Lupo, Philip J.

AbstractBackgroundPatients with alveolar rhabdomyosarcoma (ARMS) have inferior outcomes compared to patients with embryonal rhabdomyosarcoma (ERMS) and more effective chemotherapy options are needed for these patients. Vinorelbine is a semisynthetic vinca alkaloid that has clinical activity in relapsed rhabdomyosarcoma (RMS) when used alone or in combination with cyclophosphamide.AimsThe goal of our study was to evaluate whether RMS histology subtype influences response rate to vinorelbine alone or in combination.Materials & MethodsFive Phase 2 trials that enrolled RMS patients were included in the meta‐analysis. Two studies evaluated vinorelbine alone, two studies evaluated vinorelbine in combination with low dose oral cyclophosphamide, and one study evaluated vinorelbine and intravenous cyclophosphamide in combination with temsirolimus or bevacizumab. All RMS patients had relapsed or refractory disease and had received at least one prior therapy. Response was reported according to RECIST1.1 and was defined as a complete or partial response. Response data was obtained from published results or from trial principal investigator. RMS NOS patients were grouped with ERMS patients for this analysis. Summary estimates comparing differences between ARMS and ERMS response rates were generated using a random‐effects model to account for heterogeneity among the studies.ResultsOne hundred fifty‐six enrolled patients evaluable for response were included in the meta‐analysis, 85 ARMS, 64 ERMS and 7 RMS‐NOS. The combined effect generated from the random‐effects model demonstrated a 41% increase (p = 0.001, 95% CI; 0.21–0.60) in response to vinorelbine as a single agent or in combination in patients with ARMS compared to patients with ERMS. There was no significant difference in the rate of progressive disease between patients with ARMS compared to ERMS (p = 0.1, 95%CI; −0.26–0.02).DiscussionVinorelbine is an active agent for the treatment of relapsed or refractory RMS and a meta‐analysis of Phase 2 studies shows that radiographic responses in patients with ARMS were significantly higher than ERMS or RMS‐NOS.ConclusionThese data support further investigation of vinorelbine in newly diagnosed patients with RMS particularly those with alveolar histology.

AbstractBackgroundPediatric brain tumor survivors are at risk for poor social outcomes. It remains unknown whether cognitive sparing with proton radiotherapy (PRT) supports better social outcomes relative to photon radiotherapy (XRT). We hypothesized that survivors treated with PRT would outperform those treated with XRT on measures of cognitive and social outcomes. Further, we hypothesized that cognitive performance would predict survivor social outcomes.ProcedureSurvivors who underwent PRT (n = 38) or XRT (n = 20) participated in a neurocognitive evaluation >1 year post radiotherapy. Group differences in cognitive and social functioning were assessed using analysis of covariance (ANCOVA). Regression analyses examined predictors of peer relations and social skills.ResultsAge at evaluation, radiation dose, tumor diameter, and sex did not differ between groups (all p > .05). XRT participants were younger at diagnosis (XRT M = 5.0 years, PRT M = 7.6 years) and further out from radiotherapy (XRT M = 8.7 years, PRT M = 4.6 years). The XRT group performed worse than the PRT group on measures of processing speed (p = .01) and verbal memory (p < .01); however, social outcomes did not differ by radiation type. The proportion of survivors with impairment in peer relations and social skills exceeded expectation; χ2(1) = 38.67, p < .001; χ2(1) = 5.63, p < .05. Household poverty predicted peer relation difficulties (t = 2.18, p < .05), and verbal memory approached significance (t = −1.99, p = .05). Tumor diameter predicted social skills (t = −2.07, p < .05).ConclusionsRegardless of radiation modality, survivors are at risk for social challenges. Deficits in verbal memory may place survivors at particular risk. Results support monitoring of cognitive and social functioning throughout survivorship, as well as consideration of sociodemographic risk factors.

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.