Relationship between EGFR expression, EGFR mutation status, and the efficacy of chemotherapy plus cetuximab in FLEX study patients with advanced non-small-cell lung cancer

INTRODUCTION: The phase III FLEX study (NCT00148798) in advanced non-small-cell lung cancer indicated that the survival benefit associated with the addition of cetuximab to cisplatin and vinorelbine was limited to patients whose tumors expressed high levels of epidermal growth factor receptor (EGFR) (immunohistochemistry score of >/=200; scale 0-300). We assessed whether the treatment effect was also modulated in FLEX study patients by tumor EGFR mutation status. METHODS: A tumor mutation screen of EGFR exons 18 to 21 included 971 of 1125 (86%) FLEX study patients. Treatment outcome in low and high EGFR expression groups was analyzed across efficacy endpoints according to tumor EGFR mutation status. RESULTS: Mutations in EGFR exons 18 to 21 were detected in 133 of 971 tumors (14%), 970 of which were also evaluable for EGFR expression level. The most common mutations were exon 19 deletions and L858R (124 of 133 patients; 93%). In the high EGFR expression group (immunohistochemistry score of >/=200), a survival benefit for the addition of cetuximab to chemotherapy was demonstrated in patients with EGFR wild-type (including T790M mutant) tumors. Although patient numbers were small, those in the high EGFR expression group whose tumors carried EGFR mutations may also have derived a survival benefit from the addition of cetuximab to chemotherapy. Response data suggested a cetuximab benefit in the high EGFR expression group regardless of EGFR mutation status. CONCLUSIONS: The survival benefit associated with the addition of cetuximab to first-line chemotherapy for advanced non-small-cell lung cancer expressing high levels of EGFR is not limited by EGFR mutation status.

Second ESMO consensus conference on lung cancer : pathology and molecular biomarkers for non-small-cell lung cancer

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The Second ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on management of patients with nonsmall- cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, early stage disease, locally advanced disease and advanced (metastatic) disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on recommendations for pathology and molecular biomarkers in relation to the diagnosis of lung cancer, primarily non-small-cell carcinomas.

Shifting from production to purpose : facilitating design-led change in a small family-owned enterprise

This research was embedded as a Design-led Innovation catalyst within a family-owned small business, to explore the application of a design program to achieve organizational change. Based on the findings two new models for increasing design integration within an organisation were proposed, establishing a range of pre-requisites needed for a firm to progress. Struggling firms may leverage their use of design and strategy by embedding a catalyst in a new cross-disciplinary role providing the necessary internal assistance. The study demonstrated that even non-design or strategy-inclined family-owned SMEs could benefit from embarking on a design-led journey to boost their competitive preparedness.

Very small field dosimetry

This thesis investigated in detail the physics of small X-ray fields used in radiotherapy treatments. Because of this work, the ability to accurately measure dose from these very small X-ray fields has been improved in several ways. These include scientifically quantifying when highly accurate measurements are required by introducing the concept of a very small field, and by the invention of a new detector that responds the same in very small fields as in normal fields.

Small and medium enterprises using software as a service : exploring the different roles of intermediaries

Software as a Service (SaaS) can provide significant benefits to small and medium enterprises (SMEs) due to advantages like ease of access, 7*24 availability, and utility pricing. However, underlying the SaaS delivery model is often the assumption that SMEs will directly interact with the SaaS vendor and use a self-service approach. In practice, we see the rise of SaaS intermediaries who can support SMEs with sourcing and leveraging SaaS. This paper reports on the roles of intermediaries and how they support SMEs with using SaaS. We conducted an empirical study of two SaaS intermediaries and analysed their business models, in particular their value propositions. We identified orientation (technology or customer) and alignment (operational or strategic) as themes for understanding their roles. The contributions of this paper include: (1) the identification and description of SaaS intermediaries for SMEs based on an empirical study and (2) understanding the different roles of SaaS intermediaries, in particular a more basic role based on technology orientation and operational alignment and a more value adding role based on customer orientation and strategic alignment. We propose that SaaS intermediaries can address SaaS adoption and implementation challenges of SMEs by playing a basic role and can also aim to support SMEs in creating business value with SaaS based solutions by playing an added value role.

Using qualitative mixed methods to study small health care organizations while maximising trustworthiness and authenticity

Background The primary health care sector delivers the majority of health care in western countries through small, community-based organizations. However, research into these healthcare organizations is limited by the time constraints and pressure facing them, and the concern by staff that research is peripheral to their work. We developed Q-RARA—Qualitative Rapid Appraisal, Rigorous Analysis—to study small, primary health care organizations in a way that is efficient, acceptable to participants and methodologically rigorous. Methods Q-RARA comprises a site visit, semi-structured interviews, structured and unstructured observations, photographs, floor plans, and social scanning data. Data were collected over the course of one day per site and the qualitative analysis was integrated and iterative. Results We found Q-RARA to be acceptable to participants and effective in collecting data on organizational function in multiple sites without disrupting the practice, while maintaining a balance between speed and trustworthiness. Conclusions The Q-RARA approach is capable of providing a richly textured, rigorous understanding of the processes of the primary care practice while also allowing researchers to develop an organizational perspective. For these reasons the approach is recommended for use in small-scale organizations both within and outside the primary health care sector.

Corneal confocal microscopy shown an improvement in small-fibre neuropathy in subjects with type 1 diabetes on continuous subcutaneous insulin infusion compared to multiple daily injection

Improved glycemic control is the only treatment that has been shown to be effective for diabetic peripheral neuropathy in patients with type 1 diabetes (1). Continuous subcutaneous insulin infusion (CSII) is superior to multiple daily insulin injection (MDI) for reducing HbA1c and hypoglycemic events (2). Here, we have compared the benefits of CSII compared withMDI for neuropathy over 24months....

Audit pricing and product differentiation in small private firms : evidence from Thailand

Purpose – There is limited evidence on how differences in economic environments affect the demand for and supply of auditing. Research on audit pricing has mainly focused on large client markets in developed economies; in contrast, the purpose of this paper is to focus on the small client segment in the emerging economy of Thailand which offers a choice between auditors of two different qualities. Design/methodology/approach – This paper is based on a random stratified sample of small clients in Thailand qualifying for audit exemption. The final sample consists of 1,950 firm-year observations for 2002-2006. Findings – The authors find evidence of product differentiation in the small client market, suggesting that small firms view certified public accountants as superior and pay a premium for their services. The authors also find that audit fees have a positive significant association with leverage, metropolitan location and client size. Audit risk and audit opinion are not, however, significantly associated with audit fees. Furthermore, the authors find no evidence that clients whose financial year ends in the auditors’ busy period pay significantly higher audit fees, and auditors engage in low-balling on initial engagements to attract audit clients. Research limitations/implications – The research shows the importance of exploring actual decisions regarding audit practice and audit pricing in different institutional and organizational settings. Originality/value – The paper extends the literature from developed economies and large/listed market setting to the emerging economy and small client market setting. As far as the authors are aware, this is the first paper to examine audit pricing in the small client market in an emerging economy.

Job embeddedness and the importance of retaining small firm employees

Small firms identify retention of staff as a significant problem. Voluntary turnover of talented staff can be costly, especially in small firms where there are few slack resources. However, there is scant research on retention in small firms. We use the concept of Job Embeddedness to understand why small firm employees stay. The concept refers to the totality of forces that embed employees in their jobs and it consists of three dimensions: fit, links, and sacrifice. Seven propositions are outlined comparing the ways fit, links and sacrifice might play out for small and large firm employees. Through testing these propositions small firm owner-managers may have a better understanding of what can be done to retain employees and maintain firm performance.

Constraints and characteristics of flexible work arrangements in small not-for-profit firms

There is a great deal of research that examines flexible working arrangements, but this work tends to be concentrated in large organisations. This research examines the approach taken to flexible working arrangements in five small community based, not for profit organisations. We present three propositions that aim to understand the constraints and the characteristics of flexible work in this rarely studied sector.

Phylogenetics of small horseshoe bats from east Asia based on mitochondrial DNA sequence variation

We undertook analyses of mitochondrial DNA gene sequences and echolocation calls to resolve phylogenetic relationships among the related bat taxa Rhinolophus pusillus (sampled across China), R. monoceros (Taiwan), R. cornutus (main islands of Japan), and R. c. pumilus (Okinawa, Japan), Phylogenetic trees and genetic divergence analyses were constructed by combining new complete mitochondrial cytochrome-b gene sequences and partial mitochondrial control region sequences with published sequences. Our work showed that these 4 taxa formed monophyletic groups in the phylogenetic tree. However, low levels of sequence divergence among the taxa, together with similarities in body size and overlapping echolocation call frequencies, point to a lack of taxonomic distinctiveness. We therefore suggest that these taxa are better considered as geographical subspecies rather than distinct species, although this should not diminish the conservation importance of these island populations, which are important evolutionarily significant units. Based on our findings, we suggest that the similarities in body size and echolocation call frequency in these rhinolophids result from their recent common ancestry, whereas similarities in body size and call frequency with R. hipposideros of Europe are the result of convergent evolution.

Mitochondrial membrane potential in a small subset of artemisinin-induced dormant plasmodium falciparum parasites in vitro

Artemisinin induced dormancy is a proposed mechanism for failures of mono-therapy and is linked with artemisinin resistance in Plasmodium falciparum. The biological characterization and dynamics of dormant parasites are not well understood. Here we report that following dihydroartemisinin (DHA) treatment in vitro, a small subset of morphologically dormant parasites was stained with rhodamine 123 (RH), a mitochondrial membrane potential (MMP) marker, and persisted to recovery. FACS sorted RH-positive parasites resumed growth at 10,000/well while RH-negative parasites failed to recover at 5 million/well. Furthermore, transcriptional activity for mitochondrial enzymes was only detected in RH-positive dormant parasites. Importantly, after treating dormant parasites with different concentrations of atovaquone, a mitochondrial inhibitor, the recovery of dormant parasites was delayed or stopped. This demonstrates that mitochondrial activity is critical for survival and regrowth of dormant parasites and that RH staining provides a means of identifying these parasites. These findings provide novel paths for studying and eradicating this dormant stage.