Quinn D.I.,University of Southern California |
Tangen C.M.,Statistical Center |
Hussain M.,University of Michigan |
Lara P.N.,University of California at Davis |
And 12 more authors.
The Lancet Oncology | Year: 2013
Background: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. Methods: In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m2 every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00134056. Findings: 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Interpretation: Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. Funded: National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories. © 2013 Elsevier Ltd.
Tadros N.N.,Oregon Health And Science University |
Bland L.,Oregon Health And Science University |
Legg E.,Oregon Health And Science University |
Olyaei A.,Oregon Health And Science University |
Conlin M.J.,Portland Veterans Administration Medical Center
BJU International | Year: 2013
Objectives: To determine the incidence of severe pain after ureteric stent removal. To evaluate the efficacy of a single dose of a non-steroidal anti-inflammatory drug (NSAID) in preventing this complication. Patients and Methods: A prospective, randomised, double-blind, placebo-controlled trial was performed at our institution. Adults with an indwelling ureteric stent after ureteroscopy were randomised to receive either a single dose of placebo or an NSAID (rofecoxib 50 mg) before ureteric stent removal. Pain was measured using a visual analogue scale (VAS) just before and 24 h after stent removal Pain medication use after ureteric stent removal was measured using morphine equivalents. Results: In all, 22 patients were enrolled and randomised into the study before ending the study after interim analysis showed significant decrease in pain level in the NSAID group. The most common indication for ureteroscopy was urolithiasis (14 patients). The proportion of patients with severe pain (VAS score of ≥7) during the 24 h after ureteric stent removal was six of 11 (55%) in the placebo group and it was zero of 10 in the NSAID group (P < 0.01). There were no complications related to the use of rofecoxib. Conclusions: We found a 55% incidence of severe pain after ureteric stent removal. A single dose of a NSAID before stent removal prevents severe pain after ureteric stent removal. © 2012 BJU International.
Muldoon L.L.,Oregon Health And Science University |
Gahramanov S.,Oregon Health And Science University |
Li X.,Oregon Health And Science University |
Marshall D.J.,Ortho Biotech Oncology R and D |
And 4 more authors.
Neuro-Oncology | Year: 2011
We used dynamic MRI to evaluate the effects of monoclonal antibodies targeting brain tumor vasculature. Female athymic rats with intracerebral human tumor xenografts were untreated or treated with intetumumab, targeting aV-integrins, or bevacizumab, targeting vascular endothelial growth factor (n = 4-6 per group). Prior to treatment and at 1, 3, and 7 days after treatment, we performed standard MRI to assess tumor volume, dynamic susceptibility-contrast MRI with the blood-pool iron oxide nanoparticle ferumoxytol to evaluate relative cerebral blood volume (rCBV), and dynamic contrast-enhanced MRI to assess tumor vascular permeability. Tumor rCBV increased by 27 ± 13% over 7 days in untreated rats; intetumumab increased tumor rCBV by 65±10%, whereas bevacizumab reduced tumor rCBV by 31 ±10% at 7 days (P <.001 for group and day). Similarly, intetumumab increased brain tumor vascular permeability compared with controls at 3 and 7 days after treatment, whereas bevacizumab decreased tumor permeability within 24 hours (P =.0004 for group, P =.0081 for day). All tumors grew over the 7-day assessment period, but bevacizumab slowed the increase in tumor volume on MRI. We conclude that the vascular targeting agents intetumumab and bevacizumab had diametrically opposite effects on dynamic MRI of tumor vasculature in rat brain tumor models. Targeting αv-integrins increased tumor vascular permeability and blood volume, whereas bevacizumab decreased both measures. These findings have implications for chemotherapy delivery and antitumor efficacy. © The Author(s) 2010.
Harriff M.J.,Portland Veterans Administration Medical Center |
Harriff M.J.,Oregon Health And Science University |
Cansler M.E.,Oregon Health And Science University |
Toren K.G.,Oregon Health And Science University |
And 6 more authors.
PLoS ONE | Year: 2014
Mycobacterium tuberculosis (Mtb) is transmitted via inhalation of aerosolized particles. While alveolar macrophages are thought to play a central role in the acquisition and control of this infection, Mtb also has ample opportunity to interact with the airway epithelium. In this regard, we have recently shown that the upper airways are enriched with a population of non-classical, MR1-restricted, Mtb-reactive CD8+ T cells (MAIT cells). Additionally, we have demonstrated that Mtb-infected epithelial cells lining the upper airways are capable of stimulating IFNγ production by MAIT cells. In this study, we demonstrate that airway epithelial cells efficiently stimulate IFNγ release by MAIT cells as well as HLA-B45 and HLA-E restricted T cell clones. Characterization of the intracellular localization of Mtb in epithelial cells indicates that the vacuole occupied by Mtb in epithelial cells is distinct from DC in that it acquires Rab7 molecules and does not retain markers of early endosomes such as Rab5. The Mtb vacuole is also heterogeneous as there is a varying degree of association with Lamp1 and HLA-I. Although the Mtb vacuole shares markers associated with the late endosome, it does not acidify, and the bacteria are able to replicate within the cell. This work demonstrates that Mtb infected lung epithelial cells are surprisingly efficient at stimulating IFNγ release by CD8+ T cells.
Ahern D.K.,Harvard University |
Ahern D.K.,Brigham and Women's Hospital |
Woods S.S.,Oregon Health And Science University |
Woods S.S.,Portland Veterans Administration Medical Center |
And 5 more authors.
American Journal of Preventive Medicine | Year: 2011
Patients are using healthcare technologies for a variety of reasons. Recently, the Meaningful-Use rule was released by the Centers for Medicare and Medicaid Services, providing some initial guidance for patient-facing technologies. There needs to be more of an understanding of patients' needs and how these technologies can be utilized effectively. This article provides a framework for organizing patient-facing technologies into categories of meaningful use, and how these technologies can improve healthcare quality, safety, and population health. Barriers to achieving meaningful use of HIT and unintended consequences of patient-facing technologies are discussed. The success of healthcare reform is predicated on achieving improved health outcomes and reduced costs, which can be accomplished only by activating patients to become more engaged in their own care. Patient-facing technologies are likely to play a critical role in supporting patients to become more informed and activated and may also improve efficiencies. Further research is needed to identify the most useful and effective technologies for patients. © 2011 American Journal of Preventive Medicine.
Maier M.M.,Oregon Health And Science University |
He H.,Program Design and Evaluation Service |
Schafer S.D.,HIV STD TB Program |
Ward T.T.,Portland Veterans Administration Medical Center |
Zaman A.,Oregon Health And Science University
AIDS Care - Psychological and Socio-Medical Aspects of AIDS/HIV | Year: 2014
Approximately 287,000 individuals in the USA are coinfected with HIV and hepatitis C. Recently, new hepatitis C regimens have become available, increasing rates of sustained virologic response in the monoinfected, with studies evaluating their success in the coinfected under way. Previous investigators estimated eligibility for hepatitis C therapy among the coinfected patients, but all had significant methodological limitations. Our study is the first to use a multi-year, statewide, population-based sample to estimate treatment eligibility, and the first to estimate eligibility in the setting of an interferon-free regimen. In a population-based sample of 161 patients infected with HIV and hepatitis C living in Oregon during 2007-2010, 21% were eligible for hepatitis C therapy. Despite the anticipation surrounding an interferon-sparing regimen, eligibility assuming an interferon-free regimen increased only to 26%, largely due to multiple simultaneous contraindications. Obesity was described for the first time as being associated with decreased eligibility (OR: 0.11). Active alcohol abuse was the most common contraindication (24%); uncontrolled mental health (22%), recent injection drug use (21%), poor antiretroviral adherence (22%), and infection (21%) were also common excluding conditions. When active drug or alcohol abuse was excluded as contraindications to therapy, the eligibility rate was 34%, a 62% increase. Assuming an interferon-free regimen and the exclusion of active drug or alcohol abuse as contraindications to therapy, the eligibility rate increased to 42%. Despite the availability of direct-acting anti-viral regimens, eligibility rates in HIV-hepatitis C virus (HCV) coinfection are modest. Many factors precluding hepatitis C therapy are reversible, and targeted interventions could result in increased eligibility. © 2014 © 2014 Taylor & Francis.
Cohen R.G.,University of Idaho |
Gurfinkel V.S.,Oregon Health And Science University |
Kwak E.,Macalester College |
Warden A.C.,University of Idaho |
And 2 more authors.
Neurorehabilitation and Neural Repair | Year: 2015
Background. Parkinson's disease (PD) is associated with stooped postural alignment, increased postural sway, and reduced mobility. The Alexander Technique (AT) is a mindfulness-based approach to improving posture and mobility by reducing muscular interference while maintaining upward intentions. Evidence suggests that AT can reduce disability associated with PD, but a mechanism for this effect has not yet been established. Objective. We investigated whether AT-based instructions reduce axial rigidity and increase upright postural alignment, and whether these instructions have different effects on postural alignment, axial rigidity, postural sway, and mobility than effort-based instructions regarding posture. Method. Twenty subjects with PD practiced 2 sets of instructions and then attempted to implement both approaches (as well as a relaxed control condition) during quiet standing and step initiation. The "Lighten Up" instructions relied on AT principles of reducing excess tension while encouraging length. The "Pull Up" instructions relied on popular concepts of effortful posture correction. We measured kinematics, resistance to axial rotation, and ground reaction forces. Results. Both sets of experimental instructions led to increases in upright postural alignment relative to the control condition. Only the Lighten Up instructions led to reduced postural sway, reduced axial postural tone, greater modifiability of tone, and a smoother center of pressure trajectory during step initiation, possibly indicating greater movement efficiency. Conclusion. Mindful movement approaches such as AT may benefit balance and mobility in subjects with PD by acutely facilitating increased upright postural alignment while decreasing rigidity. © American Society of Neurorehabilitation.
Suhler E.B.,Portland Veterans Administration Medical Center |
Suhler E.B.,Oregon Health And Science University |
Lim L.L.,Oregon Health And Science University |
Lim L.L.,University of Melbourne |
And 10 more authors.
Ophthalmology | Year: 2014
Objective: To determine whether rituximab, a monoclonal antibody against the B-lymphocyte antigen CD20, is effective in the treatment of refractory noninfectious scleritis.Design: Prospective, dose-ranging, randomized, double-masked phase I/II clinical trial.Participants: Twelve patients with noninfectious scleritis refractory to systemic corticosteroid and ≥1 other systemic immunosuppressive agent were enrolled from January 2007 to March 2010. Intervention: Subjects were randomly assigned to 500 (n = 5) or 1000 mg (n = 7) dosing arms of rituximab intravenous infusions (500 or 1000 mg), given at study days 1 and 15. Initial responders with breakthrough inflammation after study week 24 were offered treatment with an additional cycle of 2 open-label rituximab 1000 mg infusions.Main Outcome Measures: Primary outcomes were reduction of inflammation, as measured with a validated scleritis disease grading scale (SGS) and reduction in corticosteroid dose by ≥50%. Patients were characterized as responders to study therapy if ≥1 of these endpoints showed improvement and neither showed evidence of worsening. Secondary outcomes were improvement in visual acuity, reduction in pain, and improvement in patient and physician-reported global health assessment.Results: Of 12 enrolled patients, 9 met the SGS endpoint at or before week 24, and 4 additionally were able to reduce corticosteroid dose by ≥50%. With regard to secondary outcome measures, 11 and 9 patients showed improvement in patient and physician global health scores, respectively, and 7 patients had reduction in pain. Of 9 initial responders, 7 experienced breakthrough inflammation after 24 weeks and were treated with a second cycle of rituximab infusions. Four patients had significant objective or subjective worsening within 8 weeks of receiving rituximab; this event was averted in subsequent patients by treatment with peri-infusional oral corticosteroid. No other significant adverse events were noted. No differences in efficacy, toxicity, or likelihood of retreatment were noted between the dosing arms.Conclusions: Rituximab was effective treatment for 9 of 12 enrolled patients with refractory, noninfectious scleritis at 24 weeks, although 7 required reinfusion with rituximab to maintain inflammatory control. The treatment was well-tolerated, and peri-infusional inflammatory exacerbations were managed successfully with oral corticosteroids. Further long-term studies are warranted to determine the safety and efficacy of rituximab in treating noninfectious scleritis and other ocular inflammatory diseases. © 2014 by the American Academy of Ophthalmology.
Gahramanov S.,Oregon Health And Science University |
Muldoon L.L.,Oregon Health And Science University |
Li X.,Oregon Health And Science University |
Neuwelt E.A.,Oregon Health And Science University |
Neuwelt E.A.,Portland Veterans Administration Medical Center
Radiology | Year: 2011
Purpose: To evaluate the consistency of tumor blood volume measurements and antiangiogenic therapy efficacy assessments with a low-molecular-weight gadolinium-based contrast agent (GBCA, gadodiamide) versus an iron oxide nanoparticle (ferumoxytol) in the presence or absence of a loading dose of contrast agent before perfusion magnetic resonance (MR) imaging (preload method). Materials and Methods: The protocol was approved by the institutional animal care and use committee. U87MG tumor cells were implanted intracerebrally in 13 rats. All 13 rats underwent 11.75-T MR imaging with gadodiamide (60 μL) 13 days after tumor implantation. The next day, nine rats underwent MR imaging with ferumoxytol (60 μL). Immediately after ferumoxytol imaging, six rats received bevacizumab (45 mg/kg). MR imaging was repeated 48 hours after bevacizumab treatment with gadodiamide and 72 hours after treatment with ferumoxytol. Each study included three consecutive dynamic susceptibility- weighted contrast material-enhanced (DSC) MR acquisitions, which were performed without preload, with single-dose preload, and with double-dose preload. Tumor relative cerebral blood volume (rCBV) was estimated from each DSC MR acquisition. Two-way repeated measures analysis of variance was performed to test for differences between groups with both contrast agents. Results: DSC MR imaging with gadodiamide and without preload showed low rCBV (≤1.75) in nine of the 13 tumors; estimated rCBV increased progressively with both single- and double-dose preloads (P <.001). Conversely, rCBVs obtained with ferumoxytol were high (> 1.75) and remained constant with all three acquisitions. The magnitude of rCBV decrease after bevacizumab administration was dependent on the dose of gadodiamide preload, whereas the magnitude of rCBV decrease with ferumoxytol was constant regardless of whether contrast agent preload was used. Conclusion: With GBCA, tumor rCBV can be underestimated without preload and becomes dose dependent with preload correction. Conversely, ferumoxytol provides consistent assessment of tumor rCBV and antiangiogenic therapy efficacy. © RSNA, 2011.
Wolff F.,MaineHealth Center for Tobacco Independence |
Hughes J.R.,University of Vermont |
Woods S.S.,Portland Veterans Administration Medical Center
Journal of Smoking Cessation | Year: 2013
Tobacco dependence is characterised as a chronic, relapsing disorder that typically requires multiple quit attempts before successful, long-term abstinence is achieved (Steinberg, Foulds, Richardson, Burke, & Shah, 2006). Best practice, evidence-based treatment includes multiple-session counselling and pharmacotherapy, or the combination of both (Fiore et al., 2008). The field has moved past the notion that tobacco dependence is simply a bad habit, a vice, or a moral deficiency that can be overcome by willpower or education alone (Mars & Ling, 2008). However, the language used in discussing treatment has not always been consistent with this evidence. Some words and phrases used lend themselves to varied meanings, and could lead to significant misunderstanding not only among professionals in the field, but also among the general public (O'Brien, 2010; Davis, 1992; Perkins, 1999; Hughes, 2013). In this paper, we discuss some commonly used, problematic terminology, and suggest more appropriate terms (Table 1). © The Author(s), published by Cambridge University Press on behalf of Australian Academic Press Pty Ltd 2013.