Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials

Background We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. Methods Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. Findings Median follow-up in LUX-Lung 3 was 41 months (IQR 35–44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31–37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28·2 months (95% CI 24·6–33·6) in the afatinib group and 28·2 months (20·7–33·2) in the pemetrexed-cisplatin group (HR 0·88, 95% CI 0·66–1·17, p=0·39). In LUX-Lung 6, median overall survival was 23·1 months (95% CI 20·4–27·3) in the afatinib group and 23·5 months (18·0–25·6) in the gemcitabine-cisplatin group (HR 0·93, 95% CI 0·72–1·22, p=0·61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33·3 months (95% CI 26·8–41·5) in the afatinib group versus 21·1 months (16·3–30·7) in the chemotherapy group (HR 0·54, 95% CI 0·36–0·79, p=0·0015); in LUX-Lung 6, it was 31·4 months (95% CI 24·2–35·3) versus 18·4 months (14·6–25·6), respectively (HR 0·64, 95% CI 0·44–0·94, p=0·023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27·6 months (19·8–41·7) in the afatinib group versus 40·3 months (24·3–not estimable) in the chemotherapy group (HR 1·30, 95% CI 0·80–2·11, p=0·29); in LUX-Lung 6, it was 19·6 months (95% CI 17·0–22·1) versus 24·3 months (19·0–27·0), respectively (HR 1·22, 95% CI 0·81–1·83, p=0·34). In both trials, the most common afatinib-related grade 3–4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3–4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3–4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). Interpretation Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

On Ordinal VC-Dimension and Some Notions of Complexity

We generalize the classical notion of Vapnik–Chernovenkis (VC) dimension to ordinal VC-dimension, in the context of logical learning paradigms. Logical learning paradigms encompass the numerical learning paradigms commonly studied in Inductive Inference. A logical learning paradigm is defined as a set W of structures over some vocabulary, and a set D of first-order formulas that represent data. The sets of models of ϕ in W, where ϕ varies over D, generate a natural topology W over W. We show that if D is closed under boolean operators, then the notion of ordinal VC-dimension offers a perfect characterization for the problem of predicting the truth of the members of D in a member of W, with an ordinal bound on the number of mistakes. This shows that the notion of VC-dimension has a natural interpretation in Inductive Inference, when cast into a logical setting. We also study the relationships between predictive complexity, selective complexity—a variation on predictive complexity—and mind change complexity. The assumptions that D is closed under boolean operators and that W is compact often play a crucial role to establish connections between these concepts. We then consider a computable setting with effective versions of the complexity measures, and show that the equivalence between ordinal VC-dimension and predictive complexity fails. More precisely, we prove that the effective ordinal VC-dimension of a paradigm can be defined when all other effective notions of complexity are undefined. On a better note, when W is compact, all effective notions of complexity are defined, though they are not related as in the noncomputable version of the framework.

Why the “Big Deal” continues to persist

The advantages of bundling e-journals together into publisher collections include increased access to information for the subscribing institution’s clients, purchasing cost-effectiveness and streamlined workflows. Whilst cataloguing a consortial e-journal collection has its advantages, there are also various pitfalls and the author outlines efforts by the CAUL (Council of Australian University Libraries) Consortium libraries to further streamline this process, working in conjunction with major publishers. Despite the advantages that publisher collections provide, pressures to unbundle existing packages continue to build, fuelled by an ever-increasing selection of available electronic resources; decreases in, and competing demands upon, library budgets; the impact of currency fluctuations; and poor usage for an alarmingly high proportion of collection titles. Consortial perspectives on bundling and unbundling titles are discussed, including options for managing the addition of new titles to the bundle and why customising consortial collections currently does not work. Unbundling analyses carried out at Queensland University of Technology during 2006 to 2008 prior to the renewal of several major publisher collections are presented as further case studies which illustrate why the “big deal” continues to persist.

Achieving better stewardship of major infrastructure assets through configuration of governance arrangements utilising Stewardship Theory

Major infrastructure assets are often governed by a mix of public and private organizations, each fulfilling a specific and separate role i.e. policy, ownership, operation or maintenance. This mix of entities is a legacy of Public Choice Theory influenced NPM reforms of the late 20th century. The privatization of the public sector has resulted in agency theory based ‘self-interest’ relationships and governance arrangements for major infrastructure assets which emphasize economic efficiency but which do not do not advance non-economic public values and the collective Public Interest. The community is now requiring that governments fulfill their stewardship role of also satisfying non-economic public values such as sustainability and intergenerational responsibility. In the 21st century governance arrangements which minimize individual self-interest alone and look to also pursue the interests of other stakeholders have emerged. Relational contracts, Public-Private Partnerships (PPP’s) and hybrid mixes of organizations from the state, market and network modes (Keast et al 2006) provide options for governance which better meet the interests of contractors, government and the community there is emerging a body of research which extends the consideration of the immediate governance configuration to the metagovernance environment constituted by hierarchy, regulation, industry standards, trust, culture and values. Stewardship theory has reemerged as a valuable aid in the understanding of the features of governance configurations which establish relationships between principal and agent which maximize the agent acting in the interests of the principal, even to the detriment of the agent. This body of literature suggests that an improved stewardship outcome from infrastructure governance configurations can be achieved by the application of the emerging options as to the immediate governance configuration, and the surrounding metagovernance environment. Stewardship theory provides a framework for the design of the relationships within that total governance environment, focusing on the achievement of a better, complete stewardship outcome. This paper explores the directions future research might take in seeking to improve the understanding of the design of the governance of major, critical infrastructure assets.

From surfboard wax to salient health inequity : School programs to develop globally aware and active citizens

During the past century, significant improvements in the prevention, detection and treatment of infectious disease have positively impacted upon quality and quantity of life for many people worldwide. Despite this progress, there are large numbers of people currently living in developing regions of the world where infectious disease continues unabated. SurfAid International is a humanitarian organisation that has brought significant health improvements to the people living on the Mentawai and Nias islands of Indonesia. The SurfAid International Schools Program aims to develop global citizenship and social responsibility by providing a bridge between school settings and the critical work of SurfAid International. This paper provides a rationale for the development of contextualised school based programs and identifies potential impact upon the thoughts and actions of young people in schools.

A brief motivational intervention for substance misuse in recent-onset psychosis

Substance misuse is common in early psychosis, and impacts negatively on outcomes. Little is known about effective interventions for this population. We report a pilot study of brief intervention for substance misuse in early psychosis (Start Over and Survive: SOS), comparing it with Standard Care (SC). Twenty-five in-patients aged 18-35 years with early psychosis and current misuse of non-opioid drugs were allocated randomly to conditions. Substance use and related problems were assessed at baseline, 6 weeks and 3, 6 and 12 months. Final assessments were blind to condition. All 13 SOS participants who proceeded to motivational interviewing reported less substance use at 6 months, compared with 58% (7/12) in SC alone. Effects were well maintained to 12 months. However, more SOS participants lived with a relative or partner, and this also was associated with better outcomes. Engagement remained challenging: 39% (16/41) declined participation and 38% (5/13) in SOS only received rapport building. Further research will increase sample size, and address both engagement and potential confounds.

Multicomponent kinetic spectrophotometric determination of pefloxacin and norfloxacin in pharmaceutical preparations and human plasma samples with the aid of chemometrics

A spectrophotometric method for the simultaneous determination of the important pharmaceuticals, pefloxacin and its structurally similar metabolite, norfloxacin, is described for the first time. The analysis is based on the monitoring of a kinetic spectrophotometric reaction of the two analytes with potassium permanganate as the oxidant. The measurement of the reaction process followed the absorbance decrease of potassium permanganate at 526 nm, and the accompanying increase of the product, potassium manganate, at 608 nm. It was essential to use multivariate calibrations to overcome severe spectral overlaps and similarities in reaction kinetics. Calibration curves for the individual analytes showed linear relationships over the concentration ranges of 1.0–11.5 mg L−1 at 526 and 608 nm for pefloxacin, and 0.15–1.8 mg L−1 at 526 and 608 nm for norfloxacin. Various multivariate calibration models were applied, at the two analytical wavelengths, for the simultaneous prediction of the two analytes including classical least squares (CLS), principal component regression (PCR), partial least squares (PLS), radial basis function-artificial neural network (RBF-ANN) and principal component-radial basis function-artificial neural network (PC-RBF-ANN). PLS and PC-RBF-ANN calibrations with the data collected at 526 nm, were the preferred methods—%RPET not, vert, similar 5, and LODs for pefloxacin and norfloxacin of 0.36 and 0.06 mg L−1, respectively. Then, the proposed method was applied successfully for the simultaneous determination of pefloxacin and norfloxacin present in pharmaceutical and human plasma samples. The results compared well with those from the alternative analysis by HPLC.

Spatial Science News from QUT, Urban Development, November 2009.

Brief overview of topics/issues of interest end of 2009, including Spatial Science Students undertake Variety of Research Projects; labs and offices on the move again); Congratulations to Surveying Student Project- QSEA awards.