Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

Treatment rationale study design for the MetLung trial : a randomized, double-blind phase III study of onartuzumab (MetMAb) in combination with erlotinib versus erlotinib alone in patients who have received standard chemotherapy for stage IIIB or IV met-positive non-small-cell lung cancer

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC. © 2012 Elsevier Inc. All Rights Reserved.

Work integrated learning: Exposure to professional practice : expectations and challenges

Prior to graduation engineering students are expected to provide evidence of relevant experience in the workplace. This experience is expected to provide opportunities for exposure to the profession and to help students develop confidence, skills and capabilities as emerging professionals. This investigation considers the expectations and challenges in implementing WIL programs in different contexts. While this will inform the next iteration of engineering course development at QUT the issues and interventions described provide useful insights into options available and engineering curriculum design more broadly. This comparative analysis across three phases highlights expectations and challenges including stakeholder responsibilities, expectations, and assessment. The study draws on the findings of a 2005 investigation into the purpose and provision of WIL and findings of a 2012 Faculty review of the current WIL model. The enhancement of WIL through a series of developmental phases highlights strengths and weaknesses of various models. It is anticipated that this investigation will inform course development decisions on a whole-of-course approach to WIL that improves student engagement and learning experience. The importance of WIL is not disputed. However with industry expectations, increasing student numbers and cohort diversity the ways in which students and industry currently engage in WIL are not sustainable and more creative, flexible and engaging approaches are needed.

Creating efficiencies in teaching : where are the right resources when you need them?

Early career engineering academics are encouraged to join and contribute to established research groups at the leading edge of their discipline. This is often facilitated by various staff development and support programs. Given that academics are often appointed primarily on the basis of their research skills and outputs, such an approach is justified and is likely to result in advancing the individual academic’s career. It also enhances their capacity to attract competitive research funding, while contributing to the overall research performance of their institution, with further potential for an increased share of government funding. In contrast, there is much less clarity of direction or availability of support mechanisms for those academics in their role as teachers. Following a general induction to teaching and learning at their institution, they would commonly think about preparing some lecture materials, whether for delivery in a face-to-face or on-line modality. Typically they would look for new references and textbooks to act as a guide for preparing the content. They would probably find out how the course has been taught before, and what laboratory facilities and experiments have been used. In all of these and other related tasks, the majority of newly appointed academics are guided strongly by their own experiences as students, rather than any firm knowledge of pedagogical principles. At a time of increased demands on academics’ time, and high expectations of performance and productivity in both research and teaching, it is essential to examine possible actions to support academics in enhancing their teaching performance in effective and efficient ways. Many resources have been produced over the years in engineering schools around the world, with very high intellectual and monetary costs. In Australia, the last few years have seen a surge in the number of ALTC/OLT projects and fellowships addressing a range of engineering education issues and providing many resources. There are concerns however regarding the extent to which these resources are being effectively utilised. Why are academics still re-inventing the wheel and creating their own version of teaching resources and pedagogical practice? Why do they spend so much of their precious time in such an inefficient way? A symposium examining the above issues was conducted at the AAEE2012 conference, and some pointers to possible responses to the above questions were obtained. These are explored in this paper and supplemented by the responses to a survey of a group of engineering education leaders on some of the aspects of these research questions. The outcomes of the workshop and survey results have been analysed in view of the literature and the ALTC/OLT sponsored learning and teaching projects and resources. Other factors are discussed, including how such resources can be found, how their quality might be evaluated, and how assessment may be appropriately incorporated, again using readily available resources. This study found a strong resonance between resources reuse with work on technology acceptance (Davis, 1989), suggesting that technology adoption models could be used to encourage resource sharing. Efficient use of outstanding learning materials is an enabling approach. The paper provides some insights on the factors affecting the re-use of available resources, and makes some recommendations and suggestions on how the issue of resources re-use might be incorporated in the process of applying and completing engineering education projects.

Provisional matrix deposition in hemostasis and venous insufficiency: Tissue preconditioning for nonhealing venous ulcers

Significance: Chronic wounds represent a major burden on global healthcare systems and reduce the quality of life of those affected. Significant advances have been made in our understanding of the biochemistry of wound healing progression. However, knowledge regarding the specific molecular processes influencing chronic wound formation and persistence remains limited. Recent Advances: Generally, healing of acute wounds begins with hemostasis and the deposition of a plasma-derived provisional matrix into the wound. The deposition of plasma matrix proteins is known to occur around the microvasculature of the lower limb as a result of venous insufficiency. This appears to alter limb cutaneous tissue physiology and consequently drives the tissue into a ‘preconditioned’ state that negatively influences the response to wounding. Critical Issues: Processes, such as oxygen and nutrient suppression, edema, inflammatory cell trapping/extravasation, diffuse inflammation, and tissue necrosis are thought to contribute to the advent of a chronic wound. Healing of the wound then becomes difficult in the context of an internally injured limb. Thus, interventions and therapies for promoting healing of the limb is a growing area of interest. For venous ulcers, treatment using compression bandaging encourages venous return and improves healing processes within the limb, critically however, once treatment concludes ulcers often reoccur. Future Directions: Improved understanding of the composition and role of pericapillary matrix deposits in facilitating internal limb injury and subsequent development of chronic wounds will be critical for informing and enhancing current best practice therapies and preventative action in the wound care field.

Urinary biomarkers of physical activity : candidates and clinical utility

Chronic physical inactivity is a major risk factor for a number of important lifestyle diseases, while inappropriate exposure to high physical demands is a risk factor for musculoskeletal injury and fatigue. Proteomic and metabolomic investigations of the physical activity continuum - extreme sedentariness to extremes in physical performance - offer increasing insight into the biological impacts of physical activity. Moreover, biomarkers, revealed in such studies, may have utility in the monitoring of metabolic and musculoskeletal health or recovery following injury. As a diagnostic matrix, urine is non-invasive to collect and it contains many biomolecules, which reflect both positive and negative adaptations to physical activity exposure. This review examines the utility and landscape of biomarkers of physical activity with particular reference to those found in urine.

The highly abundant urinary metabolite urobilin interferes with the bicinchoninic acid assay

Estimation of total protein concentration is an essential step in any protein- or peptide-centric analysis pipeline. This study demonstrates that urobilin, a breakdown product of heme and a major constituent of urine, interferes considerably with the bicinchoninic acid (BCA) assay. This interference is probably due to the propensity of urobilin to reduce cupric ions (Cu2+) to cuprous ions (Cu1+), thus mimicking the reduction of copper by proteins, which the assay was designed to do. In addition, it is demonstrated that the Bradford assay is more resistant to the influence of urobilin and other small molecules. As such, urobilin has a strong confounding effect on the estimate of total protein concentrations obtained by BCA assay and thus this assay should not be used for urinary protein quantification. It is recommended that the Bradford assay be used instead.

Neutrophil oxidative burst is primed by supernatant from stored red cells : implications for Transfusion-Related Acute Lung Injury (TRALI)

Aim/Background: Transfusion-related acute lung injury (TRALI) is a potentially fatal adverse transfusion reaction. It is hypothesised to occur via a two-insult mechanism: the recipient’s underlying co-morbidity in addition to the transfusion of blood products activate neutrophils in the lung resulting in damaged endothelium and capillary leakage. Neutrophil activation may occur by antibody or non-antibody related mechanisms, with the length of storage of cellular blood products implicated in the latter. This study investigated non-antibody mediated priming and/or activation of neutrophil oxidative burst. Methods: A cytochrome C reduction assay was used to assess priming and activation of neutrophil oxidative burst by pooled supernatant (SN) from day 1 (D1; n=75) and day 42 (D42; n=113) packed red blood cells (PRBC). Pooled PRBC-SN were assessed in parallel with PAF (priming), fMLP (activating), PAF + fMLP (priming + activating) and buffer only (negative) controls. Cytochrome C reduction was measured over 30min at 37oC (inclusive of 10min priming). Neutrophil activation by PRBC-SN was assessed cf. buffer only and neutrophil priming by PRBC-SN was assessed by co-incubation with fMLP cf. fMLP alone. One-way ANOVA; Newman-Keuls post-test; p<0.05; n=10 independent assays. Results: Neither D1- nor D42- PRBC-SN alone activated neutrophil oxidative burst. In addition, D1-PRBC-SN did not prime fMLP-activated neutrophil oxidative burst. D42-PRBC-SN did, however, prime neutrophils for subsequent activation of oxidative burst by fMLP, the magnitude of response being similar to PAF (a known neutrophil priming agonist). Conclusion: These findings are consistent with the two-insult mechanism of TRALI. Factors released into the SN during PRBC storage contributed to neutrophil priming synergistically with other neutrophil stimulating agonists. This implicates PRBC storage duration as a key factor contributing to non-immune neutrophil activation in the development of TRALI in patients with pre-disposing inflammatory conditions.

Stored blood products augment inflammation in a two-event model of Transfusion Related Acute Lung Injury (TRALI)

Aim/Background TRALI is hypothesised to develop via a two-event mechanism involving both the patieint's underlying morbidity and blood product factors. The storage of cellular products has been implicated in cases of non-antibody mediated TRALI, however the pathophysiological mechanisms are undefined. We investigated blood product storage-related modulation of inflmmatory cells and medicators involved in TRALI. Methods In an in vitro mode, fresh human whole blood was mixed with culture media (control) or LPS as a 1st event and "transfused" with 10% (v/v) pooled supernatant (SN) from Day 1 (d1, n=75) or Day 42 (D42, n=113) packed red blood cells (PRBCs) as a 2nd event. Following 6hrs, culture SN was used to assess the overall inflammatory response (cytometric bead array) and a duplicate assay containing protein transport inhibitor was used to assess neutrophil- and monocyte-specific inflmamatory responses using multi-colour flow cytometry. Panels: IL-6, IL-8, IL-10, IL-12, IL-1, TNF, MCP-1, IP-10, MIP-1. One-way ANOVA 95% CI. Results In the absence of LPS, exposure to D1 or D42 PRBC-SN reduced monocyte expression of IL-6, IL-8 and Il-10. D42 PRBC-SN also reduced monocyte IP-10, and the overall IL-8 production was increased. In the presence of LPS, D1-PRBC SN only modified overall IP-10 levels which were reduced. However, cf LPS alone, the combination of LPS and D42 PRBC-SN resulted in increased neutrophil and monocyte productionof IL-1 and IL-8 as well as reduced monocyte TNF production. Additionally, LPS and D42 PRBC-SN resulted in overall inflmmatory changes: elevated IL-8,

A Human identification technique using images of the iris and wavelet transform

A new approach for recognizing the iris of the human eye is presented. Zero-crossings of the wavelet transform at various resolution levels are calculated over concentric circles on the iris, and the resulting one-dimensional (1-D) signals are compared with model features using different dissimilarity functions.

A security system based on human iris identification using wavelet transform

A security system based on the recognition of the iris of human eyes using the wavelet transform is presented. The zero-crossings of the wavelet transform are used to extract the unique features obtained from the grey-level profiles of the iris. The recognition process is performed in two stages. The first stage consists of building a one-dimensional representation of the grey-level profiles of the iris, followed by obtaining the wavelet transform zerocrossings of the resulting representation. The second stage is the matching procedure for iris recognition. The proposed approach uses only a few selected intermediate resolution levels for matching, thus making it computationally efficient as well as less sensitive to noise and quantisation errors. A normalisation process is implemented to compensate for size variations due to the possible changes in the camera-to-face distance. The technique has been tested on real images in both noise-free and noisy conditions. The technique is being investigated for real-time implementation, as a stand-alone system, for access control to high-security areas.

Student focus and prioritization of design parameters in first-year engineering design projects

BACKGROUND Research on engineering design is a core area of concern within engineering education and a fundamental understanding of how engineering students approach and undertake design is necessary in order to develop effective design models and pedagogies. Understanding the factors related to design experiences in education and how they affect student practice can help educators as well as designers to leverage these factors as part of the design process. PURPOSE This study investigated the design practices of first-year engineering students’ and their experiences with a first-year engineering course design project. The research questions that guided the investigation were: 1. From a student perspective, what design parameters or criteria are most important? 2. How does this perspective impact subsequent student design practice throughout the design process? DESIGN/METHOD The authors employed qualitative multi-case study methods (Miles & Huberman, 1994) in order to the answer the research questions. Participant teams were observed and video recorded during team design meetings in which they researched the background for the design problem, brainstormed and sketched possible solutions, as well as built prototypes and final models of their design solutions as part of a course design project. Analysis focused on explanation building (Yin, 2009) and utilized within-case and cross-case analysis (Miles & Huberman, 1994). RESULTS We found that students focused disproportionally on the functional parameter, i.e. the physical implementation of their solution, and the possible/applicable parameter, i.e. a possible and applicable solution that benefited the user, in comparison to other given parameters such as safety and innovativeness. In addition, we found that individual teams focused on the functional and possible/ applicable parameters in early design phases such as brainstorming/ ideation and sketching. When prompted to discuss these non-salient parameters (from the student perspective) in the final design report, student design teams often used a post-hoc justification to support how the final designs fit the parameters that they did not initially consider. CONCLUSIONS This study suggests is that student design teams become fixated on (and consequently prioritize) certain parameters they interpret as important because they feel these parameters were described more explicitly in terms how they were met and assessed. Students fail to consider other parameters, perceived to be less directly assessable, unless prompted to do so. Failure to consider other parameters in the early design phases subsequently affects their approach in design phases as well. Case studies examining students’ study strategies within three Australian Universities illustrate similarities with some student approaches to design.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

Purpose The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). Patients and Methods In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). Results A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. Conclusion Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Symptom control and quality of life in lux-lung 3 : a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutations

Purpose Patient-reported symptoms and health-related quality of life (QoL) benefits were investigated in a randomized, phase III trial of afatinib or cisplatin/pemetrexed. Patients and Methods Three hundred forty-five patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma were randomly assigned 2:1 to afatinib 40 mg per day or up to six cycles of cisplatin/pemetrexed. Lung cancer symptoms and health-related QoL were assessed every 21 days until progression using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and Lung Cancer-13 questionnaires. Analyses of cough, dyspnea, and pain were preplanned, including percentage of patients who improved on therapy, time to deterioration of symptoms, and change in symptoms over time. Results Questionnaire compliance was high. Compared with chemotherapy, afatinib significantly delayed the time to deterioration for cough (hazard ratio [HR], 0.60; 95% CI, 0.41 to 0.87; P = .007) and dyspnea (HR, 0.68; 95% CI, 0.50 to 0.93; P = .015), but not pain (HR, 0.83; 95% CI, 0.62 to 1.10; P = .19). More patients on afatinib (64%) versus chemotherapy (50%) experienced improvements in dyspnea scores (P lt; .010). Differences in mean scores over time significantly favored afatinib over chemotherapy for cough (P lt; .001) and dyspnea (P = .001). Afatinib showed significantly better mean scores over time in global health status/QoL (P = .015) and physical (P = .001), role (P = .004), and cognitive (P lt; .007) functioning compared with chemotherapy. Fatigue and nausea were worse with chemotherapy, whereas diarrhea, dysphagia, and sore mouth were worse with afatinib (all P = .01). Conclusion In patients with lung adenocarcinoma with EGFR mutations, first-line afatinib was associated with better control of cough and dyspnea compared with chemotherapy, although diarrhea, dysphagia, and sore mouth were worse. Global health status/QoL was also improved over time with afatinib compared with chemotherapy.