Citations

Abstract BACKGROUND: Glioma accounts for ~27% of all primary brain tumors and is responsible for ~13,000 cancer-related deaths in the US each year. Glioma tumors can be broadly classified into glioblastoma (GBM) and lower-grade non-GBM. Typically gliomas have a poor prognosis irrespective of medical care, with the most common form, GBM, having a five-year survival rate of only 5%. While genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, individual studies have had limited power to identify risk loci. METHODS: We performed the largest glioma GWAS to date, comprising a meta-analysis of six existing GWAS (6,405 cases, 14,100 controls) as well as new GWAS from the Glioma International Case Control Consortium (GICC; 4,572 cases and 3,286 controls) and University of California, San Francisco (UCSF)-Mayo (1,519 cases, 804 controls), totaling 12,496 cases (6,191 classified as GBM, 5,819 as non-GBM) and 18,190 controls. RESULTS: We identified five new risk loci for GBM at 1p31.3 (rs12752552; near JAK1, P=2.04×10-9, odds ratio (OR)=1.22), 11q14.1 (rs11233250; P=9.95×10-10, OR=1.24), 16p13.3 (rs2562152; near MPG, P=1.93x10-8, OR=1.21), 16q12.1 (rs10852606; HEATR3, P=1.29×10-11, OR=1.18), 22q13.1 (rs2235573; P=1.76×10-10, OR=1.15) and eight for non-GBM at 1q32.1 (rs4252707; MDM4, P=3.34×10-9, OR=1.19), 1q44 (rs12076373; AKT3, P=2.63×10-10, OR=1.23), 2q33.3 (rs7572263; near IDH1, P=2.18×10-10, OR=1.20), 3p14.1 (rs11706832; LRIG1, P=7.66×10-9, OR=1.15), 10q24.33 (rs11598018; OBFC1, P=3.39×10-8, OR=1.14), 11q21 (rs7107785; P=3.87×10-10, OR=1.16), 14q12 (rs10131032; P=5.07x10-11, OR=1.33) and 16p13.3 (rs3751667; P=2.61×10-9, OR=1.18). Case-only analyses confirmed the specificity of 11q14.1, 16p13.3 and 22q13.1 associations for GBM and 1q44, 2q33.3, 3p14.1, 11q21 and 14q12 for non-GBM tumors. In the combined meta-analysis, among previously published glioma risk SNPs, those for all glioma at 17p13.1 (TP53), GBM at 5p15.33 (TERT), 7p11.2 (EGFR), 9p21.3 (CDKN2B-AS1) and 20q13.33 (RTEL1) and for non-GBM at 8q24.21 (CCDC26), 11q23.2, 11q23.3 (PHLDB1) and 15q24.2 (ETFA) showed even greater evidence for association. SNPs at 10q25.2 and 12q12.1 for non-GBM tumors retained genome-wide significance (i.e. P<5.0x10-8). Associations at the previously reported loci for GBM at 3q26.2 (near TERC) and 12q23.33 (POLR3B) did not retain statistical significance. CONCLUSIONS: Our findings substantiate genetic susceptibility to GBM and non-GBM glioma being highly distinct, consistent with their distinctive molecular profiles presumably resulting from different etiological pathways. Functional analyses should lead to further insights into the biological basis of the different glioma histologies. Such information can inform gene discovery initiatives and therefore have a measurable impact on the successful development of new therapeutic agents. Citation Format: Ben Kinnersley, Beatrice S. Melin, Jill S. Barnholtz-Sloan, Margaret R. Wrensch, Christoffer Johansen, Dora Il’yasova, Quinn Ostrom, and members of GICC, Karim Labreche, Jeanette E. Eckel-Passow, Paul A. Decker, Marianne Labussière, Ahmed Idbaih, Khe Hoang-Xuan, Anna-Luisa Di Stefano, Karima Mokhtari, Jean-Yves Delattre, Pilar Galan, Konstantinos Gousias, Johannes Schramm, Minouk J. Schoemaker, Sarah J. Fleming, Stefan Herms, Stefanie Heilmann, Marcus M. Nöthen, Heinz-Erich Wichmann, Stefan Schreiber, Anthony Swerdlow, Mark Lathrop, Matthias Simon, Marc Sanson, Preetha Rajaraman, Stephen Chanock, Martha Linet, Zhaoming Wang, Meredith Yeager, Rose K. Lai, Elizabeth B. Claus, Sara H. Olson, Robert B. Jenkins, Richard S. Houlston, Melissa L. Bondy. Genome-wide association study of glioma reveals specific differences in genetic susceptibility to glioblastoma and non-glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1302. doi:10.1158/1538-7445.AM2017-1302

Purpose: Several studies have demonstrated that patients have a poor understanding of prognosis, survival, and effectiveness of chemotherapy, particularly in the setting of advanced cancer. This study examines oncology patients’ understanding of their illness based on accurate reporting of stage at diagnosis and knowledge of cancer status (ie, free of cancer or in remission v active disease). Materials and Methods: Two hundred eight patients with cancer previously treated at our large community-based cancer institute participated in the Consumer-Based Cancer Care Value Index field survey. Electronic medical record documentation of stage at diagnosis and cancer status was compared with patients’ self-reported responses. Concordance of responses and variables influencing discordance were evaluated. Results: In 51.0% of patients, self-reported cancer stage matched the abstracted stage, with the highest concordance in patients with advanced cancer (72%) versus patients with stage I to III disease (36.4% to 61.5%). Unexpectedly, discordance was lower among patients with advanced cancer compared with patients with stage I to III cancer ( P = .0528). Patients who were concordant for cancer stage at diagnosis were significantly more likely to be female ( P = .001), be younger than age 65 years ( P = .01), have an income > $60,000 ( P = .03), and have more education ( P = .02). In 64.4% of patients, self-reported cancer status (ie, free of cancer or in remission v active disease) matched the abstracted status. Nearly 30% of patients were not sure about their status, even when they were free of cancer or in remission. Conclusion: Our findings confirm that more than one quarter of patients with advanced cancer have poor illness understanding and highlight that an even greater number of patients with early stage I to III cancer have poor illness understanding. These observations highlight the need to improve illness understanding for patients across the entire cancer continuum.

Pulmonary vein stenosis (PVS) is a luminal narrowing of extrapulmonary pulmonary veins. In pediatric patients, it arises following repair of congenital heart disease, particularly anomalous pulmonary venous return; in lung disease, especially prematurity; and rarely in isolation. The etiology is unknown and the course often fatal without lung transplantation. We hypothesized that systematic clinicopathologic review of pediatric PVS could provide further pathogenic insight. We included patients who underwent first resection of pulmonary venous tissue for symptomatic PVS at our pediatric referral center from 1995 to 2014. Clinical records and hematoxylin and eosin slides were reviewed. Subsets were immunostained for smooth muscle actin, Ki-67, β-catenin, estrogen receptor, and other markers and analyzed forUSP6gene rearrangement. A total of 97 patients (57% male; median age: 6 mo) were identified. Overall, 59 (61%) had prior congenital heart disease repair, 35 involving pulmonary vein manipulation. Samples included 213 separate anatomic sites (median: 2/patient). Histologically, all showed sparsely cellular intimal expansion composed of haphazardly arranged fibroblasts with slender nuclei in myxoid matrix. This tissue merged with underlying collagen. Most samples had a variably continuous sheath of cardiomyocytes. Ancillary tests supported a reactive fibroblastic proliferation; in particular, fibroblasts showed cytoplasmic β-catenin localization, no estrogen receptor expression, and noUSP6rearrangement. At last follow-up (mean: 2.3 y), 46% of patients had died of disease. Pediatric PVS uniformly consists of a paucicellular fibrointimal proliferation, irrespective of clinical scenario. It may be best conceived of as a form of reactive hyperplasia. As with other forms of vascular remodeling, trauma (iatrogenic or occult) is likely an inciting factor. A comprehensive understanding of the surgical pathology of PVS may further inform therapeutic strategies in this lethal disease.

Abstract Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial. Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R β-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years. Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs. 51, P = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R− tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42). Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R− breast tumors. Clin Cancer Res; 23(15); 4203–11. ©2016 AACR.

Background: The use of a trabecular metal revision shell with metal augmentation to fill segmental or irregular defects during complex revision hip arthroplasty has been shown to provide good short-term results in prior published series. Longer-term results of the several cup-augment constructs used clinically are not known. The objective of this study was to report, with minimum 5-year radiographic and clinical follow-up, the outcome of these various constructs in revision total hip arthroplasty. Methods: Eighty-four patients (85 hips) underwent revision total hip arthroplasty with use of porous tantalum augments between 2000 and 2007 at a single institution and were retrospectively reviewed. Fifty-seven of the patients (58 hips) had clinical and radiographic follow-up at a minimum of 5 years. At the time of revision, the majority of the hips had acetabular defects classified as Paprosky Type 3A (28 of 58, 48%) or Type 3B (22 of 58, 38%). Eleven (19%) of the hips also had preoperative pelvic discontinuity. All hips were assessed clinically at a minimum of 5 years with use of the Mayo hip score. Postoperative radiographs were reviewed for implant stability, the presence and location of radiolucent lines and healing of the discontinuity if present. Results: In 2 (3%) of the 58 hips, the constructs failed because of aseptic loosening of the acetabular component and re-revision was indicated. Six (10%) of the 58 hips demonstrated a radiolucent line between the trabecular metal shell and bone in DeLee and Charnley zone 3. In 1 hip that underwent re-revision and in 5 of the 6 hips with a zone-3 radiolucency, a pelvic discontinuity was present at the time of the index revision. The mean preoperative Mayo hip score was 35.7, which improved to 61.9 at 3 months and was 61.7 at the minimum 5-year follow-up. Conclusions: With failure defined as aseptic loosening requiring repeat revision surgery, this cohort demonstrated 97% survivorship and maintained satisfactory hip function at the minimum 5 years after the index revision surgery. Six of the 11 hips with preoperative pelvic discontinuity either failed or developed a radiolucency in zone 3 and are considered at risk for future revision. Pelvic discontinuity should prompt consideration of the addition of adjunctive fixation or the use of alternative techniques. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.