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Thomas G.W.,Swedish Medical Center | Rael L.T.,Swedish Medical Center | Bar-Or R.,Swedish Medical Center | Mains C.W.,St. Anthony Hospital | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Breakdown of endothelial barrier function is a hallmark event across a variety of pathologies such as inflammation, cancer, and diabetes. It has also been appreciated that steroid hormones impart direct biological activity on endothelial cells at many levels. The purpose of this investigation was to explore the effect of the androgen-like steroid, danazol, on endothelial cell barrier function . in vitro. Primary human endothelial cells exposed to 0.01-50. μM danazol were evaluated for changes in permeability. We found that danazol altered endothelial permeability in a biphasic manner in which nanomolar concentrations enhance barrier function while micromolar concentrations are detrimental. Monitoring of trans-endothelial electrical resistance demonstrated that these barrier enhancing effects were rapid (within 5. min) and lasted for over 24. h. Analysis of intracellular f-actin organization showed that barrier enhancement also correlated with the formation of a submembranous cortical actin ring. Conversely, at higher danazol concentrations, contractile cell phenotypes were observed, represented by stress fiber formation. Competitive binding studies performed using steroid hormone receptor antagonists proved that this activity is the result of androgen and estrogen receptor ligation. These findings suggest that low dose danazol may provide a therapeutic window for diseases involving vascular leakage. © 2012 Elsevier Inc. Source

Carr L.L.,National Jewish Health | Chung J.H.,National Jewish Health | Achcar R.D.,National Jewish Health | Lesic Z.,St. Anthony Hospital | And 6 more authors.
Chest | Year: 2015

BACKGROUND: Current understanding of the clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is poor and based predominantly on small case series. In our clinical experience, we have found that the diagnosis of DIPNECH is frequently delayed because respiratory symptoms are ascribed to other lung conditions. The objectives of this study were to collect and analyze longitudinal clinical data on pulmonary physiology, chest high-resolution CT (HRCT) imaging, and therapies to better delineate the course of disease. METHODS: We established a cohort of patients (N = 30) with DIPNECH seen at our institution. We used descriptive statistics to summarize cohort characteristics and longitudinal analytic techniques to model FEV 1 % predicted (FEV1 %) over time. RESULTS: All subjects were women who presented with long-standing cough and dyspnea. The majority had an FEV1 % < 50% at the time of diagnosis. Forty percent were given a diagnosis of asthma as the cause for physiologic obstruction. The mean FEV 1 % for the entire cohort showed no statistically significant decline over time, but 26% of the subjects experienced a 10% decline in FEV 1 within 2 years. Among the pathology samples available for review, 28% (five of 18) had typical carcinoids and 44% had associated constrictive bronchiolitis. We propose clinical diagnostic criteria for DIPNECH that incorporate demographic, pulmonary physiology, HRCT imaging, and transbronchial and surgical lung biopsy data. CONCLUSIONS: DIPNECH is a female-predominant lung disease manifested by dyspnea and cough, physiologic obstruction, and nodules on HRCT imaging. Additional research is needed to understand the natural history of this disease and validate the proposed diagnostic criteria. © 2015 American College of Chest Physicians. Source

Salottolo K.,Swedish Medical Center | Stewart Levy A.,InterMountain Neurosurgery | Slone D.S.,Swedish Medical Center | Slone D.S.,Aurora University | And 4 more authors.
JAMA Surgery | Year: 2014

IMPORTANCE: The Glasgow Coma Scale (GCS) is used frequently to define the extent of neurologic injury in patients with a traumatic brain injury (TBI). Whether age affects the predictive ability of the GCS for severity of TBI (determined by the Abbreviated Injury Scale [AIS] score) remains unknown. OBJECTIVE: To investigate the effect of age on the association between the GCS and anatomic TBI severity. DESIGN, SETTING, AND PARTICIPANTS: We examined all patients with a TBI, defined by diagnostic codes 850 to 854 from the International Classification of Diseases, Ninth Revision, Clinical Modification, who were admitted to 2 level I trauma centers from January 1, 2008, through December 31, 2012. EXPOSURES: We compared elderly (≥65 years) and younger (18-64 years) adults with TBI. MAIN OUTCOMES AND MEASURES: We examined differences by age in GCS category (defined by emergency department GCS as severe [3-8], moderate [9-12], or mild [13-15]) at each level of TBI severity (head AIS score, 1 [minor] to 5 [critical]). Cochran-Armitage Χ2 trend tests and stepwise multivariate linear and logistic regression models were used. RESULTS: During the study period, 6710 patients had a TBI (aged <65 years, 73.17%). Significant differences in GCS category by age occurred at each AIS score (P ≤ .01 for all). In particular, among patients with an AIS score of 5, most of the elderly patients (56.33%) had a mild neurologic deficit (GCS score, 13-15), whereas most of the younger patients (63.28%) had a severe neurologic deficit (GCS score, 3-8). After adjustment, the younger adults had increased odds of presenting with a severe neurologic deficit (GCS score, 3-8) at each of the following AIS scores: 1, 4.2 (95%CI, 1.0-17.6; P = .05); 2, 2.0 (1.0-3.7; P = .04); 3, 2.0 (1.2-3.5; P = .01); 4, 4.6 (2.8-7.5; P < .001); and 5, 3.1 (2.1-4.6; P < .001). The interaction between age and GCS for anatomic TBI severity remained significant after adjustment (estimate, -0.11; P = .005). CONCLUSIONS AND RELEVANCE: Age affects the relationship between the GCS score and anatomic TBI severity. Elderly TBI patients have better GCS scores than younger TBI patients with similar TBI severity. These findings have implications for TBI outcomes research and for protocols and research selection criteria that use the GCS. Copyright 2014 American Medical Association. All rights reserved. Source

Davis J.N.,Dell | Medbery C.,St. Anthony Hospital | Sharma S.,St Marys Medical Center | Pablo J.,St. Joseph Candler Hospital | And 4 more authors.
Radiation Oncology | Year: 2015

Background: The purpose of this study was to evaluate treatment patterns and outcomes of stereotactic body radiotherapy (SBRT) for centrally located primary non-small cell lung cancer (NSCLC) or lung metastases from the RSSearch® Patient Registry, an international, multi-center patient registry dedicated to radiosurgery and SBRT. Methods: Eligible patients included those with centrally located lung tumors clinically staged T1-T2 N0, M0, biopsy-confirmed NSCLC or lung metastases treated with SBRT between November 2004 and January 2014. Descriptive analysis was used to report patient demographics and treatment patterns. Overall survival (OS) and local control (LC) were determined using Kaplan-Meier method. Toxicity was reported using the Common Terminology Criteria for Adverse Events version 3.0. Results: In total, 111 patients with 114 centrally located lung tumors (48 T1-T2,N0,M0 NSCLC and 66 lung metastases) were treated with SBRT at 19 academic and community-based radiotherapy centers in the US and Germany. Median follow-up was 17 months (range, 1-72). Median age was 74 years for primary NSCLC patients and 65 years for lung metastases patients (p < 0.001). SBRT dose varied from 16 - 60 Gy (median 48 Gy) delivered in 1-5 fractions (median 4 fractions). Median dose to centrally located primary NSCLC was 48 Gy compared to 37.5 Gy for lung metastases (p = 0.0001) and median BED10 was 105.6 Gy for primary NSCLC and 93.6 Gy for lung metastases (p = 0.0005). Two-year OS for T1N0M0 and T2N0M0 NSCLC was 79 and 32.1 %, respectively (p = 0.009) and 2-year OS for lung metastases was 49.6 %. Two-year LC was 76.4 and 69.8 % for primary NSCLC and lung metastases, respectively. Toxicity was low with no Grade 3 or higher acute or late toxicities. Conclusion: Overall, patients with centrally located primary NSCLC were older and received higher doses of SBRT than those with lung metastases. Despite these differences, LC and OS was favorable for patients with central lung tumors treated with SBRT. Reported toxicity was low, although low grade toxicities were observed in patients where dose tolerances approached or exceeded published guidelines. Prospective studies are needed to further define the optimal SBRT dose for this cohort of patients. Trial registration: Clinicaltrials.gov Identifier: NCT01885299. © 2015 Davis et al.; licensee BioMed Central. Source

Davis J.N.,The Radiosurgery Society | Medbery III C.,St. Anthony Hospital | Sharma S.,St Marys Medical Center | Danish A.,Riverview Medical Center | Mahadevan A.,Harvard University
Radiation Oncology | Year: 2013

Background: The RSSearch™ Registry is a multi-institutional, observational, ongoing registry established to standardize data collection from patients treated with stereotactic radiosurgery (SRS) and/or stereotactic body radiotherapy (SBRT). This report describes the design, patient demographics, lesion characteristics, and SRS/SBRT treatment patterns in RSSearch™. Illustrative patient-related outcomes are also presented for two common treatment sites - brain metastases and liver metastases.Materials and methods: Thirty-nine US centers participated in RSSearch™. Patients screened for SRS/SBRT were eligible to be enrolled. Descriptive analyses were performed to assess patient characteristics, physician treatment practices, and clinical outcomes. Kaplan-Meier analysis was used to determine overall survival (OS), local progression-free (LPFS), and distant disease-free survival (DDFS).Results: From January, 2008 - January, 2013, 11,457 patients were enrolled. The median age was 67 years (range 7-100 years); 51% male and 49% female. Forty-six percent had no prior treatment, 22% had received chemotherapy, 19% radiation therapy and 17% surgery. There were 11,820 lesions from 65 treatment locations; 54% extracranial and 46% intracranial. The most common treatment locations were brain/cranial nerve/spinal cord, lung, prostate and liver. Metastatic lesions accounted for the majority of cases (41.6%), followed by primary malignant (32.9%), benign (10.9%), recurrent (9.4%), and functional diseases (4.3%). SRS/SBRT was used with a curative intent in 39.8% and palliative care in 44.8% of cases. The median dose for all lesions was 30 Gy (range < 1 - 96.7 Gy) delivered in a median number of 3 fractions. The median dose for lesions in the brain/cranial nerve/spinal cord, lung, liver, pancreas and prostate was 24, 54, 45, 29 and 36.25 Gy, respectively. In a subset analysis of 799 patients with 952 brain metastases, median OS was 8 months. For patients with a Karnofsky performance score (KPS) > 70, OS was 11 months vs. 4 months for KPS ≤ 70. Six-month and 12-month local control was 79% and 61%, respectively for patients with KPS ≤ 70, and 85% and 74%, respectively for patients with KPS > 70. In a second subset analysis including 174 patients with 204 liver metastases, median OS was 22 months. At 1-year, LPFS and DDFS rates were 74% and 53%, respectively. LPFS.Conclusion: This study demonstrates that collective patterns of care and outcomes research for SRS/SBRT can be performed and reported from data entered by users in a common database. The RSSearch™ dataset represents SRS/SBRT practices in a real world setting, providing a useful resource for expanding knowledge of SRS/SBRT treatment patterns and outcomes and generating robust hypotheses for randomzed clinical studies. © 2013 Davis et al.; licensee BioMed Central Ltd. Source

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