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There are no previously published studies examining opioid doses administered to opioid-tolerant cancer patients during emergency department (ED) encounters.To determine if opioid-tolerant cancer patients presenting with acute pain exacerbations receive adequate initial doses of as needed (PRN) opioids during ED encounters based on home oral morphine equivalent (OME) use.We performed a retrospective cohort study of opioid-tolerant cancer patients who received opioids in our ED over a two-year period. The percentage of patients who received an adequate initial dose of PRN opioid (defined as ≥10% of total 24-hour ambulatory OME) was evaluated. Logistic regression was used to establish the relationship between 24-hour ambulatory OME and initial ED OME to assess whether higher home usage was associated with higher likelihood of being undertreated.Out of 216 patients, 61.1% of patients received an adequate initial PRN dose of opioids in the ED. Of patients taking200 OMEs per day at home, 77.4% received an adequate initial dose; however, only 3.2% of patients taking400 OMEs per day at home received an adequate dose. Patients with ambulatory 24-hour OME greater than 400 had 99% lower odds of receiving an adequate initial dose of PRN opioid in the ED compared to patients with ambulatory 24-hour OME less than 100 (OR0.01, CI 0.00-0.02, P 0.001).Patients with daily home use less than 200 OMEs generally received adequate initial PRN opioid doses during their ED visit. However, patients with higher home opioid usage were at increased likelihood of being undertreated.

Expression of epidermal growth factor receptor (EGFR) may be of prognostic value in renal cell cancer (RCC). Gene amplification of EGFR was investigated in a cohort of 315 patients with advanced RCC from a previously reported randomised study. Using fluorescent in situ hybridisation, only 2 patients (0.6%) had gene amplification; therefore gene amplification is of no prognostic value in RCC.

One specific limitation to the clinical development of targeted cancer therapeutics is the lack of well-validated pharmacodynamic markers. Such tools might conceivably provide a framework within which to better evaluate the selection of specific molecules as therapeutic targets. Nevertheless, the practical application of this hypothesis in clinical development remains elusive. In this study, we present a minimally invasive pharmacodynamic assay for monitoring therapy-mediated changes in the activity of target signaling pathways by using fine needle aspiration (FNA) samples and quantitative ELISA methods. To this end, we used the HuCCT-1 cholangiocarcinoma cell line treated with gefitinib (ZD1839, Iressa), a selective blocker of the epidermal growth factor receptor (EGFR), and CI-1040, a selective inhibitor of the mitogen extracellular regulated kinase [mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase 1/2]. HuCCT-1 cells were resistant to gefitinib and CI-1040 alone but susceptible to the combination of these drugs in vitro and in vivo. This effect was associated with a greater inhibition of ERK1/2 activation, a downstream mediator in the EGFR–mitogen-activated protein/ERK kinase pathway. Using this model, we sought to assess whether FNA-obtained tumor biopsies could be used to measure signaling pathway activation. Cellular extracts prepared from FNA samples yielded adequately cellular, high-quality samples to assess therapy-mediated changes in EGFR and ERK1/2 phosphorylation by Western blotting and quantitative ELISA assays. Treatment with gefitinib alone effectively inhibited EGFR activation but failed to block ERK1/2 phosphorylation and tumor growth. Blocking was achieved by the addition of CI-1040 to the treatment regimen. These results show that the combination of serial FNA sampling with highly sensitive quantitative ELISA assays permits assessment of therapy-mediated changes in signaling pathways, which correlate well with antitumor effects. This assay is simple to implement and broadly applicable to diverse tumor types in clinical studies with cancer patients and may be useful in the development of targeted anticancer agents. [Mol Cancer Ther 2006;5(7):1895–903]

We have employed a light-absorbing electrically conductive polymer as a matrix to determine the molecular mass of small organic molecules using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. This method, which is in contrast to the usual MALDI strategy for matrix selection in which a small molecule matrix is used with a high molecular mass analyte, addresses the problem of matrix interference which limits the usefulness of MALDI-TOF for small molecule analysis. Use of negative ion mode offers advantages for this application. Using this approach, we have obtained clean molecular ion mass spectra of small organic molecules in the mass range 100-300 Da.

To assess critical care transport (CCT) crews' endotracheal intubation (ETI) attempts, success rates, and peri-ETI oxygenation.Participants were adult and pediatric patients undergoing attempted advanced airway management during the period from July 2007 to December 2008 by crews from 11 CCT programs varying in geography, crew configuration, and casemix; all crews had access to neuromuscular-blocking agents. Data collected included airway management variables defined per national consensus criteria. Descriptive analysis focused on ETI success rates (reported with exact binomial 95% confidence intervals [CIs]) and occurrence of new hypoxemia (oxygen saturation [SpO(2)] dropping below 90% during or after ETI); to assess categorical variables, Fisher's exact test, Pearson chi(2), and logistic regression were employed to explore associations between predictor variables and ETI failure or new hypoxemia. For all tests, p0.05 defined significance.There were 603 total attempts at airway management, with successful oral or nasal ETI in 582 cases, or 96.5% (95% CI 94.7-97.8%). In 182 cases (30.2%, 95% CI 26.5-34.0%), there were failed ETI attempts prior to CCT crew arrival; CCT crew ETI success on these patients (96.2%, 95% CI 92.2-98.4%) was just as high as in the patients in whom there was no pre-CCT ETI attempt (p = 0.81). New hypoxemia occurred in only six cases (1.6% of the 365 cases with ongoing SpO(2) monitoring; 95% CI 0.6-3.5%); the only predictor of new hypoxemia was pre-ETI hypotension (p0.001). A requirement for multiple ETI attempts by CCT crews was not associated with new hypoxemia (Fisher's exact p = 0.13).CCT crews' ETI success rates were very high, and even when ETI required multiple attempts, airway management was rarely associated with SpO(2) derangement. CCT crews' ETI success rates were equally high in the subset of patients in whom ground emergency medical services (EMS) ETI failed prior to arrival of transport crews.

Cyclin D1 overexpression has been associated with poor prognosis and resistance to therapy in human breast cancer. Thus, the development of therapeutic agents that selectively target cyclin D1 activity is of clinical interest. This study demonstrates that 12-oxo-phytodienoic acid (OPDA), a phytohormone with critical functions in growth and development in plants, induces growth arrest in MDA-MB-231 and T47D breast cancer cells. In response to OPDA treatment, the human breast cancer cell lines exhibit a progressive decline in cyclin D1 expression, which is tightly associated with the accumulation of hypophosphorylated form of the retinoblastoma protein (Rb) and G1 arrest. The decrease in cyclin D1 protein expression accompanies a dramatic decline in nuclear but not membranous beta-catenin expression and activation of glycogen synthase kinase-3-beta (GSK3beta) caused by inhibition of its serine-9 phosphorylation. The proteasome inhibitor MG132 blocks OPDA-mediated decrease in cyclin D1. In addition, the overexpression of T286A, a cyclin D1 mutant which is refractory to phosphorylation by GSK3beta and proteosomal degradation, is resistant to OPDA-mediated Rb dephosphorylation as well as G(1) cell cycle arrest. Thus, our results demonstrate that degradation of cyclin D1 protein is a key event in OPDA induced growth inhibition in breast cancer cells. These data provide the basic foundation for future efforts to develop OPDA-based approaches in the prevention and treatment of breast cancer and other types of cancer.