Clinical indicators of midface fracture in patients with trauma.

BACKGROUND/AIM: Midface fractures are commonly present and difficult to diagnose in trauma patients. The objective of this study was to determine clinically accessible indicators of midface fracture. MATERIAL AND METHODS: A case-control study design was used to determine clinical indicators of midface fracture. Population source was a level I trauma center registry for years 2007-2009. Cases had a documented midface fracture. Patient and trauma characteristics were compared between cases and controls. Multivariate logistic regression analysis determined significant indicators of midface fracture. RESULTS: Study sample included 83 cases and 83 frequency-matched controls. Cases had a total of 211 fractures with a median of two midface fractures per person. Common fractures were orbital (41%), malar and maxillary (28%), and nasal bones (19%). Patients with midface fracture were significantly different than patients without midface fracture in severity of injury and were more likely to have a traumatic brain injury. Significant clinical indicators of fracture were maxillary sinus opacification, ethmoid sinus opacification, forehead laceration, periorbital contusion, epistaxis, and injury mechanism (P < 0.05). Patients with midface fracture had a 63 times greater odds for maxillary sinus opacification. The multivariable model correctly classified the presence and absence of midface fracture in 95% of study sample. CONCLUSIONS: Determined indicators of midface fracture provided a high level of discrimination in fracture status. Indicators can be used by clinicians to help detect possible midface fractures. Future prospective research on midface fracture indicators can assist in establishing their generalizability and impact on fracture detection, care, and outcomes.

Hospital discharge destinations for Hispanic and non-Hispanic white patients treated for traumatic brain injury.

PURPOSE: To examine hospital discharge destinations for Hispanic and non-Hispanic white patients treated for traumatic brain injury. METHODS: Retrospective cohort study with patient matching. FINDINGS: Ethnicity status not determined a significant predictor of discharge destination (P = .2150). Patient hospital length of stay determined a significant predictor of discharge destination (P = .0072), with every 1 day increase in length of stay, resulting in a 12% increase in odds of being discharged to care facility. CONCLUSIONS: Study data suggest that length of stay can predict discharge destination for both Hispanic and non-Hispanic white patients in a medium-sized trauma center in the Midwest.

Predictors of pneumonia in trauma patients with pulmonary contusion.

The purpose of this article was to determine assessable risk levels for pneumonia in trauma patients with pulmonary contusion. A retrospective review and analysis of national trauma data of patients with pulmonary contusion were identified to develop a risk assessment model. Trauma data for 2007 were used to determine risk factors for subsequent complication of pneumonia in pulmonary contusion patients. Available patient comorbidities were considered in model development. Next, 2008 data were used to test and finalize model. Pneumonia risk was categorized into 3 ordinal levels, based on equal-sized proportions of pulmonary contusion patients. Significant risk factors for pneumonia included age, gender, pulse rate, systolic blood pressure, obesity, Glasgow Coma Scale motor score, and ventilation on admission. The final risk adjustment model had good fit and discrimination. Study analyses used more than 40 000 trauma patient data to devise assessable risk levels for pneumonia in pulmonary contusion diagnosed patients. Study data can assist in direction of care and triaging of urgent care patients at risk of pneumonia, possibly leading to mitigation and prevention of pneumonia in at risk patients. Further review of study outcomes should occur to fully understand applicability and usefulness in urgent settings.

Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.

PURPOSE: Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients. PATIENTS AND METHODS: Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief. RESULTS: Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset. CONCLUSION: Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.

Phase I dose-escalation study of the safety and pharmacokinetics of atrasentan: an endothelin receptor antagonist for refractory prostate cancer.

PURPOSE: Evidence suggests that endothelin (ET)-1 and its primary receptor, the ET(A) receptor, may contribute to the progression of prostate and other cancers. Atrasentan (ABT-627) is a highly potent, selective ET(A) receptor antagonist. This study assessed safety, maximum tolerated dose, and pharmacokinetics (PK) in patients with refractory adenocarcinomas, primarily prostate cancer. EXPERIMENTAL DESIGN: This 28-day, single-center Phase I trial evaluated the safety and PK of escalating oral atrasentan doses (2.5-95 mg) given daily (except day 2) to eligible patients >/==" BORDER="0">18 years old with an adenocarcinoma proven resistant to standard therapy. Priority was given to patients with hormone-refractory prostate cancer. After 28 days, patients without objective signs of tumor progression were eligible to continue atrasentan in an extension study. RESULTS: Thirty-nine patients (30 of whom had prostate cancer) were treated in cohorts of three patients each with escalating atrasentan doses (2.5, 5, 10, 20, 30, 45, 60, 75, and 95 mg). The most common adverse events were rhinitis, headache, and peripheral edema. Anemia consistent with a reversible hemodilution effect was observed. No maximum tolerated dose was found in the dose range studied. Atrasentan PK were characterized by rapid absorption (mean T(max) = 0.9 h), mean +/- SD oral clearance of 24 +/- 15 liters/h, and volume distribution of 726 +/- 477 liters. PK were approximately dose-proportional and time independent across doses. CONCLUSIONS: Atrasentan is well tolerated, with no dose-limiting adverse events observed up to 95 mg. Adverse events are consistent with the vasodilatory effect of the drug. PK are linear and dose-proportional; the half-life is appropriate for once-daily dosing.

Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.

PURPOSE: Prostate cancer specifically metastasizes to bone where it leads to bone formation. We previously reported that coculturing MDA PCa 2b prostate cancer cells with primary mouse osteoblasts (PMOs) induced PMO proliferation and differentiation. An osteoblastic reaction was also observed in vivo after injection of MDA PCa 2b cells into the bones of severe combined immunodeficient disease mice. The aim of this study was to identify the sequence of events that leads to these osteoblastic lesions in vivo and, using this in vitro model, to define the contributions of various genes and cellular pathways in the pathophysiology of osteoblastic bone metastases of prostate cancer. EXPERIMENTAL DESIGN AND RESULTS: We show histological evidence of de novo bone formation as early as 2 weeks after injection of MDA PCa 2b cells in the bone of severe combined immunodeficient disease mice. In vitro, we show that PMOs induce MDA PCa 2b proliferation, suggesting a synergistic paracrine loop between these cells and PMOs. Endothelin (ET)-1, which is a mitogen for several cell types, is produced by all prostate cancer cell lines tested, and Atrasentan, an antagonist of ET-1 receptor A, partially reversed PMO proliferation induced by MDA PCa 2b cells. ET-1 is known to be comitogenic with a number of growth factors, including insulin-like growth factor (IGF)-I. In this study, we report that IGF-binding protein (IGFBP)-3 transcripts (that regulate levels of free IGF) are down-regulated in prostate cancer cells cocultured with PMO, whereas prostate-specific antigen (a protease known to cleave IGFBP-3) is detected in the 150-400 ng/ml range. Accordingly, IGFBP-3 has antiproliferative effects in PMOs, which were attenuated in our in vitro system. Taken together, our studies also implicate the IGF axis to play a role in this model of bone metastases. Secondly, the transcript level of mouse double minute 2 (a protein that regulate p53) was increased in prostate cancer cells grown with PMOs. The p53-dependent and -independent oncogenic activities of mouse double minute 2 suggest that osteoblasts induce a survival advantage in prostate cancer cells. Lastly, we show that expression of osteoprotegerin is decreased and of receptor activator of nuclear factor-kappaB ligand is increased in PMOs cultured in the presence of MDA PCa 2b cells, two events associated with osteoclast activation and bone resorption. CONCLUSIONS: Our results provide evidence that multiple and distinct molecular events affecting both bone formation and bone resorption concur to the increase bone mass in prostate cancer bone metastases. These data also provide a rationale for developing therapeutic strategies designed to target these molecular changes.

A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma.

RMP-7, a bradykinin analog, temporarily increases the permeability of the blood-brain tumor barrier to chemotherapy drugs like carboplatin. We conducted a randomized, controlled trial of carboplatin and RMP-7 versus carboplatin and placebo in patients with recurrent malignant glioma. The primary outcome measure was time to tumor progression (TTP). Adults with recurrent glioblastoma multiforme or anaplastic glioma were randomized in a 1:1 ratio to receive carboplatin and either RMP-7 or placebo. Radiation therapy had failed in all patients, and they may have received prior chemotherapy. Carboplatin (dosed to achieve an area under the curve of 5 mg/ml x time for patients who had received prior chemotherapy, or 7 mg/ml x time for those who had not) was given intravenously every 4 weeks, followed by intravenous infusion of either RMP-7 or placebo (300 ng/kg). TTP, tumor response, neuropsychological assessments, functional independence, and quality of life assessments were analyzed every 4 weeks. There were 122 patients enrolled, 62 in the RMP-7 and carboplatin group and 60 in the placebo and carboplatin group. Median TTP was 9.7 weeks (95% CI, 8.3-12.6 weeks) for the RMP-7 and carboplatin group and 8.0 weeks (95% CI, 7.4-12.6 weeks) for the placebo and carboplatin group. Median survival times were 26.9 weeks (95% CI, 21.3-37.6 weeks) for the RMP-7 group and 19.9 weeks (95% CI, 15.0-31.3 weeks) for the placebo group. No differences were noted for time to worsening of neuropsychological assessments, functional independence, or quality of life assessments. The use of RMP-7 had no effect on the pharmacokinetics or toxicity of carboplatin. At the dose and schedule used in this trial, RMP-7 did not improve the efficacy of carboplatin. Recent preclinical pharmacokinetic modeling of RMP-7 suggests that higher doses of RMP-7 may be required to increase carboplatin delivery to tumor.

The burden of unhelmeted and uninsured ATV drivers and passengers.

OBJECTIVE: Injured all-terrain vehicle (ATV) riders contribute to the national trauma burden. The importance of helmet use on injury severity and outcomes in ATV drivers versus passengers that receive care is unknown along with the association of payor status and helmet use in this population. An investigation of whether helmet use protects ATV drivers and passengers resulting in less severe injuries, better outcomes, and a lower cost burden to society is to be conducted. METHODS: A retrospective review of injured ATV riders in the National Trauma Data Bank from the United States for 2000-2004. RESULTS: Helmet use status was recorded for 5897 drivers and 836 passengers; 83 percent of drivers were male; 41 percent of passengers were female. Helmets were not widely worn (35% of drivers, 19% of passengers, p < .0001) and were less common among female than male drivers who crashed and received care (26% versus 37%, p < .0001). Drivers were older than passengers (p < .0001) and had more thorax, spine, and upper extremity injuries (p < .05). Helmets protected drivers and passengers: decreased head injuries, face injuries, injury severity, and mortality with increased likelihood of being discharged home rather than elsewhere (p < .0001). Personal insurance was more frequent in helmeted riders: 66 percent versus 55 percent of helmeted versus nonhelmeted drivers (p < .0001) and 69 percent versus 55 percent of helmeted versus nonhelmeted passengers (p = .03). CONCLUSIONS: Helmets are frequently not worn by ATV riders. Helmets protect ATV drivers and passengers and decrease societal costs associated with ATV crashes.