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.

A conceptual framework for the cultural integration of cooperative learning : a Thai primary mathematics education perspective

The Thailand education reform adopted cooperative learning to improve the quality of education. However, it has been reported that the introduction and maintenance of cooperative learning has been difficult and uncertain because of the cultural differences. The study proposed a conceptual framework developed based on making a connection between Thai cultures and cooperative learning elements, and implemented a small-scale research project in a Thai primary mathematics class with a teacher and thirty-two Grade 4 students. The results uncovered that the three components including preparation of teachers, instructional strategies and preparation of students can be vehicles for the culture integration in cooperative learning.

Heritage language learning for Chinese Australians : the role of habitus

The relationship between Heritage Language and ethnic identity has gained significant research ground in social psychological and poststructural scholarship, with empirical evidence largely emerging from the North American settings. There is little pertinent sociological work conducted outside North America. To fill this gap, this sociological study sets its scene in an Australian context. Drawing on Bourdieu’s notion of habitus, the study examines the contribution of Chinese Australians’ Chineseness to their Chinese Heritage Language proficiency. Two hundred and thirty young Chinese Australians completed the online survey. Results from multiple regression indicate that habitus of Chineseness is one of the significant predictors for the Chinese Heritage Language proficiency of these young people. The study makes a theoretical contribution to investigate ethnic identity – Heritage Language link through the notion of habitus and makes a methodological contribution to quantify this habitus.

Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is commonly expressed in non-small-cell lung cancer (NSCLC) and promotes a host of mechanisms involved in tumorigenesis. However, EGFR expression does not reliably predict prognosis or response to EGFR-targeted therapies. The data from two previous studies of a series of 181 consecutive surgically resected stage I-IIIA NSCLC patients who had survived in excess of 60 days were explored. Of these patients, tissue was available for evaluation of EGFR in 179 patients, carbonic anhydrase (CA) IX in 177 patients and matrix metalloproteinase-9 (MMP-9) in 169 patients. We have previously reported an association between EGFR expression and MMP-9 expression. We have also reported that MMP-9 (P=0.001) and perinuclear (p)CA IX (P=0.03) but not EGFR expression were associated with a poor prognosis. Perinuclear CA IX expression was also associated with EGFR expression (P<0.001). Multivariate analysis demonstrated that coexpression of MMP-9 with EGFR conferred a worse prognosis than the expression of MMP-9 alone (P<0.001) and coexpression of EGFR and pCA IX conferred a worse prognosis than pCA IX alone (P=0.05). A model was then developed where the study population was divided into three groups: group 1 had expression of EGFR without coexpression of MMP-9 or pCA IX (number=21); group 2 had no expression of EGFR (number=75); and group 3 had coexpression of EGFR with pCA IX or MMP-9 or both (number=70). Group 3 had a worse prognosis than either groups 1 or 2 (P=0.0003 and 0.027, respectively) and group 1 had a better prognosis than group 2 (P=0.036). These data identify two cohorts of EGFR-positive patients with diametrically opposite prognoses. The group expressing either EGFR and or both MMP-9 and pCA IX may identify a group of patients with activated EGFR, which is of clinical relevance with the advent of EGFR-targeted therapies. © 2004 Cancer Research UK.

Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing

We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

Supporting cooperation and caring through large group experiences

Cooperation and caring are best taught within a group as it promotes connectedness, collaborative effort, and relationship building.

Cross-cultural learning experiences in architectural education

This qualitative study looks at the joint output of 20 architecture students from 2 different countries during their short respective Study Tours to each other’s country to discern the effect of cross-cultural experiences on their learning. This paper uses the students’ joint design efforts and reflective writings to investigate the outcome of this cross-cultural educational exchange. Their joint design efforts resulted in the making of small built structures, drawings and collaborative design proposals for an urban setting. In addition, a short questionnaire and personal interviews were also used as methods to gain insight into their experience and to use as a comparative study. The question is also raised in this paper of whether spontaneous friendship among students is integral to long term learning in a cross-cultural context in comparison to pre-designed learning objectives on the part of the educators. This paper also initiates the dialogue of the extent of cultural influences and universal ideas on collaborative architectural design. With increasing joint design ventures between architectural firms in different countries, there is interest in how collaborative design can be understood in a cross-cultural context. This paper examines short term cross cultural experiences and its contribution to architectural education.

An evaluation of the Australian ‘reconceptualising early mathematics learning’ project : key findings and implications

The Pattern and Structure Mathematics Awareness Project (PASMAP) has investigated the development of patterning and early algebraic reasoning among 4 to 8 year olds over a series of related studies. We assert that an awareness of mathematical pattern and structure (AMPS) enables mathematical thinking and simple forms of generalization from an early age. This paper provides an overview of key findings of the Reconceptualizing Early Mathematics Learning empirical evaluation study involving 316 Kindergarten students from 4 schools. The study found highly significant differences on PASA scores for PASMAP students. Analysis of structural development showed increased levels for the PASMAP students; those categorised as low ability developed improved structural responses over a short period of time.

Acquired differential regulation of caspase-8 in cisplatin-resistant non-small-cell lung cancer

Failure to efficiently induce apoptosis contributes to cisplatin resistance in non-small-cell lung cancer (NSCLC). Although BCL-2-associated X protein (BAX) and BCL-2 antagonist killer (BAK) are critical regulators of the mitochondrial apoptosis pathway, their requirement has not been robustly established in relation to cisplatin. Here, we show that cisplatin can efficiently bypass mitochondrial apoptosis block caused by loss of BAX and BAK, via activation of the extrinsic death receptor pathway in some model cell lines. Apoptosis resistance following cisplatin can only be observed when both extrinsic and intrinsic pathways are blocked, consistent with redundancy between mitochondrial and death receptor pathways in cisplatin-induced apoptosis. In H460 NSCLC cells, caspase-8 cleavage was shown to be induced by cisplatin and is dependent on death receptor 4, death receptor 5, Fas-associated protein with death domain, acid sphingomyelinase and ceramide synthesis. In contrast, cisplatin-resistant cells fail to activate caspase-8 via this pathway despite conserving sensitivity to death ligand-driven activation. Accordingly, caspase-8 activation block acquired during cisplatin resistance, can be bypassed by death receptor agonism.

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

Digital tablets as a tool for blended learning in power engineering education

Digital tablets have been identified as a tool for enabling blended learning and supporting online teaching and learning. A small scale trial was undertaken to assess the effectiveness of this technology when applied to power engineering education. Critical findings and experiences gained from this trial, including potential benefits, presentation techniques and the resulting student feedback are presented in this paper.

A prospective cohort study examining the preferred learning styles of acute care registered nurses

Objectives This paper reports on the preferred learning styles of Registered Nurses practicing in acute care environments and relationships between gender, age, post-graduate experience and the identified preferred learning styles. Methods A prospective cohort study design was used. Participants completed a demographic questionnaire and the Felder-Silverman Index of Learning Styles (ILS) questionnaire to determine preferred learning styles. Results Most of the Registered Nurse participants were balanced across the Active-Reflective (n = 77, 54%), and Sequential-Global (n = 96, 68%) scales. Across the other scales, sensing (n = 97, 68%) and visual (n = 76, 53%) were the most common preferred learning style. There were only a small proportion who had a preferred learning style of reflective (n = 21, 15%), intuitive (n = 5, 4%), verbal (n = 11, 8%) or global learning (n = 15, 11%). Results indicated that gender, age and years since undergraduate education were not related to the identified preferred learning styles. Conclusions The identification of Registered Nurses’ learning style provides information that nurse educators and others can use to make informed choices about modification, development and strengthening of professional hospital-based educational programs. The use of the Index of Learning Styles questionnaire and its ability to identify ‘balanced’ learning style preferences may potentially yield additional preferred learning style information for other health-related disciplines.

Challenges of knowledge integration in small and medium enterprises

This study attempts to develop a better understanding of the challenges of knowledge integration (KI) within the innovation process in Small and Medium Enterprises (SMEs). Using several case studies, this study investigates how knowledge integration may be managed within the context of innovation in SMEs. The research places particular focus on identifying the challenges of knowledge integration in SMEs in relation to three aspects of knowledge integration activities, namely knowledge identification, knowledge acquisition, and knowledge sharing. Four distinct tasks emerged in the knowledge integration process, namely team building capability, capturing tacit knowledge, role of knowledge management (KM) systems, and technological systemic integration. The paper suggests that managing knowledge integration in SMEs can be best managed by focusing on these four tasks, which in turn will lead to innovation.

National curriculum reform and equipping pre-service teachers to teach about Australia in the Asian Century

Currently a range of national policy settings are reshaping schooling and teacher education in Australia. This paper presents some of the findings from a small qualitative pilot study conducted with a group of final year pre-service teachers studying a secondary social science curriculum method unit in an Australian university. One of the study’s research objectives aimed at identifying how students reflected on their capacity to navigate curriculum change and, more specifically, on teaching about Australia and Asia in the forthcoming implementation of the first national history curriculum. The unit was designed and taught by the researcher on the assumption that beginning social science teachers need to be empowered to deal with the curriculum change they’ll encounter throughout their careers. The pilot study’s methodology was informed by a constructivist approach to grounded theory and its scope was limited to one semester with volunteer students. Of the pre-service teacher reflections on their preparedness to teach, this paper reports on the content, pedagogy and learning they experienced in one segment of the unit with specific reference to the new history curriculum’s ‘Australia in a world history’ approach and the development of Asia literacy. The findings indicate that whilst pre-service teachers valued the opportunity to engage with learning experiences which enhanced their intercultural understanding and extended their pedagogical and content knowledge on campus, the nature of the final practicum in schools was also influential in shaping their preparedness to enter the profession.