Citations

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age‐at‐diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age‐at‐diagnosis has been explored, genome‐wide association studies (GWAS) have not previously been stratified by age. Potential age‐specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age‐stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta‐analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54–63 = 1.50x10−9, OR54–63 = 1.28, 95%CI54–63 = 1.18–1.39; p64+ = 2.14x10−11, OR64+ = 1.32, 95%CI64+ = 1.21–1.43] and rs11979158 [p54–63 = 6.13x10−8, OR54–63 = 1.35, 95%CI54–63 = 1.21–1.50; p64+ = 2.18x10−10, OR64+ = 1.42, 95%CI64+ = 1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p18–53 = 9.30 × 10−11, OR18–53 = 1.76, 95%CI18–53 = 1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’‐like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p = 0.0005). Age‐specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’

Abstract Glioma incidence is highest in non-Hispanic Whites, where it occurs ~2x as frequently compared with other race/ethnicity groups. Glioma GWAS to date have included European ancestry populations only, and it is unknown whether variants identified by these analyses are associated with glioma in non- European ancestry populations. African Americans and Hispanics are admixed populations with varying proportions of European ancestry. While global ancestry may be similar within admixed groups, the proportion of European ancestry at each allele can vary across the genome. As glioma is more common in European ancestry populations, the presence of increased local European ancestry in these admixed populations could be used to identify glioma risk loci. Here we assessed whether excess European ancestry at established risk loci (Melin et al, Nature Genetics, 2017) was associated with glioma risk in non-European ancestry populations. Global ancestry was estimated using fastStructure, and local ancestry was estimated using RFMix. Both methods used 1,000 genomes project reference populations (African: YRI; European: CEU; East Asian: CHB/JPT; and Native American: CLM/PEL/MXL). We evaluated differences in local European ancestry between cases and controls using logistic regression conditioned on global European ancestry within 500kb of 25 previously identified risk variants among individuals with ≥50% African ancestry, and ≥30% Native American ancestry for all gliomas, and for grade IV glioblastoma (GBM) and grade II-III non-GBM. There were 347 individuals (184 cases and 163 controls) with ≥50% global African ancestry, and 277 individuals (153 cases and 124 controls) with ≥30% global American ancestry. There was no significant difference in proportion of global European ancestry between cases and controls with ≥50% global African ancestry (cases: 18.2%, controls: 17.7%, p=0.6834), and no significant difference in proportion of global European ancestry between cases and controls with ≥30% global American ancestry (cases: 51.1%, controls: 49.0%, p=0.2123). Among individuals with >50% African ancestry, we observed a nominally significant association between all glioma and increased local European ancestry at 7p11.2 (EGFR, pmin=0.0070) and between GBM and increased local European ancestry at 22q13.1 (CSNK1E, pmin=0.0098), both near SNPs previously associated with glioblastoma in majority European-ancestry populations. The dataset used for this analysis represents the largest collection of genotyped non-European glioma cases. These results suggest that glioma risk in African Americans may be associated with an increased local European ancestry variants at glioma risk loci previously identified in majority European ancestry populations (7p11.2 and 22q13.1). Citation Format: Quinn T. Ostrom, Kathleen M. Egan, L. Burt Nabors, Travis Gerke, Reid C. Thompson, Jeffrey J. Olson, Renato LaRocca, Sajeel Chowdhary, Jeanette E. Eckel-Passow, Georgina Armstrong, John K. Wiencke, Christopher I. Amos, Jonine L. Bernstein, Elizabeth B. Claus, Dora Il'yasova, Christoffer Johansen, Daniel H. Lachance, Rose Lai, Ryan T. Merrell, Sara H. Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Richard S. Houlston, Robert B. Jenkins, Beatrice Melin, Melissa L. Bondy, Jill S. Barnholtz-Sloan. Evaluating glioma risk associated with extent of European admixture in African-Americans and Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 233.

Background: The vertical rectus abdominis myocutaneous flap has been used to reliably reconstruct posterior soft-tissue defects following resection of high sacral tumors, providing skin and soft-tissue bulk. Current literature examining the use of these flaps for high sacral reconstruction is limited. The purpose of this study was to report the authors’ institution's outcome on the use of the vertical rectus abdominis myocutaneous flap to reconstruct a high sacral defect following an oncologic resection. Methods: Eighty-seven patients (29 female and 58 male) underwent vertical rectus abdominis myocutaneous flap surgery to reconstruct a posterior wound following high sacral tumor resection from 1994 to 2016. The mean age and body mass index were 52 years and 27.8 kg/m2, respectively. The mean follow-up was 6 years. Results: Sixty-eight patients (79 percent) sustained a complication, most commonly a wound complication [n = 41 (47 percent)]. Twenty patients (23 percent) sustained a donor-site wound complication, most commonly a wound dehiscence (n = 10). Complications resulted in a reoperation in 44 patients (51 percent), with total flap failure occurring in one (1 percent). Preoperative radiotherapy and obesity were found to increase the risk of wound complications (p = 0.004 and p = 0.02, respectively) and deep infection (p = 0.03 and p = 0.02, respectively). Conclusions: Complications were common following vertical rectus abdominis myocutaneous flap surgery; however, total flap loss was not. Patients with obesity and preoperative radiotherapy should be cautioned on their increased risk of complications. Currently, the vertical rectus abdominis myocutaneous flap is the authors’ preferred means of soft-tissue reconstruction following high sacral tumor resection. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Background: Lower extremity intercalary allograft reconstruction has traditionally been used to facilitate limb salvage. Combining the allograft with a free vascularized fibula graft has been described; however, there is a paucity of data comparing the outcome of these reconstructions. Methods: Twenty-nine pediatric patients (15 boys and 14 girls) underwent lower extremity limb salvage with the use of intercalary cadaveric allograft at a mean age of 12 years. The most common diagnosis was osteosarcoma (n = 18). Patients underwent reconstruction with an allograft alone (n = 11) or supplemented with a free vascularized fibula graft (n = 18). Results: The mean time to union of the allograft was 11 months, with 10 patients requiring additional bone grafting. There was no difference in the need for an additional bone graft (OR, 0.87; p = 1.0) between patients with a free vascularized fibula graft and those without. The allograft was revised in three patients because of fracture (n = 2) and fracture and infection (n = 1). In all of these patients, the allograft was not supplemented with a free vascularized fibula graft (p < 0.001). Five patients underwent an amputation, most commonly for disease recurrence. At last follow-up, the mean Mankin and Musculoskeletal Tumor Society rating was 90 percent, with 19 patients (66 percent) who achieved a “good” or “excellent” outcome according to the Mankin score. Conclusion: Use of an intercalary allograft to reconstruct a lower extremity provides a durable means of reconstruction; however, supplementation with a free vascularized fibula graft reduces the risk of allograft revision. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Mindfulness has gained attention in the treatment of obesity. However, there is a paucity of data on family-based training in mindful eating in children. The objective of this pilot randomized clinical trial was to evaluate the feasibility and acceptability of a family-based mindful eating intervention (MEI) in adolescents with obesity, and to compare the efficacy of the MEI versus standard dietary counseling (SDC) for decreasing weight and improving cardiometabolic risk markers. Twenty-two adolescents (age 14.5–17.9 years) and parent pairs were randomized to the MEI or SDC. The MEI was administered in four 90-min sessions over 10 weeks and SDC was provided at baseline, 12 weeks, and 24 weeks. Despite the requirement of more frequent visits with the MEI, adolescents and parents attended 100% of the sessions and there were no dropouts in that group. High density lipoprotein (HDL) cholesterol increased in the SDC group, but not in the MEI group. Adolescents receiving the MEI demonstrated an increase in awareness at 24 weeks (p = 0.01) and a decrease in distraction during eating at 12 weeks (p = 0.04), when compared with the SDC group. The family-based MEI showed feasibility and acceptability in adolescents with obesity. Future studies with more intense therapy and larger sample sizes are warranted to examine the role of mindful eating in treating pediatric obesity.

BACKGROUND This study was designed to identify preoperative predictors of survival in surgically treated patients with metastatic epidural spinal cord compression (MESCC), to examine how these predictors are related to 8 prognostic models, and to perform the first full external validation of these models in accordance with the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement. METHODS One hundred forty‐two surgically treated patients with MESCC were enrolled in a prospective, multicenter North American cohort study and were followed for 12 months or until death. Cox regression was used. Noncollinear predictors with < 10% missing data, with ≥ 10 events per stratum, and with P < .05 in a univariate analysis were tested through a backward stepwise selection. For the original and revised Tokuhashi prognostic scoring systems (PSSs), Tomita PSS, modified Bauer PSS, van der Linden PSS, Bartels model, Oswestry Spinal Risk Index, and Bollen PSS, this study examined calibration graphically, discrimination with Harrell c‐statistics, and survival stratified by risk groups with the Kaplan‐Meier method and log‐rank test. RESULTS The following were significant in the univariate analysis: type of primary tumor, sex, organ metastasis, body mass index, preoperative radiotherapy to MESCC, physical component (PC) of the 36‐Item Short Form Health Survey, version 2 (SF‐36v2), and EuroQol 5‐Dimension (EQ‐5D) Questionnaire. Breast, prostate and thyroid primary tumor (HR: 2.9; P =.0005), presence of organ metastasis (hazard ratio (HR): 2.0; P = .005) and SF‐36v2 PC (HR: 0.95; P < .0001) were associated with survival in multivariable analysis. Predicted prognoses poorly matched observed values on calibration plots; Bartels model calibration slope was 0.45. Bollen PSS (0.61; 95% CI: 0.58‐0.64) and Bartels model (0.68; 95% CI: 0.65‐0.71) had the lowest and highest c‐statistics, respectively. CONCLUSIONS The primary tumor type (breast, prostate, or thyroid), an absence of organ metastasis, and a lower degree of physical disability are preoperative predictors of longer survival for surgical MESCC patients. These results are in keeping with current models. This full external validation of 8 prognostic PSSs or model of survival in surgical MESCC patients has revealed that calibration is poor, especially for long‐term survivors, whereas discrimination is possibly helpful.