EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer : analysis of data from the phase 3 FLEX study

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=0·044). Interpretation: High EGFR expression is a tumour biomarker that can predict survival benefit from the addition of cetuximab to first-line chemotherapy in patients with advanced NSCLC. Assessment of EGFR expression could offer a personalised treatment approach in this setting. Funding: Merck KGaA. © 2012 Elsevier Ltd.

Postoperative chemotherapy for non-small cell lung cancer : a systematic review and meta-analysis

Background Postoperative chemotherapy is currently not recommended for resected non-small cell lung cancer in many countries and centers. Recently, results of several large randomized clinical trials were reported with conflicting evidence. Accordingly, we sought to determine whether postoperative chemotherapy is associated with improved survival compared with that after surgical intervention alone. Methods Randomized clinical trials with cisplatin- or uracil plus ftorafur-containing regimens were included and evaluated separately. A systematic review that included randomized clinical trials performed before 1995 was identified and found to be of adequate quality. Further randomized controlled trials were identified by searching MEDLINE, EMBASE, and the Cochrane Controlled Trials Register from 1995 through 2004. In addition, the reference lists of articles and conference abstracts were searched. The logarithm of the hazard ratio and its standard error were calculated, and a fixed-effect model was used to combine the estimates. Results There were 7200 patients enrolled in 19 trials included in the analyses. An overall estimate of 13% relative reduction in mortality (95% confidence interval, 7%-19%) was found. There was 11% relative reduction in mortality associated with postoperative cisplatin (95% confidence interval, 4%-18%; P = .004) and 17% associated with uracil plus ftorafur (95% confidence interval, 5%-27%; P = .006) compared with that after surgical intervention alone. This means that there would be an additional survivor at 5 years for 25 patients treated with cisplatin or for 30 patients treated with uracil plus ftorafur. Conclusions Postoperative chemotherapy is associated with improved survival compared with that after surgical intervention alone. Selected patients with completely resected non-small cell lung cancer should be offered chemotherapy. Copyright © 2004 by The American Association for Thoracic Surgery.

Hyperelastic constitutive relationship for the strain-rate dependent behavior of shoulder and other joint cartilages

Non-linear finite deformations of articular cartilages under physiological loading conditions can be attributed to hyperelastic behavior. This paper contains experimental results of indentation tests in finite deformation and proposes an empirical based new generalized hyperelastic constitutive model to account for strain-rate dependency for humeral head cartilage tissues. The generalized model is based on existing hyperelastic constitutive relationships that are extensively used to represent biological tissues in biomechanical literature. The experimental results were obtained for three loading velocities, corresponding to low (1x10-3 s-1), moderate and high strain-rates (1x10-1 s-1), which represent physiological loading rates that are experienced in daily activities such as lifting, holding objects and sporting activities. Hyperelastic material parameters were identified by non linear curve fitting procedure. Analysis demonstrated that the material behavior of cartilage can be effectively decoupled into strain-rate independent(elastic) and dependent parts. Further, experiments conducted using different indenters indicated that the parameters obtained are significantly affected by the indenter size, potentially due to structural inhomogeneity of the tissue. The hyperelastic constitutive model developed in this paper opens a new avenue for the exploration of material properties of cartilage tissues.

HMM relative entropy rate concepts for vision-based aircraft manoeuvre detection

Machine vision is emerging as a viable sensing approach for mid-air collision avoidance (particularly for small to medium aircraft such as unmanned aerial vehicles). In this paper, using relative entropy rate concepts, we propose and investigate a new change detection approach that uses hidden Markov model filters to sequentially detect aircraft manoeuvres from morphologically processed image sequences. Experiments using simulated and airborne image sequences illustrate the performance of our proposed algorithm in comparison to other sequential change detection approaches applied to this application.

Latex allergy : a perioperative environmental hazard

Latex allergy is a serious, possibly life threatening health hazard in the perioperative environment. Policy and procedures should be developed to identify patients who may be sensitive to latex and to ensure the avoidance of latex products in their care. Healthcare workers should also take steps to avoid exposure and protect themselves from hypersensitivity reactions.

Bike share's impact on car use : evidence from the United States, Great Britain, and Australia

There are currently more than 400 cities operating bike share programs. Purported benefits of bike share programs include flexible mobility, physical activity, reduced congestion, emissions and fuel use. Implicit or explicit in the calculation of program benefits are assumptions regarding the modes of travel replaced by bike share journeys. This paper examines the degree to which car trips are replaced by bike share, through an examination of survey and trip data from bike share programs in Melbourne, Brisbane, Washing, D.C., London, and Minneapolis/St. Paul. A secondary and unique component of this analysis examines motor vehicle support services required for bike share fleet rebalancing and maintenance. These two components are then combined to estimate bike share’s overall contribution to changes in vehicle kilometres traveled. The results indicate that the estimated mean reduction in car use due to bike share is at least twice the distance covered by operator support vehicles, with the exception of London, in which the relationship is reversed, largely due to a low car mode substitution rate. As bike share programs mature, evaluation of their effectiveness in reducing car use may become increasingly important. This paper reveals that by increasing the convenience of bike share relative to car use and by improving perceptions of safety, the capacity of bike share programs to reduce vehicle trips and yield overall net benefits will be enhanced. Researchers can adapt the analytical approach proposed in this paper to assist in the evaluation of current and future bike share programs.

Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer

OBJECTIVES: Four randomized phase II/III trials investigated the addition of cetuximab to platinum-based, first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). A meta-analysis was performed to examine the benefit/risk ratio for the addition of cetuximab to chemotherapy. MATERIALS AND METHODS: The meta-analysis included individual patient efficacy data from 2018 patients and individual patient safety data from 1970 patients comprising respectively the combined intention-to-treat and safety populations of the four trials. The effect of adding cetuximab to chemotherapy was measured by hazard ratios (HRs) obtained using a Cox proportional hazards model and odds ratios calculated by logistic regression. Survival rates at 1 year were calculated. All applied models were stratified by trial. Tests on heterogeneity of treatment effects across the trials and sensitivity analyses were performed for all endpoints. RESULTS: The meta-analysis demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival (HR 0.88, p=0.009, median 10.3 vs 9.4 months), progression-free survival (HR 0.90, p=0.045, median 4.7 vs 4.5 months) and response (odds ratio 1.46, p<0.001, overall response rate 32.2% vs 24.4%) compared with chemotherapy alone. The safety profile of chemotherapy plus cetuximab in the meta-analysis population was confirmed as manageable. Neither trials nor patient subgroups defined by key baseline characteristics showed significant heterogeneity for any endpoint. CONCLUSION: The addition of cetuximab to platinum-based, first-line chemotherapy for advanced NSCLC significantly improved outcome for all efficacy endpoints with an acceptable safety profile, indicating a favorable benefit/risk ratio.

Ozone-induced dissociation of conjugated lipids reveals significant reaction rate enhancements and characteristic odd-electron product ions

Ozone-induced dissociation (OzID) is an alternative ion activation method that relies on the gas phase ion-molecule reaction between a mass-selected target ion and ozone in an ion trap mass spectrometer. Herein, we evaluated the performance of OzID for both the structural elucidation and selective detection of conjugated carbon-carbon double bond motifs within lipids. The relative reactivity trends for \[M + X](+) ions (where X = Li, Na, K) formed via electrospray ionization (ESI) of conjugated versus nonconjugated fatty acid methyl esters (FAMEs) were examined using two different OzID-enabled linear ion-trap mass spectrometers. Compared with nonconjugated analogues, FAMEs derived from conjugated linoleic acids were found to react up to 200 times faster and to yield characteristic radical cations. The significantly enhanced reactivity of conjugated isomers means that OzID product ions can be observed without invoking a reaction delay in the experimental sequence (i.e., trapping of ions in the presence of ozone is not required). This possibility has been exploited to undertake neutral-loss scans on a triple quadrupole mass spectrometer targeting characteristic OzID transitions. Such analyses reveal the presence of conjugated double bonds in lipids extracted from selected foodstuffs. Finally, by benchmarking of the absolute ozone concentration inside the ion trap, second order rate constants for the gas phase reactions between unsaturated organic ions and ozone were obtained. These results demonstrate a significant influence of the adducting metal on reaction rate constants in the fashion Li > Na > K.

GNSS ambiguity resolution with controllable failure rate for long baseline network RTK

Many large-scale GNSS CORS networks have been deployed around the world to support various commercial and scientific applications. To make use of these networks for real-time kinematic positioning services, one of the major challenges is the ambiguity resolution (AR) over long inter-station baselines in the presence of considerable atmosphere biases. Usually, the widelane ambiguities are fixed first, followed by the procedure of determination of the narrowlane ambiguity integers based on the ionosphere-free model in which the widelane integers are introduced as known quantities. This paper seeks to improve the AR performance over long baseline through efficient procedures for improved float solutions and ambiguity fixing. The contribution is threefold: (1) instead of using the ionosphere-free measurements, the absolute and/or relative ionospheric constraints are introduced in the ionosphere-constrained model to enhance the model strength, thus resulting in the better float solutions; (2) the realistic widelane ambiguity precision is estimated by capturing the multipath effects due to the observation complexity, leading to improvement of reliability of widelane AR; (3) for the narrowlane AR, the partial AR for a subset of ambiguities selected according to the successively increased elevation is applied. For fixing the scalar ambiguity, an error probability controllable rounding method is proposed. The established ionosphere-constrained model can be efficiently solved based on the sequential Kalman filter. It can be either reduced to some special models simply by adjusting the variances of ionospheric constraints, or extended with more parameters and constraints. The presented methodology is tested over seven baselines of around 100 km from USA CORS network. The results show that the new widelane AR scheme can obtain the 99.4 % successful fixing rate with 0.6 % failure rate; while the new rounding method of narrowlane AR can obtain the fix rate of 89 % with failure rate of 0.8 %. In summary, the AR reliability can be efficiently improved with rigorous controllable probability of incorrectly fixed ambiguities.

Are in vitro estimates of cell diffusivity and cell proliferation rate sensitive to assay geometry?

Cells respond to various biochemical and physical cues during wound–healing and tumour progression. In vitro assays used to study these processes are typically conducted in one particular geometry and it is unclear how the assay geometry affects the capacity of cell populations to spread, or whether the relevant mechanisms, such as cell motility and cell proliferation, are somehow sensitive to the geometry of the assay. In this work we use a circular barrier assay to characterise the spreading of cell populations in two different geometries. Assay 1 describes a tumour–like geometry where a cell population spreads outwards into an open space. Assay 2 describes a wound–like geometry where a cell population spreads inwards to close a void. We use a combination of discrete and continuum mathematical models and automated image processing methods to obtain independent estimates of the effective cell diffusivity, D, and the effective cell proliferation rate, λ. Using our parameterised mathematical model we confirm that our estimates of D and λ accurately predict the time–evolution of the location of the leading edge and the cell density profiles for both assay 1 and assay 2. Our work suggests that the effective cell diffusivity is up to 50% lower for assay 2 compared to assay 1, whereas the effective cell proliferation rate is up to 30% lower for assay 2 compared to assay 1.

Analysis of strain-rate dependent mechanical behavior of single chondrocyte : a finite element study

Various studies have been conducted to investigate the effects of impact loading on cartilage damage and chondrocyte death. These have shown that the rate and magnitude of the applied strain significantly influence chondrocyte death, and that cell death occurred mostly in the superficial zone of cartilage suggesting the need to further understand the fundamental mechanisms underlying the chondrocytes death induced at certain levels of strain-rate. To date there is no comprehensive study providing insight on this phenomenon. The aim of this study is to examine the strain-rate dependent behavior of a single chondrocyte using a computational approach based on Finite Element Method (FEM). An FEM model was developed using various mechanical models, which were Standard Neo-Hookean Solid (SnHS), porohyperelastic (PHE) and poroviscohyperelastic (PVHE) to simulate Atomic Force Microscopy (AFM) experiments of chondrocyte. The PVHE showed, it can capture both relaxation and loading rate dependent behaviors of chondrocytes, accurately compared to other models.

Exploration of mechanisms underlying the strain-rate-dependent mechanical property of single chondrocytes

Based on the characterization by Atomic Force Microscopy (AFM), we report that the mechanical property of single chondrocytes has dependency on the strain-rates. By comparing the mechanical deformation responses and the Young’s moduli of living and fixed chondrocytes at four different strain-rates, we explore the deformation mechanisms underlying this dependency property. We found that the strain-rate-dependent mechanical property of living cells is governed by both of the cellular cytoskeleton (CSK) and the intracellular fluid when the fixed chondrocytes is mainly governed by their intracellular fluid which is called the consolidation-dependent deformation behavior. Finally, we report that the porohyperelastic (PHE) constitutive material model which can capture the consolidation-dependent behavior of both living and fixed chondrocytes is a potential candidature to study living cell biomechanics.

Traffic incident clearance time and arrival time prediction based on hazard models

Accurate prediction of incident duration is not only important information of Traffic Incident Management System, but also an ffective input for travel time prediction. In this paper, the hazard based prediction odels are developed for both incident clearance time and arrival time. The data are obtained from the Queensland Department of Transport and Main Roads’ STREAMS Incident Management System (SIMS) for one year ending in November 2010. The best fitting distributions are drawn for both clearance and arrival time for 3 types of incident: crash, stationary vehicle, and hazard. The results show that Gamma, Log-logistic, and Weibull are the best fit for crash, stationary vehicle, and hazard incident, respectively. The obvious impact factors are given for crash clearance time and arrival time. The quantitative influences for crash and hazard incident are presented for both clearance and arrival. The model accuracy is analyzed at the end.

A comparison of mathematical models for phase separation in high-rate LiFePO4 cathodes

We construct a two-scale mathematical model for modern, high-rate LiFePO4cathodes. We attempt to validate against experimental data using two forms of the phase-field model developed recently to represent the concentration of Li+ in nano-sized LiFePO4crystals. We also compare this with the shrinking-core based model we developed previously. Validating against high-rate experimental data, in which electronic and electrolytic resistances have been reduced is an excellent test of the validity of the crystal-scale model used to represent the phase-change that may occur in LiFePO4material. We obtain poor fits with the shrinking-core based model, even with fitting based on “effective” parameter values. Surprisingly, using the more sophisticated phase-field models on the crystal-scale results in poorer fits, though a significant parameter regime could not be investigated due to numerical difficulties. Separate to the fits obtained, using phase-field based models embedded in a two-scale cathodic model results in “many-particle” effects consistent with those reported recently.