend an aggressive approach including local therapy to DMS in children with stage IV RMS.