Citations

Abstract Purpose: The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA. Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.

8592 Background: Accrual to NCI clinical trials(CT)is often slower than planned at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. Methods: The NCI-MYSC AWG identified 10 potential BtA. SWOG, ECOG and Alliance investigators were queried and agreed that these barriers impede accrual (results stratified for academic and community sites). The MYSC AWG developed in collaboration with NCI and FDA strategies to overcome these barriers. Results: Strategies listed for the 3 most often cited BtA: 1. Reimbursement for CT related expenses:increase awareness of improved reimbursement for phase II CT; tailor reimbursement according to CT complexity; request funds from industry and other sources ( http://biqsfp.cancer.gov ) for qualifying ancillary CT components. 2. Spectrum of available treatment options influences CT participation: educate patients and providers about the significance of a new CT using social media, presentations at national meetings and by adding educational material to CT protocol; encourage opinion leaders and advocacy groups not to promote a new therapy as “standard” in the absence of phase III data. 3. Requirement of CT specific therapy at NCI designated sites only: “MYSC AWG Drug Administration Table” describes NCI/FDA approved rules for CT specific drug administration; CT protocol will outline which standard treatment components of a CT can be administered at any site as long as protocol specific guidelines are followed and conduct is supervised by enrolling investigator. Examples of additional strategies to overcome identified BtA: determine feasibility, indication and insurance coverage of CT specific tests during protocol development; discourage narrow eligibility criteria; avoid competing CT; allow up to 1 cycle of commercially available therapy prior to enrollment; CIRB support for phase II CT. Conclusions: The MYSC Accrual Working Group developed in collaboration with NCI and FDA strategies to overcome barriers to myeloma clinical trial accrual. These strategies may be applicable to NCI-sponsored clinical trials evaluating interventions in other diseases.

Abstract Abstract 3165 Background: Accrual to large oncology group studies in the United States is often slower than planned, especially in less common malignancies such as Multiple Myeloma (MM). To improve the treatment of patients with MM, it is essential that we address the barriers to accrual (BtA) to national clinical trials. The NCI Myeloma Steering Committee (MYSC) formed the Accrual Working Group (AWG), charged to analyze this problem. Methods: The members of the MYSC have developed a list of 10 potential BtA to NCI MM-CT under the leadership of the AWG at meetings conducted in person and by monthly telephone conference. This list was distributed via Survey Monkey among investigators and research staff of the SWOG, ECOG/ACRIN and Alliance research bases for the purpose of ranking the perceived importance of the 10 selected BtA. Responses based on a 0–5 Likert Scale were analyzed as continuous and categorical. For the latter, responses were grouped: Impedes Accrual – No (0,1), Yes (2–5); Significantly Impedes Accrual – No (0–3), Yes (4,5). Results: 246 survey responses were received. 50 participants who indicated that they had never attempted to or actually never enrolled a patient into a MM-CT were excluded. Of 196 responders, 61% had enrolled at least 5 patients, 43% practiced in academic centers (A) and 57% in community centers (C). 26% identified themselves as research staff, 74% as primarily physician investigators including Principal Investigators (12%). 78% have current access to NCI MM-CT. 46% identified their research base affiliation with SWOG, 20% with ECOG/ACRIN, 17% with Alliance, 17% as CTSU, NRG and other. The majority of survey responders confirmed agreement in the perception that all 10 identified BtA impede accrual, ranging from 60–84% depending on the specific barrier identified, while significant impediment to accrual ascribed to these BtA ranged from 22–47%. The perceived barriers most often cited as impeding accrual were (1) spectrum of available treatment options, (2) level of reimbursement for clinical trial related expenses and (3) patient‘s need for prompt treatment intervention (84%, 80%, 76% respectively). The first two barriers along with the requirement that patients receive their treatment exclusively at the NCI designated treatment site were rated most often as significantly impeding accrual (37%, 47%, 34% respectively). The first two were also identified most often as perceived BtA independent of practice setting (A, C), type of research engagement (physician investigator, research staff) and level of experience with MM-CT. Interestingly, the perception that patients must receive their treatment at the NCI designated treatment site and competing industry sponsored clinical trials were substantially more often cited as impeding accrual in academic centers compared to community centers and by physician investigators compared to research staff. The complexity of required diagnostic work up and the complexity of the treatment protocol and follow up testing were substantially more often cited as BtA in the community setting and by research staff compared to their peers in the academic setting and by physician investigators. The NCI MYSC AWG has proposed specific solutions to potentially lower perceived BtA. These include guidelines to allow protocol specific administration of commercially available agents by the patient‘s local oncologist, a simplified diagnostic work up and treatment plan and eligibility inclusion of patients who have received up to one cycle of specified urgent therapy prior to enrollment in MM-CT. Conclusions: We have queried experienced clinical investigators and research staff on 10 potential MM-CT specific BtA and found substantial consensus among responding participants in this survey. There are apparent differences in perceived BtA between the respondents from academic and community centers as well as between research staff and physician investigators. These data suggest that a structured approach to identification of BtA to clinical trials is feasible and creates opportunities to overcome them. This may have application to clinical trials across other diseases and may also lead to improvements in accrual. Disclosures: Barlogie: Celgene, IMF, MMRF, Millennium, Genzyme: Consultancy; Celgene, IMF, Millennium: Honoraria; Celgene, Novartis, NCI, Millennium, Onyx, Icon: Research Funding; GEP: Patents & Royalties.

Elderly seasonal migrators share time between homes in different states, presenting challenges for care coordination and patient attribution methods. Medicare has prioritized alternative payment models, putting health care providers at risk for quality and value of services delivered to their attributed patients, regardless of the location of care. Little research is available to guide providers and payers on the service use of seasonal migrators. The authors use claims data on fee-for-service (FFS) Medicare beneficiaries' locations throughout the year to (1) identify seasonal migrators and (2) describe the care they receive in each seasonal home, focusing on primary care and emergency department (ED) visits and the relationships between the two. In all, 5.5% of the Medicare aged FFS population were identified as seasonal migrators, with 4.1% following the traditional snowbird pattern of migration, spending warm months in the north and cold months in the south. Migrators had higher rates of ED visits and primary care treatable (PCT) ED visits than the nonmigratory groups, controlling for location, age, race, sex, Medicaid status, season, and comorbidities. They also had more visits with specialist physicians, more days with outpatient services, and more days seeing a physician in any setting. Having local primary care strongly reduced rates of both PCT ED visits and total ED visits for all migration categories, with the greatest reduction seen in PCT ED visits by migrators (local primary care was associated with a 58% reduction in PCT ED visits by snowbirds and a 65% reduction in PCT ED visits by other migrators).

Background Heart failure ( HF ) patients experience impaired functional status, diminished quality of life, high utilization of healthcare resources, and poor survival. Yet, the identification of patient‐centered factors that influence prognosis is lacking. Methods and Results We determined the association of 2 measures of self‐rated health with healthcare utilization and skilled nursing facility ( SNF ) admission in a community cohort of 417 HF patients prospectively enrolled between October 2007 and December 2010 from Olmsted County, MN . Patients completed a 12‐item Short Form Health Survey ( SF ‐12). Low self‐reported physical functioning was defined as a score ≤25 on the SF ‐12 physical component. The first question of the SF ‐12 was used as a measure of self‐rated general health. After 2 years, 1033 hospitalizations, 1407 emergency department ( ED ) visits, and 19,780 outpatient office visits were observed; 87 patients were admitted to a SNF . After adjustment for confounding factors, an increased risk of hospitalizations (1.52 [1.17 to 1.99]) and ED visits (1.48 [1.04 to 2.11]) was observed for those with low versus moderate‐high self‐reported physical functioning. Patients with poor and fair self‐rated general health also experienced an increased risk of hospitalizations (poor: 1.73 [1.29 to 2.32]; fair: 1.46 [1.14 to 1.87]) and ED visits (poor: 1.73 [1.16 to 2.56]; fair: 1.48 [1.13 to 1.93]) compared with good‐excellent self‐rated general health. No association between self‐reported physical functioning or self‐rated general health with outpatient visits and SNF admission was observed. Conclusion In community HF patients, self‐reported measures of physical functioning predict hospitalizations and ED visits, indicating that these patient‐reported measures may be useful in risk stratification and management in HF .

Background— Physical health status measures have been shown to predict death in heart failure (HF); however, few studies found significant associations after adjustment for confounders, and most were not representative of all HF patients. Methods and Results— HF patients from southeastern MN were prospectively enrolled between 10/2007 and 12/2010, completed a 12-item Short Form Health Survey (SF-12) and a 6-minute walk, and were followed through 2011 for death from any cause. Scores ≤25 on the SF-12 physical component indicated low self-reported physical functioning, and the first question of the SF-12 measured self-rated general health. Low functional exercise capacity was defined as ≤300 m walked during a 6-minute walk. Over a mean follow-up of 2.3 years, 86 deaths occurred among the 352 participants. A 1.6-fold (95% confidence interval, 1.0–2.7) and 1.8-fold (95% confidence interval, 1.1–2.9) increased risk of death was observed among patients with low self-reported physical functioning and low functional exercise capacity, respectively. Poor self-rated general health corresponded to a 2.7-fold (95% confidence interval, 1.5–4.9) increased risk of death compared with good to excellent general health. All measures equally discriminated between who would die and who would survive (C-statistics: 0.729, 0.750, and 0.740 for self-reported physical functioning, self-rated general health, and functional exercise capacity, respectively). Conclusions— Three physical health status measures, captured by the SF-12 and a 6-minute walk, equally predict death among community HF patients. Therefore, the first question of the SF-12, which is the least burdensome to administer, may be sufficient to identify HF patients at greatest risk of death.