Eric W. Ford

Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas

PURPOSE Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. METHODS AND MATERIALS We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. RESULTS Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. CONCLUSIONS The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.

Differentiation between glioma and radiation necrosis using molecular magnetic resonance imaging of endogenous proteins and peptides

It remains difficult to distinguish tumor recurrence from radiation necrosis after brain tumor therapy. Here we show that these lesions can be distinguished using the amide proton transfer (APT) magnetic resonance imaging (MRI) signals of endogenous cellular proteins and peptides as an imaging biomarker. When comparing two models of orthotopic glioma (SF188/V+ glioma and 9L gliosarcoma) with a model of radiation necrosis in rats, we could clearly differentiate viable glioma (hyperintense) from radiation necrosis (hypointense to isointense) by APT MRI. When we irradiated rats with U87MG gliomas, the APT signals in the irradiated tumors had decreased substantially by 3 d and 6 d after radiation. The amide protons that can be detected by APT provide a unique and noninvasive MRI biomarker for distinguishing viable malignancy from radiation necrosis and predicting tumor response to therapy.

Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche.

Adult hypothalamic neurogenesis has recently been reported, but the cell of origin and the function of these newborn neurons are unknown. Using genetic fate mapping, we found that median eminence tanycytes generate newborn neurons. Blocking this neurogenesis altered the weight and metabolic activity of adult mice. These findings reveal a previously unreported neurogenic niche in the mammalian hypothalamus with important implications for metabolism.

Predicting the Adoption of Electronic Health Records by Physicians: When Will Health Care be Paperless?

OBJECTIVES The purpose of this study was threefold. First, we gathered and synthesized the historic literature regarding electronic health record (EHR) adoption rates among physicians in small practices (ten or fewer members). Next, we constructed models to project estimated future EHR adoption trends and timelines. We then determined the likelihood of achieving universal EHR adoption in the near future and articulate how barriers can be overcome in the small and solo practice medical environment. DESIGN This study used EHR adoption data from six previous surveys of small practices to estimate historic market penetration rates. Applying technology diffusion theory, three future adoption scenarios, optimistic, best estimate, and conservative, are empirically derived. MEASUREMENT EHR adoption parameters, external and internal coefficients of influence, are estimated using Bass diffusion models. RESULTS All three EHR scenarios display the characteristic diffusion S curve that is indicative that the technology is likely to achieve significant market penetration, given enough time. Under current conditions, EHR adoption will reach its maximum market share in 2024 in the small practice setting. CONCLUSION The promise of improved care quality and cost control has prompted a call for universal EHR adoption by 2014. The EHR products now available are unlikely to achieve full diffusion in a critical market segment within the time frame being targeted by policy makers.

Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington's disease

Huntingtons disease (HD) is an inherited progressive neurodegenerative disorder resulting from CAG repeat expansion in the gene that encodes for the protein huntingtin. To identify neuroprotective compound (s) that can slow down disease progression and can be administered long term with few side effects in Huntingtons disease, we investigated the effect of sertraline, a selective serotonin reuptake inhibitor (SSRI) which has been shown to upregulate BDNF levels in rodent brains. We report here that in HD mice sertraline increased BDNF levels, preserved chaperone protein HSP70 and Bcl-2 levels in brains, attenuated the progression of brain atrophy and behavioral abnormalities and thereby increased survival. Sertraline also enhanced neurogenesis, which appeared to be responsible for mediating the beneficial effects of sertraline in HD mice. Additionally, the effective levels of sertraline are comparable to the safe levels achievable in humans. The findings suggest that sertraline is a potential candidate for treatment of HD patients.

Quantification of Tumor Volume Changes During Radiotherapy for Non–Small-Cell Lung Cancer

PURPOSE Dose escalation for lung cancer is limited by normal tissue toxicity. We evaluated sequential computed tomography (CT) scans to assess the possibility of adaptively reducing treatment volumes by quantifying the tumor volume reduction occurring during a course of radiotherapy (RT). METHODS AND MATERIALS A total of 22 patients underwent RT for Stage I-III non-small-cell lung cancer with conventional fractionation; 15 received concurrent chemotherapy. Two repeat CT scans were performed at a nominal dose of 30 Gy and 50 Gy. Respiration-correlated four-dimensional CT scans were used for evaluation of respiratory effects in 17 patients. The gross tumor volume (GTV) was delineated on simulation and all individual phases of the repeat CT scans. Parenchymal tumor was evaluated unless the nodal volume was larger or was the primary. Subsequent image sets were spatially co-registered with the simulation data for evaluation. RESULTS The median GTV reduction was 24.7% (range, -0.3% to 61.7%; p < 0.001, two-tailed t test) at the first repeat scan and 44.3% (range, 0.2-81.6%, p < 0.001) at the second repeat scan. The volume reduction was not significantly different between patients receiving chemoradiotherapy vs. RT alone, a GTV >100 cm(3) vs. <100 cm(3), and hilar and/or mediastinal involvement vs. purely parenchymal or pleural lesions. A tendency toward a greater volume reduction with increasing dose was seen, although this did not reach statistical significance. CONCLUSION The results of this study have demonstrated significant alterations in the GTV seen on repeat CT scans during RT. These observations raise the possibility of using an adaptive approach toward RT of non-small-cell lung cancer to minimize the dose to normal structures and more safely increase the dose directed at the target tissues.

Creating a healing environment: the importance of the service setting in the new consumer-oriented healthcare system.

EXECUTIVE SUMMARY Over the last ten years, the healthcare industry has recognized that the physical environment is a valuable resource that can and does affect all of its customers. Although most service organizations give some thought to setting, its importance to the service experience has been most thoroughly understood by those who view and treat their customers as guests, that is, the guest service industry. An excellent healing environment will reinforce excellent clinical quality, but an inferior envi‐ronment can detract from fine clinical care. One of the most important principles learned by the guest service industry is to provide the setting customers expect. Another is to create an environment that meets or exceeds customer needs for safety, security, support, competence, physical comfort, and psychological comfort. This article provides a detailed discussion of how such an environment can be created in healthcare facilities drawing from the experience of the best guest service organizations.

Inter- and intrafraction patient positioning uncertainties for intracranial radiotherapy: a study of four frameless, thermoplastic mask-based immobilization strategies using daily cone-beam CT.

PURPOSE To determine whether frameless thermoplastic mask-based immobilization is adequate for image-guided cranial radiosurgery. METHODS AND MATERIALS Cone-beam CT localization data from patients with intracranial tumors were studied using daily pre- and posttreatment scans. The systems studied were (1) Type-S IMRT (head only) mask (Civco) with head cushion; (2) Uni-Frame mask (Civco) with head cushion, coupled with a BlueBag body immobilizer (Medical Intelligence); (3) Type-S head and shoulder mask with head and shoulder cushion (Civco); (4) same as previous, coupled with a mouthpiece. The comparative metrics were translational shift magnitude and average rotation angle; systematic inter-, random inter-, and random intrafraction positioning error was computed. For strategies 1-4, respectively, the analysis for interfraction variability included data from 20, 9, 81, and 11 patients, whereas that for intrafraction variability included a subset of 7, 9, 16, and 8 patients. The results were compared for statistical significance using an analysis of variance test. RESULTS Immobilization system 4 provided the best overall accuracy and stability. The mean interfraction translational shifts (± SD) were 2.3 (± 1.4), 2.2 (± 1.1), 2.7 (± 1.5), and 2.1 (± 1.0) mm whereas intrafraction motion was 1.1 (± 1.2), 1.1 (± 1.1), 0.7 (± 0.9), and 0.7 (± 0.8) mm for devices 1-4, respectively. No significant correlation between intrafraction motion and treatment time was evident, although intrafraction motion was not purely random. CONCLUSIONS We find that all frameless thermoplastic mask systems studied are viable solutions for image-guided intracranial radiosurgery. With daily pretreatment corrections, symmetric PTV margins of 1 mm would likely be adequate if ideal radiation planning and targeting systems were available.

The effect of information technology investment on firm-level performance in the health care industry.

Background: The return on investment for information technology (IT) has been the subject of much debate throughout the history of management information systems research. Often referred to as the productivity paradox, increased IT investments have not been consistently associated with increased productivity. Understanding individual IT factors that directly contribute to business value should provide insight into the productivity paradox. Purpose: The effects of 3 different firm-level IT characteristics on financial performance in the health care industry are studied. Specifically, the effects of IT budget, IT outsourcing, and the relative number of IT personnel on firm-level financial performance are analyzed. Methods: Regression analysis of archival survey data for 914 Integrated Healthcare Delivery Systems is performed. Results: IT budgetary expenditures and the number of IT services outsourced are associated with increases in the profitability of Integrated Healthcare Delivery Systems, whereas increases in IT personnel are not significantly associated with increased profitability. Each one tenth of a percentage increase in IT expenditures is associated with approximately

Respiratory Motion Changes of Lung Tumors Over the Course of Radiation Therapy Based on Respiration-Correlated Four-Dimensional Computed Tomography Scans

100,000 in increased profit, and each additional IT service outsourced is associated with approximately