Citations

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.

AbstractObjectivesCoronary computerized tomography angiography (CCTA) is a rapidly emerging technology for the evaluation of chest pain in the emergency department (ED). We assessed trends in CCTA use and compared downstream healthcare utilization between CCTA and cardiac stress testing modalities.MethodsUsing administrative claims data (Optum Labs Data Warehouse) from over 100 million geographically diverse privately insured and Medicare Advantage enrollees across the United States, we identified 2,047,799 ED patients from January 2006 to December 2013 who presented with chest pain and had a CCTA or cardiac stress test within 72 hours. Cohorts were established based on CCTA or functional stress testing (myocardial perfusion scintigraphy [MPS], stress echocardiogram [SE], or treadmill exercise electrocardiogram [TMET]) performed within 72 hours of the ED visit. We tracked subsequent invasive cardiac procedures (invasive coronary angiography [ICA], percutaneous coronary intervention [PCI], and coronary artery bypass grafting [CABG]), repeat noninvasive testing, return ED visits, hospitalization, and the rate of acute myocardial infarction (AMI) within 30 days. We used propensity‐score matching to adjust for coronary artery disease (CAD) risk factors, Charlson‐Deyo comorbidity index, and baseline differences between patients selected for CCTA or cardiac stress testing. Logistic regression was used to measure adjusted associations between testing modality and outcomes.ResultsDuring the study period, CCTA use increased from 0.8% to 4.5% of all cardiac testing within 72 hours, a change of 434% (p‐value for trend < 0.001), while rates of other cardiac stress testing modalities decreased (–22% for TMET [p < 0.001]; –11% for SE [p = 0.11]; –6% for MPS [p = 0.04]. After matching, there was no difference in the 30‐day rate of AMI between testing modalities. Compared to MPS, CCTA was associated with higher rates of PCI (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.04 to 1.51), and CABG (OR = 1.47; 95% CI = 1.03 to 2.13). Compared to SE and treadmill stress testing, CCTA was associated with more invasive procedures, hospitalizations, return ED visits, and repeat noninvasive testing.ConclusionsCCTA use increased fourfold during the study period and was associated with higher rates of PCI, CABG, repeat noninvasive testing, hospitalization, and return ED visits.The authors have no relevant financial information or potential conflicts to disclose.

Background: Pediatric obesity is a significant public health problem with a prevalence of 16.9% among US children. School-based obesity interventions show promise for reducing adiposity in elementary age children. This pilot study evaluated the impact of the Let’s Go! 5-2-1-0 pediatric obesity intervention program in an elementary school setting. Methods: This was a cluster randomized controlled field trial comprising 8 classrooms of second- and third-grade children. The impact of implementation of a standardized 5-2-1-0 curriculum was evaluated in the classrooms by looking at health behavior (self-reported fruit and vegetable and sugar-containing beverage intake, and screen time), physical activity (steps measured by pedometer), and body mass index (BMI). Half of the classrooms were given 5-2-1-0 teaching over a 4-month period. Results: There was no statistical difference in improvement of healthy habits, BMI, or physical activity in the intervention group compared with the control group. Conclusions: The 5-2-1-0 intervention used in this study was feasible. There was no significant change in healthy habits, likely due to the small number of participants in the study. The intervention and control sites were in different classrooms and there could be factors such as teacher enthusiasm, socioeconomic factors, and individual traits affecting habits. Future studies could use pre- and post-intervention quizzes to assess healthy habits knowledge retention, involving the environments the child participates in outside of school, using research-grade pedometers or accelerometers for measuring activity data collection, and recruiting larger samples to ensure adequate statistical power.

This paper describes the goals of the American Society of Health‐System Pharmacists' Pharmacy Practice Model Initiative (PPMI) and its recommendations for health‐system pharmacy practice transformation to meet future patient care needs and elevate the role of pharmacists as patient care providers. PPMI envisions a future in which pharmacists have greater responsibility for medication‐related outcomes and technicians assume greater responsibility for product‐related activities. Although the PPMI recommendations have elevated the level of practice in many settings, they also potentially affect existing clinical pharmacists, in general, and clinical pharmacy specialists, in particular. Moreover, although more consistent patient care can be achieved with an expanded team of pharmacist providers, the role of clinical pharmacy specialists must not be diminished, especially in the care of complex patients and populations. Specialist practitioners with advanced training and credentials must be available to model and train pharmacists in generalist positions, residents, and students. Indeed, specialist practitioners are often the innovators and practice leaders. Negotiation between hospitals and pharmacy schools is needed to ensure a continuing role for academic clinical pharmacists and their contributions as educators and researchers. Lessons can be applied from disciplines such as nursing and medicine, which have developed new models of care involving effective collaboration between generalists and specialists. Several different pharmacy practice models have been described to meet the PPMI goals, based on available personnel and local goals. Studies measuring the impact of these new practice models are needed.

Objectives/HypothesisTo evaluate outcomes of salvage surgery for vestibular schwannoma (VS) that failed primary stereotactic radiosurgery (SRS).MethodsCase‐control study of 37 patients who underwent surgical resection of sporadic VS following prior SRS at two tertiary academic referral centers between 2003 and 2015. A cohort of nonirradiated control subjects, matched according to tumor size, age, and treatment center, were used as comparison.ResultsThirty‐seven patients were included. The median time from radiation to surgical salvage was 36 months (range 9.6–153 months). Following tumor progression after SRS, 18 (49%) patients underwent gross total resection, 10 (27%) underwent near‐total resection, and nine (24%) underwent subtotal resection. Postoperative complications following salvage surgery included one (3%) case of stroke, four (11%) cases of cerebrospinal fluid leak, and two (5%) cases of meningitis. Twenty‐seven (73%) patients had good postoperative facial nerve outcome (House‐Brackmann Score I–II) at long‐term follow‐up. There were no cases of tumor recurrence or regrowth after a median length of 26 months following microsurgical salvage (range 3–114 months). The rate of satisfactory postoperative facial nerve function was not different between study and control subjects (73% vs. 76%; P = 0.8); however, less‐than‐complete resection was utilized more frequently among previously radiated patients (P = 0.01).ConclusionMicrosurgical salvage of VS following primary radiation therapy is challenging. Less‐than‐complete resection is required in a greater percentage of patients to preserve facial nerve integrity and prevent neurological complications. Long‐term follow‐up is needed to determine the risk of delayed progression following incomplete tumor removal.Level of Evidence3b. Laryngoscope, 126:2580–2586, 2016

Objectives: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Materials and Methods: Eligible patients included stage II-IIIB non–small cell lung cancer, stage I central non–small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Results: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients’ refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Conclusions: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

Currently, no standard defines the clinical skills that medical students must demonstrate upon graduation. The Liaison Committee on Medical Education bases its standards on required subject matter and student experiences rather than on observable educational outcomes. The absence of such established outcomes for MD graduates contributes to the gap between program directors’ expectations and new residents’ performance. In response, in 2013, the Association of American Medical Colleges convened a panel of experts from undergraduate and graduate medical education to define the professional activities that every resident should be able to do without direct supervision on day one of residency, regardless of specialty. Using a conceptual framework of entrustable professional activities (EPAs), this Drafting Panel reviewed the literature and sought input from the health professions education community. The result of this process was the publication of 13 core EPAs for entering residency in 2014. Each EPA includes a description, a list of key functions, links to critical competencies and milestones, and narrative descriptions of expected behaviors and clinical vignettes for both novice learners and learners ready for entrustment. The medical education community has already begun to develop the curricula, assessment tools, faculty development resources, and pathways to entrustment for each of the 13 EPAs. Adoption of these core EPAs could significantly narrow the gap between program directors’ expectations and new residents’ performance, enhancing patient safety and increasing residents’, educators’, and patients’ confidence in the care these learners provide in the first months of their residency training.

Purpose The authors performed a review of 30 Accelerating Change in Medical Education full grant submissions and an analysis of the health systems science (HSS)-related curricula at the 11 grant recipient schools to develop a potential comprehensive HSS curricular framework with domains and subcategories. Method In phase 1, to identify domains, grant submissions were analyzed and coded using constant comparative analysis. In phase 2, a detailed review of all existing and planned syllabi and curriculum documents at the grantee schools was performed, and content in the core curricular domains was coded into subcategories. The lead investigators reviewed and discussed drafts of the categorization scheme, collapsed and combined domains and subcategories, and resolved disagreements via group discussion. Results Analysis yielded three types of domains: core, cross-cutting, and linking. Core domains included health care structures and processes; health care policy, economics, and management; clinical informatics and health information technology; population and public health; value-based care; and health system improvement. Cross-cutting domains included leadership and change agency; teamwork and interprofessional education; evidence-based medicine and practice; professionalism and ethics; and scholarship. One linking domain was identified: systems thinking. Conclusions This broad framework aims to build on the traditional definition of systems-based practice and highlight the need for medical and other health professions schools to better align education programs with the anticipated needs of the systems in which students will practice. HSS will require a critical investigation into existing curricula to determine the most efficient methods for integration with the basic and clinical sciences.